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84 Cards in this Set
- Front
- Back
- 3rd side (hint)
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give two names for the anucleate fragments of megakaryocytes
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platelets or thrombocytes
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what are the basic steps in primary hemostasis?
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vasoconstriction, platelet adhesion to injured endothelium, platelet activation, granule secretion, aggregation to form a platelet plug
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during platelet adhesion, glycoproteins on the platelet surface bind to what?
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collagen in the endothelium (gp1aIIa), von willlebrand factos in the endothelium (gpIbIX), and fibrinogen that will bind to other platelets (IIbIIIa)
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discuss the role of eicosanoids in platelet activation and secretion
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arachadonic acid is activated by COX which can lead to two fates. one is thromboxane synthetase that activates platelets and causes them to aggregate via platelet shape change, granule movement and secretion. the other is prostacyclin synthase (makes PGI2) from the endothelial cells will suppress platelet activation and aggregation by raising intracellular pH.
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what molecules activate phospholipase A2 (TXA2)
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thrombin, collagen, and epi
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hemophillia A is lack of what? B?
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lack of factor 8, lack of factor 9.
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how is the clotting cascade a cascade?
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amplification at each step and positive feedback by thrombin
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purpose of factor 13?
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consolidates the fibrin into a solid clot. forms an amide bond bw the gln and lys of two fibrins
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role of vitamin K?
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gamma carboxylates the precursor proteins of some factors and adds Ca so they can be incorporated into the platelet membrane
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vit K is needed for what proteins? what inhibits this modification?
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factors II, VII, IX, and X as well as proteins C and S. warfarin and dicoumarol
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where does warfarin block vit K in the vit K liver cycle?
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2,3 epoxide reductase
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inheritance patterns of hemophilia A and B?
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X linked
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describe von willebrand's disease
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def of von willebrand factor, most common congenital bleeding disorder. sxs usually mild but can be severe. note factor 8 circulates in plasma as a complex with von willebrand factor
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presence of fibrin D dimers is diagnostic for what?
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DIC
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what kind of protein is antithrombin? what does it do? with what other molecule does it do this?
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serpin. rapidly inhibits thrombin, Xa, and IX. with either heparin or cell surface GAG heperan sulfate
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describe the proteins and actions in fibrinolysis
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plasminogen binds to fibrin in clot, proteolytically activated to plasmin by TPA. both plasmin and TPA are serine proteases. urokinase is another serine protease which activates plasminogen
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what protein ensures that excess plasmin is not produced and the vessel does not start to get digested?
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PAI - plasminogen activator inhibitor.
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what proteins can be measured if the pt has had a clot and we want to know if it has started to break down?
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fibrin degradation products (FDPs)
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what is the most common cause of death in the world?
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thrombus
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what usually causes arterial thrombosis? venous thrombosis?
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arterial from ongoing vascular disease seen in DM, hyperlipidemia, hypercholesterolemia, and endothelial cell dysfunction with elevated plasma homocysteine. venous is seen with low blood flow situations
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describe two conditions that lead to thrombosis.
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factor V leiden: mutation in factor V making it resistant to inactivation by protein C. prothrombin 20210: rises in normal prothrombin and not as easily recognized by antithrombin. Note mutations in protein C also exist.
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what protects the blood from the ECM which would lead to coagulation?
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endothelium
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what is the most important aspect of coagulation cascade?
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cleavage of prothrombin to thrombin. Thrombin then forms fibrin from fibrinogen and activates the platelets to intermix the platelets with the fibrins.
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describe the clotting cascade.
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2 systems that activate it. Extrinsic: tissue injury leads to tissue factor, factor 7 is activated and binds tissue factor and it also activates factor 9. Intrinsic pathway: XII is activated and activates 11. 11 can activate 9. 9a and 7 + tissue factor then activate 10. 5 and 8 are cofactors; 8 is needed to help 9a activate 10 and 5 is needed to help 10a cleave prothrombin (factor II). thrombin can activate fibrin and factor 13 to help.... LOOK at pic on slide 7 or in first aid (1st aid is better)
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important chemistry at cleavage site of prothrombin.
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disulfide bond which when cleaved undergoes rotation to expose the active enzyme pocket
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regarding the cell, where does coagulation occur?
