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hemostasis II
cmbm exam V
68
Chemistry
Graduate
02/21/2010

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Term
what is thrombopoietin (TPO)?
Definition
the factor for hematopoietic stem cells to go toward toward megakaryocytes
Term
how do megakaryocytes produce platelets?
Definition
endomitosis, the nucleus is replicated but the DNA remains intact and starts sloughing off cells -> platelets
Term
where is TPO produced?
Definition
in the bone marrow, liver and kidney. (EPO produced in the kidney)
Term
what is the receptor for TPO?
Definition
CMPL
Term
how are platelets activated?
Definition
ADP is released by many platelets and received by P2Y1 and P2Y12 which then through signal cascades changes the conformation of GpIIb/IIIa causing it to bind fibrinogen
Term
what does platelet receptor GpIb/V/XI bind?
Definition
vWF and endothelium
Term
what is glanzmann thrombasthenia?
Definition
a deficiency in GpIIb/IIIa, which keeps the platelets from aggregating b/c they have to bind to fibrinogen to bind to each other. (a similar effect would be seen with afibrinogenemia)
Term
what is bernard soulier syndrome?
Definition
a deficiency in GpIb; therefore platelets cannot adhere to the subendothelium. (similar to vWD, where platelets cannot adhere to the endothelium)
Term
what is the specific amino acid sequence both GpIb and GpIIb/IIIa bind to in fibrinogen and vWF?
Definition
RGD: arginine, glycine, aspartate
Term
what is an additional function of vWF?
Definition
carrying/protecting factor VIII - so a vWF is similar to hemophila A
Term
what is ADAMTS-13?
Definition
a metalloprotease that cleaves vWF (a large multimeric protein produced by endothelial cells), which is itself made in the liver. ADAMTS-13 is the major regulator for vWF size and provides protection against uncontrolled platelet adhesion.
Term
how can a deficiency in ADAMTS-13 cause thrombocytopenia? what is this condition called?
Definition
an ADAMTS-13 deficiency is called thrombotic thrombocytopenia purpura and in this case, the platelts are all adhering to large vFW fragments on the subendothelium/aggregations and are not present in general circulation
Term
what causes ADAMTS-13 to cut vWF into smaller pieces?
Definition
high shear stress
Term
what two granules do platelets have?
Definition
alpha (PF4, vWF, etc) and dense granule (ADP etc)
Term
what is grey platelet syndrome?
Definition
large platelets that do not have alpha granules
Term
where do prostaglandins come from?
Definition
phospholipase A2 cuts arachidonic acid from the #2 position, COX on platelets make the prostaglandin TXA2 while COX on endothelial cells will make PGI2(prostacyclin). (TXA2 is one of the most potent vasoconstrictors known)
Term
if you eat more omega-6 FA's such as arachidonic acid, what eicosanoids will be produced in greater number?
Definition
series 2 prostaglandins (TXA2/PGI2), and series 4 leukotrienes
Term
if you eat more omega-3 FA's such as EPA (eicosapentanoic acid), what eicosanoids will be produced in greater number?
Definition
series 3 prostaglandins (antiinflammatory), series 5 leukotrienes
Term
what omega # is linoleic acid? is there a correlation with cardiovascular disease?
Definition
omega 6; of which there is a INVERSE correlation with cardiovascular disease with (it may decrease the risk of CVD)
Term
what omega # is linolenic acid? what is it said to do?
Definition
omega 3; which should decrease the amount of pro-inflammatory cytokines (TNF-alpha, IL-1, and IL-6) and also decrease CVD
Term
what happens to platelet membranes that PLA2 has cleaved all the arachidonic acid from?
Definition
the phospholipids missing an arachidonic acids "flip out" causing the surface to be negatively charged - allowing them to ready for coagulation
Term
what is found on the surface of platelets when activated?
Definition
once activated, integrins form a "surface raft" which help the platelet by allowing for stronger surface interatction/signalling events
Term
what are platelet microparticles (PMP)?
