1. ABC Advanced Bleeding Care Drug-Induced Bleeding Christian von Heymann

2. © TPWG May 2004 ABC Advanced Bleeding Care 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. © TPWG May 2004 ABC Advanced Bleeding Care 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. © TPWG May 2004 ABC Advanced Bleeding Care 4 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 Active site Exosite 1 (Fibrinogen) Exosite 2 (Heparin) Heparin molecule Thrombin

5. © TPWG May 2004 ABC Advanced Bleeding Care 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. © TPWG May 2004 ABC Advanced Bleeding Care 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. © TPWG May 2004 ABC Advanced Bleeding Care 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. © TPWG May 2004 ABC Advanced Bleeding Care 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. © TPWG May 2004 ABC Advanced Bleeding Care 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. © TPWG May 2004 ABC Advanced Bleeding Care 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. © TPWG May 2004 ABC Advanced Bleeding Care 11 Low Molecular Weight Heparin Mode 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. © TPWG May 2004 ABC Advanced Bleeding Care 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. © TPWG May 2004 ABC Advanced Bleeding Care 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. © TPWG May 2004 ABC Advanced Bleeding Care 14 Danaparoid Pharmacology 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. © TPWG May 2004 ABC Advanced Bleeding Care 15 Danaparoid-Inhibition of FXa and Thrombin “Waterfall” Model of Coagulation FIXa Thrombin FXa FXIIFXIIa FXIFXIa FIX FX FVIIaFVII Extrinsic system Vascular damage promotes tissue factor (FIII)-expression Intrinsic system contact with foreign surfaces FVIIIFVIIIa Ca 2+ PL Ca 2+ PL FIIFIIa FXIIIa FXIII Ca 2+ Prothrombin Fibrin- Monomers Fibrin s - Polymers (unstable) Fibrin i - Polymers (stable) FI Fibrinogen FVa FV MacFarlane R Nature 1964; 202: 498

16. © TPWG May 2004 ABC Advanced Bleeding Care 16 Danaparoid Algorithm 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. © TPWG May 2004 ABC Advanced Bleeding Care 17 Lepirudin Pharmacology  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. © TPWG May 2004 ABC Advanced Bleeding Care 18 Lepirudin Mode 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 Kaiser B et al. Thromb Res 1996; 82: 257 Active site Exosite 1 (Fibrinogen) Exosite 2 (Heparin) Heparin molecule Thrombin AT III UFH 12 kDa Hirudin 7 kDa Fibrinogen Lepirudin molecule

19. © TPWG May 2004 ABC Advanced Bleeding Care 19 FIXa Thrombin FXa FXIIFXIIa FXIFXIa FIX FX FVIIaFVII Extrinsic system Vascular damage promotes tissue factor (FIII)-expression Intrinsic system contact with foreign surfaces FVIIIFVIIIa Ca 2+ PL Ca 2+ PL FIIFIIa FXIIIa FXIII Ca 2+ Prothrombin Fibrin- Monomers Fibrin s - Polymers (unstable) Fibrin i - Polymers (stable) FI Fibrinogen FVa FV Lepirudin: Inhibition of Thrombin according to the “Waterfall” Model of Coagulation MacFarlane R Nature 1964; 202: 498

20. © TPWG May 2004 ABC Advanced Bleeding Care 20 Lepirudin Algorithm 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. © TPWG May 2004 ABC Advanced Bleeding Care 21 Fondaparinux Pharmacology  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. © TPWG May 2004 ABC Advanced Bleeding Care 22 Olson ST et al. J Biol Chem 1992; 267: 12528 Fondaparinux Mode of Action thrombin prothrombin fibrinogen fibrin clot extrinsic system Intrinsic system 3 AT III Xa 1 AT III 2 Fondaparinux Xa

23. © TPWG May 2004 ABC Advanced Bleeding Care 23 Fondaparinux Mode 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. © TPWG May 2004 ABC Advanced Bleeding Care 24 Fondaparinux Algorithm 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. © TPWG May 2004 ABC Advanced Bleeding Care 25 Fondaparinux Algorithm 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. © TPWG May 2004 ABC Advanced Bleeding Care 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