What a Bloody Mess!

1. What a Bloody Mess! A/Professor Kent Robinson Senior Staff Specialist, Liverpool & Campbelltown Hospitals.

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3. Objectives Aspirin and Clopidogrel Warfarin NOAC’s (Newer Oral Anticoagulants) – Dabigatran and Rivoroxaban, Apixaban

4. Summary - Aspirin and Clopidogrel. Platelets, DDAVP Minimal data on effectiveness currently

5. Summary - Dabigatran Consider dialysis Tranexamic Acid PCC’s Factor VIIa FEIBA

6. Summary - Rivoroxaban TranexamicAcid Prothrombinex (Most effective) Factor VIIa

7. Summary - Warfarin Vitamin K slow to reverse INR FFP slow to reverse effect of INR PCC results in rapid reversal of INR

8. Case 1 • 60 year old male • High Speed MVA • Severe lower back pain • HR = 110, BP 90/60, RR 16, GCS 15 • IHD, Stents 8 months ago • Aspirin and Clopidogrel

11. Aspirin • Irreversible acetylation of platelets • Rapid elimination – out of system in 45 minutes • Most centers recommend platelet transfusion (1 unit of pooled platelets) • dDAVP – vasopressin analogue (0.3mcg/kg or 20 mcg in 50 mL NS over 15-30 minutes) – increases levels of Factor VIII and vWF

12. Aspirin • Some centers recommend the use of tranexamic acid (based on reduced bleeding in cardiothoracic literature) • PATCH Study – RCT looking at the effect of platelet transfusion on patients with ICH on aspirin. (Results yet to be published)

13. Clopidogrel (Plavix) Binds ADP receptor preventing platelet aggregation (irreversible effect) Stays in the serum for approximately 8 hours following a dose. Most centers recommend platelet transfusion (2 units of pooled platelets) and the use of dDAVP.

14. Factor VIIa – Aspirin and Clopidogrel • Single study • Reversal of effect in healthy volunteers • Dosage 10-20 mcg/kg • Consider in life threatening bleeding following discussion with hematology.

16. Case 2 • 71 year old female • Abdominal Pain and Malaena • AF, Cerebrovascular Disease • Dabigatran (Pradaxa) • HR 120, BP 70/-, GCS 13

18. Dabigatran (Pradaxa) Direct thrombin inhibitor Fixed dosing ? Reliable plasma levels Minimal interactions ? No monitoring

19. Dabigatran • Rapid onset of action (2-4 hours) • Predominantly renal excretion • Indications • Prevention of VTE in orthopaedic patients • Prevention of stroke in patients with non-valvular AF

20. Dabigatran • Dosage is 150 mg BD • Statistically has lower rates of major bleeding when compared to warfarin. • Rates of ICH – relative risk reduction of 50% compared to warfarin • Slight increase in rates of myocardial infarction (RR 1.35) – not clinically or statistically significant.

21. Dabigatran Check TT or APPT – normal levels exclude the presence of significant levels of dabigatran Short duration of effect (12 hours) At Liverpool ask for a dabigatran level and they will do a HEMOCLOTthrombin inhibitor test

22. Rivoroxaban (Xarelto) • Direct inhibitors of Factor Xa • Half life 5-13 hours • Excreted via renal and hepatic pathways • Rivoroxaban dosage is 20 mg daily • Indications; • Post-op DVT prophylaxis in orthopaedic patients • Prevention of stroke in non-valvular AF • Treatment of DVT and PE

23. Rivoroxaban • Normal PT/ INR levels suggests that levels of rivoroxaban are low • For a test of rivoroxaban or apixaban, ask for an anti-Xa assay.

24. Reversibility of NOAC’s Main concern of NOAC’s is their lack of reversibility.

25. Reversibility of NOAC’s • Haemodialysis is particularly effective in dabigatran toxicity as the drug is poorly protein bound. • A single dialysis procedure will reduce plasma levels by 50% • Consider in patients with severe life threatening haemorrhage or severe renal impairment.

26. NOAC’s & PCC’s • Prothrombinex is a 3-factor concentrate (Factors II, IX and X) • Prothrombinex has greater efficacy against rivoroxaban, with less evidence for use in dabigatran.

27. NOAC’s and rFVIIa • Minor activity as a reversal agent, and should be only used when other therapies have failed. • Dose required for efficacy (100-8000 mcg/kg) is greatly in excess of the usual therapeutic dosing (30-120 mcg/kg) • Cost is approximately $1 per mcg

28. Dabigatran and FEIBA • FEIBA is a humanized monoclonal antibody fragment (Fab) with a 350 fold increase in binding to dabigatran compared to dabigatran binding to native thrombin. • FEIBA dosage 25-100 IU/kg • Cost is approximately $40 000 per dose!

31. Case 3 75 year old female Collapse while gardening GCS E2V2M4 = 8/15 Warfarin for AF

33. Reversal of Coagulopathy • Discontinuation of Warfarin • Vitamin K • FFP • PCC • Factor VIIa

34. Warfarin Discontinuation • Warfarin half life is 36-42 hours • Prolonged time for reversal by discontinuation of warfarin alone.

35. Vitamin K • Give in parenteral form for life threatening bleeding. • Anaphylactoid reaction occurs with oral & parenteral dosing. • Slow to reduce INR levels to normal range (usually 2-6 hours, but up to 24 hours)

36. FFP Average dose to maintain haemostasis is 20 ml/kg Risk of volume overload Slow to reverse anticoagulation – median 30 hours

37. Prothrombin Complex Conjugates - PCC Pooled Plasma Products Factor II, IX, X Rapid reversal – INR normal at 30/60 in 93% patients Haemostatic efficacy good – 98% 25-50 IU/kg intravenously

38. Recombinant Factor VIIa • Reduction in haematoma growth6 • No reduction in mortality. • No improvement in functional outcome.

39. Summary - Aspirin and Clopidogrel. Platelets, DDAVP Minimal data on effectiveness currently

40. Summary – Dabigatran. Consider dialysis Tranexamic Acid PCC’s Factor VIIa FEIBA

41. Summary - Rivoroxaban TranexamicAcid Prothrombinex (Most effective) Factor VIIa

42. Summary - Warfarin Vitamin K slow to reverse INR FFP slow to reverse effect of INR PCC results in rapid reversal of INR

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