Heparin induced thrombocytopenia (HIT)

An immune mediated disorder associated with exposure to heparin and occurs in approximately 2% of all patients exposed to heparin of which approximately 35% develop thrombosis.

Occurs in 0.2-5% of adults treated with heparin.

Incidence of HIT is variable depending upon type and quantity of heparin utilized in the patient’s medical and/or surgical status.

Can be seen in up to 5% of postoperative patients receiving therapeutic/prophylactic doses of unfractionated heparin.

Incidence is as low as 0.6% in nonsurgical patients treated with prophylactic/therapeutic doses of low molecular weight heparin.

Incidence is less than 0.1% in nonsurgical patients treated with heparin flushes.

Microvascular and macrovascular endothelial cell re-modelling occurs in the presence of HIT antibodies and activation of platelets.

HIT antibodies and leukocyte binding deactivates endothelial cells and causes release of tissue factor, PAI-1, cytokines, promoting platelet and monocyte binding to the endothelium.

Heparin on endothelial cells can bind PT4 forming a complex recognized by HIT antibodies.

PT4 recognizes platelet microparticles resulting in thrombosis. 


With exposure to heparin, immunoglobulins IgG antibodies are formed that recognize platelet factor4/ heparin complexes and these IgG/PF-4/heparin complexes bind to the Fc IIa receptors on platelets leading to platelet activation the release of pro-coagulants such as microparticles from platelets resulting in thrombosis.

Caused by platelet-activating immunoglobulin IgG antibodies that recognize complexes of platelet factor 4 (PF4 )to heparin.

Activation by HIT leads to thrombin generation with a hypercoagulable state and inflammation.

Up to 40% of cases occur in post cardiac surgical patients.

Surgical patients have a higher risk of HIT than medical patients.

Up to 3% of patients receiving unfractionated heparin for greater than 5 days will develop an adverse immune reaction.

Fewer than 1% of patients who receive low-molecular weight heparin develop heparin-induced thrombocytopenia.

As few as 1% of medical patients and as many as 5% of orthopedic surgical patients exposed to UFH subcutaneously develop HIT.

Associated with thrombosis in at least 50% of affected patients and thrombosis can involve the veins, arteries or even the microcirculation,

In the presence of a thrombosis discontinuation of heparin, or substitution with warfarin is associated with a subsequent risk for a symptomatic thrombosis of 35-50%, and for sudden fatal thrombosis of approximately 5 percent (Warkentin TE et al, Wallis DE et al.

Implies that all heparin preparations must be discontinued and are contraindicated.

The initiation or maintenance of warfarin therapy during an HIT-associated thrombosis is an important risk factor for microvascular thrombosis (Warkentin TE et al).

During acute HIT unfractionated heparin, low molecular weight heparin and warfarin are contraindicated.

Associated with paradoxical hypercoagulability and venous or arterial thromboses in up to 33-50% of patients.

Thrombosis occurs in most cases after platelet counts diminish by 30-50% of normal.

Risk of thromboembolism persists for up to 30 days after the discontinuance of heparin.

Thrombosis has been reported before platelet counts decline.

Mediated by antibodies targeted against the heparin and platelet factor 4 complex.

Caused by antibodies that recognizes heparin bound to platelet factor 4 on the platelet surface.

The binding of antibodies to heparin-PF4 complex, allows the antibody to bind to the Fc receptor on the platelet.

Activated Fc receptors result in loss of platelets, thrombocytopenia and platelet aggregation.

Immune complexes activate platelets via Fcgamma2 receptors, injure the endothelium and releases tissue factor, and generate platelet-derived phospholipids that support factor Xa and thrombin generation.

Related to the temporary HIT antibody level increase.

As HIT antibodies increase platelet aggregation occurs and a large number of platelets are activated, with a decrease in the number of free circulating platelets in the peripheral blood, and the increased likelihood of developing platelet rich clot formation.

Usually occurs 5 to 10 days after heparin is initiated.

