Heparin Induced Thrombocytope

niaLyndon Woytuck, BSc, MBBS student

What is HIT? Heparin-induced thrombocytopenia (HIT) is one complication of

administering heparin It is associated with serious venous and arterial thrombosis

(heparin-induced thrombotic thrombocytopenia or HITT). HIT is much less common now than it used to be, due to shorter

dosage courses using low-molecular-weight heparin rather than unfractionated heparin

Rare: 0.2% risk in all heparin exposed patients Typically occurs 5 to 14 days after starting heparin Resolves when heparin is discontinued Heparin-induced thrombosis with thrombocytopenia is

catastrophic 20% mortality, 10% amputation or severe morbidity

Thrombosis is typically white and formed predominantly of platelets and little fibrin

NB: Type 1 HIT refers to non-immune effect of heparin on platelet activation, within 2 daysType 2 HIT refers to immune mediated, referred to here and in general

Pathophysiology HIT occurs when an antibody is developed against

the heparin-platelet factor 4 complex (H-PF4). Antibodies bind to PF4-heparin complexes on the

platelet surface and induce platelet activation by cross-linking Fc receptors

Activated platelets increase release and surface expression of PF4 and create a positive feedback, with further PF4 release and platelet activation

Platelet activation results in procoagulant microparticle release, platelet consumption and thrombocytopenia

Thrombosis results due to generation of thrombin, monocyte activation, endothelial injury and inflammatory cell involvement

Heparin and haemorrhage

Heparin induced thrombosis/thrombocytopenia is rare, but a dramatic complication of heparin therapy

Most common complication of heparin is haemorrhage Greater aPTT increases the likelihood of haemorrhage,

and thus aPTT is used as a gauge to monitor heparin therapy

Haemorrhage may present from structural lesions, such as carcinoma or gastric ulcer. Search for a potential structural source if a patient on

heparin has gastrointestinal, respiratory, or urinary tract bleeding

HIT is not generally associated with bleeding

Signs and symptoms

Skin lesions at injection sites Venous limb gangrene Deep vein thrombosis or pulmonary embolism

Acute systemic reaction after IV admin: chills, fever, dyspnoea, chest pain

Platelet count fall (particularly if over 50% baseline)

Venous thromboembolism is the most common complication

HIT antibodies

Prevention and Treatment of HIT Patients receiving heparin for five days or

greater should be tested for platelet count. Avoid using unfractionated heparin. Other

possible advantages of LMWH include larger and more consistent bioavailabilty, lower risk of exsanguination, and less bone demineralization

Stop heparin if HIT is suspected, and an alternative should be used

Discontinue altogether if anti-coagulation is no longer needed

Heparin substitutes

Warfarin (coumarin family) Anti-thrombotic agents: dextran, ancrod Low-molecular-weight heparinoids: anaparoid (risk of

cross-reaction with heparin-dependent antibody) Antithrombin inhibitors: hirudin (effective, but

monitored with a special assay using ecarin snake venom, due to hirudin’s very high affinity for thrombin)

Synthetic analogues, prepared by recombinant technology or peptide synthesis

Thrombin peptide inhibitor: argatroban (easiest to use, since therapy is monitored with aPTT, similar to heparin)

Case exampleOxford Textbook of Medicine 4th edition

A 38-year-old woman is admitted for gallbladder surgery. Pre-operative coagulation screens and platelet count are normal. Surgery is performed without complication. On the seventh postoperative day, she develops pain and swelling in the right leg, and a contrast venogram confirms the diagnosis of deep vein thrombosis. A bolus of 5000 units of heparin is given followed by infusion of 1000 units/h to maintain the aPTT in the range of 45 to 60s.

On the thirteenth postoperative day, 6 days after starting heparin, she experiences sudden onset of increasing pain in the right arm. The arm is cool and dusky distally and the radial and ulnar pulses are markedly diminished. Her platelet count is 40 000/μl. A transoesophageal echocardiogram demonstrates no evidence of a mural thrombus or akinesis.

Investigations?

Case example

The patient's plasma induces aggregation of normal platelet-rich plasma in the presence of heparin, but not normal plasma does not cause aggregation. The patient’s plasma does not aggregate in the absence of heparin. Her plasma contains heparin-dependent antibodies to platelet factor 4.

Based on these findings, a diagnosis of heparin-induced thrombosis with thrombocytopenia is made.

Treatment?

Case example

Heparin is discontinued. The patient is started on argatroban and on warfarin. A white thrombus is successfully removed from the

right brachial artery by Fogarty catheter. The platelet count improves steadily over the next 10 days.

Following achievement of a therapeutic prothrombin time on warfarin, argatroban is discontinued.

The presence of a recent deep vein thrombosis and the complicating arterial occlusion are indications to continue antithrombotic treatment. She is discharged on warfarin for 3 months with the admonition that she should never again receive heparin.

References

Oxford Textbook of Medicine 4th edition (March 2003): by David A. Warrell (Editor), Timothy M. Cox (Editor), John D. Firth (Editor), Edward J., J R., M.D. Benz (Editor) By Oxford Press

Medscape. “Heparin-Induced Throbocytopenia” Accessed August 12 2015. http://emedicine.medscape.com/article/1357846-clinical#b1