Anticoagulant Therapy Ischemic Heart Disease Prevent Thrombosis Anticoagulants Antiplatelets Open artery if totally occluded Thrombolysis Coronary angioplasty

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  • Anticoagulant TherapyDeep venous thrombosisPulmonary embolism

  • Coagulation CascadeAntiagoagulant therapy is aimed at: Preventing clot in patients at riskPrevent clot extension/ embolisationDeep venous thrombosis (DVT) & pulmonary embolism (PE)Prothrombinase complex comprises the mixture of FVa/FXa in addition to calcium & phospholipidThe presence of phospholipid accelerates thrombin formation by 780-fold

  • Key Clotting FactorTHROMBIN

  • THROMBIN INHIBITORSThrombin inhibitors can either inactivate thrombin directly or block thrombin formationThrombin can be inhibited irreversibly by glycosaminoglycans like heparin through an antithrombin III-dependent mechanism The enzyme can be inhibited reversibly by hirudin and hirudin derivatives in an antithrombin III-independent mannerIn addition to inhibiting thrombin, the glycosaminoglycans also block thrombin generation

  • Antithrombin-III Dependent Thrombin InhibitorsStandard Unfractionated Heparin (UFH)Heparin is a mixture of glycosaminoglycan molecules, which are heterogenous in molecular size Antithrombin III (ATIII) binding is a necessary requirement for its anticoagulant activityAntithrombin III (ATIII) is a slow endogenous progressive inhibitor of thrombin and other clotting enzymesThe mean molecular weight of heparin is 15,000 D

  • Mode of Action of HeparinHeparin binds to ATIII through a unique pentasaccharide (light blue areas) conformational change in the reactive center of ATIII accelerating the rate of ATIII-mediated inactivation of the clotting enzymesHeparin also promotes the formation of the thrombin-ATIII complex by serving as a template that binds both thrombin and ATIIIATIII forms a 1:1 irreversible complex with the coagulation enzymesOnce this occurs, the heparin dissociates and can be reused

    Heparin

  • Heparin inactivates thrombin by binding both ATIII and thrombinTo inactivate thrombin, heparin serves as a template and binds both anti-thrombin III (ATIII) and thrombinBinding to ATIII is mediated by the unique penta-saccharide sequence on heparin Binding to thrombin occurs through the heparin-binding domain on the enzyme Conversely, to inactivate factor Xa, heparin needs only to bind to ATIII through its pentasaccharide sequenceAnti-IIa = Anti-Xa activity

  • Targets for Heparin-ATIII ComplexHeparin/ATIII inactivates several coagulation enzymes including thrombin (factor IIa) and factors Xa, IXa, & XIaThe enzyme most sensitive to inhibition is factor IIa The next most sensitive enzyme is factor XaBy inhibiting these two enzymes heparin inhibits both thrombin activity & thrombin formation

  • Limitations to the Use of Heparin

  • Low Molecular Weight Heparins (LMWHs)Low molecular weight heparins (mean molecular weight 5000 D), prepared by controlled chemical or enzymatic depolymerization of standard unfractionated heparin are about one third the size of starting materialWhereas about one third of the molecules of unfractionated heparin have the unique antithrombin III (ATIII)-binding pentasaccharide, only about 20% of LMWH chains contain the pentasaccharideEnoxaparin, dalteparin & tinzaparin are available LMWHs products

  • Mechanism of Action of Low Molecular Weight Heparin (LMWH)All LMWH molecules, which contain the unique pentasaccharide, can catalyze the inactivation of factor Xa by anti-thrombin III (ATIII)In contrast, only 25% to 50% of LMWH molecules that have the pentasaccharide sequence are long enough to interact with both ATIII & thrombinAs a result, the antithrombin (anti-factor IIa) activity of LMWH is less than its anti-factor Xa activityStandard heparin has equivalent anti-factor IIa and anti-factor Xa activity because all of the heparin chains that contain the pentasaccharide are long enough to interact with both ATIII & thrombin

  • Pharmacokinetic Profile of LMWHLMWH has a more favorable pharmacokinetic profile than standard heparin because LMWH exhibits less binding to plasma proteins & cell surfacesThe reduced binding to plasma proteins results inBetter bioavailability (90% vs. 20% for heparin)more predictable anticoagulant response Laboratory monitoring of LMWH activity is not required Heparin resistance is rare for LMWHThe reduced binding of LMWH to cell surfaces explains why it has a longer half-life than heparin (4 hr vs. 2 hr for heparin, for IV route) Given at fixed doses once to twice daily by S.C. route, in- & out-hospital

  • Biophysical Limitations of Heparin and LMWHBoth heparin and low molecular weight heparin preparations have biophysical limitations because they are unable to inactivate thrombin bound to fibrin, or to subendothelial matrix and to inhibit factor Xa within the prothrombinase complexThrombin binds to fibrin where it remains catalytically active Thrombin bound to fibrin is protected from inactivation by heparin/antithrombin III

