Term
| Stem Cell identified by ______ |
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Definition
| the CD 34 Surface Antigen |
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Term
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Definition
nourish, provide growth factors, and provide scaffolding of the pluripotent stem cells
expel proteins… |
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Term
| Granulocytes Erythocytes Megakaryocytes Monocytes |
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Definition
| (non-Lymphoid or myeloid line) |
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Term
Has a little blue-ish---left over DNA
It tells you the bone marrow is making RBCs
are about 1-1.5% |
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Definition
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Term
Responds to hypoxia
Comes from Kidney
Stimulates BFU and CFU
Enhances Iron Utilization |
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Definition
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Term
To be adequately absorbed it must be reduced
Duodenum has specific cells to absorb |
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Definition
|
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Term
______ saturation is the proportion of available sites of Transferrin occupied by the iron
RBCs have a cell surface receptor for ________ |
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Definition
|
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Term
| storage form of insoluble iron; principal site: RE system |
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Definition
|
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Term
| storage form of soluble iron absorbed in excess of immediate metabolic need |
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Definition
|
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Term
| Heme iron is the Organic / Meat Iron --- Absorbed more efficiently --- by _______ |
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Definition
|
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Term
| Receptor on RBC (on a nucleated, developing RBC, to be specific) |
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Definition
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Term
Necessary for the hemoglobin molecule
Donates electrons for generation of superoxide radical, In excess, impairs organ cellular function |
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Definition
|
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Term
| Impairs the Releasing of Stored/Absorbed Iron --- this prevents too much iron from being deposited in the body |
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Definition
|
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Term
| causes synthesis of Hepcidin ----leads to lower absorbtion, lower release of iron from cells |
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Definition
|
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Term
| causes Hepcidin to turn off --- allowing iron to be absorbed/released to blood |
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Definition
| Low iron saturation of transferrin |
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Term
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Definition
Ferritin Translation procedes
Stores Iron---because it is important to not let Iron to be free in excess |
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Term
Treated with phlebotomy to remove iron-rich RBCs
mutations of genes which control iron absorption and storage |
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Definition
Hereditary Iron Overload
“Hemochromatosis” |
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Term
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Definition
| the O2 is RELEASED better |
|
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Term
Oligosacharide chains-
Spectrin, Anchorin, Band 4.1 --- mutations lead to non-surviving cells – and hemolytic anemia |
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Definition
|
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Term
|
Definition
make energy -- keep the pump working
keep hbg reduced, w/ nadh
make enough 2,3 DPG
get rid of peroxides -- don't let globin chains get oxidized; w/ nadph |
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Term
| is converted to urobilinogen which is excreted in stool or reabsorbed and excreted by the kidney |
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Definition
| conjugated bilirubin from liver |
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Term
Estimated prevalence ~25% (~1.6 billion)
Primary cause: iron deficiency |
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Definition
|
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Term
case 1
trauma to the abdomen
nausea and thirst
diaphoretic
pale
and dizzy
Systolic BP is 100 mm Hg. lying and drops to 60 systolic when he stands
hemoglobin of 11.5
case 2
hemoglobin 8.6
heavy menstrual periods |
|
Definition
acute rbc mass loss
hypovolemia symptoms
chronic decrease in rbc mass
O2 carrying symptoms; fatigue, headache |
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Term
| Plasma Erythropoietin Level's Correlation with Hemoglobin Level |
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Definition
As hg Goes down
Erythropoietin Goes way up |
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Term
| to find out how much Reticulocytes are really being produced |
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Definition
Take the Retic Count
correct for patient's hematocrit ( retic count x patient's hematocrit/normal hematocrit)
divide by 2 to correct for reticulocytes' longevity
It should increase within 2-3 days of a major acute hemorrhage, for instance, and reach its peak in 6-10 days (aplastic crisis", is the medical term for an abnormal decrease of reticulocytes in the body)
erythrocyte to granulocyte ratio should be up in a week; rpi should be up as well >3 |
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Term
| If Hgb goes down Marrow production goes |
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Definition
| up, especially when iron is present |
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Term
Hypoproliferative Anemias
(Markedly decreased RPI) |
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Definition
Secondary aplastic “anemia” (pancytopenia)
drugs, other chemicals
Immune-mediated pancytopenia
Tumors of thymus
Bone marrow replacement
Cancer, hematological malignancy
cytokines* of inflammation
Reduced Erythropoietin Response
Renal Failure
Reduced response to, or decreased stimulus for erythropoietin secretion
Endocrinopathies
Decreased thyroid hormone |
|
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Term
| Maturation Disorders (Inappropriately low RPI) |
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Definition
erythroid precursors in marrow but with premature death
Nuclear (DNA) disorders
Cobalamin or folate def.
