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

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

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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)

n n Categories of patients 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

n n Nutrition and bleeding risk

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

Clotting factors Fibrinogen (I)LiverCryoppt Prothrombin (II) LiverPCC Factor VLiver(Cryoppt) Factor VIILiverPCC Factor VIIILiverCryopptFactor 8 Factor IXLiverPCC Factor XLiverPCC Factor XILiver (Factor XII)Liver Factor XIIILiver + Megakaryocytes Cryoppt vWFEndothelium + Megakaryocytes CryopptFactor 8

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n 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 mg/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 Anti-fibrinolytic agents

n 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 DDAVP

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 Percent of patients (%) RBC units within 48 hours NovoSeven ® (N=52) Placebo (N=59) P= ≥ 8 Boffard KD et al. J Trauma 2005;59(1):8-18

n 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 Reversal of anticoagulation Risk of bleed Difficulty in reversal OLD NEW

n 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 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 Reversal of anticoagulation

n Warfarin: Withhold wafarin and give Vit K: IV Vit K - 2 small studies –31 pts (10 received 1mg, 21 received 0.5mg IV) –50% pts with 1mg <2, –all pts with 0.5mg between INR 2 - Shetty et al 1992 –Anaphylaxis est. 3 / 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 –13/29 vs 4/30 with INR in with Vit K 1mg vs placebo –3/29 (10%) with INR with Vit K Ageno et al 2005 ORAL > IV > Subcut Reversal of anticoagulation

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

n UFH – Short T 1/2 – expectant management possible – Reversal with protamine sulphate 1mg/100IU IV Max 50mg in 10 min LMWH – Longer T 1/2, 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 T 1/2 of 20 hours, longer in renal failure – Protamine not effective – Novoseven ??? Reversal of anticoagulation

n Rivaroxaban Dabigetran Anti –Xa Dose 10mg daily T max 2.5-4h T 1/2 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 mg T max 2h T 1/ h Daily or BD dose 80% renal, 20% fecal No current antidote Possible dialysis Assay: Ecarin clotting time PPI decrease absorption

n DRUGACTUAL T 1/2 EFFECTIVETHERAPY for BLEED Aspirin15-30min4-5 daysDDAVP Platelet transfusion P 2 Y 12 receptor inhibitors: clopidogrel 8h5-7 days? DDAVP Platelet transfusion P 2 Y 12 receptor inhibitors: prasugrel 7 hours5-7 daysPlatelet transfusion P 2 Y 12 receptor inhibitors: ticagrelor 7 hours< 30% effect after 2 days Wait Reversal of anti-platelet agents

n 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 SUMMARY