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platelet & coagulation disorders
cmbm exam V
82
Chemistry
Graduate
02/17/2010

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Term
what is hemostasis?
Definition
cessation of bleeding
Term
what are the functions of the hemostatic system?
Definition
maintenance of blood fluidity w/in normal intact vessels, rapid and localized thrombosis at sits of vascular injury, and thrombus dissolution
Term
what are the components of hemostasis?
Definition
the vessel wall, platelets, and plasma protein systems (coagulation system - fibrin formation, anticoagualant system - reg of coag proteins, fibrinolytic system - fibrin dissolution)
Term
what are forces that oppose clotting?
Definition
1) negative charges on both platelets and endothelial cells 2)products released by endothelial cells: prostacyclin & nitric oxide (inhibit platelet aggregation) and a heparin-like substance that aids action of antithrombin III (antithrombin converts thrombin from a pro-coagulant to an anti-coagulant that activates protein C, which inhibits part of the coagulation cascade)
Term
what generally happens to the endothelial wall when you have a vascular injury?
Definition
the endothelial wall unsurfaces/exposes proteins that promote clotting including von willabrand factor (vWF) which binds glycoprotein Ib (GP Ib) on platelets. the platelets become activated and release their granules, which recruits more platelets and allows them to adhere to each other (platelet aggregation). the last step is when thrombin is formed and starts laying down a fibrinogen network between platelets that are aggregating.
Term
what happens first in primary hemestasis?
Definition
the injured vascular endothelium exposes sub endothelial collagen and vWF, which leads to platelet adhesion (via platelet GP Ib/IX/V to vVF) and a platelet shape change (round to disc shape, potentiates granule release and helps them undergo shape change of other receptors (GP IIB/IIa) -> which allows AGGREGATION)
Term
what are the three main steps of primary hemostasis?
Definition
platelet adhesion, activation, aggregation
Term
what is platelet adhesion largely mediated by? what does it bind?
Definition
vWF binds GP Ib/IX/V (which helps anchor platelets to collagen). german vw on 1-9-5
Term
what makes vWF?
Definition
the sub endothelium (when exposed to to endothelial damage), megakaryocytes, and platelet granules
Term
how does vWF interact with factor VIII of the coagulation cascade?
Definition
vWF complexes to factor VIII, and stabilizes it (protective function, gets it where it needs to go)
Term
what forms does vWF circulate in? which of these is the most active?
Definition
vWF circulates in various multimers; dimers, trimers, & various sizes. the high molecular weight multimers are the most active, b/c they non-covalently complex with VIII. ultimately these ultra high molecular weight multimers are cleaved by a metaloprotease called ADAMTS-13 (important in TTP)
Term
when do platelets become activated? what do they do when they are activated?
Definition
platelets become activated once they adhere to the endothelial surface, they then go from spherical to discoid shape, their GP IIb-IIa receptor helps link platelets together (aggregation), and they release granule contents which recruits more platelets
Term
what are the 2 granules platelets have, and what do they each release?
Definition
the alpha granule contains: platelet factor 4, PDGF, fibrinogen, and vWF. the dense granule contains: ADP, calcium and serotonin
Term
what mediates platelet aggregation?
Definition
fibrinogen which links platelets together by binding to the platelet receptor GP IIb-IIIa (but this would not be possible w/out the conformational shape change of the receptor) -> once this starts happening you have a framework for the clot, and it should not be easily dislodged
Term
what are some disorders of primary hemostasis?
Definition
vascular wall abnormalities (eg vasculitis), quantitative platelet disorders, qualitative platelet disorders, and vFW disease diseases (which can span both quantitative and qualitative platelet disorders)
Term
what is one of the first causes of primary hemostatic disorders? what can it be due to? what does typical evaluation for thrombocytopenia consist of?
Definition
thrombocytopenia, which can be due to: decreased marrow production, increased platelet destruction, splenic sequestration, hemodilution (increase in saline), spurious (EDTA-pseudo thrombocytopenia - result of antibody that forms against EDTA). a typical evaluation for thrombocytopenia should consist of distinguishing between decreased production and increased destruction.
Term
what is the first step in diagnosing a low platelet count?
Definition
blood smear to exclude spurious spurious thrombocytopenia where the platelets are either clumping or they are having platelet satellitism (where they start surrounding white cells or other cells)
Term
if the pt is negative for thrombocytopenia what next should be checked?
Definition
the clinical hx, has the pt recently had chemotherapy, hemodilution, or radiation therapy?
Term
if there is nothing clinical pointing to why there is a thrombocytopenia, what should be checked next?
Definition
the bone marrow should be checked for number of megakaryocytes. if they are decreased: prob CA, if they are normal/increased: prob increased destruction of platelets
Term
if there is normal or increased megakaryocytes, what should be checked next in the cast of thrombocytopenia?