Cytoplasmic disorders
Severe iron deficiency
Thalassemias |
|
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Term
| Erythroid Survival Disorders (Elevated RPI) |
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Definition
Acute blood loss
Hemolytic anemia |
|
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Term
|
Definition
elevated serum unconjugated bilirubin
elevated serum lactic dehydrogenase |
|
|
Term
| Intrinsic (intracorpuscular) hemolysis |
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Definition
Defect in membrane, hemoglobin, enzymes
Usually inherited |
|
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Term
| Extrinsic (extracorpuscular) hemolysis |
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Definition
Antibody damage, mechanical trauma, physical
Usually acquired |
|
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Term
|
Definition
Splenic mononuclear phagocyte & Liver
Within the marrow (intramedullary) due to ineffective erythropoiesis |
|
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Term
|
Definition
depletion of serum haptoglobin
Free plasma and urine hemoglobin |
|
|
Term
platelets
Cyclooxygenase 1,2 Release Arach Acid – generates Endoperoxide
Endoperoxides can generate both Thromboxane A2 and/or PGI2 |
|
Definition
| *** this is the step inhibited by Aspirin |
|
|
Term
| healthy, normal platelets produce |
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Definition
|
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Term
| Platelet secrete a variety of inflammatory modulators including ___ |
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Definition
|
|
Term
is a receptor for VIIa
VIIa binds to tissue factor, which binds to Factor X |
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Definition
|
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Term
| on the membranes, binds to Factor V; the Xa/Va activates Prothrombin |
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Definition
|
|
Term
Factor 9 is generated by XI
XI can be activated by |
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Definition
|
|
Term
| Factor XIIIa causes fibrin |
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Definition
|
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Term
on the surface
IXa and VIII binds to X --- eventually more |
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Definition
|
|
Term
XII is a contact factor – polyphosphate secreted by platelets also activates XII
Leads to |
|
Definition
| Bradykinin---a potent inflammatory mediator |
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Term
|
Definition
|
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Term
|
Definition
| VIIIa and Xa --- limits how much Thrombin is generated |
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Term
| Interaction: Hemostasis & Inflammation |
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Definition
| Cytokines: TNFa, IL1a & Endotoxin induce TF expression on monocytes |
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Term
|
Definition
stasis
hypercoagulability
vascular injury |
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Term
|
Definition
|
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Term
|
Definition
Inhibition of Platelet function
Inhibition of Thromboxane A2 by Aspirin and other NSAID
Inhibitors of Coagulation
Heparin and Related Drugs: Unfractionated heparin, LMWH,
Oral direct FXa inhibitors: Rivaroxaban, Apixaban
Coumarin type Anticoagulants – Warfarin
Inhibit gamma carboxylation of II VII IX X; by blocking the reduction of Vit K |
|
|
Term
clotting times
whole blood,
citrated w/ Ca++ added,
PL and Ca++ added,
kaolin and PL and Ca++ added, (PTT intrinsic XII)
thromboplastin and Ca++ added (PT) |
|
Definition
4-8 min
2-4 min
60-85 sec
21-32 sec
11-12 sec |
|
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Term
| Heparin is monitored by the |
|
Definition
| aPTT (activated partial thromboplastin time). |
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Term
| Warfarin is monitored by the |
|
Definition
|
|
Term
binds primarily to anti-thrombin III,
allows antithrombin III to efficiently inactivate other clotting factors: |
|
Definition
|
|
Term
Thrombocytopenia – transiently platelet count fallings
When it is prolonged, it is a big deal, it could be an antibody response to _____, so monitor it w/ _______ |
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Definition
Heparin
Activated partial thromboplastin time (aPTT)
Measures intrinsic pathway |
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Term
|
Definition
Heparin derivative:
Fondaparinux can produce a more specific response.
