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240 Cards in this Set
- Front
- Back
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Majority of coag proteins are made in the
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liver
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The end product of coagulation is
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a fibrin clot
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Activation of the coagulation pathway stimulates [dowreg]
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plasminogen activator activity -> fibrinolysis
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What regulates hemostasis?
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vascular endothelium, platlets, coagulation proteins
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Describe vascular hemostasis
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Injury -> vasospasm at site of injury
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Describe platlet activation
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adhesion, aggregation, and release of granule content -> plug
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What is the difference b/t white and red thrombi?
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white is just platlets, red has RBCs
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What causes dissolution of the clot?
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plasmin
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What procoagulant molecules does the vascular endothelium make?
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vWF, tissue factor, plasminogen activator inhibitor
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What anticoagulant moledules does the vascular endothelium make?
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tPA, thrombomodulin
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What platlet inhibitors does the vascular endothelium make?
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prostocylcin, PG2, Nitric oxide
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What clotting factors (proenzymes) does the vascular endothelium make?
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Factors V and VII
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What substances activate platlets?
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collagen, thrombin, ADP, PG1, vWF, Fibrinogen [Platlets Are Very Fat To C]
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What receptor binds platlets to collagen?
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GPIIb/IIIa
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What activates GPIIb/IIIa?
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Ca++, fibrinogen, fibronectin, vitronectin, thrombospondin, vWF
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What do platlets release upon activation?
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adenosine, ADP, Thromboxane A2, platlet-derived growth factor, platlet factor 4, seratonin, histamine, phospholipids, lipoproteins, other coagulation factors.
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What activates the intrinsic pathway?
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Contact b/t blood and exposed epithelial surfaces
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What activates the extrinsic pathway?
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Release of TF 3 from the site of injury
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Describe the intrinsic pathway cascade
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H, 12, 11, 9, 10 [hatin tight butts]
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Describe the extrinsic pathway cascade
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TF, 7, 10 [ToFu CuTS]
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Describe the common pathway cascade
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10,2,1 [also 2, 8]
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Describe the actions of thrombin
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1) converts fibrinogen to fibrin 2) Activates Factor 8 -> crosslinking fibrin 3) Combines w/ thrombomodulin to activate Protein C, which degrades activated Factor 5 and 8 4) increases platlet activation and leukocyte adhesion 5) activates thrombin-activatable fibrinolysis inhibitor (TAFI)
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Describe Antithrombin III
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1) potentiated by heparin 2) inhibits thrombin, 9, 10, 11 and 12.
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What degrades fibrin clots?
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plasmin
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How does plasmin penetrate clots?
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plasminogen binds to fibrin and fibrinogen, and is thus incorperated in the clot as it forms
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Describe tPA
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1) cleaves plasminogen to plasmin 2) inactive form released from vasculature following injury
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What inhibits circulating plasmin?
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a2-antiplasmin
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What inhibits tPA?
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plasminogen activator inhibitor
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What is factor I?
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fibrinogen
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What is factor II?
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prothrombin
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What is factor III?
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tissue factor
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What is factor IV?
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Ca++
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What is factor V?
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labile factor/proaccelerin
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What is factor VI
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unassigned
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What is factor VII
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stable factor/proconvertin
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What is factor VIII?
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antihemophilic factor
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What is factor IX
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plasma thromboplastin component/christmas factor
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What is factor X
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stuart-prower factor
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What is factor XI?
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plasma thromboplastin antecedent
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What is factor XII
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Hageman factor
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What is factor XIII?
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fibrin-stabalizing factor
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What test is most useful for monitoring high-dose heparin anticoagulation?
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ACT
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What is a normal ACT?
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70-180 seconds
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What ACT is necessary for coronary bypass?
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400-500
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What test measures the time it takes the blood to clot?
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PTT
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What is a normal PTT
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30-35 seconds
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What does PTT measure?
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The intrinsic and common pathways
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Is PTT sensitive to the inhibitory effects of heparin on thrombin, Xa and IXa?
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Yes
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What is a normal antifactor Xa assay?
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0
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What is a therapeutic antifactor Xa assay for DVT on heparin?
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0.3-0.7 units/ml
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What is a therapeutic antifactor Xa assay for DVT on LMWH?