Definition
these are tiny particles released from cells (including platelets) during apoptosis that have a negative charge which is pro-coagulant/thrombogenic. tissue factor is also found on these microparticles in encrypted form.
Term
what is the shape change that occurs when platelets are activated?
Definition
round to discoid
Term
what is the platelet cytoskeleton composed of?
Definition
actin and myosin which help tighten up the shape of activated platelets
Term
what are 2 diseases causing defects in platelet adhesion?
Definition
bernard soulier disease which is a lack of GpIb/IX/V and vWF deficiency
Term
what are 2 diseases causing problems in platelet aggregation?
Definition
glanzmann's (missing GpIIb/IIIb) or afibrinogenemia
Term
what is wiskott-aldrich?
Definition
X-linked mutation in WASP, causing hereditary thrombocytopenia
Term
what is an example of a storage pool disease?
Definition
grey platelet syndrom
Term
what usually causes TTP? what is the platelet cut off where it has to be considered?
Definition
ADAMTS-13, but also infection/autoantibodies. 140,000 is the platelet cut-off
Term
what is essential thrombocythemia?
Definition
a rare myeloid neoplastic disorder where there are too many platelets (platelets are abnormal in size and aggregate quickly and inappropriately), pts w/this tend to bleed slightly more. it can be treated with warfarin long term
Term
what does the blood coagulation cascade start with?
Definition
the extrinsic, then later it shifts to the intrinsic
Term
what part of the coagulation cascade is associated with the phospholipid surface, platelets, and blood vessels?
Definition
the intrinsic pathway
Term
what part of the coagulation cascade is associated with phospholipids and tissue factor?
Definition
the extrinsic pathway
Term
what part of the coagulation cascade is associated with thrombin and fibrin clot formation?
Definition
the common pathway
Term
what is the key to activation of the coagulation system?
Definition
thrombin, which provides feedback activations
Term
what are the 3 things that can activate factor XI in the intrinsic pathway?
Definition
XII, VII and thrombin
Term
what 2 things activate factor IX?
Definition
factor XI and VII
Term
what 2 factors activate factor X?
Definition
VII and IX
Term
what complex shifts the coagulation cascade to the intrinsic system?
Definition
tissue factor pathway inhibitor which inhibits the complex of factor VII, tissue factor, and factor X. increased thrombin concentration then activates the intrinsic side through feedback loops
Term
where is tissue factor found in it's inactive state?
Definition
tissue factor is an (internal/external) integral membrane protein usually expressed by extravascular cells (esp heart, lungs, testes, uterus, placenta) and encoded on microparticles. it is separated by a primary hemostatic barrier on blood vessels, but following injury it rapidly activates blood coagulation
Term
what is the structure of fibrinogen? where does thrombin cleave?
Definition
a mustache where alpha/beta/gama are at each end, gamma points down in the middle where the mouth would be and the alpha/beta chains point up into where the nose would be <- where thrombin cleaves, and once i does = fibrin
Term
what is a fibrin soft clot?
Definition
when thrombin cleaves the center alpha and beta chains, this spot gets sticky and it binds to the ends of other fibrin molecules non-covalently
Term
how do soft fibrin clots become hard?
Definition
factor XIII crosslinks (ligase between a lysine and a glutamine) adjacent fibrin molecules after being activated by thrombin
Term
what are the procoagulant properties of thrombin?
Definition
platelet activation (via integrin), activates factors V, VIII as well as XI and VII, it converts fibrinogen to fibrin and activates factor XIII
Term
what is the lupus antiphospholipid antibody?
Definition
people with this have no (or very minor) bleeding disorder, however, their blood is slow to clot in a test tube and they will have a prolonged PTT (b/c antibodies block the phospholipids which are part of the test). in severe cases, this can be treated with oral anticoagulants
Term
how do you determine if someone has phospholipid antibodies?
