Term
| How does the hemoglobin oxygen binding curve differ from that for myoglobin? |
|
Definition
| The curve is not hyperbolic; it is sigmoidal. This is a sign of cooperativity. |
|
|
Term
| How does cooperativity occur in hemoglobin/oxygen binding? |
|
Definition
| Cooperativity in Hb results when O2 binding to one heme affects the O2 binding properties to heme in a neighboring globin chain (remember there are 4 hemes in Hb). |
|
|
Term
| What is the hemoglobin/oxygen curve actually a hybrid of? |
|
Definition
| It is a hybrid of two normal hyperbolic curves - the high and low oxygen affinity states, i.e. relaxed and tense |
|
|
Term
| What structural changes does oxygen binding invoke in the quaternary structure of Hb? |
|
Definition
• One ab dimer rotates 15° relative to the the other ab dimer.
• Salt bridges (hydrogen bonds) between amino acid side chains of the a1 and b2 chains are are broken and reformed between new partners. |
|
|
Term
| What makes for higher O2 affinity of the R state of Hb? |
|
Definition
• It provides more optimal coordination of the Fe2+ in heme.
• There is easier “access” of O2 to heme due to less “steric hinderance” in the opening of the heme pocket. |
|
|
Term
| What is the t(1/2) for O2 release from hemoglobin? |
|
Definition
|
|
Term
| What do allosteric activators of Hb do? |
|
Definition
| Stabilize the R state and promote O2 binding |
|
|
Term
| What do allosteric inhibitors of Hb do? |
|
Definition
| Stabile the T state and make O2 binding less favorable. Promotes O2 release. |
|
|
Term
| What are the qualities of BPG? |
|
Definition
• Is at high concentrations in RBCs (~5mM).
• Is a natural product of anaerobic glycolysis in RBCs (more on that later!).
• Is an allosteric inhibitor of Hb-O2 binding.
• Promotes release of O2 from Hb.
• Binds Hb at interface of b1 and b2 chains. BPG is highly negatively charged so it binds to positively charged Lysine, Histidine side chains and amino terminus. |
|
|
Term
| Where does BPG bind to in Hb? |
|
Definition
| Binds Hb at interface of b1 and b2 chains. BPG is highly negatively charged so it binds to positively charged Lysine, Histidine side chains and amino terminus. |
|
|
Term
| How and why does HbF have a higher oxygen affinity than HbA? |
|
Definition
• The physiological basis for the ability of the fetus to withdraw O2 from the mothers circulation relies on the property that, in vivo, HbF has a higher affinity for O2 than HbA.
• The higher affinity of HbF for O2 is entirely due to its exclusion of BPG binding.
• The BPG binding pocket is less positively charged in HbF due to presence of Serine in g chains (Ser 143) in place of a Histidine (His143) in b chains. |
|
|
Term
| How does H+ affect O2/Hb binding? |
|
Definition
• H+ is displaced upon O2 binding to Hb. Therefore, increase in H+ drives the reaction backwards.
• Lower pH (higher H+ concentration) causes release of O2. This is known as the Bohr effect.
• This is a good thing! Working muscles, which demand more O2, propagate acidic conditions e.g. lactic acid. |
|
|
Term
| How does temperature affect O2/Hb binding? |
|
Definition
• The heme-O2 binding reaction is exothermic. Therefore, oxygen affinity of Hb drops with elevated temperature.
• Again, this is a good thing! Working muscles, which demand more O2, are elevated in temperature. |
|
|
Term
| How does CO2 affect O2/Hb binding? |
|
Definition
• CO2, a major product of glycolysis, is generated rapidly in tissues,especially in working muscles.
• CO2 reacts with H20 to form carbonic acid.
• Dissociated carbonic acid lowers pH and promotes O2 dissociation from Hb via the Bohr effect.
• The overall binding properties of O2 to Hb in blood can be reconstituted in a test tube by the effects of BPG and CO2 effects on purified Hb. |
|
|
Term
| What enzyme aids in transport of CO2 by Hb, and what % of CO2 transport does this account for? |
|
Definition
• Carbonic anhydrase, second most abundant enzyme in RBCs, mediates hydration of CO2 (and dehydration of carbonic acid).
• 85% of CO2 transported by this mechanism. |
|
|
Term
| What is carbaminohemoglobin? |
|
Definition
| CO2 forms a bond with the NH2-terminal amino group in the globin chains of Hb to transport CO2 (15% of all CO2 transported this way). This RXN is reversible and very pH sensitive, binds to deoxyHb preferentially. |
|
|
Term
| What is metHb and methemoglobinemia? |
|
Definition
• A fraction of the heme iron in Hb is constitutively auto-oxidized (Fe2+ to Fe3+) giving ferric hemoglobin known as methemoglobin (MetHb).
• In normal conditions, metHb is less than 1% of total Hb. metHb can elevate to >20% in methemoglobinemia. A level of 70% metHb can be fatal.
• MetHb is unable to bind and release O2.
Presence of metHb shifts O2 dissociation curve to the left. |
|
|
Term
| What is the body's natural defense against metHb? |
|
Definition
• MetHb can be “repaired” by reduction to oxyHb or deoxyHb.
• RBCs use an enzyme (MetHb-reductase) and NADH as endogenous repair mechanism. |
|
|
Term
| What are the symptoms of methemoglobinemia? |
|
Definition
• Clinical symptoms include cyanosis (bluish color in skin), “chocolate” colored blood and “black tongue”, hemolytic anemia.
• Further denaturation of globin chains forms precipitates that selectively stain in RBCs and are known as Heinz bodies. |
|
|
Term
| What are some of the major causes of methemoglobinemia? |
|
Definition
• Exposure to oxidant drugs:
Nitrites
Nitric Oxide
Nitroglycerins
Acetominophen
primaquine
• Exposure to chemicals:
Copper
Nitrates
Nitroglycerin
Naphthalene
Inherited:
• Hemoglobin M (HbM) is more susceptible to oxidation.
-several variants with affected a, b, or g chains.
-Histidine to Tyrosine mutation near heme pocket is common.
• Genetic deficiencies in the metHb-reductase enzyme compromise the RBCs ability to reduce metHB. |
|
|
Term
| How is MetHb-emia treated clinically? |
|
Definition
-removal of offending agent,
-infusion of ascorbic acid or methylene blue (reducing agents).
-Clinical note: Deficiencies in metHb-reductase are responsive to ascorbic acid whereas HbM is resistant to treatment. |
|
|
Term
| What is the general reaction for glucose metabolism in erythrocytes? |
|
Definition
Ebden-Myerholf pathyway. Glucose metabolism proceeds through anaerobic glycolysis which yields 2 ATP for each glucose. Glucose is converted to lactic acid, the byproducts (other than ATP) include NADH, NADPH, GSH, and 2,3-BPG
Glycolysis occurs in the cytoplasm. |
|
|
Term
| What pathway produces 2,3-BPG? |
|
Definition
| Rapoport-Luebering pathway branch of Ebden-Myerhof pathway |
|
|
Term
| What pathway in erythrocytes produces NADH? |
|
Definition
| MetHB reductase pathway branch of the Ebden-Myerhof pathway |
|
|
Term
| What is the hexose monophosphate shunt? |
|
Definition
| Branch of the Ebden-Myerhof pathway, through which glucose-6-phosphate can be diverted through in order to generate NADPH required for glucothione synthesis |
|
|
Term
| What are the three critical enzymes in anaerobic glycolysis? |
|
Definition
-hexokinase (HK)
-phosphofructokinase (PFK)
-pyruvate kinase (PK). |
|
|
Term
| What occurs in the priming stage of anaerobic glycolysis? |
|
Definition
HK and PFK function in the “priming stage”:
-Two ATP are required to prime the reaction.
-So…start with a 6-carbon molecule (glucose) and end with a 6 carbon molecule with 2 phosphates attached. |
|
|
Term
| What occurs in the ATP-generating stage of anaerobic glycolysis? |
|
Definition
• In the ATP generating stage one ATP is generated from each of two 1,3-BPG molecules, so a total of 2 ATP yielded at this step.
• Pyruvate Kinase (PK) mediates final ATP generating step. Again one ATP for each phosphoenol pyruvate, so another 2 ATP yielded
• So…start with two 3-carbon molecules with 2 phosphates attached and end with two 3-carbon molecules with no phosphates. |
|
|
Term
| What occurs in the metHb reductase pathway? |
|
Definition
NADH produced from G3PDH acts as a reducing cofactor for the metHb-reductase enzyme.
This is the major pathway for reducing metHb back to functional Hb. |
|
|
Term
| What occurs in the Rapoport-Luebering shunt? |
|
Definition
• 2,3 BPG results from enzyme mediated isomerization of phosphate on 1,3 BPG.
• 2,3 BPG is the most concentrated organophosphate in the RBC!
• De-phosphorylation generates 3PG, which returns to glycolytic pathway. |
|
|
Term
| What are reactive oxygen species and what do they do to RBC's? |
|
Definition
• Molecular oxygen can undergo a number of reductions which propagate reactive oxygen species (ROS) intermediates.
• ROS take several forms and cause oxidation and denaturation of proteins and lipids.
• O2-· is most common in the process of metHb formation from Hb. Also promotes cell lysis via membrane lipid oxidation.
• H2O2 is more stable than OH· yet both act to oxidize and denature Hb. |
|
|
Term
|
Definition
| GSH is the major reducing agent in the RBC. It is essential for peroxidase activity, the primary antioxidant defense mechanism. |
|
|
Term
| How is glutathione synthesized? |
|
Definition
| GSH is synthesized from three amino acids, glutamic acid, cysteine and glycine, in two enzymatic steps. |
|
|
Term
| How does glutathione act as an antioxidant? |
|
Definition
The SH group of cysteine provides the powerful antioxidant reducing potential of GSH.
Reduction reactions are coupled to the oxidation of two GSH molecules which form GSSG |
|
|
Term
| What is glutathione reductase? |
|
Definition
| The enzyme that maintains glutathione in its reduced form (GSH), as opposed to its oxidized GSSG form |
|
|
Term
| What does superoxide dismutase do? |
|
Definition
| Returns superoxide ion to molecular O2 or reduces it to H2O2 |
|
|
Term
|
Definition
| Oxidizes or reduces H2O2 to O2 or H2O respectively. Catalase is a heme containing enzyme |
|
|
Term
| What is glutathione peroxidase? |
|
Definition
| A reductase that can (other than catalase) also reduce H2O2 to H2O. Requires GSH as a cofactor reducing agent |
|
|
Term
| What is the most common RBC metabolic disorder? |
|
Definition
|
|
Term
|
Definition
• The G6PD gene is on the X chromosome and demonstrates a recessive X-linked inheritance. i.e. males are most affected.
• Deficiencies compromise the RBC defense of oxidation due to the inability to maintain reduced form of GSH.
• Two Mutations are most clinically relevant:G6PD A- (in African Americans) and G6PD Mediterranean, both generally decrease the half-life of enzyme.
• Patients experience hemolytic anemia in response to oxidative insult, e.g. drug exposure and infections.
• Treatments: avoidance of oxidant promoting compounds, transfusion, spleenectomy. |
|
|
Term
|
Definition
• PK deficiency is prevalent in the US, Europe and Japan. ~1% of US population is heterozygous.
• PK deficiency shows autosomal recessive inheritance and is the most common genetic disorder of the glycolytic pathway.
• Production of ATP is drastically reduced with PK mutation.
• Accumulation of glycolytic intermediates (e.g. 2,3 BPG) results.
• Overall decrease in ATP compromises repair processes resulting in hemolytic anemia. No effective therapy, treatments include RBC transfusions. |
|
|
Term
| How much iron does a typical diet consist of and how much of this is absorbed? |
|
Definition
| 10-20 mg/day iron, of which ~10% is absorbed |
|
|
Term
| During what periods is erythropoiesis elevated? |
|
Definition
-childhood growth and development
-menstruation
-pregnancy
-subsequent to excessive blood loss |
|
|
Term
| Describe the types of iron in food and how readily it is absorbed |
|
Definition
| e.g. inorganic (Fe2+, Fe3+ salts) or organic (heme). Heme iron is rapidly adsorbed whereas Fe3+ is not very soluble and poorly adsorbed. Fe2+ is more soluble than Fe3+. |
|
|
Term
| What type of chemical environments affect iron uptake? |
|
Definition
• low pH optimal for Fe3+ solubility (e.g. gastric acidity of stomach)
• citric acid and ascorbic acid assist iron adsorption
• Tannates (tea), phosphates (dairy) and phytates (whole grains) complex with iron and decrease adsorption. |
|
|
Term
| What are the three major compartments for iron in the body? |
|
Definition
| Functional, storage, and transport |
|
|
Term
| How many grams of total iron does the average adult have in their body? |
|
Definition
|
|
Term
| What is the percentage distribution of iron? |
|
Definition
| 70% of body iron contained in Hb in RBC's. 25% stored in ferritin and hemosiderin |
|
|
Term
|
Definition
| Converts ferric (Fe3+) to ferrous (Fe2+) iron. Found on the apical surface of the enterocyte. |
|
|
Term
| What enzyme mediates the uptake of Fe2+? |
|
Definition
| Divalent mital ion transporter, DMT-1. |
|
|
Term
| How does iron get transported to the blood plasma? |
|
Definition
| Through ferroportin located at the basal surface of the enterocyte |
|
|
Term
|
Definition
• Ferritin is a huge spherical protein (Mw=440,000 Da) consisting of 24 subunits.
• It is common to all cells. High levels occur in erythroid precursors.
• Forms a “shell” that can encompase >4500 iron atoms.
• Iron can reversibly pass through “channels” in the shell. |
|
|
Term
|
Definition
• Hemosiderin is a less-well characterized complex of iron in a ferric hydroxyphosphate form and protein.
• It is a storage compartment when ferritin capacity is exceeded.
• Hemosiderin deposits in tissues result from iron overload and contribute to organ failure. |
|
|
Term
|
Definition
• Transferrin is a medium-large soluble protein (MW=79,000 Da) that mediates iron transport between tissues.
• It is present in plasma and extracellular fluid.
• It has a two-lobe structure that binds one iron atom per lobe.
• Transferrin without iron is called apotransferrin.
• Iron must be in Fe3+ state to bind to transferrin. |
|
|
Term
| Describe the process of receptor-mediated endocytosis for transferrin |
|
Definition
• Uptake into erythroid cells is mediate by the transferrin receptor.
• Apotransferrin has low affinity for the receptor; iron-bound transferrin binds tightly to the receptor.
• Binding promotes receptor clustering and endocytosis of transferrrin-receptor complexes into an endosome.
• Acidification of endosome causes iron dissociation (but not transferrin dissociation from the receptor!).
• Transferrin is recycled and released as apotransferrin. |
|
|
Term
| What is more valuable, serum iron levels or TIBC? |
|
Definition
| Serum iron level is less informative than the ratio of serum levels to TIBC, which reveals % saturation of transferrin. |
|
|
Term
| What is acute iron toxicity? |
|
Definition
• The most common event is ingestion of iron pills.
• “Free” iron in the system causes damage via oxidation.
• Initial symptoms are gastrointestinal: vomiting, diarrhea, bleeding, followed by a “quiet phase”
• Later signs include vascular collapse, coagulation, seizures, coma. |
|
|
Term
| What are the three primary causes of chronic iron overload? |
|
Definition
• accumulation of iron from transfusion therapy
• defective erythropoiesis
• Hereditary hemachromatosis |
|
|
Term
| What is hereditary hemochromatosis? |
|
Definition
• An autosomal recessive disorder.
• Mutations affect transferrin receptor, ferroportin and receptor accessory proteins.
• Symptoms onset in middle ages (40’s for men, 60’s for women).
• Several organs targeted: liver, heart, pancreas, skin.
• Treatment: phlebotomy to remove iron. |
|
|
Term
| What is the technical definition of anemia? |
|
Definition
| A reduction below the normal limits of the total circulating red cell mass resulting in diminished oxygen transport capacity of the blood and reduced oxygen delivery to the peripheral tissues (i.e., too few red blood cells in the circulation) |
|
|
Term
| What measurements quantify anemia? |
|
Definition
• Hematocrit (Hct): The percent of a volume of whole blood that is occupied by RBC’s (%)
• Hemoglobin (Hb): The amount of hemoglobin in a standard volume of whole blood (mg/dl)
• RBC Count: The number of individual RBC’s in a standard volume of whole blood |
|
|
Term
|
Definition
| Mean Corpuscular Volume (MCV): The average size or volume of all the individual RBC’s in the sample. A population may, on average be in the normal range (“normocytic”), smaller than normal (“microcytic”), or larger than normal (“macrocytic”). Some types of anemia are characterized by typical changes in the MCV. |
|
|
Term
|
Definition
| Red Cell Distribution Width (RDW): A measure of how heterogeneous in size an RBC population is; i.e., if all the RBC’s on average are exactly the same size (have the same MCV), the RDW is small; if the distribution of RBC sizes around the mean is wide, the RDW is large. |
|
|
Term
| What is a reticulocyte count? |
|
Definition
| Reticulocytes are the youngest red cells in the peripheral blood, having just completed their maturation in the marrow; their count is a measure of the ability of the marrow to produce new RBC’s; they may be counted in the lab automatically or manually |
|
|
Term
| What are the general signs and symptoms of anemia? |
|
Definition
Pallor of skin and mucous membranes
Rapid heart rate (tachycardia)
Rapid breathing (tachypnea)
Easy fatigability with exertion
Headache
Fever |
|
|
Term
| What are the general physiological compensatory mechanisms for anemia? |
|
Definition
• “Shift to the right” of the hemoglobin/oxygen dissociation curve; with increasing 2,3 DPG the hemoglobin releases oxygen in the peripheral tissue more readily at a given pO2
• Shunting of blood from “non-essential” tissues: skin, mesenteric bed, kidneys
• Increased cardiac output (e.g., increased heart rate)
• Erythropoietin secretion by the kidneys to boost RBC production in bone marrow |
|
|
Term
| What determines the degree of symptomatology in anemia? |
|
Definition
| 1) the severity of the anemia (i.e., the lower the hemoglobin and hematocrit, the greater the symptoms) and 2) the rapidity with which the anemia developed |
|
|
Term
| What are the three basic mechanisms of anemia? |
|
Definition
Excess red cell loss (bleeding)
Shortened red cell survival (hemolysis)
Decreased red cell production (bone marrow failure) |
|
|
Term
| What happens in acute red cell loss? |
|
Definition
• Acute: the major pathophysiologic effect is simple intravascular volume loss (not decreased O2 transport)
• With increasing total blood volume loss, increasing symptoms: at 20%, tachycardia, postural hypotension; at 40%, severe shock
• Labs: initially a CBC will be normal (no anemia) as in large bleeds whole blood, not just RBC’s, is lost; the intravascular ratio of RBC’s to plasma is not changed (so normal hb and hct) |
|
|
Term
| What occurs in hemolytic anemias, in general? |
|
Definition
| Red cell survival is markedly shortened in these conditions with premature removal primarily by the spleen. As anemia develops, erythropoietin secretion rises and this drives a compensatory erythroid hyperplasia in the bone marrow to increase RBC production in order to make up for the increased RBC clearance. The reticulocyte count is always elevated. |
|
|
Term
| What are laboratory markers, in general, of increased RBC turnover? |
|
Definition
Elevated lactic dehydrogenase (LDH)
Variably elevated bilirubin (unconjugated)
Decreased haptoglobin |
|
|
Term
| What are the intrinsic and extrinsic causes of hemolytic anemias? |
|
Definition
• Intrinsic red cell defects (inherited)
○ Membrane defects
○ Enzyme deficiencies
○ Hemoglobin disorders
• Extrinsic red cell defects (acquired)
○ Immune mediated hemolysis
○ Physical causes of hemolysis (microangiopathy) |
|
|
Term
| What is the clinical presentation of hereditary spherocytosis? |
|
Definition
• Most common membrane defect; 1/5000 in No. European pop.
