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