Definition
russel's viper venom activates factor X directly (bypasses blood clotting cascade to test factor X)
Term
how do thrombin and endothelial cells inhibit thrombosis?
Definition
thrombin is inactivated by antithrombin III, and endothelial cells provide heparin to potentiate this
Term
how do endothelial cells inactivate factors X and VII?
Definition
via tissue factor pathway inhibitor
Term
how do endothelial cells inhibit platelet aggregation?
Definition
release of PGI2, NO and ADP phosphatase
Term
how do endothelial cells activate the fibrinolytic system?
Definition
by releasing tissue plasminogen activator
Term
how is protein C activated? what does it do?
Definition
protein C is activated when thrombin binds to thrombomodulin as expressed by endothelial cells at the correct time. this complex activates protein C which then inactivates factor V and VIII
Term
what does tissue factor pathway inhibitor inhibit?
Definition
extrinsic factor X activation, which needs the complex to act
Term
what causes factor V leiden? what happens as as result?
Definition
arg->gln mutation. the factor V leiden mutation leads to protein C resistance by factor V, leading to more clotting than usual (5-7x increased risk of thromboembolism)
Term
what are 2 inhibitors in the thrombolytic system?
Definition
plasmin activator inhibitor and plasmin inhibitor <- both will allow the clot to remain/continue to form
Term
what are some thrombolytic therapy agents? how are they administered?
Definition
streptokinase, urokinase, t-PA (tissue plasminogen activator, alteplase) and recombinant t-PA. these are delievered by catheter to the area of the clot except with pulmonary embolisms (b/c it will dilute the drug and break up other possibly necessary clots)
Term
what kind of protein are factors XII, XI, X, II, VII, plasmin, C1, elastase, and trypsin? what inactivates these?
Definition
serine proteases which have 3 AAs in their active site; aspartate, histadine and serine. these are inactivated by serpins which are produced in the liver, circulate the blood and suicide inhibit serine proteases and clear them from circulation
Term
what are serpins/hemostatic inhibitors that block clotting?
Definition
ATIII, C1inh, alpha1 protease inh
Term
what are serpins/hemostatic inhibitors that block fibrinolysis?
Definition
plasminogen activator inhibitors (PAI), and plasmin inhibitors
Term
what are serpins/hemostatic inhibitors that shift reactions?
Definition
TFPI shifts from extrinsic to intrinsic
Term
what does heparin do (2 things)?
Definition
binds to antithrombin III and enhances its inhibitory activity by changing its conformation and folding out and drawing targets in
Term
what are benefits of LMW heparin?
Definition
higher anti Xa/IIa activity ratio (inhibits thrombin generation, not just thrombin activity), it has a longer half life, it is more uniform/predictive, it may not react with protamine as an antidote, and it has a ****lower association with HIT
Term
are there any benefits of unfractionated heparin?
Definition
it may be better for obese, elderly, renally insufficient, and pregnant pts
Term
does LMW heparin have less of a chance of causing HIT?
Definition
yes
Term
what is HIT?
Definition
a highly prothrombotic, hypercoagulable disorder (not hemorrhagic), caused by exposure to heparin in complex with PF4 on the platelet surface, resulting in an immune rxn -> leading to a systemic thrombotic response (venous 4x more common)
Term
what is hirudin?
Definition
a direct thrombin inhibitor that is unaffected by platelet factor 4 and inactivates thrombin bound to fibrin -> more predictable anticoagulant response (derived from leeches)
Term
what can snake venoms do in terms of coagulation?
Definition
snake venom can initiate consumption of coagulant substances and; produce a protease that directly hydrolyses prothrombin, directly clots fibrinogen, activates platelets (kills small mammals by overclotting) and activates endothelial cells to produce a plasminogen activator (fibrinolysis)
Term
what happens in DIC?
Definition
in disseminated intravascular coagulation, there is consumption of all the platelets and coagulation factors resulting in extreme bleeding somewhere else
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