DRUGS AFFECTING HEMOSTASIS Flashcards
what is the chemical mechanism by which warfarin inhibits coagulation? what is the time course of the coagulation?
vitamin K is required for the synthesis of clotting factors in liver by adding a carboxy group to precursors. Warfarin inhibits this conversion as it is a vitamin k reductase inhibitor. Because of this inhibition of the synthesis of clotting factors, it doesnt have an immediate effect on clotting and onset time is a function of the half lives of the clotting factors (factor 7 = 6 hours, factor 9 = 24 hours, factor 10 = 36 hours, and factor 2 = 50 hours) –> vitamin K is also associated with the synthesis of anticoagulant factors such as protein c and s (half lives 8 hours and 30 hours respectively)
how would you treat a patient on warfarin who developed a serious intracranial bleed?
fresh frozen plasma or human prothrombin complex would be most appropriate because it contains clotting factors. Vitamin K would reverse effects of warfarin, but it would take days to synthesize sufficient quantities of clotting factors.
what genetic polymorphisms affect warfarin activity?
major factors are vitamin k oxidoreductase - accounts for 30% variability in patient response
CYP2C9 - accounts for 10% variability in patient response
genotyping a patient for these 2 genes makes it easier to find the optimal dose more rapidly, but genotyping alone doesnt accuratelt predict the exact dose, still requires fine tuning of the dose.
what is believed to be the mechanism by which warfarin can cause skin necrosis, and when is it likely to occur?
warfarin also inhibits the natural anticoagulant factors protein c and protein s. Protein c has a short half life, and early in treatment with warfarin there can be a procoagulant effect, and clotting in the skin is responsible for skin necrosis. Consistent with this, it usually occurs early in the course of warfarin anticoagulation.
contrast effects of heparin and warfarin on coagulation. How does this affect the methods by which the anticoagulation is monitored for these two drugs?
heparin has no intrinsic anticoagulant activity and accelerates the rate that antithrombin inhibits various coagulation proteases (thrombin, factor 9a, 10a of intrinsic pathway). The major effect is to increase the aPTT; has less effect on the prothrombin time. High doses of heparin affect platelet aggregation and prolong bleeding time.
warfarin inhibits synthesis of multiple vitamin k dependent clotting factors: 2, 7, 9 and 10, and has a major effect on factor 7 of the extrinsic pathway. Thus, warfarin anticoagulation in monitored by its effect on prothrombin time, which is expressed in the INR of prothrombin time of the patient relative to a standard. Levels of factor 9 or proteins c and s have no effect on INR.
the treatment of DVT usually involves heparin for 3 days until warfarin takes effect. Heparin must be given IV and requires close monitoring. It, therefore, generally requires hospitalization. What is the difference in the mechanism and the major mode of clearance of regular and LMWH and how does this difference make possible to treat with LMWH outside of hospital.
heparin is large and cleared by the reticuloendothelial system (taken up by macrophages) and thus this form of clearance is saturable – a small increase in dose can lead to a large change in the degree of anticoagulation.
LMWH is smaller, and major clearance is renal therefore effects are more predictable. Has more effects on factor 10a with less on thrombin, and LMWH has less effect on aPTT (less useful). Given that its more predictable effect and decreased need for monitoring, LMWH is easier to use and can be used in outpatient settings.
how can heparin lead to hypercoagulabiltiy and thrombocytopenia?
heparin binds to platelet factor 4, patients can develop antibodies that bind to this complex and cause platelet aggregation –> this leads to thrombosis and thrombocytopenia which can cause bleeding.
Once antibodies are cleared which takes about 100 days, if the patient is re-challenged there is no recurrence of thrombocytopenia and if it does recur, it takes long as on initial exposure. Although LMWH can also cause thrombocytopenia the incidence is <1% with LMWH compared to 5% for heparin.
what are rivaroxaban, apixaban, and edoxaban and how do they work? what are the advantages and disadvantages relative to warfarin?
direct factor 10a inhibitors. Advantage is that theyre easier to use (dose response curve is shallower) and risk of under or overcoagulation is less. Associated with less risk of serious bleeds than warfarin, but no reversal agent in case of emergency.
