Anticoagulant therapy

Background Cost

Benefit Complication

External(F7)15s Internal(F12)1 to6minute Result>prothrombin activator

prothrombin(F2)>thrombin>fibrinogen(F1)>fibrin

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 range1.0-0.1u/ml More than 1.ou/ml withACT(hemotec parker-itc

edison medtronic)350-375 secischemic complication at 7days are 34%lower than thy were ACT171-295

Heparin doses70 to 100iu/kg and target act250-350seconds 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

Threatment HITT

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 bleeding Warfarin dosage

INR 3.5-5 Decrease, do not stop drug

INR 5-8 Decrease, consider 1 mg K PO

INR 5-8, bleeding risk high Decrease, give 2.5-5 mg K PO or1 mg SQ

INR > 8 Stop drug, give 2.5-5 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 bleeding Warfarin dosage

INR 2-3.5 Decrease, look for site

INR 3.5-5 Stop drug, reinstitute at lower dose

INR 5-8 Stop drug, give 2.5 mg K PO or 1 mg SQ

INR 5-8, thrombotic risk high Stop 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 bleeding Warfarin dosage

INR 2-3.5 Stop drug, give 5 mg SQ K or IV, repeat as necessary, look for bleeding site

INR 3.5-5 ·          Stop drug, give 5-10 mg K SQ or IV, repeat·          Consider 10-15 mL/kg FFP or 25-50 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 25-50 U/kg PCCs (p. 36)

INR >8 ·          Stop drug, give10 mg K SQ or IV, repeat 6h·          Give 15 mL/kg FFP or 25-50 U/kg PCCs (p. 36)

Managing warfarin overdose

Pitfall in anticoagulant

therapy