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Drug-Induced Bleeding

Drug-Induced Bleeding. Christian von Heymann. Outline. Pharmacology of unfractionated heparin (UFH) low molecular weight heparin (LMWH) danaparoid hirudin fondaparinux Algorithm for treatment of bleeding induced by these drugs. Unfractionated Heparin (UFH) Pharmacology.

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Drug-Induced Bleeding

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  1. Drug-Induced Bleeding Christian von Heymann

  2. Outline • Pharmacology of • unfractionated heparin (UFH) • low molecular weight heparin (LMWH) • danaparoid • hirudin • fondaparinux • Algorithm for treatment of bleeding induced by these drugs

  3. Unfractionated Heparin (UFH)Pharmacology • Sulfated glycosaminoglycans • Molecular weight 3 – 30 kDa • Active binding site: sequence of five saccharides • Pentasaccharide sequence • Bioavailability: 60% after i.v.-Injection • Half-life: 60 minutes • Elimination: Not completely known • In part: Binding at endothelial surface • In part: Renal and hepatic elimination Barthels M, von Depka M. Gerinnungskompendium : Schnellorientierung, Befundinterpretation, klinische Konsequenzen 2003, 245

  4. Exosite 2 (Heparin) Heparin molecule Active site Exosite 1 (Fibrinogen) Thrombin AT III Unfractionated Heparin (UFH)Mode of Action • Heparin binds to antithrombin • Heparin-antithrombin complex • this catalyzes the formation of thrombin-antithrombin complexes • Heparin binds to thrombin via exosite 2 Thrombin

  5. Unfractionated Heparin (UFH)Mode of Action • Formation of heparin-antithrombin complexes •  heparin increases the affinity of antithrombin to thrombin by a factor of 1000 •  effect of heparin is antithrombin-dependent • Heparin-antithrombin complexes inhibit proteases: • Thrombin (FIIa) and FXa in a 1:1 ratio • FIX, XI and XII • Anticoagulant effect of heparin-antithrombin complex is dose-dependent Rosenberg ED, et al. In Hemostasis and Thrombosis 2001

  6. Unfractionated Heparin (UFH)Monitoring • Activated partial thromboplastin time (aPTT) • Therapeutic level of heparin: 0.5-1.0 IU/ml  2 – 3-fold prolongation of the aPTT Range: 30 – 40 sec (depending on the aPTT reagent used!) • Thrombin time (TT) • Point of care monitoring: • Activated coagulation time (ACT)

  7. Unfractionated Heparin (UFH)Reversal of Heparin Effect • Protamine chloride: • Formation of an inactive protamine-heparin complex • 1 IU of protamine chloride inhibits 1 IU of heparin (1 mg of protamine contains 100 IU) • Cave: overdosage of protamine • Inhibition of fibrin formation • Results in prolonged coagulation time • Increased risk of bleeding

  8. Unfractionated Heparin (UFH)Algorithm for Suspected Heparin-Induced Bleeding • Baseline monitoring of aPTT and/or ACT • Titrate protamine chloride according to the applied dose of heparin • Monitor aPTT and/or ACT closely • Target normalization of aPTT and/or ACT • Avoid excess dose of protamine • If bleeding persists despite normalisation of lab, consider other underlying cause of bleeding (e.g. factor deficiency)! • Keep in mind that bleeding might have a surgical cause and require surgical intervention!

  9. Low Molecular Weight Heparin Pharmacology • Glycosaminoglycans • Molecular weight 4 – 8 kDa • Inhibition of FXa and FIIa • Ratio 2 – 4:1 • Bioavailability: • 100% after s.c.-Injection • Half-life: • 120 – 240 minutes after i.v.-injection • 240 – 480 minutes after s.c.-injection • Elimination: • Mainly renal elimination Weitz JI N Engl J Med 1997; 337: 688

  10. Low Molecular Weight Heparin Mode of action Weitz JI N Engl J Med 1997; 337: 688; Holst J et al.Blood Coagul Fibrinolysis 1994; 5: 795