• Variable pattern of inheritance, but autosomal dominant is most common
• Most commonly presents in early childhood with symptoms of anemia
• Splenomegaly |
|
|
Term
| What is the pathophysiology of hereditary spherocytosis? |
|
Definition
• Genetically heterogeneous: most common mutations are in the genes for ankyrin and band 3 (there are others)
• These lead to destabilization of spectrin, influx of sodium into the cell, instability of the membrane with intravascular membrane loss due to shearing stresses, and the inability of the RBC to maintain a normal biconcave shape; these cells are inflexible and are removed by the RE system of the spleen |
|
|
Term
| What are the laboratory findings in hereditary spherocytosis? |
|
Definition
• Peripheral blood
○ Usually mild normocytic anemia
○ Compensatory reticulocytosis
○ Spherocytes in smear
• Bone marrow
○ Compensatory erythroid hyperplasia |
|
|
Term
| How is hereditary spherocytosis diagnosed? |
|
Definition
| Combination of family history, typical clinical presentation, and CBC findings leads to suspicion for HS; confirmatory test: osmotic fragility |
|
|
Term
| What is the course for a patient with hereditary spherocytosis? |
|
Definition
| Patients have chronic mild to moderate anemia improved by splenectomy (although the RBC defect remains |
|
|
Term
| What is Von Willebrand's disease? |
|
Definition
reduced or abnormal synthesis of vWF, poor platelet adherence to the site of injury
- Severe form is very rare (1 in 1,000,000)
- Mild form is very common (1 in 100) |
|
|
Term
| What is Bernard-Soulier syndrome? |
|
Definition
| (rare) - expression of low levels or defective GpIb-V-IX complexes --> decreased vWF binding |
|
|
Term
| What is Glanzmann's thrombasthenia? |
|
Definition
| (rare) - expression of low levels or defective GpIIb-IIIa complexes --> decreased fibrinogen binding and poor platelet aggregation |
|
|
Term
| What is clinical "bleeding time"? |
|
Definition
• The bleeding time is a clinical test in which two measured incisions are made using a spring-loaded scalpel
• The time to stop bleeding is measured (normal range 2 – 7 min)
• The bleeding time usually is prolonged in disorders of primary hemostasis
• The bleeding time does not depend on fibrin clot formation |
|
|
Term
| How is secondary hemostasis initiated? |
|
Definition
| initiated by formation of TF/Factor VIIa complex |
|
|
Term
|
Definition
| Not normally in the blood, only in subendothelium |
|
|
Term
| How are zymogens relevant to secondary hemostasis? |
|
Definition
| A series of vitamin K-dependent “zymogen” to vitamin K-dependent serine protease conversions initiated by exposed Tissue factor and small, circulating concentrations of Factor VIIa |
|
|
Term
| What occurs in the extrinsic tenase arm of the thrombin activation pathway? |
|
Definition
| TF/FVIIa (w/ Ca2+) forms FIXa and FXa |
|
|
Term
| What occurs in the intrinsic tenase arm of the thrombin activation pathway? |
|
Definition
| FVIIIa/FIXa (w/ Ca2+) forms Fxa |
|
|
Term
| What does Fxa form in the thrombrin activation pathway? |
|
Definition
| Goes to Fxa/FVa (w/ Ca2+) which will then activate thrombin |
|
|
Term
| What are the four things that thrombin can act as? |
|
Definition
| procoagulant, anticoagulant, profibrinolytic, antifibrinolytic |
|
|
Term
| What are common constituents of coagulation complexes? |
|
Definition
• Vitamin K-dependent serine protease
• Protein cofactor
• Calcium ions
• Appropriate membrane surface
- activated platelets
- subendothelial cells, typically fibroblasts
- damaged, intact endothelium |
|
|
Term
| Where is the TF/FVIIa complex found? |
|
Definition
| On the fibroblast membrane |
|
|
Term
| Where is the FVIIIa/FIXa complex found? |
|
Definition
| On the activated platelet membrane |
|
|
Term
| What enzyme activates thrombin? |
|
Definition
| Prothrombinase on the activated platelet membrane |
|
|
Term
| Where does factor Va come from? |
|
Definition
| Both plasma and platelet derived. In plasma it circulates as a procofactor, whereas in the platelet it is stored in alpha-granules in an active form. |
|
|
Term
| What is the relevance of the Fva/FXa complex formation? |
|
Definition
• localization of procoagulant activity
• amplification of the response
• modulation – protection of complex from inhibition |
|
|
Term
| What, other than clot formation, are platelets involved in? |
|
Definition
hemostasis
angiogenesis
acute and chronic inflammation
atherosclerosis
arterial thrombosis
venous thrombosis (?)
cancer
Hypothesis: Platelet subpopulations may define their various roles in these processes |
|
|
Term
| How is fibrinogen converted to fibrin? |
|
Definition
| Fibrinogen has 2 D domains, and one central E domain. Thrombin cleaves "tails" off of the E domain, rendering it "sticky" so that it can bind to D domains. This leaves a fibrin monomer and fibrinopeptides A and B after cleavage. |
|
|
Term
| How and why does crosslinking in fibrin occur? |
|
Definition
| Before crosslinking fibrin has only a gel-like texture - it is not resilient. Fibrin cross-linking between D domains is catalyzed by Factor XIIIa. |
|
|
Term
| What is the GLA domain in coagulation proteins? |
|
Definition
• Gla domains get their name because they several contain g- carboxyglutamic (Gla) resides
• -carboxylation is a vitamin K-dependent post-translational modification
• -carboxylation is necessary for vitamin K-dependent proteins to bind negatively charged phospholipids
• Binding to cell surface membranes localizes blood coagulation reactions |
|
|
Term
| How does warfarin (coumadin) act? |
|
Definition
| Inhibit Vitamin K-dependent carboxylation of glutamate residues. Warfarin blocks reformation of reduced vitamin K, which essentially stops the posttranslational modification of the glutamic acid residues at the amino-termini of the VKDP’s, since vitamin K is oxidized during the reaction. |
|
|
Term
| What are in vitro anticoagulants? |
|
Definition
• Blood clots spontaneously ex vivo
• The non-cellular part of clotted blood is called serum
• Serum is not the same as plasma, e.g., many of the clotting factors have been consumed
• Serum is appropriate for some clinical assays
• In other instances, non-clotted blood or plasma is required
• Calcium binders, citrate or EDTA, are used to prevent blood clotting |
|
|
Term
| In general, how does termination of the hemostatic process occur? |
|
Definition
The hemostatic mechanism must be shut down to avoid thrombosis and occurs through “constitutive” and “clotting-initiated” mechanisms.
“Constitutive” processes are defined by circulating, plasma inhibitors
• Inactivation of factor VIIa and factor Xa by tissue factor pathway inhibitor (TFPI)
• Inhibition of thrombin and factors Xa, VIIa and IXa by antithrombin III |
|
|
Term
|
Definition
TFPI shuts down the extrinsic pathway by initially forming an inhibitory complex with
free FXa. A TFPI/FXa complex then reacts with a TF/FVIIa complex effecting its inhibition, as well. |
|
|
Term
| What does Factor XI do and why is it important? |
|
Definition
| It is another pathway to produce Factor Ixa |
|
|
Term
| What is antithrombin III? |
|
Definition
| irreversibly inhibits the TF-FVIIa complex and the “free” VKDP serine proteases FIXa, FXa and thrombin |
|
|
Term
| How do heparin sulfates function? |
|
Definition
• Heparan sulfate proteoglycans (polysaccharides), expressed on the luminal side of vascular endothelial cells, bind both coagulation protease and ATIII.
• Binding facilitates diffusion of the reactants to each other, thus increasing the rate of the reaction.
• Heparan polysaccharides are a catalyst, but not an enzyme.
• Heparan polysaccharides also induce a conformational change in ATIII, which increases its ability to recognize factor Xa. ATIII inhibits factor Xa more effectively than it inhibits thrombin. |
|
|
Term
| How is thrombin involved in termination of the hemostatic process? |
|
Definition
| Thrombin binds to thrombomodulin expressed on endothelial cells and activates protein C to activated protein C, which proteolytically inactivates factors Va and VIIIa. Thrombin (IIa) bound to TM loses its ability to perform its procoagulant functions. IIa bound to TM can no longer cleave fibrinogen, or activate platelets, FV, FVII, FVIII or FXIII. |
|
|
Term
|
Definition
• Results from a single base substitution leading to the replacement R506 -> Q
• This substitution results in a factor Va molecule that cannot be cleaved and hence inactivated effectively by APC (APC resistance)
• Increases risk of venous thrombosis 3-8 fold for heterozygous and 30 to 140-fold for homozygous gene substitutions |
|
|
Term
| What deficiency causes hemophilia a? |
|
Definition
| Hereditary deficiency of factor VIII produces hemophilia a |
|
|
Term
| What deficiency causes hemophilia b? |
|
Definition
| Hereditary deficiency of factor IX produces hemophilia a |
|
|
Term
| What are severe hemophilia a and b due to? |
|
Definition
| Complete loss of gene expression, incomplete loss leads to milder forms. |
|
|
Term
| What is the phenotype for severe hemophilia a and b? |
|
Definition
| Severe hemophilia a and b have the same phenotype: spontaneous bleeding two or three times per month, esp. in joints. Prior to the advent of factor replacement, most patients died before age 20 |
|
|
Term
| Where are the factor VIII and IX genes located? |
|
Definition
|
|
Term
| How does fibrinolysis begin? |
|
Definition
Thrombin induces the release of tissue plasminogen activator (tPA) and urokinase
from vascular endothelial cells, thereby initiating fibrinolysis. |
|
|
Term
| What are tPA and urokinase? |
|
Definition
Released as active enzymes, tPA and urokinase catalyze the activation of
Plasminogen (Plg) -> plasmin, an enzyme that degrades fibrin. |
|
|
Term
| What is the biggest difference between tPA and urokinase? |
|
Definition
| In contrast to urokinase, tPA has a higher affinity for Plg bound to the fibrin clot and is said to be “clot-specific.” |
|
|
Term
|
Definition
Streptokinase (Str), a bacterial product, activates plasminogen by inducing a conforma-
tional change in Plg with the formed “plasmin” proteolytically activating more Plg. |
|
|
Term
|
Definition
| Catalyzes cleavage of fibrin, forming fibrin degradation products (FDPs). Also will cleave FV and FVIII. Partially regulated by the plasma protease inhibitor, alpha2-antiplasmin. |
|
|
Term
| What is the significance of fibrin degradation products (FDPs)? |
|
Definition
| FDPs (D-dimers) can be distinguised from fibrinogen degradation products, due to factor XIIIa-catalyzed crosslinking of fibrin. The D-dimer is assayed clinically in tests of possible thrombosis. |
|
|
Term
| How does alpha-thrombin become an anticoagulant/antifibrinolytic? |
|
Definition
| After binding to thrombomodulin expressed on the surface of endothelial cells. |
|
|
Term
| What are the three types of cell death? |
|
Definition
| necrosis, apoptosis, autolysis |
|
|
Term
|
Definition
• Morphologic changes in living tissue
• Degenerative action of enzymes
• Membrane damage - leakage of contents:
• Elicits inflammation
• Enzymes in blood used for diagnosis ( e.g. Cardiac enzymes) |
|
|
Term
| What morphological changes are seen in necrosis? |
|
Definition
• Increased Eosinophilia
• Cytoplasmic vacuolation
• Nuclear changes (due to DNA breakdown)
• Pyknosis - nuclear shrinkage
• Karyolysis – degradation of chromatin
• Karyorrhexis - nuclear fragmentation |
|
|
Term
| What are the four basic types of necrosis? |
|
Definition
| Coagulative, liquefactive, caseous, fat necrosis |
|
|
Term
| What is coagulative necrosis? |
|
Definition
• Primary pattern is denaturation
• Tissue architecture generally preserved
• Usually hypoxic (ischemic) injury
• Other causes:
• Freezing (frostbite)
• Burns
• Chemicals |
|
|
Term
| What are the clinical findings in coagulative necrosis? |
|
Definition
• Pain: e.g., chest pain in myocardial infarct
• Loss of cellular and organ function: e.g., heart failure or arrhythmia
• Bleeding: e.g., GI tract infarct, mucosal damage |
|
|
Term
| What is liquefactive necrosis? |
|
Definition
Primary pattern is enzyme digestion (Liquefaction)
Caused by bacterial and fungal infections |
|
|
Term
| What are the clinical findings in liquefactive necrosis? |
|
Definition
• Due to infection that causes inflammation
• Swelling (tumor)
• Redness (rubor)
• Fever (calor)
• Pain (dolor)
• Loss of Function |
|
|
Term
| What is caseous necrosis? |
|
Definition
• CASEOUS = Cheese-like
• White gross appearance
• Causes:
• Tuberculosis (TB)
• Fungi
• Rheumatoid disease (occasionally) |
|
|
Term
| What are the clinical findings in caseous necrosis? |
|
Definition
• Tuberculosis- Caseous (caseating) granulomas
• Fungal infections- Caseating and non-caseating granulomas |
|
|
Term
|
Definition
• Focal fat destruction by lipases
Causes:
• Trauma (surgery), Acute pancreatitis
• Fatty acids combine with calcium - produce saponification
• Inflammatory response
• Foamy macrophages, giant cells, and PMNs |
|
|
Term
| What are the clinical associations for fat necrosis? |
|
Definition
• Acute pancreatitis: Enzymatic damage
• Traumatic: Motor vehicle, surgery
• Necrosis of subcutaneous tissue: Breast – mimics cancer |
|
|
Term
| What are the two types of gangrene? |
|
Definition
• Dry: coagulative necrosis
• Wet: superimposed bacterial infection, liquefactive nectrosis |
|
|
Term
| What enzyme is elevated in the blood when cardiac muscle is damaged? |
|
Definition
|
|
Term
| What enzyme is elevated in the blood when the liver is damaged? |
|
Definition
| Alanine transaminase (ALT) |
|
|
Term
| What enzyme is elevated in the blood when striated muscle is damaged? |
|
Definition
|
|
Term
| What enzyme is elevated in the blood when the exocrine pancreas is damaged? |
|
Definition
|
|
Term
|
Definition
• Nuclear dissolution without loss of membrane integrity
• No inflammatory response
• Physiologic or Pathologic |
|
|
Term
| What are examples of physiological apoptosis? |
|
Definition
• Programmed destruction of cells during embryogenesis “programmed cell death”
- Developmental involution
• Elimination unwanted or harmful cells
• Hormone-dependent involution in adults
- E.g. - Ovarian follicular atresia in the menopause
- Atrophy of prostate after castration
- Regression of lactating breast after weaning |
|
|
Term
| What causes pathological apoptosis? |
|
Definition
• Cell death induced by injurious stimuli
- Anticancer drugs
• Cell death caused by viral infections
- Viral hepatitis
• Pathologic obstruction in body organs
- Due to duct obstruction in kidneys, pancreas
• Cell death in tumors
- During regression |
|
|
Term
|
Definition
• Lysis of tissue by own enzymes: E.g. Postmortem autolysis of pancreas
• Following death or removal of tissue from body (surgery)
• No inflammatory response |
|
|
Term
|
Definition
|
|
Term
|
Definition
| Mechanism of the disease; response of cells or tissues to etiologic agent, sequence of events from stimulus to disease |
|
|
Term
|
Definition
| Promonitory sympton, before recognized as disease |
|
|
Term
| What is intrinsic etiology? |
|
Definition
| Genetic cause of a disease |
|
|
Term
| What is extrinsic etiology? |
|
Definition
| Acquired cause of a disease |
|
|
Term
| What are the cell's poosible responses to injuries? |
|
Definition
| Recovery, adaptation, sublethal (reversible) damage leading to hydropic changes, and lethal (irreversible) damage leading to necrosis |
|
|
Term
| What is the point of no return in cell injury? |
|
Definition
| cellular swelling, lipid deposition, cell membrane dirupted (such as rupture of lysosome or plasma membrane) |
|
|
Term
|
Definition
• Increase in cell size (not number)
• Non-dividing cells
• Increase in the size of the organ
• Due to synthesis of more structural cell components |
|
|
Term
| What are examples of physiologic and pathologic hypertrophy? |
|
Definition
• Physiologic:
• Hypertrophy of uterus in pregnancy
• Pathologic:
• Hypertrophy of heart muscle in increased workload - Atherosclerosis, Hypertension |
|
|
Term
|
Definition
• Increase in cell number (not size)
• Increased volume of the organ or tissue
• Cells capable of mitotic division |
|
|
Term
| What are examples of physiologic and pathologic hyperplasia? |
|
Definition
• Physiologic:
• Hormonal hyperplasia
- Bone marrow hyperplasia, Breast in pregnancy
• Compensatory hyperplasia
- Bone marrow hyperplasia in anemia, Liver regeneration
• Pathologic:
• Endometrial hyperplasia – hormonal effect
- Fertile ground for cancer development
• Benign Prostatic Hyperplasia (BPH) |
|
|
Term
| What is the difference between hyperplasia and dysplasia? |
|
Definition
| Hyperplasia is controlled overgrowth, whereas dysplasia the body has lost control of growth |
|
|
Term
|
Definition
• Decrease in cell size (not number)
• Causes decrease in organ size
• Due to loss of cell substance |
|
|
Term
| What are some causes of atrophy? |
|
Definition
• Decreased workload
• Loss of innervation
• Diminished blood supply
• Loss of endocrine stimulation
• Inadequate nutrition
• Aging |
|
|
Term
|
Definition
• One cell type replaced by another
• From stem cells or undifferentiated mesenchymal cells
• Cell functions can be lost
• Named for the type it becomes
• May be an undesirable change
• May induce malignant transformation |
|
|
Term
| What is Barrett's esophagus? |
|
Definition
| Metaplasia where esophagus takes on glandular tissue appearance of GI tract |
|
|
Term
| What are risk factors for Barrett's esophagus? |
|
Definition
• 10% of patients with GERD
• Unknown why some get Barrett’s and others do not
• 30 to 100-fold risk of esophageal carcinoma
• Risk factors:
• Obesity, Male gender
• Age (mean age 63)
• Other
- Hiatal hernia
- Delayed esophageal acid clearance
- Decreased resting pressure of lower sphincter
- Alcohol and smoking |
|
|
Term
|
Definition
| Agonists occupy receptors, produce a conformational change which leads to receptor activation and thus efficacy |
|
|
Term
|
Definition
| Antagonists occupy receptors, produce no conformational change and prevent the action of agonists |
|
|
Term
| What are partial agonists? |
|
Definition
| Partial agonists occupy receptors, produce an effect which is less than the maximum obtainable with a full agonist |
|
|
Term
| What happens if an agonist and competitive antagonist are together? |
|
Definition
|
|
Term
| What happens if an agonist and noncompetitive antagonist are together? |
|
Definition
|
|
Term
| How does a partial agonist act as both agonist and antagonist? |
|
Definition
A partial agonist can compete with agonist for receptor binding
A partial agonist is less efficacious than a full agonist
Therefore, while a partial agonist alone acts as an agonist, it acts as an antagonist against a full agonist |
|
|
Term
| How does a low efficacy partial agonist act? |
|
Definition
| Low efficacy partial agonists (e.g. pindolol & other beta- blockers with ISA) almost always act clinically as antagonists |
|
|
Term
| How does a medium efficacy partial agonist act? |
|
Definition
| Moderate efficacy partial agonists (e.g. xamoterol, a b1 partial agonist) act as agonists with low and moderate underlying (sympathomimetic) activity (e.g. moderate heart failure) BUT as antagonists with high underlying (sympathomimetic) activity (e.g. severe heart failure) |
|
|
Term
| How does a high efficacy partial agonist act? |
|
Definition
| High efficacy partial agonists (e.g. buprenorphine) almost always act as full agonists except following excessive dose of agonist when they act as antagonists |
|
|
Term
| What are the 2 quantal dose-response curves produced for every drug? |
|
Definition
| Therapeutic effect and one or more for toxic effect |
|
|
Term
| What is the equation for therapeutic index? |
|
Definition
|
|
Term
| What is the safety factor equation? |
|
Definition
|
|
Term
| What does a therapeutic index (ratio) of 2.5 mean? |
|
Definition
| This means that about 2.5 times as much drug will cause a toxic effect in half the subjects as is needed to produce a therapeutic in the same proportion of subjects. However this ratio of toxic to therapeutic dose may not hold across the entire dose range if the dose-effect curves are not parallel. |
|
|
Term
| What does it mean to have a certain safety factor is > 1 or < 1? |
|
Definition
| A CSF > 1 indicates that the dose effective in 99% of the population is less than that which would be toxic in 1%. If the CSF < 1, there is overlap between the maximally effective and minimally toxic doses. |
|
|
Term
|
Definition
| Absorption, distribution, metabolism, elimination |
|
|
Term
|
Definition
|
|
Term
|
Definition
|
|
Term
| What is an additive drug interaction? |
|
Definition
|
|
Term
| What are the types of antagonism? |
|
Definition
• pharmacological
- e.g. acetylcholine & atropine on M1 receptors
• physiological
- e.g. glucocorticoids & insulin on blood sugar
• dispositional
- e.g. phenobarbitol & phenytoin (via CYP induction)
• chemical
- e.g. protamine binds heparin |
|
|
Term
| What is drug "absorption"? |
|
Definition
| The movement of the drug from its site of administration into the bloodstream |
|
|
Term
|
Definition
Bioavailability (F) is the fraction of the administered drug that reaches the systemic circulation
Drug bioavailability is a key factor in determining the onset of drug action
F = 1 (100% absorption) for i.v. drug administration and usually <1 for oral drug administration |
|
|
Term
| What is first pass metabolism? |
|
Definition
Once orally administered drugs are absorbed through the gut wall, they enter the portal circulation
The liver (and gut wall) removes drugs by ‘first pass’ metabolism, and binding so only a proportion reaches the hepatic veins and the systemic circulation.
