Heparin induced thrombocytopenia
Dr W McMeniman
Unfractionated Heparin - CPB
Reduction in platelet count to 30%
2-3 days post surgery
Short duration followed by thrombocytosis
peaking 14 days post surgery to 2-3 times
baseline level
Cause: Dilution and consumption
Non immunogenic, not associated with
thrombosis or thrombocytopenia
Platelet recovery to baseline at 1 month
Armitage’s Atlas of Clinical Hematology
Ballard J.O. JAMA 1999; 282: 310-312
HIT
IgG antibody mediated
β lymphocytes produce IgG
1-3% develop HIT
5-10 days after continued heparin exposure
Antibody t1/2 80 days
Mortality 30 %
Limb amputation 20%
HIT - Cardiac Surgery
Dilution thrombocytopenia common post
cardiac surgery
80% develop IgG antibodies
1-3% develop HIT if heparin continued beyond
1 week post operatively
Thrombocytopenia seen in 90% of HIT
Greater platelet count fall, greater likelihood of
thrombosis
Biphasic evolution of platelet count with HIT
Heparin Induced Thrombocytopenia and Cardiac Surgery
Warkentin TE, Greinarcher A, Ann Thorac Surg 2003,76:2121-31
Non HIT Causes of
Thrombocytopenia Sepsis
Drug reactions: antibiotics, antiplatelet agents
e.g. tirofiban, non steroidal anti inflammatory
Post transfusion reactions
Tumor related DIC
Pulmonary embolus
Foreign body reactions to IABP or VAD
Dilution post CPB
Thrombosis
Occurs in 40-80% of untreated HIT
Platelet drop of >50% and high IgG
concentration
Major cause of high morbidity and mortality
Arterial: Lower limb, cerebral, myocardial,
spinal, mesenteric and renal
Venous: DVT, pulmonary emboli, upper limb
saphenous vein graft occlusion
Rarely intraatrial or intraventricular
How big is the HIT problem
Antibody +ve HIT +ve
Cardiac Surgery 20-80% 2%
Orthopaedic 8-14% 4%
General Medicine 8-20% <1%
Cardiac Angiography 8-15% 1-3%
Paediatrics & Obstetrics 0-2.3% Rare
Transplantation
Neurosurgery
11%
15%
Immunoassays
Antigen assays
ELISA IgG, IgM and IgA (50-75%)
EIA IgG (55-90%)
Particle Gel Immunoassay (70-80%)
PF4 Enhanced (90-95%)
Optical density readings >1.4 (80-90%)
Platelet Activation Tests
Heparin dependent washed platelets
activation by patient serum (95-99%)
• C-Serotonin release assay with C14 (C-SRA)
• Washed Platelet activation Assay (WP-HIPA)
HIT Clinico-pathological
Diagnosis
Unexplained drop in platelet count by 30-50%
Venous or arterial thrombosis
Skin lesions at heparin injection site
Anaphylactoid reactions
HIT antibodies plus one of
Thrombocytopenia and Thrombosis
4T’S Clinical Predictor
Thrombocytopenia
Level
Timing
Alternate cause
Thrombosis
T Warkentin Annals Thoracic Surgery 2009
Clinical Entity 0 1 2
Thrombocytopenia 30% ↓
<10 x10 9/L
30-50%↓
10 x 209 /L
>50%↓
>20 x109 /L
Timing of
thrombocytopenia
<4 days Indefinite
>10 days
Definite 5-
10 days
Alternative cause of
thrombocytopenia
Definite Uncertain Nil
Apparent
Thrombosis
Skin necrosis
Anaphylactoid
reactions
No evidence Progressive
thrombosis
New
thrombosis
Scores 0-3 4-5 6-8
HIT Probability Low Medium High
Diagnostic Algorithm 4T’s score <3, low pre-test probability of HIT,
continue heparin
4T’S > 3, EIA negative, continue heparin
4T”s >3, EIA positive, do OD
OD<1 weakly positive, confirmatory test of
platelet activation necessary, prophylactic
anticoagulant
OD>1 – 1.4, strongly positive, confirmatory
tests, alternative therapeutic anticoagulant
A. Greinacher J. Thrombosis and Haemostasis 2009
Nisio M, Middeldorp S, et al.