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0.4-1.1 units/ml for BID dosing or 1-2 for QD dosing
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What does a bleeding time measure?
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the length of time bleeding continues
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What are normal bleeding times?
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Earlob = 1-4 minutes, forarm = 2-9 minutes
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What is an ideal INR for DVT, MI or Afib?
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2-3
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What is an ideal INR for pts w/ prosthetic heart valves?
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2.5-3.5
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What is a normal platlet count?
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150k-400k
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What is the minimum platlet count for surgery?
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50k
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What is the minimum platlet count for neurosurg?
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75k
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What does PT measure?
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Clotting time from activation of factor 7 to formation of a fibrin clot. Measures the integrity of the extrinsic and common pathways
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What is the lower limit of normal for PT?
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10-14
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What does thrombin time measure?
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clotting time o the last step in the clotting cascade, the conversion of fibrinogen to fibrin by thrombin
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What is thrombin time used to measure?
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Dysfibrinogenemia
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What is thrombin time sensitive to?
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antigoaculants, abnormal fibrinogen
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What is a normal thrombin time?
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<22
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What is thrombelastography?
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Measures the net product of the coagulation and fibrinolytic systems in a graphic record/shape of clot
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Describe heparin
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Large, acidic, sulfated polysaccaride polymer [normally in mast cells]
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Where does heparin come from?
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bovine/porcine lung tissue/mucosa
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What does heparin require
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Antithrombin 3 [it works by potentiating its effect]
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Besides AT3, where else does heparin stop coagulation?
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It binds to vWF, inhibiting vWF-dependent platlet function
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What effect does heparin have on plasma triglycerides?
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It decreases them
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What effect does heparin have on platlet aggregation?
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It intereferes w/ it
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Can heparin be taken PO?
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No, molecule too big, not very lipid soluble
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Where is heparin metabolized?
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In the reticuloendothelial system and liver
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What is the onset of heparin?
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IV: immediated, SQ: 2-4 hours
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What is the t1/2 of heparin
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30-300 minutes
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What increases the t1/2 of heparin?
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large doses, hepatic, renal disease, T < 37
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Is the response-curve of heparin linear?
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No, it is exponential
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What shortens t1/2 of heparin
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PE
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What is heparin dosing for a DVT?
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5000 u q 12
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What is heparin dosing for immediate anticoagulation?
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5000 u plus 1200-1600 u/hr
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What dosing is used for heparin in interventional cardiology?
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100-200 u/kg, repeat doses of 5000-10000 units
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What dose is used for cardiac surgery?
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300-400 u/kg, repeat doses of 5000-10000 units
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What effect does NTG have on heparin dosing?
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requires increased dose
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What hematologic SEs does heparin have?
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thrombocytopenia, HIT
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What bone SEs does heparin have?
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osteopenia [inhibits osteoclast releasing factors]
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What skin SEs does heparin have?
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alopecia
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What causes heparin resistance?
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AT3 deficiency
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What effect does heparin have on the liver?
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Increases hepatic transaminases, but not AlkPhos or Bili
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What effect does heparin have on vasculature
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Vasodilation -> decreased MAP, PAP
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What effect does heparin have on protein binding?
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Displaced propanolol and diazepam
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List indications for heparinization
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PE, DVT, MI, unstable angina, interventional cards, prevention of re-thrombosis, cards/vascular surgery, prevention of thrombus in extracorporeal circut, select cases of DIC, treatment of IUGR
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How is heparin monitored?
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PTT 1.5-2.5 x control [PVT, PE, unstable angina], ACT 200-400 [interventional cards], >400 [cards surg]
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How is heparin reversed?
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Protamine sulfate
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Why does Protamine reverse heparin
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Basic compound, binds to acidic heparin
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How is protamine dosed?
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1-1.3 mg per 100 units heparin remaining
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How fast is protamine's onset
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acs w/in 5 mins
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What are SEs of protamine?
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histamine release [so push slow - 50 mg over 10 mins]
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What is the clearance of protamine?
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reticuloendothelial system w/in 20 minutes
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What risk of allergy is there w/ protamine?
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Pts taking protamine-containing insulin [NPH, protamine zinc], fish allergies
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What is the weight of LMWHs?