Cellular efflux pumps in the gut also limit absorption (pumping of absorbed drug back into lumen). |
|
|
Term
| What is the equation for bioavailibility? |
|
Definition
|
|
Term
| How is Henderson-Hasselbalch used in pharmacology? |
|
Definition
| H-H Equation used to calculate the ratio of ionized (lipid impermeable) to unionized (lipid permeable) form of a drug in compartments of different pH |
|
|
Term
| What is the Henderson-Hasselbalch equation for our purposes? |
|
Definition
| pKa - pH = log [HA]/[A-] OR [BH+]/[B] (i.e. protonated over unprotonated) |
|
|
Term
| Where does the majority of drug absorption occur? |
|
Definition
| In the small intestine, despite relative pH values that indicate absorption may be better in other places. Due to the large difference in the surface area. |
|
|
Term
| What are important factors in enteric aborption, given that most occurs in the small intestine? |
|
Definition
Gastric pH & rate of gastric emptying are major determinants of delayed drug absorption
Intestinal motility also important factor in drug absorption |
|
|
Term
| What is the two compartment model? |
|
Definition
| Most common, more than one compartment model. Features two compartments - an initial rapidly distributing compartment, and a slowly distributing compartment. Rates associated include those for administration, elimination, as well as k1 and k2 for between compartments. |
|
|
Term
| What is distributation of a drug? |
|
Definition
| Passage of drugs from blood to tissues |
|
|
Term
| What is the volume of distribution? |
|
Definition
Apparent volume of body water that drug appears to distribute into to produce a drug concentration equal to that in the blood
- quantifies Distribution & a key factor in onset of drug action
- relates drug plasma concentration (C0) to amount or dose of drug in the body (Q)
- gives information on amount of drug distributed into tissues |
|
|
Term
| What is the equation for the volume of distribution? |
|
Definition
|
|
Term
| What is the typical % for TBW, ICF, and ECF? |
|
Definition
| TBW 60%, ICF 40%, ECF 20% (% body weight) |
|
|
Term
| What fractions of TBW are ICF and ECF? |
|
Definition
|
|
Term
| What do acidic drugs bind to? |
|
Definition
|
|
Term
| What do basic drugs bind to? |
|
Definition
| alpha-1-acid glycoprotein |
|
|
Term
| What is the nature of plasma protein binding of drugs? |
|
Definition
• The process is reversible (*)
• Binding sites are non-selective for similar drugs and thus one can displace another (*)
• The bound drug is inactive whilst bound and this limits systemic distribution and glomerular filtration
• Only drugs which are highly bound (>90%) and have small Vd are affected by changes in protein binding (e.g. warfarin) |
|
|
Term
| What does a high volume of distribution indicate? |
|
Definition
| High plasma protein binding drug |
|
|
Term
| What does a low volume of distribution indicate? |
|
Definition
| Drug binds DNA and is lipophilic (this leads to accumulation in fat) |
|
|
Term
| What is Vd dependent upon? |
|
Definition
| Body size, e.g. obses people have a high Vd for lipid-soluble drugs |
|
|
Term
| How does the blood-brain barrier affect drug distribution? |
|
Definition
Capillaries have high # of tight junctions between the vascular endothelial cells (better barriers)
Also, basal lamina of cap. endo. is surrounded by pericytes and glial/astrocytic sheath which provide additional barriers
Finally, unique set of ABC efflux pumps present in vasc. endo. & neurons (less accumulation)
Somewhat similar situation in testes (no glial sheath, however) – brain & testes are ‘privileged’ sites |
|
|
Term
| What is drug distribution like in the placenta? |
|
Definition
| Opposite end of barrier spectrum from BBB; especially permeable |
|
|
Term
| What is drug distribution like in fatty tissue for lipophilic drugs? |
|
Definition
| Tissue can serve as reservoir for drug upon repeated doses (e.g. thiopental) |
|
|
Term
| What is drug distribution like in calcified tissue for chelating drugs? |
|
Definition
| Drugs bind avidly to bones, teeth (e.g. tetracycline in pregnancy newborn defects (fluorescence, dysplasias, stunting, deformation)) |
|
|
Term
| What is drug distribution like for poorly transported metabolites? |
|
Definition
| Methotrexate -> MTX-polyglutamate, which is very difficult to excrete |
|
|
Term
| What are alpha and beta phases? |
|
Definition
| Distribution and elimination phases, respectively |
|
|
Term
| What are the membrane transporters / efflux pumps reponsible in excretion at the cellular level? |
|
Definition
Most important family = ABC (ATP-binding cassette) transporters
Most important member = P-glycoprotein aka multi-drug resistance protein-1 (MDR1)
Other members = MDR-related proteins, MRPs
All members catalyze the ATP-dependent transport of (generally) planar, hydrophobic molecules against their concentration gradient |
|
|
Term
| What are the significant mechansims of elimination of drugs at the systems level? |
|
Definition
• Renal excretion through urine is the major route
• Glomerular filtration rate depends on size (<40kDa), charge, & protein binding
• Drugs not bound / reabsorbed cleared at creatinine rate (125ml/min)
• Other significant routes = hepatic (through bile), and exhalation |
|
|
Term
| What are the insignificant mechansims of elimination of drugs at the systems level? |
|
Definition
• Sweat, saliva are insignificant routes of elimination
• Lactation is insignificant for maternal elimination, but may present a considerable ROA for a nursing infant |
|
|
Term
| Acidic urine favors the reabsorption of … |
|
Definition
|
|
Term
| Basic urine favors reabsorption of … |
|
Definition
|
|
Term
| In renal drug elimination, giving bicarbonate aids in … |
|
Definition
| higher pH and better excretion of A- |
|
|
Term
| In renal drug elimination, giving NH4Cl aids in … |
|
Definition
| lower pH and better excretion of BH+ |
|
|
Term
| What is zero order elimination kinetics? |
|
Definition
• Zero order kinetics: a fixed amount of the drug is metabolised in unit time (e.g. alcohol)
• No constant “t1/2” – increases with dose |
|
|
Term
| What is first order elimination kinetics? |
|
Definition
• First order kinetics: a fixed fraction of the drug is metabolised in unit time
• t1/2 constant for a comparable population
• Most drugs are metabolised by a first order process
• Amount metabolised is proportional to the concentration of the drug |
|
|
Term
| What is a drug's half-life? (definition) |
|
Definition
| Half-life (t1/2) is the time required to reduce the amount of a drug in the body by 50% |
|
|
Term
| What is the plateau principle in multiple dosing? |
|
Definition
| In 4-5 t½s, input = output, i.e. ‘Steady-state’ |
|
|
Term
| What is clearance (definition)? |
|
Definition
Clearance (CL) is the apparent volume (in liters) of blood that is cleared of a drug per unit time (min or h)
Predicts the rate of elimination in relation to the drug concentration |
|
|
Term
| What is clearance (equation)? |
|
Definition
|
|
Term
| What is the equation for half-life? (IMPORTANT) |
|
Definition
|
|
Term
| What is the equation for steady-state concentration? |
|
Definition
Css = (F x Dose)/(CL x T)
F = Bioavailability (100% =1)
T = Dose Interval |
|
|
Term
| What is the loading dose equation? |
|
Definition
| Loading Dose (LD) = Vd x Cp |
|
|
Term
| What are the three broad categories of heparin? |
|
Definition
1. Unfractionated heparin
2. Low molecular weight heparin
3. Pentasaccharides (ultra low molecular weight) |
|
|
Term
| What is the chemistry of unfractionated heparin? |
|
Definition
Mixture of sulfated mucopolysaccharides
Extracted from pork intestine or bovine lung
Various molecular weight fragments from 5,000 – 30,000 daltons |
|
|
Term
| What is the mechanism of action for unfractionated heparin? |
|
Definition
• Heparin bound to antithrombin increases the activity of antithrombin
• Indirect inhibitor of Xa and IIa (major mechanism of action) as well as IXa
• Larger heparin chains can bind thrombin directly |
|
|
Term
| How is unfractionated heparin metabolized? |
|
Definition
Metabolized by the liver and excreted in the urine
Does not cross placenta
Used in pregnancy |
|
|
Term
| How is unfractionated heparin administered? |
|
Definition
|
|
Term
| What is the half-life of unfractionated heparin? |
|
Definition
• Dose dependent absorption from subcutaneous injection sites
• ½ life, within and between patients is highly variable due to heparin-binding proteins
- Shorter ½ life in sicker people and those with large thrombi
- Average T1/2 = 90 min |
|
|
Term
| How is the administration of unfractionated heparin monitored? |
|
Definition
• The activated partial thromboplastin time (aPTT) is most sensitive to the effects of unfractionated heparin and is used clinically
• The PT is also affected by high heparin concentrations
*** This drug requires frequent monitoring and dose adjustments!!! |
|
|
Term
| What are the indications for use of unfractionated heparin? |
|
Definition
• Venous thrombosis – treatment and prevention
• Acute coronary syndromes
- Unstable angina
- Myocardial infarction
• Acute thrombotic stroke
• Extracorporeal circulation – dialysis, bypass
• Percutaneous vascular interventions
- Angioplasty, stents |
|
|
Term
| What are the complications of unfractionated heparin use? |
|
Definition
• Bleeding increased with other drugs that affect coagulation or platelet function
• Increased with invasive procedures
• Increased with renal and liver failure
• Allergy
• Impairs bone formation and enhances bone absorption (osteopenia w/ long term use)
• Thrombocytopenia |
|
|
Term
| What is the treatment of heparin related bleeding complications? |
|
Definition
• Immediate discontinuation of heparin
• Protamine – heparin antagonist
- Highly basic protein that binds heparin to inactivate it |
|
|
Term
|
Definition
• Benign drop up to 20%
• Reversible on stopping heparin |
|
|
Term
|
Definition
• Immunological reaction consisting of antibody response to heparin-platelet factor 4 complexes
• Causes platelet aggregation, activation and THROMBOSIS, not bleeding |
|
|
Term
| What are the clinical sequelae of HIT? |
|
Definition
• Venous thrombosis
• Arterial thrombosis
• death |
|
|
Term
| Describe venous thrombosis in HIT |
|
Definition
(50%)
• Deep vein thrombosis
- Lower extremity (may be bilateral), may develop venous limb gangrene
- Upper extremity (often at site of central line)
• Pulmonary embolism
• Cerebral vein thrombosis and adrenal infarction (rare) |
|
|
Term
| Describe arterial thrombosis in HIT |
|
Definition
• Lower limb arteries > upper (approx. 20% amputation rate)
• Stroke/myocardial infarction
• Heparin induced skin lesions at heparin injection sites (10-20%)
• Acute Systemic reactions after IV heparin bolus
• Inflammatory symptoms (fever, chills), cardiorespiratory symptoms, nausea, vomiting, diarrhea
• Adrenal necrosis/infarct |
|
|
Term
| When does HIT Type II occur and how is it diagnosed? |
|
Definition
• Onset 4-14 days after beginning heparin therapy
• Clinically diagnosed
• confirmed by antibody detection or special platelet aggregation tests |
|
|
Term
| How should HIT Type II be treated? |
|
Definition
• Alternative anticoagulants should be used if HIT suspected
• To avoid complications:
• monitor platelet count daily while using heparin
• Stop if clinical suspicion of HIT or a clot occurs while on heparin |
|
|
Term
| What are the four types of low molecule weight heparins? |
|
Definition
• Three preparations: enoxaparin, dalteparin, tinzaparin
• Ultra-low molecular weight heparin (pentasaccharide only)= fondaparinux |
|
|
Term
| What is the chemistry of low MW heparins? |
|
Definition
• Prepared by depolymerization of porcine heparin
• Molecular Weight: 4– 9Kdaltons, 13-22 saccharide units
• The pentasaccharide is devoid of higher molecular weight components |
|
|
Term
| What is the mechanism of action for low MW heparin? |
|
Definition
• Mechanism of inhibition is indirect (through anti-thrombin)
• Conformational change and interaction with anti-thrombin favors binding of factor Xa >>> factor IIa
• Pentasacharide (fondaparinux) inhibits factor Xa only |
|
|
Term
| How is low MW heparin metabolized/excreted? |
|
Definition
• Binds less to plasma proteins and cells
• Longer ½ life (Varies from 108-252 minutes)
• Significant excretion in the kidneys (requires increased monitoring with renal failure) |
|
|
Term
| How is low MW heparin administered? |
|
Definition
|
|
Term
| How is low MW heparin dosing monitored? |
|
Definition
• The effect of LMWH on Factor Xa activity is linearly related to the dose administered
• Plasma levels are predictable
• Monitoring is unnecessary in most patients
• If done, monitoring is via chromogenic assay to detect Anti-Xa activity obtained 4 hours after the dose of LMWH
• Groups where monitoring is performed:
Weight < 50 kg
Pregnant women
Patients with renal failure |
|
|
Term
| What are the indications for the use of low MW heparin? |
|
Definition
• DVT prophylaxis in surgery, trauma, hospitalized medical patients
• In- or outpatient treatment of venous thrombosis
• Acute coronary syndromes
• Appears safe in pregnancy (Most studied – enoxaparin) |
|
|
Term
| What are the adverse (and positive) effects of low MW heparin usage? |
|
Definition
• Bleeding
• Reversal of bleeding is much less effective with protamine (as compared to unfractionated heparin– not clinically used)
• Less documented HIT
• Osteoporosis uncommon |
|
|
Term
|
Definition
• Originally identified as a substance in spoiled sweet clover silage – caused bleeding with hypoprothrombinemia in cattle
• Rodenticides are coumarins
• Warfarin (synthetic)– primary form in US |
|
|
Term
| What is warfarin's mechanism of action? |
|
Definition
| Antagonism of vitamin K in the liver leads to synthesis of non-functional coagulation factors (FII, FVII, FIX, FX, Protein C, Protein S) |
|
|
Term
| How is warfarin metabolized and excreted and what can affect these? |
|
Definition
• Metabolized by P450 detoxification system of liver
• Genetic polymorphisms of the CYP 2C9 enzyme lead to impaired metabolism of warfarin and may require doses of drug substantially less than wild type enzyme (polymorphism occurs in approximately 1 in 10 caucasians)
• Extensively bound by plasma proteins- drugs that alter protein binding or affect the liver P450 system may potentiate or inhibit the activity of warfarin |
|
|
Term
| What are the indications for warfarin use? |
|
Definition
• Mechanical Valves
• Chronic Atrial Fibrillation
• Venous thrombosis
- Treatment of venous thrombosis
- Prevention of recurrent venous thrombosis and pulmonary embolus
- short and long-term
- Prevention of first event
- Joint replacement surgery |
|
|
Term
| How is warfarin administered? |
|
Definition
| Oral with bioavailability near 100% |
|
|
Term
| How is warfarin usage monitored? |
|
Definition
• Lab monitoring with the Prothrombin Time / INR
• Narrow therapeutic window
• Monitoring is critical to safety and efficacy
• Target range of INR depends on indication
- Ranges from 1.5 to 3.5
• Usually initiation occurs with heparin overlap |
|
|
Term
| How long does warfarin take to get to therapeutic level and why is this important? |
|
Definition
| At least 5 days. PC and PS are VKDPs with a short T1/2, so warfarin can induce thrombosis if begun without another anticoagulant |
|
|
Term
| What are the typical warfarin drug interactions? |
|
Definition
• Decreased Absorption
- Cholestyramine – nonspecifically absorbs warfarin in GI tract, decreasing anticoagulant effect
• Displacement from Plasma Albumin
- Cotrimoxazole, sulfonamides – increase anticoagulant effect
• Change in Liver Metabolism
- Increase metabolism – barbiturates (decrease effect)
- Decrease metabolism – cimetidine, cotrimoxazole (increase effect) |
|
|
Term
| How does liver disease affect warfarin use? |
|
Definition
| Increases its anticoagulant effect |
|
|
Term
| How does alcohol affect warfarin usage? |
|
Definition
| Increases its anticoagulant effect |
|
|
Term
| What are the adverse effects of warfarin? |
|
Definition
• Bleeding: Major bleeding estimated at 0.5- 1% per year
- Increased in the elderly and in combination with other anticoagulant or antiplatelet drugs
• Drug Interactions
• Tissue necrosis
Due to severe decreases in protein C and protein S levels
• Allergy
• Fetal embryopathy (especially with exposure from weeks 2 to 12 of gestation) |
|
|
Term
| During warfarin therapy, how is elevated INR managed? |
|
Definition
• Treatment depends on whether patient has active bleeding
• No bleeding
- Lower or omit next dose(s)
- Consider vitamin K
• Bleeding
- Vitamin K
- Fresh frozen plasma |
|
|
Term
| What are the absolute contraindications to warfarin therapy? |
|
Definition
• Pregnancy (absolute)
• Situations where the risk of hemorrhage is greater than the potential clinical benefits of therapy
- Uncontrolled alcohol/drug abuse
- Unsupervised dementia/psychosis
- Inability to monitor routinely
- High risk behaviors |
|
|
Term
| What are the three direct thrombin inhibitors? |
|
Definition
Argatroban
Bivalirudin
Lepirudin |
|
|
Term
| What is the mechanism of action for direct thrombin inhibitors? |
|
Definition
| Direct inhibition at thrombin active site |
|
|
Term
| How are DTI's administered and for how long? |
|
Definition
| Only IV, of short duration - inpatient uses |
|
|
Term
| What is the major difference between the DTI's Argatroban and Lepirudin? |
|
Definition
| Argatroban is cleared by the liver, Lepirudin by the kidneys |
|
|
Term
| How is the DTI Bivalirudin cleared and monitored? |
|
Definition
| Cleared by the kidneys, monitored with ACT (>350 seconds) |
|
|
Term
| What are other names for Parvovirus B19 infection? |
|
Definition
| Erythema infectiosum, Fifth's disease |
|
|
Term
| What is Parvovirus B19 infection? |
|
Definition
• Viral infection of humans
• Common
- 50% of adults
- 90% of elderly
• Worldwide distribution
• Remarkable trophism for erythroid precursors
- Cessation of red blood cell production for 5-7 days
- Marked decrease in number of reticulocytes
- Fall in hematocrit |
|
|
Term
| How is parvovirus B19 transmitted? |
|
Definition
| Respiratory droplets, blood (vertical transmission) |
|
|
Term
| What is the incubation period for parvovirus? |
|
Definition
|
|
Term
| What are the clinical manifestations of parvovirus B19? |
|
Definition
• Fifth’s disease
• Transient aplastic crisis
• Aplastic crisis
• Arthritis/arthralgia syndrome |
|
|
Term
| What is the biphasic course of Fifth's disease? |
|
Definition
• Non-specific findings
• Clear interval
• Fever and rash (children), "lacy", "slapped cheek"
• Polyarthropathy or inflammatory polyarthritis (adults) |
|
|
Term
| When is Fifth's disease typically recognized? |
|
Definition
| During the rash or joint complaints, when it is already non-infectious |
|
|
Term
| What occurs in transient aplastic crisis (TAC)? |
|
Definition
• B19 suppresses erythropoiesis for 5 to 7 days
• Reticulocytopenia leading to severe anemia
• Patients with hemolytic diseases
- Sickle cell anemia
- Thalassemias
- Acquired hemolytic anemias
• Infrequently with rash (anemia develops during viremia infectious |
|
|
Term
| What occurs in pure red-cell aplasia (PRCA)? |
|
Definition
• Develops in immunocompromised
- Congenital immunodeficiency
- AIDS
- Leukemia in remission
- Organ transplantation
• Failure to develop antibodies leads to persistent B19 replication
- No reticulocyte production
- Severe anemia
• No antibodies
- No rash
- No joint complaints |
|
|
Term
| What happens with in utero infection with parvovirus B19? |
|
Definition
• In utero infection
- Decreased or absent erythroid precursors
- Severe anemia and edema
- Congestive heart failure
- Fetal demise |
|
|
Term
| What is the treatment of Fifth's disease? |
|
Definition
|
|
Term
| What is the treatment of transient aplastic crisis? |
|
Definition
| Transfusion if symptomatic |
|
|
Term
| What is the treatment for red blood cell aplasia? |
|
Definition
|
|
Term
| What is the treatment for hydrops fetalis in parvovirus infection? |
|
Definition
|
|
Term
|
Definition
| Parasitic infection of RBC leading to periodic lysis |
|
|
Term
| What are the general symptoms of malaria? |
|
Definition
• Fever
• Anemia
• Multiple complications
• Death |
|
|
Term
| What are the laboratory findings in malaria? |
|
Definition
| Anemia, hemolysis, intraerythrocytic forms |
|
|
Term
|
Definition
| Parasitic infection of RBC |
|
|
Term
| What are the symptoms of babesiosis? |
|
Definition
• Asymptomatic
• Fever, chills, flu-like symptoms
• Much worse in immunocompromised and asplenic patients
- Death if not treated |
|
|
Term
| What are the laboratory findings in babesiosis? |
|
Definition
| Mild anemia, hemolysis, intraerythrocytic forms |
|
|
Term
|
Definition
• CD4+ T lymphocytes (helper T-cells)
• Monocytes
• CCR-5 receptor labeled cells |
|
|
Term
| What are the causes of anemia in HIV infection? |
|
Definition
• Inflammatory cytokines
• Malnutrition
• Viral infections
• Neoplasms
• Medications
- Megaloblastic! |
|
|
Term
| What are the clinical manifestations of Epstein Barr virus? |
|
Definition
• Fever
• Fatigue
• Sore throat
• Swollen lymph nodes
• Splenomegaly |
|
|
Term
| What is the Epstein Barr virus? |
|
Definition
| A herpes virus, causes mono, infects B-lymphocytes |
|
|
Term
| What are the laboratory features of EBV? |
|
Definition
• Leukocytosis (elevated white blood cell count)
- Lymphocytosis (>60%)
- Atypical lymphocytosis (>10%) |
|
|
Term
| What is a "type and screen" blood bank order? |
|
Definition
| ABO/Rh Type and Screen for unexpected RBC antibodies |
|
|
Term
| What is a "type and crossmatch "X" # of units" blood bank order? |
|
Definition
• Same as Type and Screen
• PLUS, identify “X” number of crossmatch compatible RBC units
• This is the order to SET UP blood (not the same as order to transfuse) |
|
|
Term
| What is required before a "transfuse"X" # of units" blood bank order? |
|
Definition
| Must give an order to setup blood first ("type and crossmatch") |
|
|
Term
| What is a direct Coombs test? |
|
Definition
• Also known as Direct Antiglobulin Test (DAT)
• Tests for presence of antibodies binding to patient’s (or recently transfused) RBCs in vivo |
|
|
Term
| What type of antigen are the ABO antigens, and where are they? |
|
Definition
| Carbohydrate antigens, expressed on all cells, present in plasma |
|
|
Term
| What antigen is on the O blood group? |
|
Definition
| O blood group due to presence of only the H-antigen added by fucosyltransferase |
|
|
Term
| What antigen is on the A blood group? |
|
Definition
| A blood group due to addition of N-acetylgalactosamine by A allele of a glycosyltransferase |
|
|
Term
| What antigen is on the B blood group? |
|
Definition
| B blood group due to addition of galactose by B allele of glycosyltransferase |
|
|
Term
| What type of antibodies are occur for ABO blood groups? |
|
Definition
| Naturally occurring, predominantly IgM |
|
|
Term
| How do you ABO type a patient? |
|
Definition
• Forward type
- Look for A or B antigens on patient’s RBC
• Reverse type
- Look for antibodies against A or B antigens
- Called “reverse” b/c a blood group A patient would have anti-B antibodies |
|
|
Term
| For red blood cells, what is the universal donor? |
|
Definition
| Blood group O - no A or B antigen |
|
|
Term
| For red blood cells, what is the universal recipient? |
|
Definition
| Blood group AB - patient has no anti-A or anti-B antibodies |
|
|
Term
| For platelets and plasma what is the universal donor? |
|
Definition
| Blood group AB - donor has no anti-A or anti-B antibodies |
|
|
Term
| For platelets and plasma what is the universal recipient? |
|
Definition
| Blood group O - no A or B antigen |
|
|
Term
| What is ABO crossmatching? |
|
Definition
| Aka immediate spin crossmatch. Take a pt's serum or plasma and mix with potential donor red cells. Watch for clumping. |
|
|
Term
|
Definition
• Transmembrane protein based antigen group
• Found only on red blood cells
• Composed of the following paired alleles: D/(d) C/c E/e
• Very immunogenic
• No naturally occurring antibodies
• Development of antibodies in a patient who is “negative” requires exposure by transfusion or pregnancy |
|
|
Term
| What is the particular antigen that is referred as positive or negative in A+, B-, etc. ? |
|
Definition
|
|
Term
| What are the paired alleles responsible for the different Rh antigens? |
|
Definition
|
|
Term
| How does Rh(D) differ from from ABO? |
|
Definition
• ABO antigens are carbohydrates
• Anti-A and Anti-B:
- are predominantly IgM, some IgG
- are naturally occurring
• Rh (D) antigens are proteins
• Anti-D (and other anti-Rh antibodies):
- Are predominantly IgG
- Are not naturally occurring
- Require exposure to antigen to develop antibodies (transfusion or pregnancy) |
|
|
Term
| Can you transfuse Rh+ RBCs into Rh- patient? |
|
Definition
• Can do this only once and never again because antibodies (anti-D) will form afterwards
• Do not do this in females with child-bearing potential!