NEJM 2005; 353: 1028-1040
HIT and anticoagulation
Direct thrombin inhibitors:
Bivalirudin Argatroban
Factor Xa inhibitor:
Fondaparinux and Danaparoid
Warfarin
Warfarin
Warfarin can cause gangrene with acute HIT
Depletion protein C system by further vitamin
K depletion - INR 3.5 surrogate marker
Use after recovery of platelet count 100 x109/L
5 days with alternative anticoagulant initially
Only administer vitamin K after commencing
warfarin
Agent Mode of
Excretion
Monitoring Half Life
Bivalirudin Proteolysis,
minor renal
ECT, ACT,
Factor IIa
25-30 min
Argatroban Hepato-biliary APTT, ECT 40-50 min
Lepirudin Renal APPT, ECT,
ACT
80 min
Danaparoid Renal Plasma Anti -
Xa level
18-24 hrs
Fondaparinux Renal Plasma Anti-
Xa level
17-20 hrs
Tirofiban APTT 2 hrs
Ilprost Blood pressure 20-30 min
HIT and Cardiac Surgery
American College of Chest Physicians Evidence
Based Clinical Practice Guidelines
Warkentin TE, Greinacher A, Koster A, Lincoff A.
Chest 2008 133: 340S-380S
HIT and Cardiac Surgery
Delay surgery if possible until:
EIA negative
Platelet activation tests negative
Can then use unfractionated heparin for CPB
β lymphocytes are anamnestic
Emergency HIT positive or with uncertain status:
Off Bypass Procedure
Direct thrombin inhibitors
Factor Xa inhibitors and UHF
Platelet inhibitors and UHF
Nisio M, Middeldorp S, et al.
NEJM 2005;353:1028-1040
Bivalirudin CPB anticoagulation
Bivalirudin Protocol: (Stanford)
Bivalirudin 50 mgs added to CPB prime.
Patient - bolus dose of bivalirudin 2mg/kg with an infusion of 2.75mg/kg/hr on opening the pericardium
Clearance - 80% by enzymatic degradation by thrombin and proteases, 20% by renal excretion
Renal impairment delays clearance, cleared by haemofiltration.
Monitoring: Point of care/Laboratory
Ecarin Clotting Times (ECT)
ACT-HR monitoring. ACT over 600 s.
Anti Factor IIa monitoring
Koster A et.al. Anesthesia & Analgesia
2003;96:383-386
Ecarin Clotting Time monitoring of Bivalirudin
Salemi A. et.al.
Ann Thorac Surg
2011;92:332-334
Activated Clotting Time monitoring of bivalirudin
Evaluation of Bivalirudin
Trial Authors Pt no. Surgery Monitor
Bivalirudin
versus Heparin
with Protamine
Merry A. et al
Ann Thorac
Surg 2004
100
Non
HIT
Off
Pump
CABG
ACT
EVOLUTION-
ON
Dyke M. et al
JTCS 2006
150
Non
HIT
CABG
Valve
ACT
CHOOSE-ON Koster A. et al
Ann Thorac
Surgery 2007
50
HIT
CABG
Valve
ACT
Prevention of blood pooling
Venous resevoir volume limited to 800 ml
Cardiopulmonary bypass circuit components
frequently flushed
The blood cardioplegia circuit was continuously
flushed between doses
Following bypass the venous line blood was
reinfused and the pump contents recirculated
prior to draining to the cell saver for processing
All blood potentially exposed to tissue factor e.g.
surgical field blood, returned to cell saver not
bypass circuit
Antiplatelet Agents plus UFH
47 patients with HIT
Tirofiban (Gp IIb/IIIa inhibitor) 10µg/kg bolus and infusion 0.15µg/kg/min (Restore protocol) followed by Heparin 400 IU/kg
APPT monitoring. Ultrafiltration if renal impairment
No thromboembolism, thrombosis or postoperative bleeding
Koster A, Meyer O, Fischer T, et al. J Thorac Cardiovasc Surg 2001:122:1254-1255
Koster A. Huebler S. Potapov E. Meyer O. et al. Ann Thorac Surg 2007; 83: 72-76
Prostaglandin plus UFH
9 HIT patients with pulmonary hypertension
Iloprost (prostacyclin analog) platelet activation inhibition
Infusion 15ng/kg/min with Heparin 400 IU/kg
No significant thrombosis,thromboembolism or postoperative bleeding.
Koster A. Huebler S. Potapov E. Meyer O. et al. Ann Thorac Surg 2007; 83: 72-76
Antiniou T. Kapetanakis E. Theodoraki K. Heart Surgery Forum 2002; 5: 354-357
Palmer Smith J et al. Anesthesiology; 62:363-365,1985
Conclusion
Emergency cardiac surgery requiring CPB in patients with a diagnosis of HIT requires an alternative anticoagulant to UFH
The anticoagulant must not associated with clot formation or excessive bleeding
Bivalirudin , tirofiban and ilprost have all been used successfully without thrombo embolism, thrombosis or bleeding complication
McMeniman W, Chard R, et al. Heart Lung Circulation 2012;21:295-299
Mannucci P NEJM
2004:351:683-694
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