drug-induced bleeding
DESCRIPTION
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. - PowerPoint PPT PresentationTRANSCRIPT
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Drug-Induced Bleeding
Christian von Heymann
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Outline
Pharmacology of- unfractionated heparin (UFH)- low molecular weight heparin (LMWH)- danaparoid- hirudin- fondaparinux
Algorithm for treatment of bleeding induced by these drugs
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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
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ThrombinAT 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
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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
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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)
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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
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Unfractionated Heparin (UFH)Algorithm for Suspected Heparin-Induced Bleeding
Baseline monitoring of aPTT and/or ACTTitrate protamine chloride according to the applied dose
of heparinMonitor aPTT and/or ACT closelyTarget 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!
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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
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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
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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
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Low Molecular Weight Heparin Algorithm for Suspected LMWH-Induced Bleeding
Baseline monitoring of anti-Xa-activitySubstitution 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 closelyMain 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!
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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
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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.-InjectionHalf-life: 25 h after i.v.-injectionElimination:
- Mainly renalMonitoring: anti-FXa-activityBarthels M, von Depka M. Gerinnungskompendium : Schnellorientierung, Befundinterpretation, klinische Konsequenzen 2003, 246
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Danaparoid-Inhibition of FXa and Thrombin “Waterfall” Model of Coagulation
FIXa
Thrombin
FXa
FXII FXIIa
FXI FXIa
FIX
FX FVIIa FVII
Extrinsic systemVascular damage promotes
tissue factor (FIII)-expression
Intrinsic system contact with foreign surfaces
FVIII FVIIIa Ca2+
PL
Ca2+
PLFII FIIa FXIIIa
FXIII
Ca2+
Ca2+
Prothrombin
Fibrin-Monomers
Fibrins-Polymers(unstable)
Fibrini-Polymers
(stable)
FIFibrinogen
FVa FV
MacFarlane R Nature 1964; 202: 498
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DanaparoidAlgorithm for Suspected Danaparoid-Induced Bleeding
Baseline monitoring of anti-Xa-activitySubstitution of fresh frozen plasma to restore sufficient
coagulation factor activity (i.e. FI, II, VII, VIII, IX and X)Monitor anti-Xa-activity closelyMain 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!
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LepirudinPharmacology
Polypeptide consisting of 65 amino acids- Molecular weight 7 kDa
Bioavailability: 100% after i.v.-injectionHalf-life: 60-120 minutesElimination: 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
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LepirudinMode of Action
Blocks active site and exosite 2 of thrombin- prevents breakdown of fibrinogen to fibrin monomers
Inhibits circulating and clot-bound thrombinContrary 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
ThrombinThrombinAT III
UFH12 kDa
Hirudin7 kDa
Fibrinogen
Lepirudin molecule
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FIXa
Thrombin
FXa
FXII FXIIa
FXI FXIa
FIX
FX FVIIa FVII
Extrinsic systemVascular damage promotes
tissue factor (FIII)-expression
Intrinsic system contact with foreign surfaces
FVIII FVIIIa Ca2+
PL
Ca2+
PLFII FIIa FXIIIa
FXIII
Ca2+
Ca2+
Prothrombin
Fibrin-Monomers
Fibrins-Polymers(unstable)
Fibrini-Polymers
(stable)
FIFibrinogen
FVa FV
Lepirudin: Inhibition of Thrombinaccording to the “Waterfall” Model of Coagulation
MacFarlane R Nature 1964; 202: 498
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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
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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.-InjectionHalf-life: 17 – 21 hElimination: Unchanged via kidneys
Caution: Renal insufficiency prolongs half-life!
Bauer KA Chest 2003; 124: 364S
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22Olson ST et al. J Biol Chem 1992; 267: 12528
FondaparinuxMode of Action
thrombinprothrombin
fibrinogenfibrinclot
extrinsic system
Intrinsicsystem
3
AT III Xa
1
AT III AT III
2
Fondaparinux
Xa
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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
prothrombinFondaparinux detaches from antithrombin and binds to
another antithrombin moleculeEffect of Fondaparinux is antithrombin-dependentNo specific antidote!
Monitoring: anti-Factor Xa-activity!
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FondaparinuxAlgorithm for Suspected Fondaparinux-Induced Bleeding
Baseline monitoring of anti-Xa-activitySubstitution 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 closelyMain 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!
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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
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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