Subcutaneous patient self administration |
|
|
Term
| Low Molecular Weight Heparins |
|
Definition
Come from unfractionated animal sources, but get chopped up
preferentially binds to III (antithrombin)
Enoxaparin (Lovenox)*, Dalteparin (Fragmin), Tinzaparin (Innohep), Danaparoid (structurally distinct) |
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|
Term
Different brands are NOT interchangeable in terms of dose, duration of activity, or actions at various clotting factors
Dependent upon Antithrombin III for inactivating existing clotting factors
Cannot inactivate thrombin that is already bound to a clot (only circulating thrombin) |
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Definition
|
|
Term
| Direct Thrombin Inhibitors |
|
Definition
Inhibit soluble (circulating) & clot-bound thrombin
Do NOT cause thrombocytopenia
Bleeding is major adverse effect
derived from leeches
Dabigatran; Advantages seem to be greatest for people with poor INR control.
Disadvantage: Much more expensive |
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|
Term
| Warfarin blocks the synthesis of |
|
Definition
new factors (2,7,9,10)
Protein S and Protein C – also have a need for carboxlyation. --- watch for side effects here
Contraindicated by pregnancy
Monitor by PT time – measuring extrinsic pathway – but the PT should be converted into the INR (to account for the variability between labs) |
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Term
| Corticosteroids – 50% of patients require lower warfarin dose; why? |
|
Definition
Antibiotics, Cephalosporins, disrupt the flora in the gut, thereby reducing vitamin K2 synthesis. In addition, some antibiotics like sulfamethoxazole-trimethoprim also inhibit CYP 2C9, which is responsible for metabolizing warfarin
Cholestyramine may decrease warfarin’s response by interferring with warfarin’s absorption
Cholestyramine may increase warfarin’s response by interferring with absorption of Vitamin K |
|
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Term
| Methotrexate (inhibits the |
|
Definition
| DHF reductase; used against many hyperproliferative disorders; predisposes to folate deficiencies |
|
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Term
|
Definition
Associated with autoantibodies to parietal cells, intrinsic factor
(Pernicious Anemia is one cause of B12 deficiency) |
|
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Term
| Causes microcytic, hypochromic anemia |
|
Definition
|
|
Term
|
Definition
hair-skull
Variation in shape
Hypochromic
Microcytic
Interaction with the spleen
Excess alpha deposits as Heinz Bodies*** |
|
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Term
| iron chelation therapy; in B thal tranfusions |
|
Definition
| deferoxamine subcutaneous injections nightly or oral deferasirox |
|
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Term
| presence of tetramers of both b chains (Hgb H) and g chains |
|
Definition
|
|
Term
| After examining the peripheral smear and calculating the reticulocyte index |
|
Definition
We measure
LDH
Bilirubin
The unconjugated bilirubin is elevated with extravascular hemolysis |
|
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Term
| Indicators of Intravascular Hemolysis |
|
Definition
Absence of haptoglobin (haptoglobin get depleted)
Hemoglobinuria (acute)
Hemosiderinuria (chronic) |
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Term
| So, once we have determined that hemolysis is causing the anemia, how do we determine what is causing the hemolysis? Is it a problem intrinsic to the red cell, or is the red cell merely an innocent bystander in a hostile environment? |
|
Definition
Osmotic fragility proves that they are spherocytes
Anticoagulated blood into tube; look for hemolysis
Spherocyte hemolysis isn’t as good at lower concentrations |
|
|
Term
| Cardinal Features of Hereditary Spherocytosis |
|
Definition
vertical uncoupling, with vesicle formation and loss of pieces of membrane
-splenectomy benefits |
|
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Term
|
Definition
Blister” cells with acute hemolysis after an oxidant stress in G6PD Deficiency
Denatured hemoglobin sticking to membrane
-heinz bodies
protection against falciparum malaria |
|
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Term
|
Definition
by doing a functional test for sickling
and by running a hemoglobin electrophoresis which demonstrates the presence of the abnormal band of hemoglobin S |
|
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Term
|
Definition
Fragmentation syndromes (ttp adamts 13 too many vWF; too much aggregation/microstress)
Autoimmune hemolytic anemia (Microagglutinates in a patient with cold agglutinin hemolytic anemia; The direct Coombs’ test is the hallmark of autoimmune hemolytic anemia)
Infections
Hypersplenism
drug induced (Antimicrobials account for >40%) |
|
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Term
| Testing the Coagulation System |
|
Definition
Screening Tests
Extrinsic & common pathway: Prothrombin time (PT)
Intrinsic & common pathway: Partial thromboplastin time (PTT)
Fibrinogen: Thrombin time
Specific tests:
Measure specific clotting factor activity and antigen, e.g., plasma fibrinogen, factor VIII, IX, etc.
