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

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

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

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

Summary - Rivoroxaban Tranexamic Acid Prothrombinex (Most effective) Factor VIIa

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

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

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 minutes) – increases levels of Factor VIII and vWF

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)

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.

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

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

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

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

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.

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 HEMOCLOT thrombin inhibitor test

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

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.

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

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.

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.

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

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 IU/kg Cost is approximately $ per dose!

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

Reversal of Coagulopathy Discontinuation of Warfarin Vitamin K FFP PCC Factor VIIa

Warfarin Discontinuation Warfarin half life is hours Prolonged time for reversal by discontinuation of warfarin alone.

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)

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

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% IU/kg intravenously

Recombinant Factor VIIa Reduction in haematoma growth 6 No reduction in mortality. No improvement in functional outcome.

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

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

Summary - Rivoroxaban Tranexamic Acid Prothrombinex (Most effective) Factor VIIa

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