- Anti-D Can lead to hemolytic disease of the newborn in Rh- mother who has a Rh+ fetus |
|
|
Term
| Can you transfuse Rh- RBCs into Rh+ patient? |
|
Definition
• No harm since Rh- RBC will have no anti-D
• However, should give Rh- blood only to Rh- patients (only 15% of blood donors are Rh-) |
|
|
Term
| What is hemolytic disease of the newborn (HDN)? |
|
Definition
• Mother has IgG antibodies against RBCs of the fetus
• Only IgG antibodies can pass through the placenta to destroy fetal RBCs
• Mother with anti-D and Rh+ fetus:
- High risk of HDN
• Mother with anti-A and anti-B and fetus with blood group A:
- Lower risk of HDN because most anti-A or anti-B are IgM |
|
|
Term
| What is the role of RhIG in preventing HDN? |
|
Definition
• Rh- mother can develop anti-D during pregnancy due to maternal-fetal hemorrhages
- 8% chance of anti-D formation per Rh+ pregnancy
• Use of RhIG immediately after delivery reduces risk of anti-D formation to 1-2% per Rh+ pregnancy
• Use of RhIG at 28 weeks gestation and immediately postpartum reduces risk of anti-D formation to 0.1% per Rh+ pregnancy
• RhIG does not prevent HDN due to development of other Rh antibodies (anti-c, anti-E) |
|
|
Term
| What are some other RBC antibodies that are important and when are they relevant? |
|
Definition
• Yes, there are numerous other RBC antigens that patients can form antibodies against:
- K, Jk(a), Jk(b), Fy(a), Fy(b), M, N, S,s
• They are only relevant if the patient is negative for the antigen and develop antibodies after a transfusion:
- Patient’s serum is mixed with RBCs from 2-4 different blood group O donors, representing all major RBC antigens
- If no antibodies detected, then only match for ABO/Rh |
|
|
Term
| What is an acute hemolytic transfusion reaction? |
|
Definition
• Up to 1 in 13,000 RBC transfusions
• Usually due to ABO incompatibility (83% of fatal transfusion reactions)
• Usually due to clerical error
- Majority (approx. 50%) due to error in Transfusion Administration |
|
|
Term
| What are the symptoms of acute hemolytic transfusion reactions? |
|
Definition
• Chills
• Fever
• Back pain
• Nausea
• Feeling of doom |
|
|
Term
| What is the pathogenesis of acute hemolytic transfusion reaction? |
|
Definition
| Intravascular hemolysis due to IgM anti-A or anti-B binding and activating complement |
|
|
Term
| What are the laboratory findings in acute hemolytic transfusion reaction? |
|
Definition
• Associated with positive direct Coombs test
• Free hemoglobin in plasma due to RBC lysis
• Hemoglobinuria |
|
|
Term
| What are the major outcomes in acute hemolytic transfusion reactions? |
|
Definition
| DIC (9%), renal failure (47%), death (17%), no morbidity (15%) |
|
|
Term
| What is febrile non-hemolytic transfusion reaction? |
|
Definition
• 1 to 15% of transfusions, rates are higher in patients more frequently transfused
• Release of cytokines by WBC in RBC units during storaged (IL-1, IL-6, TNF-alpha)
• Activation of donor WBC by antibodies in patient against them |
|
|
Term
| What are the symptoms of febrile non-hemolytic transfusion reaction and how is this differentiated from acute hemolytic transfusion reaction? |
|
Definition
• Indistinguishable from Acute hemolytic transfusion reaction
• Clerical check: Rule out most common cause of acute hemolytic transfusion reaction
• Examine plasma of new patient sample for visible hemolysis – should be negative
• Direct Coombs test/Direct antiglobulin test (DAT) should be negative – i.e. no antibodies binding to RBC |
|
|
Term
| If febrile non-hemolytic transfusion reaction is recurrent, what is the proper treatment? |
|
Definition
| premedicate patient with antipyretic and use leukoreduced blood |
|
|
Term
| What is as mild allergic reaction (to transfusion), symptoms, and treatment? |
|
Definition
• 1 to 3% of transfusions
• Usually allergic reaction to plasma proteins found in transfused blood leading to release of histamine by mast cells
• Symptoms: Itching, hives, rashes
• Treated with antihistamines, corticosteroids if symptoms are more severe |
|
|
Term
| What is an anaphylactic reaction to transfusion? |
|
Definition
• 1 in 20,000 to 47,000 transfusions (mainly plasma an platelet transfusions)
• Transfusion reaction associated with severe hypotension and /or respiratory distress
• NO pulmonary edema (bronchoconstriction)
• Usually due to preformed antibodies against plasma proteins (IgA, haptoglobin, C4) |
|
|
Term
| What must be checked for when treating anaphylactic reaction from transfusion? |
|
Definition
• Requires laboratory investigation to rule out IgA deficiency
• If patient is IgA-deficient and has anaphylaxis and has anti-IgA antibodies, must use IgA-deficient blood:
- Washed RBC or platelets to remove plasma proteins
- Plasma from IgA-deficient blood donors |
|
|
Term
| What is transfusion related acute lung injury (TRALI)? |
|
Definition
• 1 in 5,000 transfusions (mainly plasma and platelet transfusions)
• ARDS-like syndrome of respiratory distress within 6 hours of a transfusion
• Two proposed mechanisms:
- High concentrations of anti-HLA or leukocyte antibodies present in donor blood
- Lipid mediators released into donor blood during storage
• Non-cardiogenic pulmonary edema due to inflammatory reaction in capillaries of lung
• Usually self-limited and but may require a period of mechanical ventillation
• Leading cause of transfusion-associated deaths! |
|
|
Term
| What are the proposed mechanisms for transfusion related acute lung injury? |
|
Definition
• Two proposed mechanisms:
- High concentrations of anti-HLA or leukocyte antibodies present in donor blood
- Lipid mediators released into donor blood during storage |
|
|
Term
| What is transfusion-associated circulatory overload (TACO)? |
|
Definition
• Common! One in 356 units transfused in ICU
• Rapid or massive transfusions can precipitate this.
• More common in infants, patients > 60 yrs, patients with diminished cardiac reserve, patients with chronic anemia.
• Cardiogenic pulmonary edema due to transfusion
• Will see hypertension due to rapid expansion of intravascular space with transfusion (vs. hypotension in anaphylaxis) |
|
|
Term
| What is the lab test and treatment for transfusion-associated circulatory overload (TACO)? |
|
Definition
• BNP lab test useful to prove transfusion-induced congestive heart failure.
• Usually responsive to diuretics (transfusion-associated acute lung injury will not respond to diuretics) |
|
|
Term
| What is transfusion-associated graft versus host disease (TA-GVHD)? |
|
Definition
• Phenomenon where donor T-lymphocytes from transfused blood engraft, proliferate, and attack host tissue
• Can occur in severely immunocompromised patients due to inability to destroy “foreign” lymphocytes
• Can occur in immunocompetent patients when receiving blood from relatives or other donors with similar HLA types |
|
|
Term
| What are the symptoms of transfusion-associated graft versus host disease (TA-GVHD)? |
|
Definition
| Fever, skin rash, diarrhea, hepatitis, and marrow aplasia |
|
|
Term
| What is the treatment for transfusion-associated graft versus host disease (TA-GVHD)? |
|
Definition
• TA-GVHD is prevented by irradiation of blood in patients who are at risk
• No treatment (>90% mortality), only prevention |
|
|
Term
| What is post-transfusion purpura (PTP)? |
|
Definition
• Characterized by profound thrombocytopenia 1-3 weeks after transfusion
• Most commonly associated with antibodies against the HPA-1a antigen on GP IIb/IIIa of platelets (i.e. Patients who are HPA-1a negative)
• Antibodies destoy not only “foreign” platelets, but also patient’s own platelets
• Thrombocytopenia usually persists for 2-3 weeks and then spontaneously resolves without treatment |
|
|
Term
|
Definition
|
|
Term
|
Definition
|
|
Term
| Location of RBC formation prenatally |
|
Definition
1. yolk sac
2. liver
3. bone marrow (month 4) - main site by birth |
|
|
Term
|
Definition
- "red" marrow is active
- almost all marrow in kids is red
- red marrow shrinks after puberty so half of skeleton is red |
|
|
Term
| Response of body when need increased RBC production |
|
Definition
1. yellow marrow can be replaced by red
2. bone marrow can increease RBC production by at least 8x
3. other organs then can help like liver, spleen, and lymph nodes (extramedullary hematopoiesis |
|
|
Term
| extramedullary hematopoiesis |
|
Definition
| when other organs start contributing RBC production like liver, spleen, lymph nodes |
|
|
Term
| Life span of RBCs, platelets, neutrophils |
|
Definition
RBCs: 120 days
Neutrophils: 1 day
Platelets: 7-10 days |
|
|
Term
|
Definition
- production of lymphocytes
- produces many more than needed daily in blood
- most ly,phocytes are destroed during development
- so this process is inefficient compared to all other hematopoiesis |
|
|
Term
| All blood cells develop from... |
|
Definition
| pluripotential hematopoietic stem cells |
|
|
Term
| hematopoietic pluripotent stem cells |
|
Definition
- can differentiate into any kind of blood cell (and some others of same germ line like osteoclasts)
- gives rise to t2 multipotent stem cells: lymphoid and myeloid multipotent stem cells |
|
|
Term
| Lymphoid multipotent stem cells |
|
Definition
- gives rise to:
1. T-cells
2. B-cells
3. natural killer cells |
|
|
Term
| Myeloid multipotent stem cell |
|
Definition
- gives rise to several committed stem cells (only give rise to one type of cell) which give riser to:
1. platelets
2. neutrophils
3. eosinophils
4. basophils
5. RBCs
6. macrophages
7. dendritic cells |
|
|
Term
| Hematopoietic stem cell location |
|
Definition
- usually in bone marrow but also in peripheral circulation in small numbers
- do not differentiate in circulation because need special microenvironment, but easy to harves in blood for stem cell transplants
- receptors to go back to bone marrow to function |
|
|
Term
|
Definition
- thin-walled blood vessels that supply the bone marrow
- where new blood cells are discharged |
|
|
Term
|
Definition
- mature ones remain in bone marrow
- large (up to 60 micrometers)
- highly polyploid nucleus
- normally lie close beside blood sinuses and extend processes through hole in endothelial lining
- platelets pinch of processes into blood stream |
|
|
Term
| stem cell ratio in bone marrow |
|
Definition
|
|
Term
| Hematopoietic stem cells and stem cell replacement |
|
Definition
- used to reconstitue blood cells in aplastic anemia (failing bone marrow) or where bone marrow is chemically ablated like in leukemia
- healthy stem cells can be from an immunologically matched donor or by sorting from a sample previously taken from patient |
|
|
Term
| infrequent stem cell division is common in... |
|
Definition
several tissues including:
1. epidermis
2. gut
3. hematopoietic system
- amplified division of committed progenitor cells reduces the need for division cycles of stem cells themselves (reduces replicative senesence damaging mutations) |
|
|
Term
|
Definition
- seems to be controlled in part by specific signals generated at contracts with stromal cells
- these signals are need to keep the stem cells undifferentiated
- they are normally confined in particular niche in bone marrow and if lose contact the stem cells lost their potential |
|
|
Term
|
Definition
| - been found to contribute to stem cell fate control (which will differentiate which remain stem cells after replication) |
|
|
Term
| Bone marrow as environment for blood cell development |
|
Definition
- provides niche to develop when bound
- presents growth factors and nutrients necessary to development of blood cells |
|
|
Term
| hematopoietic growth factors |
|
Definition
- cells depend on it to support hematopoiesis
- glycoproteins
-some circulate in blood and act as hormones, others are in bone marrow either as secreted local mediators or like SCF (stem cell factor) as membrane-bound signals that act through cell-cell contact |
|
|
Term
| Hematopoietic growth factor characteristics |
|
Definition
1. mulitiple biological activities with diff. specificities and origins
2. may influence differentiation directly or indirectly
3. often enhance functional activity of terminally differentiated cell
4. most lineage specific factors inhibit apoptosis of the progenitors of the specific lineage they influence
5. the HGF receptors share important structural features
6. some HGFs may be used in clinical practive (erythropoietin and G-CSF) |
|
|
Term
| HGF that act early in process |
|
Definition
- ex: pluripotent stem cells
- such as IL-6, steel factor, and stem cell factor |
|
|
Term
| HGF that act on stem cells |
|
Definition
| - granulocyte-monocyte colony stimulating factor or GM-CSF |
|
|
Term
| HGF that work on more committed stem cells |
|
Definition
- such as GM-SCF, granulocyte colony stimulating factor (G-CSF)
- erythropoietin (EPO)
- thrombopoietin (TPO) |
|
|
Term
|
Definition
1. those that act very early
2. those that act on stem cells
3. those that work more on committed stem cells |
|
|
Term
| worn-out erythrocyte phagocytosis |
|
Definition
- in liver and spleen
- more than 10^11 RBCs removed each day
- young erythocytes protect themselves with a protein on their surface that binds to an inhibitory receptor on macrophages and prevents their phagocytosis |
|
|
Term
| body's response to lack of oxygen or shortage of erythrocytes (sensed as hypoxia) |
|
Definition
- stimulates cells in kidney to synthesize and secrete increased erythropoietin into bloodstream
- stimulates production of erythrocytes
- change is recognized within 1-2 days after increase of erythropoietin, so hormone must act on cells close to precursors of mature erythrocytes |
|
|
Term
| erythrocyte colony-forming cell |
|
Definition
- or colony-forming unit (CFU-E)
- first specific cell in erythroid pathway
- gives rise to mature erythrocytes after about six division cycles or less
- do not contain hemoglobin yet and are derived from an earlier type or progenitor cell whose proliferation does not depend on erythropoietin
- these cells depend on erythropoietin for survival and proliferation |
|
|
Term
|
Definition
- receptor dependent
- stimulates premature release of reticulocytes into blood stream
- as RBCs mature they lose their receptors so they are not responsive to EPO |
|
|
Term
| Granulocyte/macrophage progenitor cell |
|
Definition
| - form neutrophils and macrophages |
|
|
Term
|
Definition
- circulate in blood for only a few hours before migrating into CT or other sites where they survive for only a few days
- then die by apoptosis and phagocytosis by macrophages |
|
|
Term
|
Definition
- can persist for months or years outside bloodstream
- can be activated by local signals to resume proliferation |
|
|
Term
| colony stimulating factors (neutrophil and macrophage colonies) |
|
Definition
- at least 7 have been identified
- all thought to act in diff combinations to regulate selective production of these cells in vivo
- synthesized by various cell types including: endothelial cells, fibroblasts, macrophages, and lymphocytes
- concentration in blood increases in response to bacterial infection in tissue increasing the number of phagocytic cells released into bloodstream from bone marrow |
|
|
Term
|
Definition
| - used to increase the neutrophil count in patients with drug induced neutropenia as well as other conditions |
|
|
Term
| CSFs and terminally differentiated cells |
|
Definition
| - can activate the specialized functions (such as phaogcytosis of target-cell killing) of terminally differentiated cells |
|
|
Term
|
Definition
- dangerous: mutations that inhibit cell death by causing excessive production of intracellular apoptosis inhibitor Bcl-2 promote the development of cancer in B lymphocytes
- many cases of leukemia result from mutations that confer the capacity of unlimited self-renewal on committed hemopoietic precursor cells |
|
|
Term
| B-cell and T-cell development |
|
Definition
- both originate in bone marrow
- B-cells mature in bone marrow before migrating to other lymph organs
- T-lymphocytes continue their development in the thymus and may also migrate to other lymph tissues |
|
|
Term
| Assessing hematopoietic effectiveness |
|
Definition
- CBC
- bone marrow aspirate (just fluid of marrow is aspirated)
- often bone marrow biopsy as well (biopsy means particles of the bone are taken as well)
- staining can show precursor cells and their total numbers
- examination can show hypocellularity (as in aplastic disease), hypercellurity (as in increased production), and monotonous cells (far too many cells of as can occur in leukemia |
|
|
Term
| PO2 atmosphere, lungs, tissues |
|
Definition
1. atmosphere: 130 mmHg
2. lungs: 100 mmHg
3. Tissues: 20-40 mmHg |
|
|
Term
| Hemoglobin basic structure |
|
Definition
- 2 alpha and 2 beta globin chains (protein)
- and heme group (organically synthesized) |
|
|
Term
| How much hemoglobin does hte normal human body contain? |
|
Definition
|
|
Term
|
Definition
2 Fe (II) + O2 = 2 Fe(II)O2 (ferrous)
- reversible
2 Fe(II) + 3O2 = 2 Fe(III)2O3 (ferric)
- irreversible without catalyst, *** dominates so Hb must maintain ferrous Fe2+ iron state |
|
|
Term
|
Definition
- requires octahedral coordination
- 4 ligants are nitrogens in heme
- 5th is nitrogen in His-93 in globin chain (proximal His)
- 6th is from O2 which is sandwiched between the Fe2+ and His-64 (distal His) |
|
|
Term
|
Definition
- tetrapyrrole: 4 pyrrole rings: A,B,C,D
- very stable flat structure
- hydrophobic
- 8 side chain positions, 2 on each ring
- 3 side-chain flavors:
1. methyl
2. vinyl
3. proprionic acid
- all for coordinating heme in pocket of globin |
|
|
Term
| Anemia classification in clinic |
|
Definition
1. morphologic
2. pathophysiologic |
|
|
Term
| Morphologic anemia classifications |
|
Definition
1. normocytic, normochromic
2. microcytic, hypochromic
3. macrocyteic, normochromic |
|
|
Term
| Where is Heme synthesized> |
|
Definition
- in any cell with mitochondria
- used in other processes in body including cytochrome c oxidase in mitochondria
- 85% is synthesized in erythroid cells in bone marrow
- occurs in BFU-E lineage: normoblasts and reticulocytes |
|
|
Term
|
Definition
- starts in mitos, continues in cytosol, finishes in mitos
- 8 molecular intermediates in pathway
- seven (1 inside, 3 out, 3 in mito)enzymatic steps lead to heme |
|
|
Term
| Rate limiting steps in heme synthesis |
|
Definition
Step 1: succinyl-CoA + glycine to delta aminolevulinic acid (ALA)
Step 7: protoporphyrin IX to ferro-protoporphyrin IX (Heme) |
|
|
Term
|
Definition
- forms delta ALA from succinyl-CoA and glycine (condensation reaction)
- rate limiting enzyme
- needs Vit B6 (co-factor) for catalytic activity
- erthroid ALA-synthase is encoded by gene on X chromosome (sex-linked inheritance |
|
|
Term
|
Definition
- rate determining enzyme (protoporphyrin IX to ferro-protoporphyrin IX - heme)
- FE 2+ incorporation causes H ion displacement
- ferrochelatase ahs 2 sulfahydryl groups (SH) in its active site that hold the Fe2+ (important in plumbism: lead poisoning) |
|
|
Term
| ALA-synthase (ALAS) up regulation |
|
Definition
- upregulated in response to increased iron (Fe2+) in erythroid cells
- ALAS mRNA has cis-acting iron response element that modulates rate of translation of mRNA to protein |
|
|
Term
| Down regulation of heme synthesis |
|
Definition
1. feedback inhibition regulates heme synthesis at 2 levels: ALAS and ferrochelatase
2. heme directly inhibits the catalytic activity of ALAS
3. Elevated heme levels inhibit transport of ALAS from cytosol to mito
4. similarly elevated heme reduces iron uptake thereby limiting substrate for ferrochelatase
5. also lower iron slows ALAS translation via IRE |
|
|
Term
| Anemia of lead poisoning (plumbism) |
|
Definition
- subclass of sideroblastic anemia named for feature of iron deposits seen in staining of normoblasts in marrow
- caused from lead exposure from : paint, gas fumes, lead pipes in plumbing, contaminated foods
- Pb targets many molecules vital to cell metabolism, heme synthesis pathway especially sensitive
- ALA dehydratase (step 2-3) and ferrochelatase most sensitive Pb targets in pathway
- Pb directly inhibits enzymes by interacting with SH groups or displacing metal ions (also alters iron uptake) |
|
|
Term
| Plumbism clinical findings |
|
Definition
Presenting symptoms: abdominal pain, motor neuropathy (palsy)
clinical assays:
- blood lead levels
- urinary ALA levels
- measurement of iron and protoporphyrin IX accumulation in RBCs
Hematology: ofton normocytic and chromic
- microcytic and hypochromic with chronic exposure (sometimes basophilic stippling due to iron induced aggregates or ribosomes |
|
|
Term
|
Definition
| - through removal of Pb source and orchelation therapy with EDTA or dimercapto-succinate |
|
|
Term
| Congenital ALA-synthase deficiency |
|
Definition
- present with sideroblastic anemia: erythrocytes are hypochromic and microcytic
- affected families show x-linked inheritance
- mutations in ALAS gene cluster around the sequences that encode the enzyme active site and vit B6 binding site |
|
|
Term
|
Definition
- rare
- arise from specific inherited defects in enzymes of heme pathway
- seven distinct porphyrias described that correlate with deficiencies in each of the enzymes
- clinical manifestations result from toxicity of accumulated porphyrin intermediates |
|
|
Term
| Acute intermittent porphyria |
|
Definition
(AIP)
- manifests neurological and psychiatric illness, visceral pain
- accumulation of ALA and porphobilinogen (PBG) results from 1
1. inhibition of pBG degeneration
2. reduced heme production increases ALA-synthase levels
- treatment with analgesics for pain, maintaine morale, alleviate fear, infusion of hematin (Fe3+ heme) |
|
|
Term
| Congenital erythropoietic porphyria |
|
Definition
- manifests cutaneous scarring due to photosensitivity
- accumulated isomers of uro'gen and copro'gen result from inhibition of dehydration
- these compounds cause oxidative damage when exposed to light
- treatment with spleenectomy or transfusion
(porphyrin ring intermediates are sensitive to light) |
|
|
Term
| Composition of globin chains |
|
Definition
- alpha: 141 AAs (alpha and zeta) unstable, form precipitates if join with 4 chains
- beta: 146 AAs (varieties: beta, gamma, delta, epsilon) |
|
|
Term
|
Definition
| Early zeta (alpha chain) and epsilon (beta chain) |
|
|
Term
| hemoglobin chain changes in utero |
|
Definition
- coincides with where the chains are being made
- yolk sac production makes zeta epsilon
- second trimester alpha and gamma chains in liver (fetal hemoglobin)
- around birth gamma chain production dies off and we see increase in beta (HEA adult hemoglobin) some alpha delta as well |
|
|
Term
| levels of alpha-like and beta-like polypetide chain regulation |
|
Definition
- assembly of the tetramers relies on stoichiometric amounts of each
- levels are highly coordinated through mechanisms that regulate transcription and translation of Globin genes
- chaperone proteins put the dimers and tetramers together
*** very few free alpha or beta chains in cell |
|
|
Term
| Where are alpha-like genes found? |
|
Definition
| - cluster on chromosome 16 |
|
|
Term
| Where are beta -like genes found? |
|
Definition
|
|
Term
| Regulation of beta-like and alpha-like genes |
|
Definition
| - "cis-acting" sequences act to regulate transcription: promoters, enhancers, silencers |
|
|
Term
| Hemoglobin gene switching |
|
Definition
- not responsive to environmentl cue (hormones)