Delay of 5-10 days for the development of thrombocytopenia occurs in patients without previous heparin exposure or who have a remote exposure of more than 100 days, whereas a decline in platelet count may occur in hours in patients with a history of recent exposure and detectable levels of circulating PF4-heparin antibodies.

2 clinical forms: type I benign in nature and characterized by thrombocytopenia that is reversible, and type II which is an immune mediated process with severe complications.

Type I is non immune HIT, benign in nature and affects up to 10% of patients receiving heparin therapy, and is associated with a mechanism of action of direct interaction between heparin in platelets.

In Type I HIT, the platelet count is greater than 100,000 and the mild thrombocytopenia resolves within five days even with continued heparin use, all within two days if the heparin is discontinued.

Asymptomatic patients with type I disease need no specific therapy except stoppage of heparin

Thrombocytopenia is usually moderate.

Thrombocytopenia Is the most common clinical feature, and thrombosis occurs in up to 60% of patients either on the same day when thrombocytopenia develops or even preceding thrombocytopenia.

Thrombocytopenia seldom worse than a count below 100,000 per cubic mm and rarely associated with bleeding.

Up to 10% of patients with HIT do not have thrombocytopenia.

Some patients will have a proportional fall in the platelet count of 30-50% even if the nadir account stays above 150,000/units per micrograms per liter.

Up to 30% of patients may initially present with thrombosis rather than thrombocytopenia.

The lowest platelet counts are reached about five days after the onset of the declining platelet count, and counts begin to rise approximately 2 days after heparin therapy is discontinued returning to normal within 14 days in most patients.

Type II HIT, immune mediated approximately 8% of patients who receive heparin therapy develop antibodies but do not experience thrombocytopenia.

Type II HIT immune mediated, 1-5% of patients receiving heparin develop antibodies and manifest with thrombocytopenia.

Recovery of platelet count may take longer than 14 days in some patients.

Associated with more than 30 times increased thrombotic risk than in control populations.

Risk of thrombosis remains elevated for days to weeks after the cessation of heparin and even after platelet counts recover.

Atypical manifestations of the process can occur and include skin necrosis, venous gangrene of the extremities and anaphylaxis.

Clotting may make amputation necessary and in severe cases can lead to death.

Most common test to detect heparin antibodies is an ELISA-based assay using heparin and platelet factor 4, with 90% sensitivity and specificity.

Elisa test less specific in HIT after coronary artery bypass surgery, with approximately 20% of patients having a positive assay.

Presence of HIT-antibody alone does not necessarily correlate with clinical symptoms and antibodies not associated with clinical symptoms are termed non-functional.

Antibodies typically remain in circulation for 90 days.

Three alternative anticoagulants are lepirudin, danaproid and argatroban.

30-day risk of thrombosis up to 52% in patients managed by discontinuing UFH or LMWH alone, therefore anticoagulation with a direct thrombin inhibitor such as lepirudin or argatroban is indicated.

Leads to enhanced thrombin generation and paradoxical development of new thrombi.

In most patients it is advisable to avoid any future heparin exposure.

Subsequent anticoagulation needs for thrombosis prophylaxis, acute thrombosis treatment may require repeat therapy with direct thrombin inhibitors.

Danaproid drug of choice in pregnancy.

Orthopedic surgery has a higher risk of HIT than many other situations with surgery and heparin exposure.

There are more patients with positive serological assays for HIT without thrombocytopenia than patients with positive serology and thrombocytopenia with or without thrombosis, and such patients have no clinical disease.

About 30-50% of patients have a positive serological test following coronary artery bypass surgery associated with thrombocytopenia, but most do not have thrombosis.

Three non-heparin anticoagulants available for HIT: hirudin, argatroban and danaparoid, and to other anticoagulants fondaparinux, and bivalirudin can be used quotations “off-label” for this process.

The anticoagulants available for HIT are divided into two groups A) long acting, anti-thrombin three-dependent, factor Xa inhibiting oligosaccharides(danaparoid, fondaparinux) and B) short acting anti-thrombin three-independent, thrombin inhibiting agents (hirudin, bivalirudin, argatroban) known as direct thrombin inhibitors.

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