  11. Low Molecular Weight HeparinMode of Action • Formation of heparin-antithrombin-complexes •  LMW heparin increases the affinity of antithrombin for thrombin by a factor of 1000 •  effect of LMW heparin is antithrombin-dependent • Heparin-antithrombin-complexes inhibit proteases: • FXa and thrombin (FIIa) in a 2 – 4:1 ratio • FIX, XI and XII • Reversal • Protamine chloride inhibits antithrombin activity of LWMH • No specific antidote for anti-FXa-activity! Weitz JI N Engl J Med 1997; 337: 688; Holst J et al.Blood Coagul Fibrinolysis 1994; 5: 795

  12. Low Molecular Weight Heparin Algorithm for Suspected LMWH-Induced Bleeding • Baseline monitoring of anti-Xa-activity • Substitution of fresh frozen plasma to restore sufficient coagulation factor activities (i.e. FI, II, VII, VII and IX) • A single dose of protamine chloride to reduce bleeding might be helpful • No data from the literature! • Monitor anti-Xa-activity closely • Main target: reduction of blood loss • normalization of anti-Xa-activity may be used for monitoring • Always keep in mind that bleeding may have a surgical cause and require surgical intervention!

  13. Low Molecular Weight Heparin Algorithm for Suspected LMWH-Induced Bleeding • If the previously described treatment algorithm fails and life-threatening bleeding persists: • A single bolus of recombinant factor VIIa may be tried, although there are conflicting results in the literature • Plasmapheresis ? (experience from only one case report) Ng HJ et al.Ann Hematol 2003; 82: 257; Chan S et al.J Thromb Haemost 2003; 1: 760; Sabloff M, Wells PS Blood Coagul Fibrinolysis 2000; 11: 395

  14. DanaparoidPharmacology and Monitoring • Glycosaminoglycans • 85% heparan sulfate • Molecular weight 4-10 kDa • Inhibition of FXa and FIIa (ratio 22:1) • Also inhibition of FIXa • Bioavailability: 100% after s.c.-Injection • Half-life: 25 h after i.v.-injection • Elimination: • Mainly renal • Monitoring: anti-FXa-activity Barthels M, von Depka M. Gerinnungskompendium : Schnellorientierung, Befundinterpretation, klinische Konsequenzen 2003, 246

  15. Intrinsic system Extrinsic system contact with foreign surfaces Vascular damage promotes tissue factor(FIII)-expression FXII FXIIa FX FXI FXIa FVIIa FVII FIX FIXa Ca2+ PL FVIII FVIIIa FXa FXIII FV FVa Ca2+ Ca2+ PL FXIIIa FII FIIa Prothrombin Thrombin Ca2+ FIFibrinogen Fibrin- Monomers Fibrins- Polymers (unstable) Fibrini- Polymers (stable) Danaparoid-Inhibition of FXa and Thrombin “Waterfall” Model of Coagulation MacFarlane R Nature 1964; 202: 498

  16. DanaparoidAlgorithm for Suspected Danaparoid-Induced Bleeding • Baseline monitoring of anti-Xa-activity • Substitution of fresh frozen plasma to restore sufficient coagulation factor activity (i.e. FI, II, VII, VIII, IX and X) • Monitor anti-Xa-activity closely • Main target: reduction of blood loss • Normalization of anti-Xa-activity may be used for monitoring • Plasmapheresis in life-threatening bleeding! • No specific antidote! • Always keep in mind that bleeding may have a surgical cause and require surgical intervention!

  17. LepirudinPharmacology • Polypeptide consisting of 65 amino acids • Molecular weight 7 kDa • Bioavailability: 100% after i.v.-injection • Half-life: 60-120 minutes • Elimination: Unchanged via kidneys • No antidote! • Caution: • Renal insufficiency prolongs elimination half-life to 60 h Hafner G et al.J Lab Med 2000; 24: 172; Vanholder R et al.Thromb Haemost 1997; 77: 650

  18. Fibrinogen Exosite 2 (Heparin) Heparin molecule Hirudin 7 kDa Active site Exosite 1 (Fibrinogen) UFH 12 kDa Thrombin AT III Thrombin LepirudinMode of Action • Blocks active site and exosite 2 of thrombin • prevents breakdown of fibrinogen to fibrin monomers • Inhibits circulating and clot-bound thrombin • Contrary to heparin, the effect of lepirudin is not antithrombin-dependent • Inhibition of thrombin-mediated platelet activation Lepirudin molecule Kaiser B et al.Thromb Res 1996; 82: 257

