Heparin-induced thrombocytopenia

Other Names: HIT; Heparin-induced thrombocytopenia Heparin-induced thrombocytopenia (HIT) is an adverse reaction to the drug heparin resulting in an abnormally low amount of platelets (thrombocytopenia). HIT is usually an immune response which typically occurs 4-10 days after exposure to heparin; it can lead to serious complications and be life-threatening. This condition occurs in up to 5% of those who are exposed to heparin. Characteristic signs of HIT are a drop in platelet count of greater than 50% and/or the formation of new blood clots during heparin therapy.

Symptoms

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Autoimmune thrombocytopenia
• Hypercoagulability
• Thromboembolism

30%-79% of people have these symptoms

• Arterial thrombosis(Blood clot in artery)
• Deep venous thrombosis(Blood clot in a deep vein)
• Increased serum serotonin

5%-29% of people have these symptoms

• Cerebral ischemia(Disruption of blood oxygen supply to brain)
• Disseminated intravascular coagulation
• Increased inflammatory response
• Mesenteric venous thrombosis
• Myocardial infarction(Heart attack)
• Pulmonary embolism(Blood clot in artery of lung)
• Stroke

Pathophysiology

HIT is caused by the formation of antibodies that activate platelets following heparin administration.

The principal antigen is a complex of heparin and [[platelet factor 4]] (PF4), a small positively charged molecule of uncertain biological function, normally found in α‐granules of platelets. When heparin binds with PF4, it undergoes a conformational change and becomes immunogenic , leading to the generation of heparin–PF4 antibodies (HIT antibodies), most frequently IgG.The heparin–PF4–IgG multimolecular immune complex then activates platelets via their FcγIIa receptors, causing the release of prothrombotic platelet‐derived microparticles, platelet consumption, and thrombocytopenia. These microparticles in turn promote excessive thrombin generation, frequently resulting in thrombosis. The antigen–antibody complexes also interact with monocytes, leading to tissue factor production, and antibody‐mediated endothelial injury may occur. Both of these latter processes may contribute further to the activation of the coagulation cascade and thrombin generation.

Diagnosis

IT may be suspected if blood tests show a falling platelet count in someone receiving heparin, even if the heparin has already been discontinued. Professional guidelines recommend that people receiving heparin have a complete blood count (which includes a platelet count) on a regular basis while receiving heparin. The diagnosis of HIT remains a clinical one, supported by confirmatory laboratory testing. The criteria for diagnosis of HIT include:

• normal platelet count before the commencement of heparin

• thrombocytopenia defined as a drop in platelet count by 30% to <100×109/l or a drop of >50% from the patient's baseline platelet count

• onset of thrombocytopenia typically 5–10 days after initiation of heparin treatment, which can occur earlier with previous heparin exposure (within 100 days)

• acute thrombotic event

• the exclusion of other causes of thrombocytopenia

• the resolution of thrombocytopenia after cessation of heparin

• HIT antibody seroconversion

However, not all people with a falling platelet count while receiving heparin turn out to have HIT. The timing, severity of the thrombocytopenia, the occurrence of new thrombosis, and the presence of alternative explanations, all determine the likelihood that HIT is present. A commonly used score to predict the likelihood of HIT is the "4 Ts" score. A score of 0–8 points is generated; if the score is 0–3, HIT is unlikely. A score of 4–5 indicates intermediate probability, while a score of 6–8 makes it highly likely. The first screening test in someone suspected of having HIT is aimed at detecting antibodies against heparin-PF4 complexes. This may be with a laboratory test of the enzyme-linked immunosorbent assay type. This ELISA test, however, detects all circulating antibodies that bind heparin-PF4 complexes, and may also falsely identify antibodies that do not cause HIT. Therefore, those with a positive ELISA are tested further with a functional assay. This test uses platelets and serum from the patient; the platelets are washed and mixed with serum and heparin. The sample is then tested for the release of serotonin, a marker of platelet activation.

If this serotonin release assay (SRA) shows high serotonin release, the diagnosis of HIT is confirmed. The SRA test is difficult to perform and is usually only done in regional laboratories.

If someone has been diagnosed with HIT, some recommend routine Doppler sonography of the leg veins to identify deep vein thromboses, as this is very common in HIT.

Treatment

Given the fact that HIT predisposes strongly to new episodes of thrombosis, simply discontinuing the heparin administration is insufficient. Generally, an alternative anticoagulant is needed to suppress the thrombotic tendency while the generation of antibodies stops and the platelet count recovers. Various nonheparin agents are used as alternatives to heparin therapy to provide anticoagulation in those with strongly suspected or proven HIT: danaparoid, fondaparinux, bivalirudin, and argatroban. The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition. Lepirudin (Brand name: Refluden) For anticoagulation in patients with heparin-induced thrombocytopenia and associated thromboembolic disease in order to prevent further thromboembolic complications.

Epidemiology

Up to 8% of patients receiving heparin are at risk to develop HIT antibodies, but only 1–5% on heparin will progress to develop HIT with thrombocytopenia and subsequently one-third of them may suffer from arterial and/or venous thrombosis.

NIH genetic and rare disease info

• NIH info on Heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia is a rare disease.

Heparin-induced thrombocytopenia Resources
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