Management of bleeding
Andrew McDonald
Alberts Cellular Therapy
“All bleeding
eventually stops”
n
Modified Virchow’s triad
Blood flow
Size
BP
BLEEDING
Coagulation
Platelets
Clotting factors
Fibrinolytic system
Vessel wall
Endothelial activation
Collagen disorders
Age
Corticosteroids
n
• n
n
n
Thrombin generation
LOW [Thrombin]
• VIII activation and release from
vWF
HIGH [Thrombin]
• Fibrin formation
• TAFI activation
• V activation and release from
platelets
• Platelet activation
• XI activation
• XIII activation
• Protein C activation (with
thrombomodulin)
n
Categories of patients
•• Known
“bleeders”
n
– Anticoagulants or antiplatelet 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
Strategies for stopping bleeding
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
Clotting factors
Fibrinogen (I)
Liver
Cryoppt
Prothrombin
(II)
Liver
Factor V
Liver
Factor VII
Liver
Factor VIII
Liver
Factor IX
Liver
PCC
Factor X
Liver
PCC
Factor XI
Liver
(Factor XII)
Liver
Factor XIII
Liver +
Megakaryocytes
Cryoppt
vWF
Endothelium +
Megakaryocytes
Cryoppt
PCC
(Cryoppt)
PCC
Cryoppt
Factor 8
Factor 8
n
• n
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
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
rhVIIa (Novoseven)
–
–
–
–
Massive trauma
Massive APH / PPH
Cardiac surgery
ICH
Percent of patients (%)
• Registered for bleeding in haemophilia with inhibitors
• Used as a general haemostatic in severe life threatening bleeding
100
90
80
70
60
50
40
30
20
10
0
≥8 0
P= 0.019
Placebo
NovoSeven®
(N=52)
(N=59)
5 10 15 20 25 30 35 40 45 50
RBC units within 48 hours
Boffard KD et al. J Trauma 2005;59(1):8-18
• Expensive – reimbursement issues
• Increased thrombotic events (OR 1.6)
• Dose 90ug/kg; not effective in severe acidosis, hypothermia, and
low platelets
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
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
n
Reversal of anticoagulation
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
– 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
Shetty et al 1992
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
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 ???
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
n
Reversal of anti-platelet agents
DRUG
ACTUAL T1/2
EFFECTIVE
THERAPY for
BLEED
15-30min
4-5 days
DDAVP
Platelet
transfusion
P2Y12 receptor
inhibitors:
clopidogrel
8h
5-7 days
? DDAVP
Platelet
transfusion
P2Y12 receptor
inhibitors:
prasugrel
7 hours
5-7 days
Platelet
transfusion
P2Y12 receptor
inhibitors:
ticagrelor
7 hours
< 30% effect
after 2 days
Wait
Aspirin
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