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on the surface of the activated platelet or damaged endothelial cell, thus localizing clotting to damaged area
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vitamin K dependent factors? What does vit K do to them?
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2,7,9,10. it gamma carboxy glutamates them: adds COO- groups to glutamates, leads to binding of Ca, this leads to binding to the cell surface. Thus vit K is needed for these puppies to bind to the cell surface. Note that the cofactors, 5 and 8, are already bound to the cell surface via Ca
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what is warfarins mechanism of action.
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blocks gamma carboxyglutamation from vit D of factors 2,7,9, and 10
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where is thrombin cleaved and where do the fragment and the active enzyme go after this?
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enzyme leaves the cell surface and goes into the plasma and the fragment stays on the surface of the platelet/damaged epi cell. The half life of the thrombin enzyme is very short, so it only acts on fibrinogen close by.
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how do most of the factors bind to the cell surface?
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via Ca++
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role of activated 13?
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crosslinks the fibrin molecules
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how does plasminogen bind the clot.
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thrombin actually clips a portion of plasminogen to expose a lysine to bind the clot
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where does TPA work?
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the bound plasminogen in the clot is activated to plasmin so the clot is eaten from the inside out
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H and PE specefics for clotting disorders.
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family Hx, past surg or trauma, medication and diet hx, ETOH use (most of the clotting factors are in the liver), concomitant diseases including liver disease, surgery, antibiotics, collagen vascular disease. Look at the sites of blood loss and amount
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differentiate between PT and PTT
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PT measures the time for the extrinsic pathway (abiltiy for 7 to activate 10 to activate 2 and then fibrin) to form a fibrin. PTT measures the time for the intrinsic system (12 to 9 with 5 and 8 to 2) to form fibrin
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what can cause abnormal PT?
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factor 7 def, early vit K def, mild liver disease, short half life of factor 7 (4 to 6 hours)
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what step in the clotting cascade only occurs in the body, not in the test tube
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7a turning on 9.
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what disease causes the PT and PTT tests to be very prolonged, but they have normal clot times in the body?
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lupus
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what percent activity of any factor will lead to normal clotting?
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50%, this is why you must think about half life when giving warfarin
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time it takes to reach steady state with warfarin?
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5 days, due to half lives of factors 2,9, and 10 being very long. Only 7 is short, therefore co treat with heparin for the first few days.
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describe the 1 to 1 mix and possible results.
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if pt serum gives abnormal PT or PTT, then take one part pt plasma and 1 part normal plasma (only need 50% of factor activity for normal clotting). If we get a complete correction then pt has a factor def. If we have an incomplete correction then there is an inhibitor present. note that incubation is used to detect slow inhibitors like some antibodies.
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describe what an abnormal PTT can mean
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deficiencies with NO bleeding can be prekallikrein def, high molecular weight kininogen, factor 12. def with bleeding are 9, 11 (may or may not have bleeding), and 8. heparin in the pt. Inhibitors that could be present are lupus anticoagulant (no bleeding) or factor 8 inhibitor (bleeding)
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describe what can cause a prolonged PT and PTT
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common pathway factor - 2,5, or 10. vit K def or warfarin. Liver disease. Heparin. Multiple factors depleted like in DIC
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describe the thrombin time When will it be long? What is the difference between reptilase time and thrombin time?
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add thrombin and see how long it takes for fibrin to form. It will be long in hypofibrinogenemia, dysfibrinogenemia, elevated levels of FDPs (fibrin degradation products), presence of heparin. Reptilase uses snake thrombin and it will have a longer fibrin forming time for the same stuff as human thrombin except heparin. thus to test for heparin use reptilase.
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if all coagulation tests are abnormal, what can be the problems?
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severe liver disease, severe dilutional coagulopathy, DIC, hypo or dysfibrinogenemia… seen a lot in trauma pts given lots of blood (Hct only I guess…) but no plasma to replace the clotting factors
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liver disease can cause what issues?
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vit K dependent factors are all screwed. As well as all other factors except VII-VWF and XIII that are not made in the liver. Liver also is used to clear activated factors anf FSP's, so if liver is diseased bleeding may be rampant due to factors not being cleared. platelets are screwed bc splenomegaly occurs with liver disease and the spleen sucks the platelets up.