- perhaps responds to genetic clock
- both alpha and beta clusters have 5-pime "master" region that interacts with promoters of individual globin genes |
|
|
Term
| Promoter for beta cluster |
|
Definition
|
|
Term
|
Definition
| - hypersensitivity domain (HS) |
|
|
Term
Heme regulation of globin synthesis
(will likely be on test) |
|
Definition
- heme and globin biosynthesis are tightly regulated
- heme acts directly to modulate translation mechanisms producing globin polypeptide
- in absence of heme, a heme-controlled inhibitor (HCI) accumulates and has a high activity
- does not act at transcription level but translation**** |
|
|
Term
Heme controlled inhibitor
(will be on test) |
|
Definition
- present in absence of heme to prevent globin production
- it's a kinase that phosphorylates and stalls the cycling of the eIF2 initiator of protein translation *** |
|
|
Term
|
Definition
- imbalance of alpha and beta
- diverse group of heritable disorders resulting from deleterious mutations causing reduced or terminated synthesis of one or more globin chains
- gernerally hypochromic (not enough hemoglobin) and microcytic RBCs
- could also have premature hemolysis o fperipheral RBCs with destruction of erythroid cells in the marrow
- these result from excessive accumulation of either alpha or beta globin chains |
|
|
Term
|
Definition
- large deletions most common (don't make enough alpha)
- two alpha genes/per chromosome (4 total)
- deletions show quantitatice effects reflecting number of genes mutated |
|
|
Term
|
Definition
- most common is beta zero(superscript) where no beta chains produced
- point mutations common, deletions rare
- heterozygotes are mildly affected
- homozygosity is life threatening (alpha alone just precipitates out and can't be functional at all |
|
|
Term
|
Definition
- microcytosis
- hypochromia
- sopme nucleated RBCS
- dilated diploic space
- subperiosteal growth gives "hair-on-end" appearance |
|
|
Term
| Molecular phenotypes and compensatory mechanisms for alpha thalassemia |
|
Definition
- tetramer formation by beta-like genes
- B4 = HbH
- gamma4 = Hb Barts
- HbH and Hb Barts have higher affinity for O2 and are not effective transporters |
|
|
Term
| Molecular phenotypes and compensatory mechanisms for beta thalassemia |
|
Definition
- alpha chains precipitate, denature to form inclusion bodies (heinz bodies) in cells
- cause RBC deformity, membrane instability, hemolysis
- in B zero the gamma chain production can persist to partially compensate (HbF) |
|
|
Term
|
Definition
- HbS
- results from mutations in the beta chain of Hb that promote self-aggregation of Hb in fibrils
- a Glu to Val AA change at position 6 in beta chain most common
- fibril formation precipitates from deoxy form of HbS |
|
|
Term
| Intrinsic defects causing decreased RBC survival |
|
Definition
1. membrane
2. enzyme
3. hemoglobin |
|
|
Term
| Glucose-6-phosphate dehydrogenase deficiency clinical |
|
Definition
- episodic anemia beginning in childhood
- patients are non-anemic prior to exposure to oxidizing stresses; however, following exposures (drugs, chemicals, infections) the patients become anemic |
|
|
Term
| Glucose-6-phosphate dehydrogenase deficiency distribution and genetics |
|
Definition
- ethically distributed: most common in African, Mediterranean, middle eastern, and asian populations
- x-linked inheritance |
|
|
Term
|
Definition
- >100 polymorphic forms worldwide
- most not pathologic and don't cause anemia
- most common disease causing variants:
1. G6PD A- : 10-15% of normal enzyme activity
2. G6PD Med: 1% of normal enzyme activity |
|
|
Term
| G6PD deficiency anemia hemolysis |
|
Definition
- causes hemolytic anemia
- in exposure to oxidative stress the oldest RBCs (with decreased G6PD) with least residual G6PD activity are hemolyzed in the spleen |
|
|
Term
| Oxidative stresses causing hemolysis in G6PD deficiency (drugs) |
|
Definition
anti-malarials: primaquine, chloroquine, pentaquine
- Anti-bacterials: sulfamethoxazole, sulfanilamide
- many others including analgesics |
|
|
Term
| Oxidative stresses causing hemolysis in G6PD deficiency (chemicals) |
|
Definition
- diet: fava beans ("favism")
- mothballs (para-aminobenzoic acid) |
|
|
Term
| Oxidative stresses causing hemolysis in G6PD deficiency (infections) |
|
Definition
- many viral and bacterial infections, especially when severe
- viral hepatitis
- pneumonia |
|
|
Term
|
Definition
- more common among mediterranean blacks
- fava beans in diet cause oxidative stress that causes hemolytic anemia in those genetically susceptible |
|
|
Term
| G6PD deficiency lab findings in peripheral blood |
|
Definition
1. normal hb/hvt prior to oxidative exposure, then mild to severe anemia (depending on G6PD variant) develops shortly after
2. reticulocytosis
3. Bite cells and blister cells in the peripheral smear |
|
|
Term
| G6PD deficiency bone marrow lab findings |
|
Definition
| - compensatory erythroid hyperplasia driven by erythropoietin during the anemia phase; normal bone marrow findings when not anemic |
|
|
Term
| How to diagnose G6PD deficiency |
|
Definition
| - Heinz body preparation from blood sample screen; quantitation of G6PD level in RBC's by specialty lab to confirm (test when patient is NOT anemic) |
|
|
Term
| Short term G6PD deficiency course |
|
Definition
1. hemolysis begins 1 to 3 days after exposure
2. with brisk reticulocytosis patients may not become evidently anemic (compensated hemolysis) depending on G6PD variant, but most will
3. since reticulocytes have the highest level of G6PD even in deficient patients do not collect blood sample in acute setting to measure G6PD levels |
|
|
Term
| Long term course of G6pD deficiency |
|
Definition
1. patients are at life-long risk for anemia following oxidative exposures
2. counsel patients to avoid these stresses when possible (drugs, food) |
|
|
Term
|
Definition
- structurally abnormal hemoglobin that functions poorly and causes pathologic changes to red cells
- caused by mutation in coding region of the globin chain gene |
|
|
Term
|
Definition
| - decreased synthesis of (usually) structurally normal globin chains, either alpha or beta, due to mutations or deletions of the specific globin chain gene |
|
|
Term
| Clinical presentation of sickle cell disease |
|
Definition
1. found almost exclusively in blacks
2. onset within first year of life
3. chronic moderate to severe anemia
4. clinically recognized "crises"
- splenomegaly initially followed eventually by splenic autoinfarction; this predisposes to infections, particularly by encapsulated bacteria
- skeletal changes seen in X-rays, especially in skull bones |
|
|
Term
| mutation in sickle cell disease |
|
Definition
| - glutamic acid (negative charge) to valine (neutral charge) |
|
|
Term
| HbSS (homozygote with sickle cell) |
|
Definition
- alters the hydrogen bonding between and the stability of the globin chain interaction
- in conditions of deoxygenation, acidosis, dehydration HbS polymerizes, at first reversible, but eventually irreversibly
- this process damages the RBC membrane causing calcium influx, water loss, and increased cell stickiness
- induces sickle shape and leads to premature RBC clearance by the spleen and vasoocclusion |
|
|
Term
| What cause the RBCs to sickle |
|
Definition
1. high total amount of intracellular Hb (intracellular dehydration)
2. an elevated proportion of HbS; when other Hbs are present in sufficient quantity to interfere witht he ability of HbS molecules to polymerize and sickle |
|
|
Term
| Peripheral blood in sickle cell disease |
|
Definition
1. moderate to severe normocytic anemia with high RDW
2. sickled cells and target cells in peripheral smear
3. reticulocytosis
4. hyperbilirubinemia |
|
|
Term
| Bone marrow in sickle cell disease |
|
Definition
- erythroid hyperplasia (except in aplastic crisis)
- may develop bone marrow fibrosis |
|
|
Term
| Diagnostic test for sickle cell disease |
|
Definition
| - hemoglobin electrophoresis |
|
|
Term
| Homozygotes with sickle cell disease clinical course |
|
Definition
1. chronic lifelong anemia with end organ ischemic damage
2. periodic painful crises
3. "sequestration crises"
4. Aplastic crises
5. overal 50% survival by age 50 |
|
|
Term
| Therapy for sickle cell anemia |
|
Definition
- supportive
- alkylating agents (ex: hydroxyurea) to increase HbF |
|
|
Term
|
Definition
- occurs in children prior to splenic atrophy
- sudden massive splenomegaly with increased sequestration of RBC's
- profound anemia
- usually transient |
|
|
Term
| Heterozygotes with sickle cell disease clinical course |
|
Definition
- sickle trait
- much reduced but not absent symptomatology
- near normal life span
- some protection against falciparum malaria |
|
|
Term
|
Definition
- infection with parvovirus arrests erythroid maturation in the marrow so RBC production stops
- this, together with continued rapid clearance of sickled cells from the blood by the spleen
- leads to profound anemia |
|
|
Term
| anemia of decreased RBC survival extrinsic factors |
|
Definition
1. immune hemolytic anemis: see autoimmunity section
2. physical mediators of hemolysis |
|
|
Term
| microangiopathic hemolysis |
|
Definition
- heterogenous group of anemias that result from intravascular (not spleen mediated) RBC destruction due to collisions with or trauma from intravascular lesions or abnormal endothelial cells
1. disseminated intravasclar coagulation
2. arteritis
3. malignant hypertension
4. mechanical heart valves
- anemia is normo to microcytic with schistocytes in the smear |
|
|
Term
|
Definition
| - vessel wall inflammation seen in some collagen vascular diseases |
|
|
Term
|
Definition
| - narrowed arterioles, scarred endothelium |
|
|
Term
|
Definition
| - used in valve surgery; create shear stress |
|
|
Term
|
Definition
- in G6PD deficiency
-- Oxidative stress collapses the hemoglobin (globin chains) and then the aggregates get removed in spleen leaving the rest of the RBC intact but leaving a funny shape (many times get back out in circulation) |
|
|
Term
| Production anemias account for... |
|
Definition
|
|
Term
|
Definition
Marrow incapable of producing enough new RBCs to replace the senescent ones being cleared from the blood
- erythropoietin levels and bone marrow morphology vary widely from subtype to subtype
- reticulocyte count low for all |
|
|
Term
|
Definition
- most common worldwide
- women have 25% less total iron than males so more common in females (less stores in female so lower ferritin) |
|
|
Term
| Iron distribution (males) |
|
Definition
Hemoglobin: 66%
Ferritin (storage): 30%
Myoglobin: 4%
Plasma: <1%
Various enzyms: <1% |
|
|
Term
| iron loss in males and non-menstruating females |
|
Definition
- 1 mg per dy so must absorb that much in diet
- |
|
|
Term
|
Definition
| - at level of proximal small bowel mucosa (duodenum) where 5-10% of total daily intake is absorbed |
|
|
Term
| Body compensation when losing Fe |
|
Definition
- from growth, menstruation, chronic bleeds
- absorption can be increased to 20-30% of intake (1 mL RBCs has 1Mg Fe) |
|
|
Term
|
Definition
- absorbed into intestinal mucosa
- temporarily stored in mucosa cell (ferritin)
- passed to plasma and bound to transferrin which transports to storage sites (ferritin, macrophages, Hb) |
|
|
Term
| Ferritin (storage) levels in male vs female |
|
Definition
| 400 mg in female 1000 mg in male |
|
|
Term
|
Definition
| - crucial channel that allows the iron to get out of mucosal cell to plasma and transferrin which transports where iron needs to go |
|
|
Term
|
Definition
- pallor
- fatigue
- pallor of nail beds and mucosa
- concave nailbeds (in very severe cases)unique to iron deficiency
- iron deficiency interferes with CT in very advanced cases and causes the nailbeds
- chapping at corners of lips also found in iron deficiency |
|
|
Term
| Stages of iron deficiency |
|
Definition
1. iron depletion: Fe loss exceeds absorption, no hematologic consequences yet
2. iron deficiemt erythropoiesis without anemia: Fe is close to depleted and serum markers of iron homeostasis are abnormal, but no anemia
3. iron deficiency anemia: iron stores depleted, anemia is now present with subsequent microcytosis |
|
|
Term
| Causes of iron deficiency |
|
Definition
- nutritional: poor intake (vegans) or increased need (growth during: infancy, early adolescence, and also pregnancy)
2. bleeding: pathologic (gastrointestinal and genitourinary lesions; intestinal parasites; drugs) and physiologic (menstruation)
3. malabsorption: post-gastrectomy, diffuse intestinal disease |
|
|
Term
| Iron deficiency in peripheral blood lab |
|
Definition
1. progressive mild to moderate microcytic anemia with high RDW
2. low reticulocyte count (and low)
3. hypochromic RBC's in PB smear
4. serum iron studies: low serum iron, low serum ferritin, high transferrin; low transferring saturation
5. thrombocytosis |
|
|
Term
| Bone marrow lab results in iron deficiency anemia |
|
Definition
- erythroid hyperplasia driven by erythropoietin, but ineffective (ex: not productive of new RBCs)
- no detectable storage iron by Prussian blue stain
- RBCs undergo apoptosis because can't complete without iron |
|
|
Term
| Therapy of iron deficiency |
|
Definition
- oral supplementation: compliance difficult because many people don't handle it well
- or search for cause without an obvious reason: GU or GU |
|
|
Term
|
Definition
- unusual form
- megalo: large, Blastic: immature
- the myeloid precursors in bone marrow, especially RBCs look large and somewhat primitive if compared to normal counterparts |
|
|
Term
| What causes megaloblastic anemia? |
|
Definition
- vitamin B12 deficiency and folate
- they are critical to DNA synthesis (of T)
- when deficient DNA synthesis slows and cell division stops |
|
|
Term
|
Definition
- cobalamin
- in animal proteins
- large body stores relative to consumption: 2-5 mg (daily requirement is 2-3 microg) |
|
|
Term
| Absorption of vitamin B12 |
|
Definition
- after ingestion, B12 travels to duodenum
- a protein intrinsic factor is secreted by the parietal cells of the stomach and in the duodenum intrinsic factor binds to B12
- the comp-lex travels to the terminal ileum where it is absorbed
- the B12 is passed into the serum where it is carried by transcobalamin |
|
|
Term
|
Definition
- methyl donor intermediary in synthesis of thymidine
- role in CNS function, but unclear of nature possibly related to myelin synthesis
- can also produce neurological symptoms |
|
|
Term
|
Definition
- it is regenerated after transferring methyl group
- converts homocysteine to methionine
- eventually thymidine made |
|
|
Term
|
Definition
- can cause B12 deficiency
- autoimmune gastritis
- most common in US, middle age and older
- gastric parietal cells are lost due to autoantibodies so no intrinsic factor is secreted leading to no absorption of B12
- neurologic component to PA also present (neuropathies, cerebellar signs)
- get B12 deficiency post-gastrectomy (4-5 years after) |
|
|
Term
|
Definition
1. pernicious anemia
2. intestinal disorders: ileal resection, malabsorption syndromes, tapeworms
3. chronically low intake (malnourished) |
|
|
Term
|
Definition
- dietary source: green vegetables, liver, added as supplement to many foods
(flour and cereal)
- body stores: 5-10mg (small relative to consumption)
- daily requirement: 50-200 microg
- absorption: proximal jejunum
- function: final intermediary in synthesis of thymidine
- gets used up.. constantly drawing on stores |
|
|
Term
| Causes of folic acid deficiency |
|
Definition
1. dietary deficiency: relatively low body stores: those with poor diets and who avoid green vegetables at risk
2. intestinal diseases: malabsorption syndromes
3. increased requirements: pregnancy, infancy, hemolytic anemia, malignancy
4. folic acid antagonists: methotrexate |
|
|
Term
| peripheral blood in megaloblastic anemia |
|
Definition
1. moderate to marked macrocytic anemia with high RDW
2. low reticulocytes
3. macroovalocytes in smear
4. leukopenia and thrombocytopenia sometimes
5. low level of B12 or folate
6. B12 deficiency: elevated methylmalonic acid, elevated byproduct of high homocysteine metabolism
7. folic acid deficiency: high homocystein level but normal methylmalonic acid level |
|
|
Term
| Folic acid deficiency and pregnancy |
|
Definition
| - found to cause neural tube defects |
|
|
Term
| Bone marrow and megaloblastic anemia |
|
Definition
- hypercellular with erythroid hyperplasia (ineffective erythropoiesis)
- morphologically abnormal myeloid maturation |
|
|
Term
|
Definition
- in megaloblastic anemia
- large oval RBCs with no pale center
- lots of Hb in cells because maturation is delayed and gets more Hb synthesis |
|
|
Term
| Theraopy for megaloblastic anemia |
|
Definition
- must identify deficiency
- folic acid supplements given to B12 deficient will correct anemia but won't reverse neurologic changes
- folic acid: oral supplementation except with deficiency due to GI tract disease
B12: parenteral supplementation (intramuscular); by unclear mechanism, 1% hgih oral doses of B12 will be absorbed in the absence of intrinsic factor |
|
|
Term
| Anemia of inflammation/ chronic disease |
|
Definition
- AI/ACD
- second most common (after iron deficiency)
- found in 50% of hospitalized patients usually overshadowed by primary illness
- an anemia that occurs secondary to another systemic disease (ex: infections, malignancy, autoimmunity etc) |
|
|
Term
| How do chronic diseases cause anemia? |
|
Definition
- result in elevated levels of circulating inflammatory cytokines, especially IL-6, IFN-gamma, TNF-alpha, and IL-1beta
- pathogenesis:
1. variably shortened RBC survival
2. elevated hepciden secretion (IL-6 increases hepatic hepciden production) |
|
|
Term
|
Definition
- diminished erythropoietin release by the kidney
- degradation of ferroportin channels results in abnormal iron metabolism
- prevents iron passage out of macrophage stores (unavailable for RBC precursors
- they develop intracellular iron deficiency despite abundant storage iron
- prevents transfer of dietary iron from GI mucosal cells into plasma so dietary iron is not absorbed |
|
|
Term
|
Definition
| - certain bacteria require presence of elevated iron, so hepcidin may have anti-microbial effects |
|
|
Term
| Peripheral blood Lab findings in anemia of chronic disease |
|
Definition
1. mild to moderate normocytic anemia with normal RDW, sometimes microcytic so may be confused with Fe deficiency
2. low reticulocyte count
3. serum iron studies: low iron, low transferrin, high ferritin |
|
|
Term
| Bone marrow lab findings in anemia of chronic disease |
|
Definition
| Normocellular to hypocellular with variable erythroid compartment, though usually not erythroid hyperplasia; abundant storage iron, few iron bearing erythroid precursors |
|
|
Term
|
Definition
- iron bearing RBC precursor
- ferritin granules found normally in these |
|
|
Term
| Anemia of chronic disease sideroblasts |
|
Definition
- no ferritin granules in erythroid precursors in ACD because ofthe block in iron transfer into them
- lack blue granules normally found in these sideroblasts |
|
|
Term
| Anemia of chronic renal failure |
|
Definition
- anemia is invariable in chronic renal failure
- pathophysiology:
1. diminished EPO secretion by the failing kidney
2. ineffective erythropoiesis
3. shortened RBC survival in toxic plasma
4. increased bleeding
5. in dialysis patients, iron deficiency develops due to rEPO use combined with blood loss (GI bleeding, phlebotomy, catheter placement, dialysis tubing etc). They are also at risk for folate and B12 deficiency |
|
|
Term
|
Definition
| chemical cytokine produced by liver |
|
|
Term
| Peripheral blood findings in anemia of chronic renal failure |
|
Definition
1. anemia which is at first mild but, as CRF worsens, becomes severe
2. normocytic with normal RDW
3. low reticulocyte count
4. echinocytes (burr cells) in smear (spiky looking) |
|
|
Term
| Therapy of anemia of chronic renal failure |
|
Definition
1. use of erythropoiesis-stimulating agents (ESA's) is in debate
2. In many studies, Hb levels near the reference range are achievable with some evidence for improvement
3. adverse events (chiefly cardiovascular), however may negate the benefit of higher Hb levels
4. issue is controversial due to variation in:
a. parameters used to measure benefit
b. target Hb levels nd timing and doses used in the studies
c. causative factor responsible for adverse events (higher Hb levels vs side effects of ESAs vs other)
d. enormous financial impact of outcome studies |
|
|
Term
|
Definition
| - stem cell failure leading to the loss of normal myeloid precursors; the marrow becomes incapable of synthesizing new blood cells |
|
|
Term
| Pathophysiology of aplastic anemia |
|
Definition
- stem cell injury or suppression
- 30% of cases occur after known toxic exposure in a dose dependent, predictable manner (drugs, chemicals etc) or idosyncratic manner (drugs, certain types of hepatitis)
- 70% are idiopathic, the mechanism probably involves either:
1. increased susceptibility to injury acquired by pluripotential stem cells
2. T lymphocyte mediated immune suppression or destuction of stem cells |
|
|
Term
| anemia of chronic kidney disease and bleeding |
|
Definition
| platelet damage so increased bleeding with kidney disease |
|
|
Term
| Aplastic anemia clinical presentation |
|
Definition
- all ages male and female
- bleeding symptoms most common; fatigue related to anemia; rarely infection due to neutropenia |
|
|
Term
| aplastic anemia peripheral blood |
|
Definition
1. moderate to severe normocytic to slightly macrocytic anemia with normal RDW
2. low reticulocyte count
3. thrombocytopenia and neutropenia |
|
|
Term
| Aplastic anemia bone marrow |
|
Definition
- marked hypocellularity
- rare hematopoietic cells
- abundant stroma and fat |
|
|
Term
|
Definition
1. patients require intense transfusion support
2. control and/or cure may be achieved with: immunosuppressive drugs (ATG, cyclospoine etc)
- HLA matched allogeneic bone marrow transplantation
3. small proportion of patients will evolve into a mylopdysplastic syndrome or acute leukemia (ex: support for genetic mutations as a cause of AA) |
|
|
Term
| Carbon monoxide poisoning |
|
Definition
Mortality: 25-40% die during exposure
- hundreds of accidental deaths
- fewer intentional
Morbidity:
- 15-40% survivors with neuropsychological deficits
- chronic exposure to low CO levels leads to a myriad of debilitating effects |
|
|
Term
| Carbon monoxide description |
|
Definition
1. colorless
2. tasteless
3. odorless
4. non-irritating
- poisoning frequently misdiagnosed |
|
|
Term
|
Definition
- incomplete combustion of carbon based fuels
- risks: improperly ventilated heating systems: gas, wood, kerosene
- petrol exhaust fumes |
|
|
Term
|
Definition
- combines with Hb with an affinity 200-250 times that of O2
- decreased O2 carrying capacity
- shifts O2 dissociation curve to the left |
|
|
Term
|
Definition
| CO must bind at an angle so it doesn't bind as readily allowing O2 to bind |
|
|
Term
| Signs and symptoms of acute CO poisoning |
|
Definition
Symp:headache, nausea, vomiting, dizziness, fatigue, weekness, irritability
Neuro signs: Confusion, disorientation, visual disturbance, syncope, seizures, CHERRY RED LIPS |
|
|
Term
|
Definition
| - memory, headache, dizziness, depression, fatigue, vision problems, tremor, concentration problems etc |
|
|
Term