Measure von Willebrand factor antigen & activity
Test for inhibitors: Mixing studies then specific assays |
|
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Term
|
Definition
| platelet adhesion & aggregation is simulated in vitro |
|
|
Term
|
Definition
. Decreased Production
Bone Marrow Disease
2. Increased Destruction
Immune and Non-Immune
3. Abnormal Distribution
Splenomegaly |
|
|
Term
| Idiopathic (Autoimmune) Thrombocytopenic Purpura (ITP |
|
Definition
auto antibody binding to megakaryocytes
diagnosis of exclusion: No other cause of platelets, especially drugs
Prednisone
Rituximab
Splenectomy |
|
|
Term
| Inherited Platelet Dysfunction |
|
Definition
Mild thrombocytopenia with large bizarre platelets
Bernard Soluier Syndrome
Glanzmann thrombasthenia
Secondary to deficiency of GP11b-IIIa |
|
|
Term
| Acquired Platelet Dysfunction |
|
Definition
|
|
Term
| HEMOPHILIA Factor VIII or IX Deficiency |
|
Definition
| Severity of bleeding correlates with severity of factor deficiency |
|
|
Term
| VON WILLEBRAND DISEASE (VWD) |
|
Definition
Mostly autosomal dominant
Mucocutaneous bleeding |
|
|
Term
| Bleeding in Liver Disease |
|
Definition
| Clotting factor deficiencies |
|
|
Term
|
Definition
Vitamin K is required for gammacarboxylation & proper function of factors II, VII, IX & X
Prolonged PT & PTT |
|
|
Term
| Disseminated Intravascular Coagulation (DIC) |
|
Definition
Infections
Metastatic cancer, acute leukemia
Anaphylactic
ABO incompatible
cytokine-mediated disorder: TNF, IL1, IL2…….play key role in pathogenesis
Patients who present with bleeding:
fresh frozen plasma (FFP), platelets, cryoprecipitate.
Patients who present with thrombotic complications: Heparin |
|
|
Term
| P vera and other myeloproliferative |
|
Definition
|
|
Term
|
Definition
A tyrosine kinase inhibitor taken indefinitely
Imatinib mesylate (Gleevec™)
dasatinib (Sprycel™)
nilotinib (Tasigna™ )
Hydroxyurea |
|
|
Term
| Agnogenic myelofibrosis with myeloid metaplasia |
|
Definition
Tear drop and nucleated erythrocytes
marrow fibrosis |
|
|
Term
| thrombopoietin or increased sensitivity to thrombopoietin |
|
Definition
|
|
Term
| thrombopoietin or increased sensitivity to thrombopoietin |
|
Definition
|
|
Term
| Chronic Neutrophilic Leukemia |
|
Definition
Chronic myelogenous leukemia must be ruled out
This is an aggressive disorder, often refractory to therapy. |
|
|
Term
|
Definition
increased cellularity, reticulin and abnormal megakaryocytes
Increased MCV, Aniso/poikilocytosis, Pelger-Huet polymorphonuclear cells, Monocytosis
sideroblast iron trapped in mitos
The 5q- Syndrome
Normal to increased platelet counts with monolobular megakaryocytes
Macrocytic anemia with modest leukopenia |
|
|
Term
| Hodgkin’s Disease (Lymphoma) |
|
Definition
Historically used MOPP (mechlorethamine, vincristine (oncovin), procarbazine, and prednisone) – side effects are limiting
first line
ABVD
Adriamycin
(Doxorubicin. Hydroxydaunarubicin)
Bleomycin
Vinblastine
Dacarbazine |
|
|
Term
| Anthracycline Antibiotics |
|
Definition
Intercalates double helix; Antibiotic; creates ROS
Doxorubicin (Adriamycin, Hydroxydaunarubicin)
Works in S phase
Uncoils DNA
These species can then react with O2 to produce O2- and H2O2 which cause DNA cleavage and lipid peroxidation. |
|
|
Term
|
Definition
M phase
Epithelium lining gut, hair follicles
