Management of bleeding

Andrew McDonaldAlberts Cellular Therapy

“All bleeding eventually stops”

n Modified Virchow’s triad

BLEEDING

Blood flowSizeBP

Vessel wallEndothelial activation

Collagen disordersAge

Corticosteroids

CoagulationPlatelets

Clotting factorsFibrinolytic system

n

• n

n

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) Liver Cryoppt

Prothrombin (II)

Liver PCC

Factor V Liver (Cryoppt)

Factor VII Liver PCC

Factor VIII Liver Cryoppt Factor 8

Factor IX Liver PCC

Factor X Liver PCC

Factor XI Liver

(Factor XII) Liver

Factor XIII Liver + Megakaryocytes

Cryoppt

vWF Endothelium + Megakaryocytes

Cryoppt Factor 8

n

• n

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 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

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

Perc

ent

of

pati

ents

(%

)

0102030405060708090

100

RBC units within 48 hours 0 5 10 15 20 25 30 35 40 45 50

NovoSeven® (N=52)

Placebo

(N=59)

P= 0.019

≥ 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 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

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 INR @24h <2, – all pts with 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

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 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 ???

Reversal of anticoagulation

n Reversal of anticoagulation

Rivaroxaban Dabigetran

• 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

nDRUG ACTUAL T1/2

EFFECTIVE THERAPY for

BLEED

Aspirin 15-30min 4-5 days DDAVPPlatelet

transfusion

P2Y12 receptor inhibitors: clopidogrel

8h 5-7 days ? DDAVPPlatelet

transfusion

P2Y12 receptor inhibitors: prasugrel

7 hours 5-7 days Platelet transfusion

P2Y12 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