  • Other Injectable Antithrombotic AgentsFondaparinux, a pentasaccharide, is an AT-III-dependent selective factor Xa inhibitorIt is indicated for the prevention of venous thrombosis associated with orthopedic surgeryAdministered >6 hours postoperatively and dose adjusted for renal impairment Tests for Monitoring Antithrombotic TherapyProthrombin time (PT)/International Normalization Ratio (INR), usual target is 2-3 times normalActivated partial thromboplastin time (aPTT)- (serum UFH)Anti-Xa activity for LMWHs-treatment in cases of unexpected bleeding & pregnant women

  • Therapeutic UsesHeparin should be given either by IV or S.C. injection with onset of action of few minutes and 1-2 hr respectivelyLMWHs is given by S.C. routeI.M. injection produces hematoma formationTreatment of deep-vein thrombosis Treatment of pulmonary embolismPrevention of postoperative venous thrombosis in patients in acute MI phase or one undergoing elective surgeryReduction of coronary artery thrombosis after thrombolytic treatmentAnticoagulant of choice in pregnant women

  • Adverse EffectsBleeding: Bleeding time monitoring is essential, less with LMWHsTreatment involves injection of antidote protamine sulphate (1mg Iv for each 100 units of UFH) (reversal of effect)Thrombosis: AT-III inactivation may lead to potent activation of many clotting factors & hence paradoxically increasing thrombosis riskThrombocytopenia: UFH-induced thrombocytopenia (HIT) is a life-threatening immune reaction that occurs in up to 3% of patients on heparin therapy for 5-14 daysIt induces platelet activation & endothelial damage with enhanced thrombi formation & paradoxical thrombosis A non-immunologic reversible HIT may occur in early phase of therapy due to direct effect of UFH on plateletsLMWHs, though of lower risk, are contraindicated with HIT

  • Adverse EffectsOsteoporosis occurs with large doses of UFH >20,000 U/day for 6 months or longerHyperkalemia rarely occurs with UFHIt is attributed to inhibition of aldostetone secretionIt occurs with both low- & high-dose UFH therapyOnset is quick within a week after therapy initiationIt is reversible by therapy discontinuationDiabetic & renal failure patients are at higher riskHypersensitivity: (Antigenicity due to animal source)rarely occurring reactions include urticaria, rash, rhinitis, angioedema & reversible alopecia

  • ContraindicationsHypersensitivity to heparinActive bleeding or hemophiliaSignificant throbocytopenia, purpuraSevere hypertensionIntracranial hemorrhageUlcerative GIT lesionsActive TBRecent surgery in CNS, eyeAdvanced hepatic or renal disease

  • Direct Thrombin InhibitorsHirudin Hirugen & HirlugA, HirudinA leech-derived protein, a potent & specific inhibitor of thrombinIt binds to both the substrate recognition site and the catalytic center. The hirudin-thrombin complex slowly dissociatesB, Hirugen A synthetic peptide analogue of the carboxy terminal of hirudin It binds to the substrate recognition site of thrombin

  • Direct Thrombin Inhibitors (DTI)C, Hirulog is a synthetic bivalent inhibitor of thrombin comprised of a catalytic site inhibitor linked to hirugen. Thus, hirulog interacts with both the substrate recognition site and the catalytic center of thrombin. D, Catalytic site inhibitors interact with the active center of thrombin

  • Inhibition of Bound ThrombinNeither heparin/ATIII nor LMWH/ATIII are an effective inhibitor of fibrin-bound thrombin because the heparin-binding site on thrombin is masked when the enzyme is bound to fibrinIn contrast, the ATIII-independent thrombin inhibitors are able to inactivate fibrin-bound thrombin as well as free thrombin

  • In vivo studies with direct thrombin inhibitorsIn experimental animals, hirudin, hirulog, and inhibitors of the catalytic site of thrombin are more effective than heparin in preventing extension of venous thrombosis, preventing platelet-dependent arterial thrombosis, and accelerating thrombolysisPreliminary studies in humans also suggest that the direct thrombin inhibitors are more effective than heparin in venous thrombosis, in unstable angina, and in the setting of thrombolytic therapy

  • Clinically Approved Direct Thrombin InhibitorsLepirudin, recombinant hirudin-like peptide, has been approved for IV anticoagulant use in HIT patients, has renal clearanceIt has potential use in unstable angina patients (Circulation 2001; 103: 1479)Bivaluridin, a bivalent DTI, used by IV route for patients undergoing percutaneous coronary interventionArgatroban, a small monovalent (thrombin active site only) molecule, with DTI activity, used similarly in HIT patients, has hepatic clearanceaPTT is used to monitor activity for these agents

  • DIRECT FACTOR Xa INHIBITORS There are two direct factor Xa inhibitors, the tick anticoagulant peptide (TAP