| Treatment of acute CO poisoning |
|
Definition
- remove from source of exposure (protect yourself! could pass out and need help yourself)
- 100% oxygen (maybe hyperbaric O2) |
|
|
Term
| Prevention of CO poisoning |
|
Definition
| 1. install CO detector 2. service heating elements 3. common sense |
|
|
Term
| If CO is toxic why is it produced in the body |
|
Definition
| - when breakdown heme it is converted to bilirubin with heme oxidase which releases CO |
|
|
Term
|
Definition
- colorless gas with a faint bitter almond-like odor
- widely used chemical: medullurgy, paints, mining, photography
- lethal poison as CN ion |
|
|
Term
|
Definition
- from burning synthetic materials and inhaling it
- organic nitriles converted to cyanide in the body (ingestion) |
|
|
Term
|
Definition
- inhibition of cytochrome oxidase
- paralysis of electron transport
- no aerobic metabolism
- pyruvate is converted to lactate (severe metabolic acidosis)
- ONLY anaerobic respiration! |
|
|
Term
| What happens to oxygen carrying capacity with CN poisoning |
|
Definition
|
|
Term
| CN poisoning: clinical features |
|
Definition
| - major symptoms are due to tissue hypoxia 1. central nervous system: dizziness, vertigo, headache, anxiety confusion, hyperthermia, seizures, paralysis, coma and death 2. Gastrointestinal system: acidic and burning taste, throat numbness, salivation, frothing at mouth, nausea and vomiting |
|
|
Term
| Clinical features of CN poisoning |
|
Definition
HAPPENS FAST
1. respiratory system: initially tachypnea (too fast) and dyspnea (hard and deep) develop due to stimulation of respiratory center and carotid chemoreceptors caused by local hypoxia
- irregular respiration (short inspiration long exp)
- pulmonary edema etc |
|
|
Term
|
Definition
- remove from source
- oxygen (prob won't help)
- generate methemoglobinemia (usually bad, but but turn out to have iron in Fe3+ state and cyanide will bind to the new Fe3+ state)
- methemoglobinemia causes decreased O2 carrying capacity - so not easy and without risks |
|
|
Term
|
Definition
- amyl or sodium nitrite
- nitrites oxidize Hbs iron from ferrous state to ferric state converting Hb to metHb
- CN preferentially bonds to metHb rather than cytochrome oxidase converting metHb into cyanmetHb
- adding sodium thiosulfate converts cyanmetHb to thiocyanate, sulfite and Hb
- the thiocyanate is excreted in urine |
|
|
Term
| Vitamin B12 and CN treatment |
|
Definition
- binds cyanide to form cyanocobalamin
- eliminated through urine |
|
|
Term
|
Definition
1. Hb + amyl or Na nitrite = metHb
2. CN- + metHb = cyanometHb
3. CN-cytochrome oxidase + metHb = cytochrome oxidase +cyanometHb
4. cyanometHb + thiosulfate = SCN- + sulfite + metHb
OR
1. hydroxycobalamin + CN- = cyanocobalamin |
|
|
Term
| If CN is toxic why is it found in plants and animals |
|
Definition
| - because it is toxic! To fight off enemies/ predators |
|
|
Term
|
Definition
- cannot be destroyed
- cannot be decontaminated
- highly toxic
- ubiquitous
- can be stored in body for long time |
|
|
Term
| Biological essential heavy metals |
|
Definition
Na, K, Ca: ion pumps
Fe: ox transport
Zn: co-factor
Co: DNA synthesis |
|
|
Term
| Heavy metals with no biologic relevance |
|
Definition
| Cadmium, mercury, arsenic, lead |
|
|
Term
|
Definition
- ALA-dehydratase and ferrochelatase most sensitive Pb targets in pathway
- Pb directly inhibits enzymes interacting with sulfhydryl groups or displacing metal ions
- often normocytic and chromic
- chronic exposure causes hypochromic and microcytic
- sometimes basophilic stippling due to iron induced aggregates of ribosomes |
|
|
Term
|
Definition
- neurotoxicity
- developmental delay/disability
- lower IQ |
|
|
Term
| Symptoms of lead toxicity in adults |
|
Definition
headache
abdominal pain
memory loss
kidney failure
weakness
pain and tingling |
|
|
Term
| Symptoms of lead toxicity in children |
|
Definition
- often NOTHING
- abdominal pain
vomiting
irritability
loss of appetite
loss of milestones
behavioral problems |
|
|
Term
| Diagnosis/clinical signs of lead poisoning |
|
Definition
- blood levels
- lead line on gingival border
- writst-drop (from renal failure)
- frowth arrest lines (lead lines) in bones of child who recovered from lead poisoning |
|
|
Term
| Treatment of lead poisoning |
|
Definition
Chelation
- formation of metal ion complex
- chelating agent binds with very high affinity for metal of interest but low for essential metals |
|
|
Term
| Chelated metal complex characteristics |
|
Definition
1. stable
2. readily excreted (water soluble)
3. non toxic |
|
|
Term
| Calcium sodium EDTA as chelator |
|
Definition
1. potent chelator of 2+ and 3+ cations (given as calcium salt to reduce hypocalcemia)
- prinicple treatment for lead
- highly polar
- given intravenously
- does not enter cells
- major toxicity is renal (renal tubular necrosis) |
|
|
Term
|
Definition
- oral treatment of lead poisoning
- toxicity: gastrointestinal distress, CNS effects, skin rash, elevation of liver enzymes |
|
|
Term
|
Definition
| - hyperbilirubinemia/jaundice |
|
|
Term
|
Definition
- decreased synthesis of beta globin chain
- primarily caused by mutations in the regulatory (non-coding) portion of the beta globin chain gene
- transcribed mRNA is abnormal and has a very short half-life NO TRANSLATIOn
- thal minor is heterozygote
- thal major homozygote |
|
|
Term
| beta thalassemia heterozygotes |
|
Definition
| - the one healthy allele nearly compensates so mild or no anemia is present |
|
|
Term
| Skeletal deformities from anemia |
|
Definition
| - hypoxia increases erythropoietin production which causes marrow expansion and thus skeletal abnormalities |
|
|
Term
| Clinical presentation of homozygous beta thalassemia |
|
Definition
- severe anemia presents in infancy with failure to thrive, lethargy, irritability, jaundice, splenomegaly, and bone abnormalities
- transfusion therapy is initiated early |
|
|
Term
| Clinical presentation of heterzygous beta thalassemia |
|
Definition
- frequently asymptomatic, may be discovered incidentally
- mild anemia may cause mild problems |
|
|
Term
| peripheral blood in homozygous beta thalassemia |
|
Definition
1. marked microcytic anemia (MCV 50-70) with high RDW
2. circulating RBC precursors
3. Target cells and markedly hypochromic RBC's on peripheral smear |
|
|
Term
| Bone marrow of homozygous beta thalassemia |
|
Definition
| - hypercellularity with marked erythroid hyperplasia; the marrow expansion induces the bony abnormalities seen on X-ray |
|
|
Term
| Peripheral blood of heterozygous beta thalassemia |
|
Definition
1. mild or absent anemia, microcytic with normal RDW
2. elevated RBC count
3. Target cells on smear |
|
|
Term
| Diagnosing beta thalassemia |
|
Definition
- other than symptoms and CBC
- no HbA and >90% HbF, HbA2 elevated
- hetero:mildly elevated Hb A2 and HbF |
|
|
Term
| Beta Thalassemia and iron absorption |
|
Definition
| - increased iron absorption in GI tract induces overload and toxicity that leads to heart failure, diabetes, and other complications |
|
|
Term
| Target cell in beta thalassemia |
|
Definition
| - excess membrane to cytoplasm ratio |
|
|
Term
|
Definition
- loss of alpha alleles on chromosome 16 due to large deletions of coding regions (not point like beta)
- excess beta chains complex and cause both intramedullary cell death and increased RBC clearance
- there are 4 different alpha alleles so 4 different places for syndromes to arise |
|
|
Term
| One deletion of alpha thalassemia |
|
Definition
- silent carrier
- no symptoms or anemia |
|
|
Term
| Two deletion alpha thalassemia |
|
Definition
- thal trait
- like hetero beta thal: mild microcytic anemia, few symptoms |
|
|
Term
| Three deletion alpha thal |
|
Definition
- Hb H disease
- presents in infancy with moderate microcytic anemia
- complexes of 4 beta chains are seen (Hb H) and can be detected with Hb electrophoresis |
|
|
Term
|
Definition
- hydrops fetalis
- since there are no substitutes for alpha chains, when all alleles are deleted no hemoglobin can be synthesized and usually the infant is stillborn |
|
|
Term
| Peripheral blood in alpha thalassemia |
|
Definition
- 2 deletion: mild microcytic anemia; target cells on smear; no abnormal hemoglobins on electrophoresis
- 3 deletion: moderate microcytic anemia; schistocytes (fragmented RBCs) on smear; mild hyperbilirubinemia; Hb H seen on electrophoresis |
|
|
Term
| Heterozygous clinical course |
|
Definition
- well tolerated with little morbidity
- affords some protection from falciparum malaria |
|
|
Term
| Bone marrow of alpha thalassemia |
|
Definition
| - varying degrees of erythroid hyperplasia in all |
|
|
Term
| Diagnosis of alpha thalassemia |
|
Definition
1. 1 deletion - pedigree analysis
2. 2 deletion - no symptoms but discovered with microcytosis in CBC; diagnosis inferred with normal iron studies and normal hemoglobin electrophoresis; family history may be known
3. 3 deletion - symptomatic infant will provoke CBC with typical findings; Hb electrophoresis should reveal Hb H |
|
|
Term
| Difference between 2 deletion alpha thal and hetero thal |
|
Definition
| - elevated Hb F and HbA2 in beta thal |
|
|
Term
|
Definition
| the vertebrate normal defense mechanism to prevent blood loss |
|
|
Term
|
Definition
| - pathological extension of the normal hemostatic mechanism |
|
|
Term
| Megakaryocytes and platelets |
|
Definition
- 400-8,000 platelets from one mature megakaryocyte cytoplasm
- mature megakaryocytes acquire proteins from plasma or make new proteins and package both types of proteins into platelet granules |
|
|
Term
| Platelet half-life, description |
|
Definition
- no nucleus
- half-life is 5-7 days |
|
|
Term
|
Definition
- in inert form, must be activated subsequent to initiation of the response
- contain various hemostatic constituents in their granules that are poised for immediate activation at the site of injury |
|
|
Term
|
Definition
| - platelet plug formation at site of injury 1. damaged endothelial cells cause: - transient casoconstriction - endothelin secretion by endothelium 2. exposed subendothelial components: vWF (GP1B-IX) and collagen (GPVI) attach to receptors on platelets |
|
|
Term
|
Definition
| - contain coagulation proteins |
|
|
Term
|
Definition
|
|
Term
|
Definition
- "the platelet glue of hemostasis"
- multimer (mainly in ball of yarn configuration but may be in extended linear form) made up of repeating subunits
- also carrier protein for coagulation factor VIII in plasma |
|
|
Term
|
Definition
1. vWF: strong
2. Collagen: strong
3. ADP: secreted from platelet dense granules "weak"
4. thromboxane A2: prostaglandin - weak (inhibited by aspirin)
5. Thrombin: product of coagulation cascade - STRONGEST |
|
|
Term
|
Definition
| - Activated platelet forms pseudopodia and increases its surface area |
|
|
Term
| Platelet aggregation events |
|
Definition
1. pseudopod formation
2. extrusion of alpha and dense granules: ADP, serotonin, fribinogen, vWF, factor V
3. Induction of receptor-mediated intracellular signaling cascades
- synthesis and release of thromboxane A2
- G protein-coupled thrombin receptor pathways
- ADP receptor mediated pathways
4. Exposure of plasma membrane phosphatidylserine and expression of membrane receptors for procoagulant proteins
5. aggregation by formation of fibrinogen GpIIb-IIIa complex |
|
|
Term
| Fibrinogen and platelet plug |
|
Definition
| - binds to activated GpIIb-IIIa membrane receptors effectively bridging platelets to each other |
|
|
Term
|
Definition
- substrate for blood clot formation
- found in platelet alpha granules |
|
|
Term
|
Definition
- reduced or abnormal synthesis of vWF
- poor platelet adherence to site of injury
- severe form very rare (1/million)
- mild common (1/100) |
|
|
Term
| Bernard-Soulier syndrome (rare) |
|
Definition
- expression of low levels or defective GpIb-V-IX complexes
- decreased vWF binding |
|
|
Term
| Glanzmann's thrombasthenia |
|
Definition
- rare
- expression of low levels or defective GpIIb-IIIa complexes = decreased fibrinogen binding and poor platelet aggregation |
|
|
Term
|
Definition
- clinical test in which 2 measured incisions are made using a spring loaded scalpel
- the time to stop bleeding is measured (normal 2-7 min)
- the bleeding time usually is prolonged in disorders of primary hemostasis
- does not depend on fibrin clot formation |
|
|
Term
|
Definition
- fibrin clot formation
- initiated by tissue factor/factor VIIa complex |
|
|
Term
|
Definition
| - expressed by subendothelial fibroblasts exposed only subsequent to endothelial denudation |
|
|
Term
|
Definition
| - required for conversion of zymogens to serine proteases initiated by exposed tissue factor and small, circulating concentrations of factor VIIa |
|
|
Term
|
Definition
| - any chemical substance capable of affecting a physiological function of living organism |
|
|
Term
| Acid/base chemistry of drugs |
|
Definition
| - most are weak acids or weak bases |
|
|
Term
|
Definition
| - neutrality allows for higher lipid solubility and easier passage into/out of cells |
|
|
Term
|
Definition
1. covalent: very strong and often irreversible under biologic conditions
2. electrostatic bonds: much more common than covalent bonding (range from strong to weak)
3. hydrophobic bonds: usually quite weak; important in interactions of highly lipid-soluble drugs with cell membranes & in interaction of drugs with receptor pockets |
|
|
Term
| Stereochemical effects of drug-receptor interactions |
|
Definition
| - assymmetric/chiral stereocenters in drugs present specific binding requirements in cognate receptors |
|
|
Term
| Stereochemical effects of drugs |
|
Definition
| - enantiomers can have different pharmacodynamics and pharmacokinetics |
|
|
Term
| what influences receptor interactions of drugs? |
|
Definition
| - size and shape defines range and specificity of receptor interactions |
|
|
Term
| Ad and dis of orally administered drugs |
|
Definition
Advantages: convenient, do not have to be sterile, can be offered in several forms
Disadvantages: absorbed in GI tract and enter portal blood supply before entering central which can result in extensive "first pass" metabolism of the drug before it can take any action |
|
|
Term
| Intravenous administration |
|
Definition
Bio: 100
Char: most rapid onset |
|
|
Term
| Intramuscular administration |
|
Definition
Bio: 75 to 100
Char: large volumes often feasible; may be painful |
|
|
Term
| Subcutaneous administration |
|
Definition
Bio: 75-100
Char: smaller volumes than IM; may be painful |
|
|
Term
|
Definition
Bio: 5 to 100
Char: most convenient; first-pass effect may be signifant |
|
|
Term
|
Definition
Bio: 30 to less than 100
Char: less first-pass effect than oral |
|
|
Term
| Inhalation administration |
|
Definition
Bio: 5 to less than 100
Char: often very rapid onset |
|
|
Term
| Transdermal administration |
|
Definition
Bio: 80 to 100
Char: usually very slow absorption; used for lack of first-pass effect; prolonged duration of action |
|
|
Term
|
Definition
- what the drug does to the body
- drug effect:
1. drug-receptor interaction
2. agonist,antagonist or partial agonist
3. what effect a drug has (beta blocker, H2 antagonist)
4. what side effects it has |
|
|
Term
|
Definition
- what the the body does to the drug
- ADME
A: absorption
D: distribution
M: Metabolism
E: excretion |
|
|
Term
| Graphing pharmacokinetics |
|
Definition
| - concentration (Y) vs time |
|
|
Term
| Graphing pharmacodynamics |
|
Definition
| - concentration vs effect (Y) |
|
|
Term
| Pharmacokinetics and pharmacodynamics graphed |
|
Definition
|
|
Term
|
Definition
- typically non-specific
- can't fit as many chemical substituents to make it so |
|
|
Term
|
Definition
| - not distributed throughout the body effectively |
|
|
Term
| intrarterial administration |
|
Definition
- contrast agents
- some meds |
|
|
Term
| intraperitoneal administration |
|
Definition
| - becoming more important for chemo for ovarian cancer especially |
|
|
Term
| Main classes of drug receptors |
|
Definition
1. receptors for lipid-soluble
2. ligand-regulated transmembrane enzymes
3. ion cheannels
4. G-protein coupled receptors |
|
|
Term
|
Definition
| - strength/durability of interaction |
|
|
Term
|
Definition
- semi-log plot (linear with log scale)
- % maximal effect (Y) vs [drug]
- allows for wider range of numbers that would be collapsed if it wasn't log |
|
|
Term
|
Definition
- found on log dose-effect curve
- point where shape of curve changes is midway point
- half-maximal effect
- that concentration is the effective concentration that gives you half max effect and is used for comparison |
|
|
Term
|
Definition
1. maximal effect that a drug can produce
2. determined mainly by the properties of the drug and its receptor/effector system
3. important clinical parameter |
|
|
Term
|
Definition
1. amount of a drug needed to produce a given effect (often as EC50 or ED (dose)50)
2. determined mainly by the affinity of the drug for receptor
3. potency affect drugs dosage
4. [D] to reach 50% max effect (EC50) |
|
|
Term
|
Definition
| - occupy receptors, produce a conformational change which leads to receptor activation and thus efficacy |
|
|
Term
|
Definition
| - occupy receptors, produce a conformational change which leads to receptor activation and thus efficacy |
|
|
Term
|
Definition
- occupy receptors
- produce no conformational change and prevent the action of agonists |
|
|
Term
|
Definition
| - occupy receptors, produce an effect which is less than the maximum obtainable with a full agonist |
|
|
Term
| What do you suspect in a bleeding newborn? |
|
Definition
| - suspect vitamin K or congenital disease |
|
|
Term
| History questions required for bleeding |
|
Definition
1. does patient display excessive, prolonged, recurrent, or delayed bleeding
2. has the patient had an opportunity to bleed excessively and what happened?
3. Is there a family history? |
|
|
Term
| Physical exam for bleeding |
|
Definition
1. petechial vs soft tissue bleeding
2. bizarre pattern of lesions
3. signs of liver failure or cirrhosis? (decreased coag factors)
4. telangiectasisias - blood can be blanched away (osler-weber-rendu syndrome) |
|
|
Term
|
Definition
- blood that has extravasated out of blood vessels
- usually < 2mm |
|
|
Term
|
Definition
- usually 2-10 mm in diameter
- extravasated blood
- can go to ecchymosis (>10 mm) large bruise |
|
|
Term
| Primary hemostasis defects |
|
Definition
- platelets
- superficial skin, mucous membranes, nose, GI, GU bleeding
- petechiae and exhymoses
- autosomal dominant |
|
|
Term
| Defects of secondary hemostasis |
|
Definition
- plasma protein defects
- delayed for hours/days after trauma
- deep joint bleeding, muscle bleeding, retroperitoneal bleeding
- find hematomas, hemarthroses
- autosomal or X-linked recessive
- requires sustained systemic therapy |
|
|
Term
|
Definition
1. platelet abnormalities
2. blood vessel abnormalities
3. clotting factor deficiencies (hemophilias)
4. excess clot breakdown (fibrinolysis) |
|
|
Term
|
Definition
1. liver disease (site of clotting factor synthesis
2. Vitamin K deficiency
3. autoimmune disease (platelet destruction)
4. trauma |
|
|
Term
|
Definition
| prothrombin time/International Normalized Ratio |
|
|
Term
|
Definition
| - activated partial thromboplastin time |
|
|
Term
|
Definition
- low platelet count
0 no risk of spontaneous bleeding until under 10,000/microL |
|
|
Term
| Why visual review of peripheral blood smear can be helpful |
|
Definition
- rules out artificially low platelet count due to platelet clumping in tube
- offer clues regarding nature of thrombocytopenia |
|
|
Term
|
Definition
-mean platelet volume
- large platelet: new platelets
- Small platelets: older platelets |
|
|
Term
|
Definition
| - suggestive of increased production to compensate for increased destruction |
|
|
Term
| Limitations of bleeding time test |
|
Definition
- normal range is wide so not very sensitive
- problems with consistency: requires experienced personnel, depth of wound or length of incision and skin thickness affects results
- results are not valit if platelet count is less than 100,000/ microL
- not predictive of bleeding risk when used as a general screening test before surgery |
|
|
Term
|
Definition
-replaced bleeding time
- in vitro bleeding time
- measure time required for platelets to plug a microscopic hole in a membrane as blood passes through hole
-"closing time"
- valid in thrombocytopenic patients
- machine available 24/7
- minimal training
- more sensitive in detecting von Willebrand's disease |
|
|
Term
| Testing extrinsic pathway coagulation factors |
|
Definition
|
|
Term
| Testing intrinsic pathway coagulation factors |
|
Definition
| - partial thromboplastin time (PTT) |
|
|
Term
|
Definition
- performed by adding brain tissue thromboplastin (tissue factor and phospholipids) and calcium to citrated plasma and measures clotting time
- measures coagulant activities of extrinsic pathway: FVII, X, V,
- detects deficiencies when lower than 40% of normal
- fibrinogen deficiency (less than 100 mg/dL) will also give abnormal results
- useful in monitoring patients on coumadin therapy (vitamin K antagonist)
- also useful detecting vitamin K deficiency due to other causes
- not affected by heparin (use PTT)
- normal range for prothrombin time varies between hospitals |
|
|
Term
| Why does prothrombin time vary from hospital to hospital |
|
Definition
1. diff hospitals use diff thromboplastins in their assy and therefore have different normal ranges
2. international normalized ratio (INR) was created so patients on coumadin could be treated and evaluated in the same way in any hospital |
|
|
Term
|
Definition
INR = (PT of patient/mean PT of normal range) ^ISI
- all thromboplastins used in the prothrombin assay are supplied with a normalizing factor called the international sensitivity index (ISI) from the manufacturer of the assay |
|
|
Term
|
Definition
- INR of 1 is approximately 100% of normal coagulation factors
- INR 1.4 to 1.6 is approximately 40% coagulation factors
- increased risk of bleeding at 1.7 or higher |
|
|
Term
| Activated partial thromboplastin time |
|
Definition
- aPTT or PTT
- "partial" because tissue factor is missing (only phospholipid is used)
- activated because particulate matter is used to activate the contact pathway
- FXII, FXI, FIX, FVIII, FX, FV
- prolonged clot time may indicate factor deficiency (30-40% of normal)or in the presence of inhibitorsL heparin, lupus anticoagulant (LA), fibrin-fibrinogen degradation products, specific factor inhibitors (usually antibodies) |
|
|
Term
| Fibrinogen concentration measurement |
|
Definition
- usually measured functionally by adding high concentration of thrombin to plasma to induce a clot
- cannot distinguish between hypofibrinogenemia vs dysfibrinogenemia
- chemical or immunologic assays need to be used to distinguish these two possibilities
- normal hemostasis maintained until fibrinogen concentration is below 100 mg/dL |
|
|
Term
|
Definition
- almost always indicates a coagulation factor deficiency
- liver disease
- vitamin K deficiency
- coumadin therapy |
|
|
Term
|
Definition
- can be due to:
1. coagulation factor deficiency
2. fibrinogen deficiency
3. heparin contamination of patient sample
4. inhibitor or antibody against coagulation factors |
|
|
Term
| If high PTT check the following before more tests |
|
Definition
1. is patient on anticoagulant?
