Heparin-induced thrombocytopenia (HIT) is a complication of heparin treatment where antibodies form against platelet factor 4-heparin complexes, activating platelets and potentially causing thrombosis. It typically occurs 5-14 days after starting heparin and is treated by discontinuing heparin and using alternative anticoagulants like argatroban. A case example is presented of a woman who developed deep vein thrombosis and arterial thrombosis after gallbladder surgery treated with heparin, and was diagnosed with HIT when her platelets dropped and she tested positive for HIT antibodies.

1. Heparin Induced
Thrombocytopenia
Lyndon Woytuck, BSc, MBBS student

2. 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 days
Type 2 HIT refers to immune mediated, referred to here and in general

3. 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

4. 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

5. 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

6. 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

7. 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)

8. Case example
Oxford 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?

9. 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?

10. 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.

11. 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