 Background  Cost  Benefit  Complication

 External(F7)15s  Internal(F12)1 to6minute  Result>prothrombin activator prothrombin(F2)>thrombin>fibrinogen(F1)>fib rin

 Clot formation: fibers+platlet+red cell+plasma  Restrictive clot formation: antithrombin3+thrombin(12_20minute)  Clot retraction: 30to60minute  Clot leases During 24hours TPA release injury endothelium and activated plasminogen>plasmin(fibrinolisin)>leases: Fibrinogen,prothrombin,F5,F7

 Anticoagulant drugs : 1 __ HEPARIN  UFH or LMWH ?

 Heparin(UFH) release from mast cell basophile around capillary and concentration lung and liver  UFH : heterogenus mixture glycosaminoglycant with MW3000 to30,000 only one third is active anticoagulant with bind antithrombin and increase activation 1000X for neutralize troponin and F9,F10,F11,F12

 Half life: dependent dose 25U/kg 30min  100u/kg60min  400u/kg150min  aPTT only sensetive heparin range u/ml  More than 1.ou/ml withACT(hemotec parker-itc edison medtronic) secischemic complication at 7days are 34%lower than thy were ACT  Heparin doses70 to 100iu/kg and target act seconds but with GP2b/3a inhibitor 40-70iu/kg target ACT 200to 250sec

 Low molecular weight hepaarins(LMWH)  Manifactured from UFH withchemical or enzymatic fragment s one third size  Binds less readily to plasma protein, more resistant to neutralization by platelet F4(half life4hours),less effect on platelet function  Relatively selective inactivation factor xa

 Complication:  Bleeding,predispose with increase risk was :age,alcohol,aspirin,,renal failure, serious concurrent illness. LMWH risk more increase in RF  Prothamine sulfat dose not comletly effective in reverse antifactor xa activity inLMWH

 Thrombocytopenia: tow type  Begins 4-14 days exceptions are in patient received heparin the past three month.50% drop in platelet count  Dose depended 15% benign and self limited  Immune form(HIT) paradoxically cause serious arterial and venous thrombosis(HITT) mechanism interaction antibody IgG with complex of heparin and platelet factor4 is released on activation

 Declin inplatlet count in HIT is usually:50;000 to 60,000/mm3  Immune –mediated HIT is not heparin dose dependent even heparin flushes  HIT no single definitive laboratory test(platlet activation assay, serotonin release assay)  When HIT is suspected heparin discotinude but HIT is associated with marked hypercoagulable state with 30to 50% thrombosis in 30 days after diagnosis

 No LMWH because strong cross reaction with HIT  No warfari  Tow direct Thrombin inhibitors :lepirudin and argatroban and pentasacaride fondaparinux(binding platlet factor4)

 2-Warfarin(coumadin)  Vitamin K antagonist Vkh2 is cofactor forF2(prothrombin)F7,F9,F10  Mean plasma half life` 40hours metabolism is affected allelic variant of P450,CYP2C9 homozygous for active alleles with low warfarin dose and high bleeding complication and polimorphism in VK epoxid reductase(VKOR)gene also influence anticoagulant respone  Drugs: propranolol,amiodaron,clofibrate,cimetidine……increase warfarin levels and cholestyramine rifampin …..decreas high VK in diet(nutritional supplement) 

 Loading doses of warfarin should not be used  Because:VK dependent factors have different half life F7 shortest initial increase INR withsevere F& deficiency state while still failing to provide antithrombotic effect.  Reduction in plasma level protein C (VK dependent anticoagulant with shortest HL) Lead to transient paradoxical hypercoagulated state.

No bleedingWarfarin dosage INR 3.5-5Decrease, do not stop drug INR 5-8Decrease, consider 1 mg K PO INR 5-8, bleeding risk highDecrease, give mg K PO or1 mg SQ INR > 8Stop drug, give mg K PO or 2-3 mg SQ INR > 8, bleeding risk high  Stop drug, give 5 mg K PO or 3-5 mg SQ  Consider 10 mL/kg FFP or 25 U/kg PCCs (p. 36) Minor bleedingWarfarin dosage INR 2-3.5Decrease, look for site INR 3.5-5Stop drug, reinstitute at lower dose INR 5-8Stop drug, give 2.5 mg K PO or 1 mg SQ INR 5-8, thrombotic risk highStop drug, do not give K INR > 8  Stop drug, give 5 mg K PO or 2-5 SQ  Consider 10 mL/kg FFP or 25 U/kg PCCs (p. 36) Major bleedingWarfarin dosage INR 2-3.5Stop drug, give 5 mg SQ K or IV, repeat as necessary, look for bleeding site INR  Stop drug, give 5-10 mg K SQ or IV, repeat  Consider mL/kg FFP or U/kg PCCs (p. 36) INR 5-8  Stop drug, give 5-10 mg K SQ or IV, repeat  Give 15 mL/kg FFP or U/kg PCCs (p. 36) INR >8  Stop drug, give10 mg K SQ or IV, repeat 6h  Give 15 mL/kg FFP or U/kg PCCs (p. 36) Managing warfarin overdose

 Pitfall in anticoagulant therapy