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describe DIC
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excessive/uncontrolled thrombin generation everywhere leads to small vessel occlusion and microangiopathic hemolytic anemia. Eventual consumption of factors and fibrinolysis lead to bleeding. Consumption of platelets leads to thrombocytopenia. So basically have clotting and bleeding and then you die
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treatment of DIC?
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treat the underlying issue (like the infection). If you need to treat hematologically, usually give heparin bc of microvascular coagulation… need an expert to treat, this is toughy
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purpose of antithrombin III. Role in DIC? What drug adds to it?
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blocks all serine protease: 2,7,9,10. note in DIC it is used up quickly bc it binds ser proteases irreversibly to inhibit them. AT III becomes much more potent when heparin is added
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ppl with congenital lack of antithrombin III usually present with what?
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DVT
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describe the cascade initiated by thrombomodulin.
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thrmobin binds thrombomodulin, activates protein C, protein C then activates protein S. So S and C can go and proteolyzed V and VIII. Note deficiency in these proteins is similar to deficiency in ATIII - can lead to DVTs
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all the activities of thrombin?
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activates fibrinogen, platelets, protein C and S, opens up/activates factors V and VIII, converts 12a to 12f which can help activate plasminogen and complement, activates 13, puts plasminogen in the clot
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describe the acquired coagulator inhibitors.
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heparin or antibodies (specefic to factors like factor 8, lupus anticoagulant broad spectrum) . Note while lupus is more of a nuissance only, inhibitors to factor 8 can be deadly… they can occur in hemophiliacs who have been given serum factor 8 for years or sometimes the antibody appears post partum
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5 facts about the lupus anticoagulant…
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it is caused by an antiphospholipid Ab. Will cause prolonged PTT and normal PT, can cause a false positive for syphilis dx test, no bleeding in vivo, but it can bind thrombomodulin and cause excessive thrombosis.
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describe what can cause venous and arterial thrombi.
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venous: stasis, hypercoaguable states, humoral coagulation. Arterial is vascular injury, hypercoaguable states, platelet issues.
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what are the hereditary hypercoaguable states?
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AT3 def, protein C and S def, homocystinuria (vessel damage from def of MTHF reductase), Factor V leiden - resistant to protein C, prothrombin - 20210A (AT3 resistant)
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hypercoaguable states that can be acquired?
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stasis, smoking, birth control, myeloproliferative disease, lupus, vascular injury from trauma, cancer, pregnancy or post partum
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None
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how do you evaluate thrombocytopenia
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platelet count will be under 100K (normal range is 150 to 300K), bleeding problems usually begin to occur under 50K. Severe bleeding under 10K. Always confirm on peripheral smear, note a giant platelet is young
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what usually is the reason for a false positive of thrombocytopenia in a blood sample analyzed by a culture counter?
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the sample is shaken up or improperly taken, platelets start to clump, counter reads them as bigger than platelets so it does not count them as platelets. Note sometimes they bind to the white cell and clump there as well
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H and PE findings associated with thrombocytopenia?
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bleeding history, associated diseases like cancer, AIDS, autoimmune disease. Drugs that inhibit platelets like NSAIDS or immune drugs that destroy them. On exam look for petechiae
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difference bw petechiae and vasculitis?
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vasculitic lesions are palpable
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thrombocytopenia lab tests?
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CBC to check for marrow problem, coagulation tests bc associated with DIC, chemistry tests: liver and kidney issues, LDH content to check for hemolysis.
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causes of thrombocytopenia?
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problems with production, distribution or increased destruction of platelets
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describe possible marrow states in thrombocytopenia?
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leukemia, aplastic anemia (no blood cells getting made), B12/folate def, chemo/radiation, myelophthistic process (marrow is replaced by something that should not be replacing it), and destruction of only megakaryocytes via drugs, lupus, or virus
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describe idiopathic thrombocytopenic purpura in all aspects.
