Management of bleeding

1. Management of bleeding Andrew McDonald Alberts Cellular Therapy “All bleeding eventually stops”

2. n Modified Virchow’s triad Blood flow Size BP BLEEDING Coagulation Platelets Clotting factors Fibrinolytic system Vessel wall Endothelial activation Collagen disorders Age Corticosteroids

3. n • n

4. n

5. n Thrombin generation LOW [Thrombin] • VIII activation and release from vWF • V activation and release from platelets • Platelet activation • XI activation HIGH [Thrombin] • Fibrin formation • TAFI activation • XIII activation • Protein C activation (with thrombomodulin)

6. n Categories of patients • n • Known “bleeders” • Anticoagulants or anti-platelet agents • Other drugs • Starch vol expanders, cephalosporins • Inherited • Acquired • ITP • Inhibitors • Cirrhosis • Uraemia • Unknown • With bleeding history • Unexpected bleed • Type of bleed: • ACUTE vs CHRONIC • Minor • Major • Admission required •  2 units RBC • Critical organ • Life threatening • ICH • Massive GIT • Airway

7. n Nutrition and bleeding risk • n

8. n Strategies for stopping bleeding Make a better clot Hold on to clot Make a better clot in the first place Tranexamic acid Drug • DDAVP • Oestrogen • Factor 8 concentrate • Activated rVIIa (Novoseven) • PCC (plasma derived – Haemosolvex) • Fibrin glue Transfusion • FFP • Platelets • Cryoprecipitate • [RBC]

9. Clotting factors

10. n • n

11. n Anti-fibrinolytic agents • Tranexamic acid –synthetic lysine analogue • Blocks lysine binding site on plasminogen, preventing activation to plasmin • Oral / mouthwash / IV • Typical dose 1-1.5G 6-8 hourly (range dose 2.5-100mg/kg) • Useful in: • Menorrhagia • Dental extractions • Major surgery – orthopaedic, cardiac, urologic • Bleeding associated with • Mild Haemophilia A and VWD • Platelet disorders • Risk of thrombosis low

12. n DDAVP • Modified analogue of ADH (AVP) • IV formulation (dose 0.3ug/kg/day) • NB tachyphylaxis (25% less effective on day 2) • Oral tabs and low dose nasal spray not effective for haemorrhage • Increases endogenous factor 8 and VWF levels (via V2 receptor) • Useful in mild Haemophilia A and Type 1 VWD • Also useful in platelet derived bleeding • Mild inherited cytopathies • Antiplatelet agents • Mild/mod thrombocytopenia • Contraindicated in known coronary artery disease • Side effect – headache, flushing, hyponatraemia

13. 100 90 80 70 60 Placebo (N=59) Percent of patients (%) 50 NovoSeven® (N=52) 40 P= 0.019 30 20 10 0 ≥ 8 0 5 10 15 20 25 30 35 40 45 50 RBC units within 48 hours rhVIIa (Novoseven) • Registered for bleeding in haemophilia with inhibitors • Used as a general haemostatic in severe life threatening bleeding • Massive trauma • Massive APH / PPH • Cardiac surgery • ICH • Expensive – reimbursement issues • Increased thrombotic events (OR 1.6) • Dose 90ug/kg; not effective in severe acidosis, hypothermia, and low platelets Boffard KD et al. J Trauma 2005;59(1):8-18

14. n Reversal of anticoagulation • All anticoagulants increase bleeding risk • Scoring systems to predict, but bleeding often unpredictable • HAS-BLED score • Hypertension,abnormal kidney/liver, Stroke, Bleeding history, labile INR, Elderly (>65), Drugs/alcohol Risk of bleed OLD NEW Difficulty in reversal

15. n Reversal of anticoagulation Warfarin: Withhold warfarin only: • 2 older case series total 299 pts, with 352 INR values >6 • 2 pts (0.6%) suffered haemorrhage Glover et al 1995 Lousberg et al 1998 • 1104 pts with INR >5 • 30 day incidence of major bleeds low at 1.3% • Subanalysis of 42 pts (4.3%) with INR >9 - incidence major bleeds 9.6% (4pts) - more likely to receive Vitamin K (62% vs 7%) Garcia et al 2006

16. n Reversal of anticoagulation Warfarin: Withhold wafarinand give Vit K: • IV VitK - 2 small studies • 31 pts (10 received 1mg, 21 received 0.5mg IV) • 50% pts with 1mg INR @24h <2, • all ptswith 0.5mg between INR 2 - 5.5 @24h Shetty et al 1992 • Anaphylaxis est. 3 / 10 000 administrations • Oral Vit K 1 – 2.5 mg safe and no risk of warfarin resistance • 7 small studies: less bleeding with Vit K use and more rapid control • 59 pts with mechanical heart valve with INR 6 - 12 • 13/29 vs 4/30 with INR in range @24h with Vit K 1mg vs placebo • 3/29 (10%) with INR <1.8 @24h with Vit K Ageno et al 2005 ORAL > IV > Subcut

17. n Reversal of anticoagulation Warfarin: Urgent reversal • CNS or vital organ haemorrhage • Major bleed (requiring admission, transfusion RBC) • Uncertainty of variable vs fixed dose PCC - Haemosolvex

18. n Reversal of anticoagulation • UFH • Short T1/2 – expectant management possible • Reversal with protamine sulphate 1mg/100IU IV • Max 50mg in 10 min • LMWH • Longer T1/2, but more predictable, less bleeding • Prolonged effect in renal dysfunction • Protamine sulphate 50-70% effective • Dose as above or 0.5-1mg/mg enoxaparin • Fondaparinux • Long T1/2 of 20 hours, longer in renal failure • Protamine not effective • Novoseven ???

19. n Reversal of anticoagulation Dabigetran Rivaroxaban • Anti –Xa • Dose 10mg daily • Tmax 2.5-4h • T1/2 5-9h, 9-13h (elderly) • Daily dose • 66% faecal, 33% renal • PCC / VIIA / FEIBA for bleeding • Assay: anti-Xa • Drug interaction CYP3A4 • Anti-thrombin • Dose 150-200mg • Tmax 2h • T1/2 14-17 h • Daily or BD dose • 80% renal, 20% fecal • No current antidote • Possible dialysis • Assay: Ecarin clotting time • PPI decrease absorption

20. n Reversal of anti-platelet agents

21. n SUMMARY • Chronic bleeding • Lab tests – make a diagnosis • Acute bleed with anticoagulants • Reverse as per guidelines • Acute bleed – unexpected • TEG and lab • Tranexamic acid/DDAVP/FFP