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2000-10000 daltons
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How does the mech of act compare b/t heparin and LMWH?
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LMWH has reduced ability to inativate thrombin, but can inactivate Xa
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Why can LMWH be given w/out checking levels?
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Reduced protein binding -> more predictable dose-response
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What is the t1/2 of LMWH?
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4-5 hrs [longer than UFH, d/t less binding in reticuloendothelial system]
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How does LMWH compare to heparin w/ re: HIT?
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Less, d/t decreased binding to platlets and PF4
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How does LMWH compare to heparin re: bone loss
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Less, d/t less binding to osteoblasts
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How is LMWH cleared?
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renal
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What should be checked before LMWH?
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cretinine, platlets
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How is LMWH monitored?
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anti-Xa units (0.5-1 unit/ml)
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Does LMWH effect PTT or PT?
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No
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What is prophylactic dosing for lovenox?
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30 mg BID or 40 QD
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What is regular dosing for lovenox?
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1 mg/kg BID
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What is prophylactic dosing for dalteparin?
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5000 u qd SQ
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What is dalteparin dosing for DVT?
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200u/kg
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What is dalterparin dosing for unstable angina?
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150 u/kg
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What are brands of LMWHs?
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lovenox, dalterparin [fragmin], tinzeparin [innohep], ardeparin [normiflo], nadroparin [fraxiparine], reviparin [vlicarine]
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What reverses LMWH? What is the dose?
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Protamine reverses ~65% of activity; dose=1 mg/mg Lovenox w/in 8 hrs, 0.5 mg/mg lovenox > 8 hrs.
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What is danapriod?
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LMW compound from porcine GI mucosa, w// heparan, dermatan and chronitin sulfrate
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What is the action of danapriod?
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Binds to AT3 -> inhibits thrombin and Xa
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What is the peak of danapriod?
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4-5 hrs
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What is the class of danapriod?
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heparinoids
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How is danapriod cleared?
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renal
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Describe the t1/2 of danapriod?
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Two T1/2: 7 hrs for AT3 effects, 24 hours for Xa effect
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How id danaproid monitored?
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Anti-factor Xa
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What reverses danapriod?
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Nothing
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What is fondaparinux?
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synthetic anticoagulant, binds to AT3 and inhibits Xa
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How is fondaprarinux administered?
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SQ
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What is the T1/2 of fondaprarinux?
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15 hrs
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How is fondaparinux eliminated?
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unchanged, by kidneys
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What is drotercogin alpha?
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recombinant activated protein C. Inactivated 5a and 8a, has anti-inflamatory effects
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What is drotercogin alpha used for?
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severe sepsis
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What is the major side effect of drotercogin alpha?
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bleeding
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Is warfarin a racemix mixture?
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Yes
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How does warfarin work?
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Inhibts the hepatic conversion of Vitamin-K dependent coagulation proteins [2, 7, 9 and 10], and inhibits protein C and S
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How is warfarin absorbed?
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in the gut
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Is warfarin bound?
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99% bound to albumin
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What is the Vd of warfarin?
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Small [0.14 L/kg], simillar to albumin
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When is warfarin's peak plasma?
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2-8 hrs
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What is warfarin's duration of action
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2-5 days
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What is the t1/2 of warfarin?
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40 hrs
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Where is warfarin metabolized/excreted?
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metabolized in liver, extreted in urine or feces
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What is the dosing of warfarin?
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2-10 mg/day PO
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What causes resistance to warfarin [lifestyle]
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excessive VitK intake [may need > 20 mg/day]
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What causes susceptibility to warfarin [genetic]
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10-20% caucasians, 5% AA and asians require < 1.5 mg/day d/t CyP450 variant
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How is warfarin dosing monitored?
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INR [ideal = 2-3]
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How long does it take to acheive therapeutic anticoagulation w/ warfarin?
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2-4 days [overlap 4-5 days w/ heparin]
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What common drug potentiated warfarin?
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tylenol
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What dermal SEs does warfarin have?
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skin necrosis to trunk/thighs d/t venule/capilary thrombosis in SQ tissue; occurs w/in 3-8 days. More common in Pts w/ protein C/S defficiency
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How long does it take for INR to return to normal post warfarin?