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usually autoimmune (anti platelet Abs), can be drug related, NO splenomegaly, can have collagen vascular disease, cancer and AIDS. Anti platelet antibody and then RE system clears it. In adult it is chronic. In child it is acute (viral usually). Treatment: prednisone - BV effect/stabiliztion in hours, in days dec in RE clearance in liver and spleen of tagged platelets, weeks leads to immunosuppression, taper when normal count for two weeks over 3 to 4 months. can give plasma Ig to fool the spleen somehow, splenectomy, then immunosuppressive drugs like cyclophosphamide or azathioprine or ratuxin (this is the order of these therapies)
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describe pathogenesis of thrombotic thrombocytopenic purpura.
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platelets activate and clump, clots in microcirculation - simillar to DIC. Classic pentad: microangiopathic hemolytic anemia, thrombocytopenia, renal failure, fever, altered mental status.
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how do you distinguish between TTP and DIC?
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TTP will have all normal PT, PTTs, and other coagulation tests. While DIC will have abnormal PT,PTT's fibrin counts etc.
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what adheres the platelet to the damage endothelium? What allows platelets to bind to each other?
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factor 8: von wilibrund factor (VWF) note the platelet is then activated and releases granules (via arachadonic acids) to attract other platelets. Once platelet is activated, the fibrin receptor allows them to bind each other
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H and PE stuff you wanna know for platelet disorders. Lab evaluation?
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fam hx, DRUGS (so many drugs can cause platelet disorders), concomitant diseases (uremia - myeloproliferative disease), petechiae or eccymosis. Platelet count, bleeding time (physical observation not PT etc), platelet aggregation (for rare, weird inborn platelet errors)
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describe what is cleaved when fibrinogen is cleaved to fibrin and the effect this has.
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fibrinogen has peptides A and B on each end which are negatively charged. They push away from other negative fibrinogens. Cleavage allows Ca to bind and thus a positive charge is introduced and now a fibrin mesh can form
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what is a measure of fibrin being digested by plasmin?
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fibrin D dimer in the blood
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only way to test for a factor 13 def?
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urea on the clot, 13 makes the fibrin bonds insoluble, but they still form
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random fact, coagulation is a balancing act of anticoagulation and clotting… this is why we do not get a pulmonary embolus every time we sit with our legs crossed.
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boo ya ka sha
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describe factor V leiden.
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mutation in factor V to where it cannot be degraded by protein C, thus it can lead to a thrombophilia (excessive clotting)
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describe why you give aspirin to prevent heart attacks and warfarin to prevent DVT.
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arterial clotting has more to do with platelets and asprin prevents this while venous clotting is usally due to clotting factors therefore warfarin and other humoral agents against clotting factors are important
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describe the risks associated with clotting in ATIII def, protein C and S def, and factor V leiden.
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ATIII def has like 80% chance so you treat with warfarin. Factor V leiden is low, like 10% at most, so watch it and look for other risks. C and S def is 15 to 20% chance of clot… warfarin has 1 to 2% chance of fatal blled per year, so longterm treatment might be worse than the disease in this case.
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what are the acquired thrombophilic causes and what is the significance in someone with a hypercoaguable disease like protein C and S def?
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lupus, myeloproliferative diseases. Vascular injury, birth control pills, pregnancy, post partum, stasis, smoking ,cancer. If any of these states occur, you may need to prophylactically treat the patient to prevent clotting.
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what effect does ITP have on bleeding time and why?
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it actually decreases it bc the platelets that are not destroyed are young and strong and work harder. Most platelet disorders cause prolonged bleeding times
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inheritied diseases that cause abnormal platelet fxn?
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von willies disease, bernard soullier (adhesion to form giant platelets, Ib receptor def), aggregation defects include glanzmans thrombasthenia (primary - Iib-IIIa receptor defs) and secondary causes - ASA, storage pool disease
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in terms of VWF-VIII, what componenets are needed to get a normal PTT?
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VIIIc (clotting part from liver) bound to VIII-vWF (from subendothelium).
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biochemically what can the platelets to aggregate in circulation in TTP?
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there is a protease called atoms 13 that chews up vWF to make it smaller in circulation so as not to cause clumping, some TTP pts have an Ab against this protease, so the big vWF is circulating and causing platelets to aggregate
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differentiate hemophilia from vW disease based on PTT and bleeding time
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hemo has abnormal PTT only, whereas VW has both abnormal
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what does VIII antigen test look for?
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only VIII-VWF - thus abnormal in vW
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ristocetin aggregation tests for what?
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vW if it is abnormal
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