Definition
other marrow elements. if RBCs & WBCs are normal, then peripheral destruction is possible (disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura (TTP), various drugs, SLE, or very last: idiopathic thrombocytopenic purpura). if RBCs & WBCs are abnormal, leukemias are possible
Term
what is one way that a false postive for a high WBC count would be taken?
Definition
platelet clumps can be read as lymphocytes (if you see platelet clumps, be wary of the other results)
Term
what is satellitism?
Definition
EDTA antibodies are involved in platelets sticking to neutrophils, which can be read as a giant neutrophil by an automated analyzer
Term
why might there be decreased marrow production of platelets?
Definition
reduced or ineffective megakaryoctyopoiesis
Term
what are causes for reduced megakaryocytes?
Definition
marrow infiltration, marrow aplasia, or congenital abnormalities
Term
how does marrow infiltration happen?
Definition
tumors (leukemia, disseminated cancer can squeeze out normal elements), fibrosis (CMPD), infection (granulomatous - TB, sarcoidosis, can also squeeze out normal megakaryocytes)
Term
how does marrow aplasia happen? what is it?
Definition
this is where a lot of normal marrow elements are missing, it can be idiopathic, due to immune problems, cytotoxic drugs, chemicals (benzene), radiation
Term
what are congenital abnormalities that can lead to reduced megakaryocytes?
Definition
congential amegakaryocytic thrombocytopenia, thrombocytopenia w/absent radii
Term
what are causes for ineffective megakaryocytopoiesis?
Definition
megaloblastic anemia, myelodysplasia, drugs (alcohol/thiazides), infections (measles, HIV), congenital abnormalities (wiskott-alrich, may hegglin)
Term
how should bone marrow appear?
Definition
some fat globules. % cells should be 100 - the person's age (ex. 30 year old should have 70% cells and 30% fat). megakaryocytes, WBC/RBC precursors should be visible
Term
if a pt has thrombocytopenia and has normal bone marrow, what is probably the issue?
Definition
peripheral destruction of platelets
Term
what is seen with infiltration of bone marrow by a tumor?
Definition
strings of adenocarcinoma displacing normal tissue with lighter pink fibrosis in the background
Term
what is seen with infiltration of bone marrow by fibrosis?
Definition
bone marrow being replaced by fibrotic tissue
Term
what is seen with infiltration of bone marrow by a granulomas?
Definition
with TB/sarcoidosis, giant cells squeezing out normal cells
Term
how does marrow aplasia appear histologically?
Definition
mostly fat with just a few fibroblasts
Term
how does the rar thrombocytopenia absent radius syndrome (TAR) present?
Definition
low platelet count, skeletal & hematological abnormalities related to the simulatenous development of the hear, the radii, and the megakaryocytes at 6-7 wks gestation. (these pt usually have a life-long platelet dependence)
Term
what size are platelets in most inherited platelet disorders? is there any that have small platelets?
Definition
most inherited platelet disorders lead to large platelets, wiskott aldrich is one of the few that has small platelets
Term
what is the may hegglin anomaly?
Definition
an autosomal dominant disorder w/ varying thrombocytopenia, purpura (small bruises due to lack of platelets), giant platelets (about the same size as neutrophils), and dohle body-like inclusions in neutrophils (fragment of the rough ER generally seen in toxic granulation, b/c neutrophils are kicked out of bone marrow too early and the ER isn't mature)
Term
what is wiskott-aldrich syndrome?
Definition
an IgM deficiency (immune deficiency) pts present w/atopic conditions like allergies/eczema. SMALL PLATELETS and increased risk of autoimmune disease/hematologic malignancy
Term
what are the 2 main causes for increased platelet destruction?
Definition
immune and non-immune thromocytopenia
Term
what are 2 causes for immune thrombocytopenia?
Definition
autoantibody-mediated: autoimmune disease (SLE), lymphomas, drugs (heparin, quinidine, sulfa), infections (EBV, HIV, CMV), and idiopathic (ITP - diagnosis of exclusion) alloantibody-mediated: fetal-maternal incompatibility, post-transfusion purpura, and platelet refractoriness
Term
what causes non-immune thrombocytopenia?
Definition
thrombotic microangiopathies (DIC, TTP, HUS) and mechanical causes such as prosthetic heart valves
Term
what is idiopathic thrombocytopenic purpura? when is it seen? what organ carries out most of the destruction?
Definition
it is called idiopathic; but it is thought to be related to IgG forming against membrane glycoproteins (GP IIb/IIIa—platelet aggregation) (GPIb/IX—which helps in platelet adhesions). it is seen after viral infections (body mistakes GP receptor for virus). the spleen is the major site of antibody-coated platelet removal
Term
what is seen on a peripheral smear in diagnosis of ITP?