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3 days
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How is an INR > 5 w/ warfarin tx'd?
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VitK 5-10 mg PO or IV -> normal INR w/in 12-24 hours
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How is an INR > 20 w/ warfarin tx'd?
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FFP 1-15 ml/kg [2-4 units], supplemented w/ vit K
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What reduces the absorption of warfarin?
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resins
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What effect does nephrotic syndrome have on warfarin?
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decreased pro -> decreased binding
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What increases clearance of warfarin?
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Induction by rifampicin, barbituate of phenytoin
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What decerases clearance of warfarin?
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Amio, flagyl, cimetidine
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What increases the bleeding tendency of warfarin?
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NSAIDs
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What is hirudin?
|
A thrombin inhibitor dericed from leeches which directly inhibits thrombin
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What is lepirudin?
|
recombinant hirudin
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What is the t1/2 of lepirudin?
|
1.3 hrs
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How is lepirudin cleared?
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renal
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How is lepirudin monitored?
|
PTT 1.5-2.5
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What is the reversal agent for lepirudin?
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None
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Whar are SEs of lepirudin?
|
thrombin-lepirudin antibodies -> enhanced anticoagulant effect
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What is bivalirudin?
|
synthetic hirudin
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How is bivalirudin administered?
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IV
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What is the peak of bivalirudin?
|
4 hours
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What is the t/12 of bivalirudin?
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30 mins
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How is bivalirudin monitored?
|
PTT, ACT
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What is the reversal agent for bivalirudin?
|
none
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What is bivalirudin used for?
|
Tx of HIT, combines w/ ASA for pTCA
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What is argatorban?
|
synthetic compound based on l-arginine, binds to thrombin, increases NO release
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What is the T1/2 of argatroban?
|
40-50 mins
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How is argatroban eliminated?
|
metabolized in liver, excreted in bile
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How is argatroban monitored?
|
PTT 1..5 - 3x baseline
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What is argatroban used for?
|
HIT
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What is ximelagratran?
|
Direct thrombin inhibitor
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How is ximelagratran given?
|
PO
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What is the efficacy of ximelagratran?
|
=warfarin
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Does ximelagratran require monitoring?
|
no
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What facilitates platlet aggregation?
|
Thromboxane (Tx), ADP, fibrin and seratonin
|
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What inhibits platlet aggregation?
|
prostacyclin, cAMP
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How does ASA work?
|
Blocks synthesis of TxA2 by blocking COX [inhibited for life of platlet], and prevents the release of ADP from platlets
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Does ASA bind proteins?
|
Yes, albumin
|
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What is the T1/2 of ASA?
|
15 minutes
|
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Does ASA undergo 1st pass metabolism?
|
Yes, extensive
|
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Where is ASA cleared?
|
Liver, plasma, RBCs, excreted in urine
|
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How long before high-risk surgery should ASA be d/c'd?
|
5-7 days
|
|
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What are the SEs of ASA?
|
GI mucosal erosian, decreased renal blood-flow, bleeding
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What is the dose of ASA
|
80-325 mg/day
|
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How is ASA level monitored?
|
Bleeding time
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What is dipryamadole?
|
Decreases platlet adhesion and enhances effect of NO in decreasing platlet aggregation. Increases adenosine, which stimulates adenylate cyclase, increasing cAMP, which inhibits CA++ release, decreases seratonin and ADP
|
|
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Is dipryamadole protein bound?
|
Yes, highly
|
|
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How is diprymadle cleared?
|
hepatic metabolism, metabolites excreted in bile
|
|
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What is the t1/2 of diprymadole?
|
10 hours
|
|
|
What are the indications for dipryamadole?
|
thromboembolism prophylaxi in combination w/ warfarin for prosthetic heart valves
|
|
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What do ADP receptor blockers do?
|
They block the receptor on platlet surface, inhibiting platlet activation, aggregation and degranulation. Irreversible. Given as prodrugs
|
|
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What is ticlopidine?
|
A ADP receptor blocker
|
|
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is ticlopidine highly bound?
|
98% protein bound
|
|
|
When is maximal effect of ticlopidine?
|
8-11 days
|
|
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What is the t1/2 of ticlopidine?