2. is there a possibility of heparin contamination
3. is patient actively bleeding or is this a preop evaluation of a non-bleeding patient with an isolated abnormal PTT? |
|
|
Term
|
Definition
- half patient, half patient plasma
- repeat PTT
- if deficiency expect that mixing would give normal results
- If inhibitor present mixing study would not correct normal value |
|
|
Term
| If deficiency found on 50:50 mix |
|
Definition
- order individual factor level assays
- rule out deficiencies in FVIII, IX, XI
- deficiencies in FXII, prekallikreins, and kininogens usually not clinical significant cause of bleeding |
|
|
Term
| If inhibitor is causing long PTT time |
|
Definition
| - additional testing needed to confirm presence of lupus anticoagulant vs. specific factor inhibitor |
|
|
Term
|
Definition
- antibody usually against phospholipid component of the PTT assay
- most frequent cause of prolonged PTT that is not corrected with 50:50 mixing study
- when of sufficient concentration, can also affect the PT assay
- paradoxically associated with thrombosis and not with bleeding! |
|
|
Term
| Treating elevated PT and PTT due to coumadin therapy |
|
Definition
1. stop coumadin
2. administration of Vit. K
3. administration of frozem plasma (quick and only temporary correction) |
|
|
Term
| Correcting Elevated PTT due to heparin therapy |
|
Definition
1. stop heparin
2. administer protamine to neutralize heparin (potamine positive, heparin negative)
3. plasma is not used |
|
|
Term
|
Definition
- made from fresh frozen plasma but is more concentrated
2. contains only vWF, FVIII, FXIII, Fibrinogen
- not all
- used for low fibrinogen levels
- not first line therapy for patients with hemophilia A or von willebrand |
|
|
Term
|
Definition
- fresh frozen plasma
- (80-100% of all coagulation factors- in 1x solution, may need large values) |
|
|
Term
| Correction of coagulation defects of plasma |
|
Definition
- only when vit. K is ineffective or not fast-acting enough
- used in opatients with INR>1.7 with active bleeding ro during surgery
- only temporary (half-life of FVII in tranfused plasma is 3-5 hrs; complete correction of INR to 1 is not necessary and possibly futile |
|
|
Term
| When to tranfuse platelets for thrombocytopenia |
|
Definition
1. when platelet count is below 10,000 per microL
- no increased risk of bleeding until below 10,000
- if fevrile or septic keep platelet count above 20,000 per microL
2. if actively bleeding or increased risk of bleeding in non-expandable space (Cranium) keep platelet count above 100,000 per microL |
|
|
Term
| When to not transfuse for thrombocytopenia |
|
Definition
1. thrombotic thrombocytopenia purpoura (TTP)
2. Immune thrombocytopenia purpura (ITP)
3. Heparin-induced thrombocytopenia (HIT)
4. Unless actively bleeding, the transfusion of platelets in these patients is contraindicated
5. platelet transfusions either ineffective or might precipitate thrombosis |
|
|
Term
|
Definition
| - escape of blood outside of vessels (into tissue or cavities, or out of the body) |
|
|
Term
|
Definition
|
|
Term
| major mechanisms for cause of hemorrhage |
|
Definition
1. vessels
2. platelets: low count or function
3. coagulation factors: decreased or function problem |
|
|
Term
| Cause of hemhorrage vascular disease |
|
Definition
| - with rupture or leakage (atherosclerosis, arterititis, aneurysms. includes ulcers, polyps, tumors, infarcts, trauma) |
|
|
Term
| Low platelet count and hemorrhage |
|
Definition
| - below 10-15,000 per cubic mm or low function |
|
|
Term
|
Definition
| - platelet or capillary abnormality |
|
|
Term
|
Definition
- greater than 1 cm
- coagulation factor abnormality |
|
|
Term
|
Definition
| - multifocal hemorrhage into skin |
|
|
Term
|
Definition
1. acuteL red or purple collection of blood
2. chronic or old: brown discoloration of skin, maroon paste-like material (endometriotic cyst) |
|
|
Term
|
Definition
- black stool
- usually blood from upper GI tract |
|
|
Term
|
Definition
| - bright red blood per rectum (BRBPR) |
|
|
Term
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
|
|
Term
| Clinical effects of hemorrhage |
|
Definition
1. anemia
2. pallor
3. tachycardia
4. tachypnea
5. weakness
6. dyspnea on exertion
7. angina
8. hypotension, shock |
|
|
Term
| Significance of hemorrhage depends on: |
|
Definition
1. location
2. rate/volume: rapid vs slo
3. duration
4. comorbid diseases: emphysema, anemia, heart disease |
|
|
Term
|
Definition
| - increased amount of blood within the tissues, within blood vessels |
|
|
Term
|
Definition
1. increased blood volume (active, usually physiologic)
2. blockage, causing back-up (passive, pathologic) |
|
|
Term
|
Definition
- enlarged vessels on esophagus
- can be caused by portal hypertension
- perhaps from cirrhosis of the liver |
|
|
Term
| Types of passive congestion |
|
Definition
1. local: venous thombosis
2. Diffuse: congestive heart failure more diffuse |
|
|
Term
| Morphology of acute congestion |
|
Definition
| - tissues with acute congestion are red or purple, engorged, swollen, often edematous |
|
|
Term
| Morphology of chronic congestion |
|
Definition
| - usually brown, fibrotic in micro |
|
|
Term
| congestion causes (diffuse and local) |
|
Definition
- diffuse: heart failure
- locak: usually blockage toward hear |
|
|
Term
|
Definition
| - increased water within the tissues (can be intra- or extra- cellular, but not in the blood vascular space) |
|
|
Term
| Lung edema and congestion means.. |
|
Definition
| - indicative of left heart failure |
|
|
Term
|
Definition
| - edema in peritoneal cavity |
|
|
Term
|
Definition
|
|
Term
|
Definition
| 1. increased hydrostatic pressure: pressure of fluids going out (iliac vein thrombus, heart failure, beaver dam)lymphatics can't bring the large volumes of fluid back to heart 2. decreased oncotic pressure: protein in plasma pulls fluid in, but if can't make the protein because of liver failure or lost protein then get less inward flow at vein level 3. increased permeability: ex sepsis toxic effect on endothelium 4. lymphatic obstruction: with tumor or large mass like hematoma |
|
|
Term
|
Definition
- swelling and wetness of tissues
- reversible pitting when pressed against |
|
|
Term
|
Definition
- kidney disease (lose protein into urine
- leaky bowel (lose protein into bowel)
- liver disease (failure to make protein and portl hypertension)
- congestive heart failure (CHF)
- venous thrombosis |
|
|
Term
| What is the most common acquired cause of primary (platelets) and secondary (coagulation) defects? |
|
Definition
|
|
Term
| Hemostatic defects in liver disease-proposed mechanisms |
|
Definition
1. impaired coagulation
2. thrombocytopenia and platelet function defects
3. disseminated intravascular coagulation
4. systemic fibrinolysis |
|
|
Term
| What causes impaired coagulation in liver disease? |
|
Definition
1. decreased hepatic synthesis of clotting and fibrinolytic factors
2. vitmin K deficiency (could be from alcohol use and poor intake of vit K)
3. dysfibrinogenemia (fibrinogen that is produced is defective and not function) |
|
|
Term
| Thrombocytopenia and platelet function defects in liver disease |
|
Definition
1. hypersplenism: trap platelets in large spleen
2. filure to clear platelet inhibitors
3. immune destruction
4. decreased platelet production (low thrombopoietin production) |
|
|
Term
| Disseminated intravascular coagulation in liver disease |
|
Definition
1. procoagulants released from hepatic cells (clots in bad places)
2. endotoxins in portal circulation
3. failure to clear activated clotting factors
4. reduced antithrombin and protein C
5. elevated cytokines
6. other concurrent events (sepsis, peritoneovenous shunts) |
|
|
Term
| Systemic fibrinolysis and liver disease |
|
Definition
1. reduced alpha-2-anti-plasmin
2. failure to clear fibrinolytic enzymes
3. reduced clearance of tissue plasminogen activator |
|
|
Term
| If prothrombin time is normal and PTT is abnormal which enzymes of the PTT pathway must be normal? |
|
Definition
|
|
Term
| Vitamin K dependent factors |
|
Definition
|
|
Term
| When to suspect Hemophilia A and B |
|
Definition
| When easy bruising and abnormal bleeding in male |
|
|
Term
|
Definition
- factor VIII deficiency
- occursin 1 of every 5000 live male births
- x-linked
- accounts for 0-85% of hemophilia cases
- incidence of hemophilia is equal across all ethnic and racial groups |
|
|
Term
|
Definition
- factor IX deficiency
- also an X-linked
- occurs in 1 of every 30,000 live male births
- accounts for 15-20% of hempphilia cases
- incidence of hemophilia is equl across ethnic and racial groups |
|
|
Term
| Hemophilia A and B random mutations |
|
Definition
| - approximately 30% of hemophiliacs present as spontaneous mutations with no prior family history |
|
|
Term
| Hemophilia A and B in females |
|
Definition
1. Homozygosity
2. lyonization of factor VIII or factor IX in carries (normal X inactivated)
3. hemizygosity of the X chromosome (Turner's syndrome) |
|
|
Term
| Hemophilia and hemarthrosis/hemophilic arthropathy |
|
Definition
1. joint bleedina dn subsequent destruction
2. knee most affected (50% of all events)
3. can lead to destruction of join once bleeding becomes recurrent in same joint (target joint)
4. range of motion becomes limited despite therapy
5. best treatment is to prevent spontaneous joint bleeding with clotting factor replacement |
|
|
Term
| Intramuscular bleeding in hemophilia |
|
Definition
1. 2nd most common site of bleeding
2. usually due to trauma or over-exertion
3. bleeding into closed fascial compartments can lead to compartment syndrome (ischemia, nerve damage)
4. can be life threatening if large amount of blood is lost into muscle with no readily noticeable changes (thigh compartment) |
|
|
Term
| Intracranial hemorrhage in hemophilia |
|
Definition
1. most common cause of death from bleeding in hemophiliacs
2. can occur with minimal trauma or spontaneously (50% of time)
3. 50% of the intracranial bleeds lead to neurologic sequelae
4. 30% of intracranial bleeds lead to death
5. treatment with clotting factor replacement is indicated prior to any testing if intracranial hemorrhage is suspected after trauma |
|
|
Term
| Hemophilia A and B lab diagnosis |
|
Definition
1. only activated partial thromboplastin time (PTT) is abnormal
2. Normal prothrombin time (PT), platelet count, and platelet function (PFA-100)
3. 50:50 mix of normal plasma and patient sample should correct PTT to normal range, consisten with a deficiency
4. need to order special tests for factor VIII or factor IX levels to determine whether hemophilia A or B |
|
|
Term
|
Definition
1. use recombinant clotting factor first! (huge problem with aids )
2. use monoclonal antibody purified concentrates second
3. use cryoprecipitate or plasma tranfusion as last resort
4. for mouth or GI bleeds, drugs that block fibrinolysis (prevent clot breakdown) can be used initially prior to factor replacement |
|
|
Term
| Hemophilia and antibodies against clotting factors |
|
Definition
1. upt to 50% of patients with severe hemophilia A and 3-4% of patients ith hemophilia B will develop inhibitors (antibodies against factors VIII or IX)
2. inhibitors should be suspected when replacement of coagulation factors in known hempphiliacs is less than 60% of expected increase |
|
|
Term
| Factor VII and hemophilia antibodies |
|
Definition
1. presence of inhibitors (antibodies against FVIII or FIX) require the use of recombinant activated factor VII to bypass these inhibitors
2. acquired hemophilia can also occur in platients ith normal expression of factors VIII or IX, but ho develop an autoantibody
3. these inhibitors can mimic a lupus anticoagulant (the difference however, is that the patient is bleeding witha factor VIII inhibitor, whereas they would not be bleedinmg with a true lupus anticoagulant |
|
|
Term
| Von Willebrand Disease vs Hemophilia |
|
Definition
- appears in females similar to hemophilia
- Genes for factors VIII nd IX are on X chromosome whereas vWF is on 12
- patients can have platelet defects and deficient factor VIII |
|
|
Term
|
Definition
- vWF is carrier for factor VIII in plasma
- it binds FVIII protecting it from proteolysis and prolonging its half life |
|
|
Term
| Clinical presentation of von Willibrand Disease |
|
Definition
1. o.82% to 1.6% of population have vWD
2. wide spectrum of severity of bleeding symptoms, therefore may present at any age
3. moderate to severe vWD presents in childhood or young adult
5. males and females equal
6. bleeding manifestations similar to those observed in platelet disorders |
|
|
Term
|
Definition
1. bleeding time
2. FVIII activity
3. vWF antigen levels (usually immunoassay)
4. vWF acitivity: usually measured as ristocetin cofactor activity (platelet aggregation studies) |
|
|
Term
|
Definition
1. type 1: partial quantitative deficiency of vWF
2. Type 2: qualitative deficiency of vWF (15-30% of cases)
3. Type 3: nearly complete deficiency of vWF
4. Platelet type: qualitative defect in platelet GPIb with increased affinity for vWF |
|
|
Term
| Assays to differentiate the common types of vWD |
|
Definition
1. ristocetin induced platelet aggregation (ristocetin binds to vWF on platelets causing aggregation)
2. vWF multimer analysis (amount and variation in presence of high molecular weight multimers |
|
|
Term
| Platelet aggregation studies with ristocetin |
|
Definition
- decreased light transmission when platelets don't aggregate because they block light
- increased light transmission when aggregate because they fall to bottom of tube so light can pass |
|
|
Term
|
Definition
1. partial quantitative deficiency
2. ristocetin induced platelet aggregation - decreased
3. vWF multimers - decreased amount, but same low vs high molecular weight distribution |
|
|
Term
| vWD type 2A characteristics |
|
Definition
1. ristocetin induced platlet aggregation decreased
2. vWF multimers: disproportionate loss of high molecular weight multimers
- quantitative defects |
|
|
Term
| vWD type 2B characteristics |
|
Definition
1. quantitative defects
2. ristocetin induced platelet aggregation increased
2. vWF multimers - no disporportionate loss of high molecular weight multimers comp[ared to type 2A |
|
|
Term
|
Definition
1. 2M: variant with decreased platelet dependent function not caused by absence of high MW multimers
2. 2N- variant with marked decreased affinity for FVIII |
|
|
Term
|
Definition
- nearly complete deficiency of vWF
2. ristocetin induced platelet aggregation nearly absent
3. vWF multimers very little seen |
|
|
Term
|
Definition
1st choice: DDAVP (desmopressin, synthetic analogue of anti-diuretic hormone (ADH))
2nd: affinity-purified vWD
3rd: cryoprecipitate as last resort |
|
|
Term
|
Definition
1. DDAVP sometimes tried (less effective
2. affinity-purified vWF |
|
|
Term
|
Definition
1. Avoid DDAVP (theoretical thrombosis/thrombocytopenia
2. affinity purified vWF |
|
|
Term
|
Definition
1. affinity-purified vWF
2. DDAVP has no value |
|
|
Term
|
Definition
- rare
- presents same fashion as patients with severe hemophilia
- PT is abnormal and PTT is normal
- factor VII is first factor to disappear with coumadin or vitamin K deficiency
- treat with vitamin K, plasma or with recombinant factor VII depending on cause |
|
|
Term
| Factor XII and other contact factor deficiencies |
|
Definition
1. prolonged PTT
2. normal PT
3. no increased risk of bleeding
4. no factor replacement is require even in bleeding patient |
|
|
Term
|
Definition
1. found in 8% of ashkenazi jews as partial defiicency
2. prolonged PTT
3. normal PT
4. no bleeding risk until factor level is below 15-20%
5. treatment is usually plasma transfusion |
|
|
Term
| Types of platlet disorders |
|
Definition
1. thrombocyteopenia: low platelets
2. platlet function disorders |
|
|
Term
| Causes of thrombocytopenia |
|
Definition
1. increased platelet destruction or sequestration (increaed number of large platelets)
2. decreased platelet production (number of young or large platelets low)
3. hereditary thrombocytopenias (family history
- often mild and asymptomatic (some exceptions when thrombocytopenia is severe)
Miscellaneous: liver disease, renal disease |
|
|
Term
| Causes of increased platelet destruction or sequestration |
|
Definition
1. immune causes:
a. primary: idiopathic or immune thrombocytopenia purpura (ITP), post-transfusion purpura (PTP)
b. secondary: infection, systemic lupus erythematosis (SLE), malignacy, drugs (heparin-induced)
2. non-immune causes:
a. disseminated intravascular coagulopathy (DIC)
b. hypersplenism
c. thrombotic thrombocytopenia purpura (TTP) |
|
|
Term
| Causes of decreased platelet production |
|
Definition
1. Aplastic anemia
2. Fanconi’s pancytopenia
3. Marrow infiltrative processes
4. Malignancies
5. Myelofibrosis
6. Osteopetrosis
7. Infection
8. Amegakaryocytic thrombocytopenia
9. Nutritional deficiencies
10. Drug or radiation-induced |
|
|
Term
| Types of immune thrombocytopenias |
|
Definition
1. Autoimmune thrombocytopenia
2. Primary and Secondary immune 3. thrombocytopenic purpura (ITP)
4. Alloimmune thrombocytopenia
5. Neonatal alloimmune thrombocytopenia
6. Post-transfusion purpura
7. Refractoriness to platelet transfusions |
|
|
Term
| Autoimmune thrombocytopenia |
|
Definition
Primary Immune Thrombocytopenic Purpura (ITP)
Mild to severe bleeding disorder
Can occur any age after 3 months
Characterized by petechiae, skin and mucosal bleeding, menorrhagia, gastrointestinal bleeding, central nervous system bleeding (1% of cases) |
|
|
Term
| Autoimmune thrombocytopenia acute and chronic forms |
|
Definition
Two forms of primary immune thrombocytopenic purpura:
1.Childhood (acute)
- Commonly follows viral infections
- Usually self-limited (6-12 months) with spontaneous remission
2. Adult (chronic form)
- May last indefinitely
- Diagnosis of exclusion after secondary and hereditary causes are excluded
- Platelet autoantibodies detected in 50-75% of patients (no prognostic significance) |
|
|
Term
| Childhood (acute) immune thrombocytopenic purpura (ITP) |
|
Definition
- Equal frequency in males and females
- Peak incidence occurs b/t ages of 3-5 years
- Steroid therapy used if thrombocytopenia is severe
- 80% of children with ITP have acute form with spontaneous recovery
- Remainder have chronic ITP
- These patients often did not have a viral prodrome |
|
|
Term
| Adult (chronic) immune thrombocytopenic purpura (ITP) |
|
Definition
- Occurs mainly in adult women < 40 years
- 3 times more females affected than males
- Large platelets found in blood smears consistent with increased platelet production
- Onset of disease often insidious (nosebleeds, easy bruising, bleeding from gums)
- Sudden onset of heavy bleeding is not usual presentation, but has been observed |
|
|
Term
| Treatment of chronic immune thrombocytopenic purpura (ITP) |
|
Definition
1. Initially responsive to high dose glucocorticoids- most patients (75-85%) relapse eventually
2. Intravenous immunoglobulins (IVIG) effective in 2/3 of patients (durable remission)
3. Intravenous anti-Rh antibody if patient is Rh-positive (cause hemolytic anemia)
4. Rituximab (monoclonal antibody against B-cells) recently found to be effective
5. Splenectomy for refractory cases
6. Additional chemotherapy considered for cases still refractory after splenectomy (vincristine, cyclophosphamide) |
|
|
Term
| Secondary immune thrombocytopenic purpura |
|
Definition
- Comprise 40-50% of cases of immune thrombocytopenias
- Remains a diagnosis of exclusion in patients with systemic diseases
Possible causes include:
1. Systemic lupus erythematosus (SLE) – thrombocytopenia may precede other symptoms of this autoimmune disease
2. Chronic lymphocytic leukemia (CLL) – 2% of patients with CLL have an autoantibody produced by a B-cell clone
3. Hodgkin disease – 1% of patients develop ITP
4. HIV infection - thrombocytopenia most common hematologic manifestation for these patients
5. Heparin-induced thrombocytopenia (HIT) |
|
|
Term
| Heparin-induced thrombocytopenia (HIT) |
|
Definition
1. Caused by an immune reaction directed against a complex of heparin and platelet factor 4 (PF4)
2. Binding of certain IgG antibodies to PF4 produces immune complexes that activate platelets and promote thrombosis
3. Highest risk groups are cardiac, vascular, and orthopedic surgery patients receiving 1-2 weeks of heparin
- 1-5% of these patients develop HIT |
|
|
Term
| Clinical Features of Heparin-induced thrombocytopenia (HIT) |
|
Definition
1. Drop in platelet count starts 5-10 days after heparin therapy is begun
2. Can occur as rapidly as 24 hours if patient has been exposed to heparin in the past 100 days |
|
|
Term
| Treatment for heparin-induced thrombocytopenia |
|
Definition
- stop use of heparin and use anti-coagulation
- Patient will have a short duration of increased risk for thrombosis due to HIT. |
|
|
Term
| Thrombotic thrombocytopenic purpura (TTP) – signs and symptoms |
|
Definition
Primary diagnostic criteria:
1. Low platelet count and, Microangiopathic hemolytic anemia
(Red cell fragmentation (schistocytes)
Accelerated red cell production and destruction)
2. Immune destruction of red cells excluded
3. No antibodies against RBCs or bound to RBCs
4. No clinically apparent alternative explanation for low platelet count and anemia
0ther common clinical features:
1. Renal function abnormalities
2. Neurologic abnormalities
3. Weakness
4. Abdominal symptoms (nausea, vomiting, diarrhea, pain)
5. Fever (high fever with chills is evidence against TTP and favor sepsis) |
|
|
Term
| Thrombotic thrombocytopenic purpura (TTP) – Frequency and Mortality |
|
Definition
1. 3.7 cases per year per 1 million US residents
2. Incidence increasing 5-7 fold in recent years
3. Approx. 90% mortality prior to use of plasma exchange
4. Approx. 80 to 90% survival with plasma exchange
5. Therefore, low threshold for plasma exchange with cases of suspected TTP |
|
|
Term
| Pathogenesis of thrombotic thrombocytopenic purpura |
|
Definition
1. Formation of ultralarge von Willebrand factor multimers
2. Due to deficiency in metalloprotease required for cleaving vWF into smaller multimers
3. Acquired disease when due to autoantibody formation
4. Congenital disease when due to decrease protease production
5. main diff between this and vWF is no activation of coagulation cascade |
|
|
Term
| Clinical categories of thrombotic thrombocytopenic purpura (TTP) |
|
Definition
Children – 2 categories
1. Bloody diarrhea caused by entero-hemorrhagic E. coli infection with acute renal failure
- Usually associated with E. coli strain 0157:H7
2. Usually treated as a separate but related disease known as hemolytic-uremic syndrome (HUS)
Idiopathic TTP without acute renal failure (bloody diarrhea rare) |
|
|
Term
| Adult Clinical categories of TTP |
|
Definition
Adults – 3 categories
1. Idiopathic – may or may not have acute renal failure
2. Pregnancy associated – distinction from pre-eclampsia-eclampsia-HELLP syndrome not always possible
3. Drug associated:
- Immune-mediated: quinine, ticlopidine, clopidogrel
- Dose related drug toxicity: mitomycin C, cyclosporine, FK506 |
|
|
Term
| Other causes of thrombocytopenia, hemolysis, and schistocytosis besides TTP that should be considered |
|
Definition
Disseminated intravascular coagulopathy (DIC)
Pre-eclampsia/eclampsia
HELLP syndrome (pre-clampsia- associated hemolytic anemia with elevated LFTs and low platelet count, won't improve when kid is born)
Malignant hypertension
Severe vasculitis |
|
|
Term
| Treatment options for TTP |
|
Definition
1. Plasma exchange
- Removal of ultra-large vWF multimers
- Removal of auto-antibodies against protease
- Replenishment of protease with donor plasma
2. Plasma transfusion until patient able to receive plasma exchange |
|
|
Term
| Aspirin-associated platelet defects - History |
|
Definition
1. Association between gastrointestinal bleeding and aspirin ingestion noted in 1938
2. Prolongation of bleeding time by aspirin noted in the 1950’s
3. Excessive prolongation of bleeding time by aspirin in von Willebrand disease was originally proposed as a diagnostic method by AJ Quick in 1970 |