Definition
large immature platelets (platelet counts are down, so the bone marrow will respond by kicking out less mature platelets) more granules are also seen
Term
what is seen in the bone marrow in diagnosis of ITP?
Definition
increased and immature megakaryocytes
Term
what are the 2 forms of ITP, which is more common?
Definition
chronic ITP is more common, it is seen in young adult women and is a diagnosis of exclusion. acute ITP is seen in children, usually preceded by a viral illness and is self-limited/generally resolves in 6 months
Term
how is vFW supposed to circulate and interact with ADAMTS-13?
Definition
vFW is supposed to circulate as a series of multimers, with the high weight multimers being the most active and non-covalently bonded to factor VIII. ADAMTS-13 is supposed to cleave the ultra-high molecular weight multimers.
Term
what is thrombotic thrombocytopenic purpura?
Definition
TTP occurs when ADAMTS-13 which is on endothelial cell binding sites and is supposed to cleave ultra-high molecular weight vFW is ineffective, inefficient or inhibited by another substance. these pts have huge multimers of vFW circulating that can cause abnormal thrombus formation which can be life threatening
Term
what can go wrong with ADAMTS-13 and vFW?
Definition
ADAMTS-13 is on endothelial cell binding sites and is supposed to cleave ultra-high molecular weight vFW, but sometimes it is ineffective, inefficient or inhibited by another substance. these pts have huge multimers of vFW circulating that can cause abnormal thrombus formation which can be life threatening.
Term
what is TPP?
Definition
thrombotic thrombocytopenic purpura is a disorder of vFW, where it is secreted in a larger pentamer form that cannot be processed by ADAMTS-13 and is super thrombotic
Term
how is TPP aquired? what does it cause?
Definition
TPP can be inherited (deficiency of protease) or aquired (auto antibodies to protease). TTP causes activation of platelets and inappropriate thrombus formation
Term
how would a normal and TPP pt's plasma gels compare?
Definition
a normal pt would have multiple bands representing multiple vFW weights but no ultra high weight vFWs. TPP pt would have all the multimers including the ultra high weight ones
Term
b/c pts form platelet thrombi in microvasculature what will the pt present with (clinical pentad)?
Definition
thrombocytopenia (platelets are consumed in coagulation process), microangiopathic hemolytic anemia (red blood cells travel through these damaged vessels, they are fragmented resulting in intravascular hemolysis), neurologic abnormalities (headaches), renal abnormalities (dec urination, elevated creatinine), fever, peripheral smear, and schistocytes (fragmented portions of cells)
Term
how do schistocytes form in TTP?
Definition
microthrombi in vasculature lead to fibrin strands across which RBCs shear themselves into portions that look like helments: schistocytes. (other portion will re-seal upon itself and form microsphericytes)
Term
how is TTP diagnosed?
Definition
blood is drawn for ADAMTS-13 level and tested against and ADAMTS-13 inhibitor BEFORE giving a pt a plasma transfusion (b/c you'd be measuring the donor's levels) - but do not delay tx while wating for results
Term
how is TTP treated?
Definition
Term
how is TTP treated?
Definition
plasmapheresis is used to remove the ADAMTS-13 inhibitor in pt plasma and it is replaced with fresh frozen plasma
Term
what is hemolytic uremic syndrome?
Definition
this disease looks very similar to TTP, but it is caused by a shiga-like toxin produced by e. coli (infectious gastroenteritis), which damages endothelial cells to such an extent that widespread thrombi/platelet aggregation cause microangiopathic hemolytic anemia because fibrin strands and RBCs getting sheared (schistocytes). renal vasculature is the first to be hit and can lead to acute renal failure
Term
what are 3 forms of alloimmune thrombocytopenia?
Definition
neonatal alloimmune thrombocytopenia (NAIT), post-transfusion purpura (PTP), and platelet refractoriness
Term
what is neonatal alloimmune thrombocytopenia (NAIT)? what is the tx?
Definition
98% of the population have platelets with AI antigens on their surface, but if a mother is PA-, she will form antibodies that will begin to attack the fetal platelets - can cause severe intraventricular hemorrhage. tx consists of transfusing the fetus w/the mothers AI- platelets
Term
what is post-transfusion purpura (PTP)?
Definition
an antibody response in PL AI - pts to transfused PL AI + positive platelets (only 2% of pop is PL AI -). it classically presents as severe thrombocytopenia in female blood recipients a wk after transfusion, (often happens to women sensitized in the past), the recipients platelets are destroyed as well as those transfused in a process that isn't well understood, but pts will usually recover within several weeks.
Term
what is platelet refractoriness?
Definition
repeatedly transfused pts (like leukemia patients who have had bone marrow wiped out) start producing anti HLA (another platelet antigen) antibodies, and start to not have a good response to platelets - so platelets have to be found that lack HLA to be transfused
Term
why is it helpful to look at platelet data in the form of a lab graph function?