|
8-13 hours, but increases to 4-5 days w/ repeat dosing
|
|
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How is ticlopidine cleared?
|
Metabolized in liver, excreted in urine/feces
|
|
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What are the SEs of ticlopidine?
|
Severe neutropenia, agranulocytosis, thrombocytopenic purpura, bleeding
|
|
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What are the indications of ticlopidine?
|
CVA prophylaxis
|
|
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What is clopidogrel?
|
A ADP receptor inhibitor; similar to ticlopidine, but less thrombocytopenia/leukopenia
|
|
|
What are the SEs of clopidogrel?
|
aplastic anemia, bleeding
|
|
|
What is the dose of clopidogrel?
|
75 mg QD
|
|
|
What are the indicatons for clopidogrel?
|
CVA, MI, stent occlusion
|
|
|
What are GPIIb/IIIa receptor inhibitors
|
block the binding of fibrinogen, vWF and other ligands to platlet receptor
|
|
|
What is abciximab?
|
A fragmet on the monoclonal GPIIb/IIIa receptor antibody
|
|
|
What is the t1/2 and action of abciximab?
|
t1/2 = 30 min, action = 18-24 hrs
|
|
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What is eptifibatide?
|
GPIIb/IIIa inhibitor
|
|
|
What is tirofiban?
|
GPIIb/IIIa inhibitor
|
|
|
How are GPIIb/IIIa inhibitors monitored?
|
ACT 200-400 seconds
|
|
|
What are the indications for GP IIb/IIIa inhibitors?
|
unstable angina, PTCA, coronary stenting
|
|
|
How are GPIIb/IIIa inhibitors reversed for surgery?
|
platlets or cryo
|
|
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What is the indication for thrombolytics?
|
CVA, PE, CV thrombosis
|
|
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What is TPA?
|
increases plasminogen -> plasmin 100x faster, poor plasminogen activator in the absence of fibrin
|
|
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What is the T1/2 of tPA?
|
5-10 mins
|
|
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What is the duration of action of tPA?
|
2-10 mins
|
|
|
Where is tPA metabolized?
|
liver
|
|
|
What are recombinant tPAs?
|
alteplase, reteplase, tenecteplase
|
|
|
What is urokinase?
|
extract from kidney cells, converts fibrin bound plasminogen to plasmin
|
|
|
What is the duration of urokinase?
|
< 20 mins
|
|
|
What is streptokinase
|
Forms complex w/ plasminogen that converts it to a plasminogen activator complex
|
|
|
What is the duration of aciton of streptokinase?
|
20-25 mins
|
|
|
What SEs does streptokinase have?
|
Antibody formation -> decreased effectivenss, or allergic rxn; also not fibrin specific, and can produce generalized thrombolysis
|
|
|
What is anistreplase?
|
Prodrug: streptokinase and recombinant plasminogen. Duration of action = 1-2 hrs
|
|
|
How are thrombolytics monitored?
|
thrombin time
|
|
|
What are the SEs of thrombolytics?
|
bleeding -> tx'd w/ FFP, cryo, platlets, antifibrinolytics
|
|
|
What is aminocaproic acid?
|
inhibitor of plasminogen, blocks interaction of plasmin w/ fibrin, inhibits fibrinolysis
|
|
|
What is the t1/2 of aminocaproic acid?
|
2 hrs
|
|
|
How is aminocaproic acid cleared?
|
renal
|
|
|
What are the indications for aminocaproic acid?
|
hemophiia, bleeding from fibrinolytic therapy, prophylaxis for intercranial aneurism
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What are the SEs for aminocaproic acid?
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intravascular thrombosis
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What is aprotinin?
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antifibrinolytic dervice from bovine lungs, reduces contact and TF activation, inhibits platlets, finbrinolysis and complement.
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What are the SEs of aprotinin?
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anaphylactic rxn, renal/CV toxicity
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What is the t1/2 of aprotinin?
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150 mins
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What is the use of aprotinin?
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peri-operative bleeding
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What lab values does aprotinin change?
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prolongs ACT -> false elevation
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What is desmopressin acetate?
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synthetic vasopressin -> increased factor 8, increases endothelial release of vWF in pts w/ mild hemophilia
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What is the duration of DDAVP?
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8-10 hrs
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