Drug-tubulin complex cannot assemble into MT. |
|
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Term
|
Definition
| Targets DNA (intercalation) and interacts with metal, oxygen and reducing agent (NADPH) to generate free radicals. |
|
|
Term
|
Definition
| Alkylating agent--- a simple one; modifies major groove of DNA |
|
|
Term
Non-Hodgkin Lymphoma (NHL)
indolent
Most common is the follicular lymphoma |
|
Definition
CHOP + rituximab
Cyclophosphamide, Hydroxydaunarubicin (doxorubicin or adriamycin), Oncovin (vincristine), Prednisone |
|
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Term
|
Definition
| CD20 antigen on most B-cell non-Hodgkin’s |
|
|
Term
| Acute Lymphoblastic Leukemia (ALL) |
|
Definition
environmental mutagens
Induction – Multiple drugs in an aggressive manner to achieve a clinical remission.
Consolidation – The induction is followed by a similarly intensive and rigorous therapy (using a different drug combination) to minimize resistance and effect a “cure”
Avoid anthracyclines and alkylating agents (mutagenic)
Maintenance (generally for ALL in children) – Low dose monthly therapies to maintain remission.
MTX + mercaptopurine |
|
|
Term
|
Definition
TH-Folate is single carbon carrier in purine/pyr synthesis; carries carbons to the scaffold
Converts U to T
So the drug MTX is an analog
Blocks DHF reductase
Cancer cells don’t take it in as well as normal cells
So supplement with Leucovorin (THF)---to replenish the tHF for DHF reductase in normal cells |
|
|
Term
|
Definition
Asparagine is biosynthesized from aspartate
Give asparaginase to break down asparagine;
Tumor cells can’t make own asp… |
|
|
Term
| Acute Myelogenous Leukemia |
|
Definition
In APL
All-trans-retinoic acid --- induces differentiation/maturation
Works in like 90% of patients |
|
|
Term
| Chronic Lymphocytic Leukemia |
|
Definition
CLL is almost identical to small lymphocytic lymphoma (SLL: one of the myriad forms of NHL: 4%-5%).
Watchful waiting
Fludarabine + Rituximab |
|
|
Term
|
Definition
Treatment:
Imatinib (Philadelphia Chromosome-Positive)
Dasatinib
Nilotinib |
|
|
Term
|
Definition
BCR-ABL tyrosine kinase activity resulting from Philadelphia chromosome translocation present in >90% of CML patients and 10-25% of Acute Lymphocytic Leukemia patients.
Gleevec is a selective inhibitor of BCR-ABL. |
|
|
Term
| Chronic Myelogenous Leukemia (CML) – Blast Crisis |
|
Definition
| Disease progression on Imatinib |
|
|
Term
|
Definition
Treatments:
Bortezomib
The proteosome is a multiprotein complex
Velcade is a specific and reversible inhibitor of proteosome activity. |
|
|
Term
|
Definition
| Particularly toxic to T cells |
|
|
Term
|
Definition
Nelarabine
Tositumab
New anti CD20 antibody (like rituximab) – B-cell NHL |
|
|
Term
|
Definition
1 – Most anti-neoplastic agents target dividing cells, or target selective growth factors or signal transduction pathways..
2 – Therapeutic regimens are combinatorial (multiple mechanisms of action and limiting toxicities)
3 – Cancer cells have multiple and evolving mechanisms of resistance.
4 – Cytotoxic drugs attack cell division mechanisms (DNA synthesis, chromosomal segregation, chromosome structure)
5 – Immunosuppression (generalized or selective with antibodies) is effective for hematological malignancies |
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