Definition
you can see if platelet counts drop dramatically after a transfusion (spleen is consuming platelets/infection) or flatline/go nowhere (platelet refractoriness)
Term
what is heparin induced thrombocytopenia (HIT)?
Definition
HIT type II (type I is clinically insignificant) is where antibodies are formed against platelet factor 4 and administered heparin complexes. this becomes problematic when the antibody binds to also platelet Fc receptors and triggers release of additional PF4. (PF4 can also bind to the body's own heparin-like glycoaminoglycans & cause endothelial damage). HIT presents as a life threatening thrombosis (paradoxical b/c heparin is supposed to thin blood)
Term
how are qualitative disorders diagnosed if platelets appear normal on a peripheral smear?
Definition
uremia, DIC, myelopeoliferative disorders should be ruled out, if they are then common things like vFW disorders can be screened for (VIII complex, vWF antigen, multimeric analysis, etc), if these are normal -> check platelet aggregation
Term
what is platelet function testing?
Definition
machines that help simulate what would happen in the body at the site of injury and looks at how well a thrombus will form by measuring: 1)whole blood flow through a capillary device stimulating primary hemostasis and 2)how much time it takes to form over a clot over a hole in the capillary system
Term
how is the platelet aggregation test performed?
Definition
a specimen of platelet rich plasma prepared from citrated (non EDT) blood (it should be cloudy), aggregating agent is added and light transmission is measured. once platelets begin to aggregate, it should clump and light should be able to carry through. the aggregometer records the amount of light transmitted through the specimen as platelets clump and the speciment clears.
Term
what does a normal platelet aggregation test look like?
Definition
a bump at the beginning, a primary wave (aggregating agents starts to work), and a secondary wave (when platelets degranulate)
Term
is a normal aggregation wave seen with epinephrine, collagen, ADP, and ristocentin?
Definition
yes
Term
what common inherited bleeding disorder can platelet aggregation tests be used to diagnose?
Definition
vWF disease (quantitative type 1,3 or qualitiative type 2a,b)
Term
what are vFW diseases type 1 and 3?
Definition
vFWD type 1 (very common) is a decrease in all polymeric forms of vFW. type 3 is an absence of all polymeric forms (rare)
Term
what are vFW diseases type 2a and 2b?
Definition
type 2a is a lack of intermediate and high molecular weight multimers = loss of vWF functionality. type 2b is a lack of high molecular weight multimers = increased affinity for GIb
Term
is a normal aggregation wave seen with epinephrine, collagen, ADP, and ristocentin with pts with vFW disease?
Definition
yes except for ristocentin
Term
what are the features of type I vFW disease?
Definition
it is autosomal dominant, there is a decrease in all multimers, decrease in RIPA (ristocetin induced platelet aggregation), decrease in VIII activity (because it is not protected by vFW)
Term
how does RIPA respnd to vFWD type 2B?
Definition
RIPA increases
Term
what are some inherited qualitative platelet disorders?
Definition
bernard-soulier syndrome, glanzmann, thrombasthenia, and storage pool disease
Term
what can cause aquired qualitative platelet disorders (more common)?
Definition
drugs (ASA, GPIIb-IIIa antagonists), hematologic disorders (CMPD, MDS, acute leukemia), autoimmune disorders, and uremia
Term
what is bernard-soulier syndrome? what is seen in a smear for bernard-soulier syndrome?
Definition
a rare autosomal recessive disorder causing deficiency of GPIb-IX (portion of the Ib/IX/V complex) and defective platelet adhesion (to vessel wall). large platelets and thrombocytopenia are seen in a smear. severe bleeding. and decreased RIPA are seen clinically. it looks similar to vWF disease
Term
what is glanzmann thrombasthenia? how does it appear in a blood smear?
Definition
a rare autosomal recessive deficiency in GPIIb-IIIa and defective platelet aggregation w/all agonists except ristocetin (opposite of bernard-soulier). it appears as normal platelet size and number in a blood smear but presents clinically as severe bleeding
Term
what are storage pool diseases?
Definition
these are more common than other inherited qualitative disorders and fall into 2 subgroups: storage pool deficiency (decrease in dense granules, alpha granules or both) and platelet release defect (defect in signal transduction). defective platelet aggregation w/all agonists IN THE SECOND WAVE except ristocetin
Term
how do vWFD and bernard-soulier respond to platelet aggregation?
Definition
normal aggregation with all agonists except ristcetin
Term
how does glanzmann's respond to platelet aggregation?
Definition
abnormal aggregation with all agonists except ristocetin
Term
how do storage pool defects respond to platelet aggregation?
Definition
abnormal secondary wave of aggregation with all agonists except ristocetin
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