|
|
Term
| Aspirin-associated platelet defects - Mechanism |
|
Definition
1. Anti-thrombotic effect due to inhibition of platelet aggregation (but not platelet adhesion)
2. Cyclooxygenase-1 (COX-1) permanently inhibited (acetylated) by aspirin
3. Impairs synthesis of thromboxane A2, which has potent platelet-aggregating activity |
|
|
Term
| Aspirin-associated platelet defects – Duration of effect |
|
Definition
1. Platelet aggregation studies impaired for up to a week or more from just a single dose!
2. Bleeding time returns to normal within 2-3 days b/c assay is less sensitive |
|
|
Term
| Indications for Aspirin Therapy |
|
Definition
1. Primary prevention of myocardial infarction (MI)
2. Secondary prevention of MI
3. Secondary prevention of stroke after temporary ischemic attack (TIA) or stroke
4. Acute therapy of MI
5. Acute therapy of unstable angina
6. Prevention of saphenous vein bypass graft thrombosis |
|
|
Term
| Effect of aspirin on surgical bleeding? |
|
Definition
Controversial
1. Prospective study showed increased blood loss during surgery when aspirin used within 12 hours of cardiac bypass surgery
2. Multiple studies show conflicting results when aspirin used within 1 week of surgery – no effect vs. increased bleeding |
|
|
Term
| What causes thrombosis generally |
|
Definition
1. abnormal blood flow
2. endothelial injury
3. hypercoagulability |
|
|
Term
| Clinical presentation of DVT |
|
Definition
- swollen
- red
- painful leg
- swelling can also compromise arterial circulation (rare) |
|
|
Term
| Where do vlots usually form in DVT |
|
Definition
- in valve pockets where stasis and hypoxia is greatest
- they develop then work their way out and block flow |
|
|
Term
|
Definition
| - layering of platelet rich (light) then fibrin rich (dark red) clot (like rings of tree) see in DVT |
|
|
Term
|
Definition
Phlebitis = inflammation in wall
thrombis = clot in vessel wall |
|
|
Term
|
Definition
- clot in lungs
- can cause heart failure
- can infarct and become hemorrhagic
- pumping blood for non blocked artery into necrotic tissue causes hemorrhage |
|
|
Term
|
Definition
- VTE
- 3rd most common vascular disease
- life threatening
- 75% of deaths due to PE occur during first hospital admission |
|
|
Term
|
Definition
- 50% of people with DVT of leg have asymptomatic PE
- 80% of patients with PE have DVT |
|
|
Term
|
Definition
- less than half of all fatal PE are detected before death
- 80% of DVT are clinically silent |
|
|
Term
| Who is at high risk for venous thrombosis |
|
Definition
1. prolonged bed rest or immobilizatiom
2. stroke
3. tissue damage
4. cancer
5. antiphospholipid antibody syndrome
6. heparin induced thombocytopenia |
|
|
Term
| Who is at low risk for venous thrombosis |
|
Definition
1. congestive heart failure
2. nephrotic syndrome
3. obesity
4. varicose veins
5. long distance travel
6. hyperestrogenic states (pregnancy, hormone therapy)
7. oral contraceptives
8. smoking
9. age |
|
|
Term
|
Definition
- first DVT before 50 years of age
- recurrent DVT
3. positive family history |
|
|
Term
| Genetic risk factors for VTE |
|
Definition
Common:
1. mutation in factor V gene (Factor V Leiden)
2. mutation in prothrombin gene
3. mutations in homocysteine metabolism pathway
4. high levels of FVIIIC probably genetically determined)
Rare
1. antithombin III deficiency
2. protein C deficiency
3. protein S deficiency
Very Rare
1. fibrinolysis defects |
|
|
Term
| Homozygous Protein C deficiency |
|
Definition
- can develop neonatal pupura fulminans
- full thickness skin necrosis
- babies will die without anticoagulant therapy or protein C concentrate |
|
|
Term
|
Definition
1. prophylactic anticoagulation in high risk patients
2. heparin followed by coumadin in established DVT/PE
3. Major PE may require fibrinolytic therapy or surgical removal
4. duration: initial event with triggering risk factor 3-6 mos; spontaneous initial event 6 mos |
|
|
Term
| riteria for long term therapy of DVT/PE |
|
Definition
1. presence of more than one genetic defect
2. initial life-threatening thrombosis
3. cerebral, mesenteric, portal or hepatic vein thrombosis
4. 2 or more spntaneous thrombotic events |
|
|
Term
| Long term complications of VTE |
|
Definition
- recurrence rate is high
- post-thrombotic syndrome is common even when the DVT has been treated PTS may cause leg ulcer |
|
|
Term
| Post phlebitic venous insufficiency |
|
Definition
- causes post-thrombotic syndrome
- faulty valves with out-pouching that decreases blood flow to heart so less O2 blood gets to parts of body and ulcers can form |
|
|
Term
| Treatment of post phlebitic syndrome |
|
Definition
1. surgical support hose following initial event (graded material kind of milks leg)
2. venous ulcers may require special dressings and skin grafting |
|
|
Term
| How to treat an occluded coronary artery |
|
Definition
| - balloon angioplasty and stenting to re-open vessel |
|
|
Term
|
Definition
before death
- dryish on surface of vein, flow lines on surface of platelet, fibrin, platelet etc
- distends vein as opposed to post-mortem which does not distend |
|
|
Term
|
Definition
- septic: thrombi can have organisms in it if the person is also septic
- bland: regular thrombi don't hear people talk about them as bland |
|
|
Term
|
Definition
1. stenosis or blockage of lumen = ischemia or infarct
2. venous occlusion = local congestion or edema or pulmonary embolism
3. left heart valve/chamber thrombi = systemic embolism |
|
|
Term
|
Definition
1. resolve without a trace
2. propagate (grow)
3. embolize (travel)
4. organize (get fibrous)
5. recanalize (new lumens)
6. calcify (phlebolith) |
|
|
Term
|
Definition
- fibrotic
- endothelial cells and fibroblasts
- indicative of longer lasting |
|
|
Term
|
Definition
- bolus of material which travels through the vascular system (gas, liquid or solid)
- most common is thromboembolism
- usually lodge in next branching capillary bed/ vessel |
|
|
Term
| result of multiple small emboli as opposed to large |
|
Definition
small: heart failure and or infarcts
large: sudden death |
|
|
Term
| Examples of solid, gas, and liquid emboli |
|
Definition
| Solid: thrombus is most common; also foreign bodies (bullet, catheter tip) Liquid: amniotic fluid, contrast material, soft tissue trauma or fracture gas: air (can get in through IV site if rip it out), nitrogen bends as in tunnel workers and divers (if go too low too fast) |
|
|
Term
|
Definition
| - systemic vein, through a septal defect int he heart, to systemic circulation |
|
|
Term
|
Definition
| - from systemic veins to pulmonary arteries |
|
|
Term
|
Definition
| - heart or aorta to systemic circulation |
|
|
Term
|
Definition
| - huge emboli in main pulmonary arteries, not main site of thrombi |
|
|
Term
|
Definition
| - recognizable by cholesterol clefts formed by fat solvation so fat is white and cholesterol is fat and is taken out and leaves a hole where blood vessels are so you know it's this |
|
|
Term
|
Definition
- localized area of ischemic necrosis
- usually caused by vascular blockage
- takes 406 hrs to be seen microscopically |
|
|
Term
|
Definition
- hazard of orthopedic surgery specifically
- fat comes out of the damaged bones |
|
|
Term
|
Definition
1. bland (usual) vs septic
2. arterial (pale) vs venous (hemorrhagic)
- arterial more common because atherosclerosis is common |
|
|
Term
|
Definition
- varies with different tissues and durations: pale, roughly wedge-shaped in solid organs with single blood supply (kidneys and spleen ex)
- hemorrhagic in soft organs with a dual blood supply (lungs, bowel) |
|
|
Term
|
Definition
- vary in appearance with age
- infarcts heal from outside
- become more shrunken and fibrous |
|
|
Term
|
Definition
- decreased blood flow to an organ or tissue
- often distinguished from infarction clinically |
|
|
Term
|
Definition
| - areas infarcted and infected |
|
|
Term
| Disseminated intravascular coagulation def |
|
Definition
| - acquired syndrome characterized by the intravascular activation of coagulation with loss of localization arising from different causes. It can arise from and cause damage to microvasculature, which if sufficiently severe can produce organ dysfunction |
|
|
Term
|
Definition
| - a secondary complication of many different disorders - intermediary mechanism of disease, not a disease itself |
|
|
Term
|
Definition
1. obstetric complications (abruptio placentae, retained dead fetus, septic abortion, amniotic fluid embolism, toxemia)
2. infections (gram negative sepsis, meningococcemia and other specific agents, waterhouse-fridericksen syndrome)
3. neoplasms (mucin producing solid tumors (troussseau's syndrome/overcompensated DIC, acute promyelocytic - decompensated DIC)
4. massive tissue injury
5. miscellaneous: shock, snake bite, giant hemagioma etc |
|
|
Term
|
Definition
1. activation of coagulation sequence: thrombi throughout microcirculation
2. consumption of platelets and coagulation factors to sub-hemostatic levels
3. activation of fibrinolysis (destroy clots)
4. tissue hypoxia;microinfarcts
5. hemorrhage from (minor) trauma due to consumption/depletion of clotting factors and fibrinolysis destroying clots. |
|
|
Term
|
Definition
- low platlets
- fibrinogen low
- PT prolonged
- PTT prolonged
- D-dimer level up from fibrin degradation products (was cross-linked before chopped up so are digesting clots) |
|
|
Term
|
Definition
| - microangiopathic hemolytic anemia (schistocytes) |
|
|
Term
| Gram negative sepsis and DIC |
|
Definition
- waterhouse-fredrickson
- meningiococcemia
- causes bilateral adrenal hemorrhages |
|
|
Term
|
Definition
1. treat the underlying cause. this is key ***
2. resuscitate (with platelets electrolytes, not literally)
3. replacement of blood
4. heparin in patients with clinical thrombosis
4. inhibitor concentrates (antithrombin, activated protein C) |
|
|
Term
|
Definition
| - one dilated pupil, one not - can indicate problem with intracranial procees |
|
|
Term
| Mechanisms of decompensated intravascular coagulation |
|
Definition
1. stimulus: massive tissue destruction, sepsis, or endothelial damage
2. release of tissue factor and platelet aggregation by endothelial injury
3. widespread microvascular thrombosis
4. activation of plasmin, vascular occlusion, comsumption of clotting factors and platelets
5. ischemic tissue damage, microangiopathic hemolytic anemia and bleeding from fibrinolysis |
|
|
Term
| Overcompensated DIC: Trousseau's syndrome |
|
Definition
- from metastatic cancer
- migratory thrombophlebitis
- get emboli, infartions etc
- more thrombosis and infarct and less bleeding |
|
|
Term
| Mechanism of Trousseau's syndrome |
|
Definition
1. mucinous carcinomas tend to produce substances that cause hyper-coagulabiltiy (get extra fibrinogen) but release these substances slowly. This allows time for the liver and bone marrow to catch up and actually exceed the demand for platelets and coagulation factors
- get overcompensated DIC |
|
|
Term
| Trousseau's syndrome treatment |
|
Definition
| removal of metastatic carcinoma (usually impossible) |
|
|
Term
|
Definition
- 90%
- microthrombosis, with lysis (as in massive trauma, sepsis, amniotic fluid embolism)
- PTT, PT, FDPs up, Fibinogen, platelets and coag factors down
- remove underlying cause |
|
|
Term
| Labs for overcompensated DIC |
|
Definition
- PT and PTT vary
- fibrinogen and platelets may be hihg
- FDP's usually up |
|
|
Term
| Mechanisms for termination of drug action |
|
Definition
1. redistribution
2. metabolism/biotransformation
3. excretion |
|
|
Term
| Consequences of drug metabolism |
|
Definition
1. general: drug plus enzyme = metabolites
2. Major: drug goes to inactive more polar more readily excreted molecule
3. Minor:
- inactive to active
- toxic to non
- non-toxic to toxic |
|
|
Term
| Phase I of drug metabolism |
|
Definition
| - functionalization reactions that introduce or expose a functional group on parent compound (ex: oxidation) NON-SYNTHETIC |
|
|
Term
|
Definition
| - covalent conjugation of parent and endogenous compounds - SYNTHETIC |
|
|
Term
| Trend to get more readily excreted compounds (pharm) |
|
Definition
| - lipophilic to hydrophilic |
|
|
Term
| Enzymes associated with phase II |
|
Definition
- hepatic microsomal enzymes: oxidation, conjugation
- hepatic non-microsomal enzymes: acetylation, sulfation, GSH, etc
- extrahepatic microsomal enzymes; oxidation and conjugation |
|
|
Term
|
Definition
| 1. oxidation rxns: cytochrome P450 (CYP) mediated |
|
|
Term
|
Definition
- NADPH + H+ + O2 + Drug to NADP+ + H2O + Oxidized Drug
- Carbon monoxide binds to the reduced Fe(II) heme and absorbs at 450 nm (origin of enzyme family name)
- CYP monooxygenase enzyme family is major catalyst of drug and endogenous compound oxidations in liver, kidney, G.I. tract, skin, lungs
- Oxidative reactions require the CYP heme protein, the reductase, NADPH, phosphatidylcholine and molecular oxygen
- CYPs are in smooth endoplasmic reticulum (microsomes) in close association with NADPH-CYP reductase in 10/1 ratio
- The reductase serves as the electron source for the oxidative reaction cycle
Susceptable to induction and inhibition (to FX on drug metab)
OXIDATION and REDUCTION |
|
|
Term
|
Definition
- Families - CYP plus arabic numeral (>40% homology of amino acid sequence, eg. CYP1)
- Subfamily >55% homology of amino acid sequence; eg. CYP1A
- Subfamily - additional arabic numeral when more than 1 subfamily has been identified; eg. CYP1A2
- Italics indicate gene (CYP1A2); regular font for enzyme |
|
|
Term
|
Definition
1. Twelve CYP gene families have been identified in humans, and the categories are based upon protein sequence homology
2. Most of the drug metabolizing enzymes are in CYP 1, 2, & 3 families.
3. Frequently, two or more enzymes can catalyze the same type of oxidation, indicating redundant and broad substrate specificity.
4. CYP3A4 is very common to the metabolism of many drugs; its presence in the GI tract is responsible for poor oral availabilty of many drugs |
|
|
Term
|
Definition
- Chemically diverse small molecules are converted, generally to more polar compounds
- Aliphatic hydroxylation, aromatic - hydroxylation
- Dealkylation (N-,O-, S-)
- N-oxidation, S-oxidation
- Deamination
- Dehalogenation |
|
|
Term
| factors influence CYP enzymes |
|
Definition
| many factors in nutrition, smoking, alcohol, drugs, environment and genetic polymorphisms can effect the CYP levels |
|
|
Term
induction of CYPS by Pregnane-x receptor
(PXR) |
|
Definition
| - molecular mechanism for protection against xenobiotics (foreign chemicals) |
|
|
Term
|
Definition
1. large, elliptical hydrophobic cavity
2. cavity changes shape to accommodate different ligands (ideally suited to function as xeno-sensor)
3. ligand-bound PXR forms DNA-binding complex with the retinoid X receptor (RXR) to CYP transcription
- these factors bind PXR and then CYP is transcribed to bind the chemicals |
|
|
Term
|
Definition
- Two major categories of CYP inducers
Phenobarbital is prototype of one group - enhances metabolism of wide variety of substrates by causing proliferation of SER and CYP in liver cells.
- Polycylic aromatic hydrocarbons are second type of inducer (ex: benzo[a]pyrene).
- Induction appears to be environmental adaptive response of organism
- Orphan Nuclear Receptors (e.g. PXR) are regulators of drug metabolizing gene expression |
|
|
Term
|
Definition
- Grapefruit juice
- Ketoconazole, Omeprazole (all azole drugs)
- Cimetidine
- Probenecid
- Macrolides (e.g. erythromycin) |
|
|
Term
|
Definition
- Phenobarbital
- St. Johns Wort
- Polycyclic aromatic hydrocarbons (PAHs) |
|
|
Term
| Grapefruit juice: inhibition of CYPs |
|
Definition
- GJ caused 62% reduction in small bowel enterocyte 3A4 and 3A5 protein; liver not as markedly effected (i.v. pharmacokinetics unchanged)
- GJ effects last ~4 h, require new enzyme synthesis
- Effect cumulative (up to 5x Cmax) and highly variable among individuals depending upon 3A4 small bowel basal levels
- GJ or G (not OJ) elevates plasma peak drug concentration, not elimination t1/2
GJ reduces metabolite/parent drug AUC ratio
- decrease normal capacity of metabolism (increased drug or lasts longer in presence of inhibitors like GJ) |
|
|
Term
| Non-CYP drug biotransformations |
|
Definition
- Oxidations/Reductions (all phase I)
- Hydrolyses
- Conjugation (Phase 2 Rxns)
- Major Conjugation Reactions
- Glucuronidation (high capacity)
- Sulfation (low capacity)
- Acetylation (variable capacity)
Examples:Procainamide, Isoniazid
Other Conjugation Reactions: O-methylation, S-methylation, Amino acid conjugation (glycine, taurine, glutathione)
- Many conjugation enzymes exhibit polymorphism |
|
|
Term
|
Definition
Definition: the use of genetic information to
1) explain interindividual differences in drug responses or to
2) individualize dosages for patients with known genetic polymorphisms. |
|
|
Term
|
Definition
genetically determined abnormal drug response
Ex: allergies |
|
|
Term
|
Definition
- Estimated rate of 40-60%
- Erratic compliance can lead to discontinuation
- Poor compliance/persistence a problem in chronic conditions (e.g. hypertension)
- Some discontinuation associated with side effects or “feeling better” (no perceived continued need for medication) |
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