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

ABCABCAdvanced Bleeding

Care

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!

© TPWG May 2004


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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


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!

© TPWG May 2004


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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

© TPWG May 2004


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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!

© TPWG May 2004


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FondaparinuxAlgorithm for Suspected Fondaparinux-Induced Bleeding


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!

© TPWG May 2004


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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

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

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Transcript of ABC Advanced Bleeding Care Drug-Induced Bleeding Christian von Heymann.