  19. Intrinsic system Extrinsic system contact with foreign surfaces Vascular damage promotes tissue factor(FIII)-expression FXII FXIIa FX FXI FXIa FVIIa FVII FIX FIXa Ca2+ PL FVIII FVIIIa FXa FXIII FV FVa Ca2+ Ca2+ PL FXIIIa FII FIIa Prothrombin Thrombin Ca2+ FIFibrinogen Fibrin- Monomers Fibrins- Polymers (unstable) Fibrini- Polymers (stable) Lepirudin: Inhibition of Thrombinaccording to the “Waterfall” Model of Coagulation MacFarlane R Nature 1964; 202: 498

  20. LepirudinAlgorithm for Suspected Hirudin-Induced Bleeding • Baseline monitoring of aPTT and/or ECT (ecarin clotting time) • Substitution of fresh frozen plasma to restore sufficient thrombin activity • High volume haemodialysis with high flux haemofilters to speed up elimination should be considered even in patients without renal insufficiency • Monitor aPTT and/or ECT closely • Monitoring of platelet function (e.g. platelet function analyzer, PFA-100) may be required • Consider substitution of platelet concentrates • Target normalization of aPTT (e.g. 30 – 40 sec.) and/or ECT (e.g. 40 – 60 sec) according to lab methods used • Always keep in mind that bleeding might have a surgical cause and require surgical intervention! Willey ML et al.Pharmacotherapy 2002; 22: 492

  21. FondaparinuxPharmacology • Consists of five sulfated saccharides which represent active binding site of unfractionated heparin • Pentasaccharide • Molecular weight 1,728 Da • Selective blockade of FXa (not thrombin) • Bioavailability: 100% after s.c.-Injection • Half-life: 17 – 21 h • Elimination: Unchanged via kidneys • Caution: Renal insufficiency prolongs half-life! Bauer KA Chest 2003; 124: 364S

  22. Intrinsic system extrinsic system 1 2 3 Xa Xa AT III AT III AT III Fondaparinux thrombin prothrombin fibrin clot fibrinogen FondaparinuxMode of Action Olson ST et al.J Biol Chem 1992; 267: 12528

  23. FondaparinuxMode of Action • Fondaparinux binds to antithrombin and induces a conformational change • The affinity of antithrombin to Factor Xa is increased • Antithrombin binds to Factor Xa and inhibits activation of prothrombin • Fondaparinux detaches from antithrombin and binds to another antithrombin molecule • Effect of Fondaparinux is antithrombin-dependent • No specific antidote! • Monitoring: anti-Factor Xa-activity!

  24. FondaparinuxAlgorithm for Suspected Fondaparinux-Induced Bleeding • Baseline monitoring of anti-Xa-activity • Substitution of fresh frozen plasma to restore sufficient coagulation factor activities • i.e. FI, II, VII, VII and IX • fibrinogen concentrates might be required • Monitor anti-Factor Xa-activity closely • Main target: reduction of blood loss • normalization of anti-Xa-activity may be used for monitoring • Always keep in mind that bleeding may have a surgical cause and require surgical intervention!

  25. FondaparinuxAlgorithm for Suspected Fondaparinux-Induced Bleeding • If the above described treatment fails and bleeding persists, administration of recombinant factor VIIa might be indicated • Recombinant factor VIIa (90 µg/kg) reversed fondaparinux-induced fibrinolysis and increased thrombin formation time in healthy volunteers Bijsterveld NR et al.Circulation 2002; 106: 2550; Lisman T et al.J Thromb Haemost 2003; 1: 2368

  26. Conclusion • Protamine should be considered in reversing the effect of unfractionated heparin • Protamine might partially reverse the effect of LMWH • rFVIIa should be able to reverse anticoagulation induced by direct thrombin inhibitors • rFVIIa was effective in reversing the anticoagulant effects of Fondaparinux in healthy volunteers • Danaparoid-induced bleeding remains a problem because no antidote is available at the moment

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