Heparin-induced thrombocytopenia (HIT) with or without thrombosis (HITT) is thrombocytopenia (low platelet counts) due to the administration of heparin. While it is mainly associated with unfractioned heparin (UFH), it can also occur with expsoure to low-molecular weight heparin (LMWH), but at significantly lower rates. Despite the low platelet count, it is a thrombotic disorder, with very high rates of thrombosis, in the arteries with or without venous complications.

HIT typically develops 4-14 days after the administration of heparin. Heparin (UFH) is used in cardiovascular surgery, as prevention or treatment for deep-vein thrombosis and pulmonary embolism and in various other clinical scenarios. LMWH is increasingly used in outpatient prophylaxis regimes.

There are two forms of HIT. Type II HIT is the main adverse effect of heparin use.

• Type I - Patients have a transient decrease in platelet count without any further symptoms. This recovers even if heparin is continued to be administered. Platelet counts rarely fall below 100. It occurs in 10-20% of all patients on heparin. It is not due to an immune reaction and antibodies are not found upon investigation.

• Type II - This form is due to an autoimmune reaction with antibodies formed against platelet factor 4 (PF4), neutrophil-activating peptide 2 (NAP-2) and interleukin 8 (IL8) which form complexes with heparin. The most common being to the heparin-PF4 complex. It appears that heparin binding to platelet factor 4 causes a confomational change in the protein, rendering it antigenic. The antibodies found are most commonly of the IgG class with or without IgM and IgA class antibodies. IgM and IgA are rarely found without IgG antibodies. Type II HIT develops in about 3% of all patients on UFH and in 0.1% of patients on LMWH, and causes thrombosis in 30% to 40% of these patients. The other patients are able to compensate for the activation of haemostasis that leads to thrombosis. Clot formation is mainly arterial and rich in platelets ("white clot syndrome"), in contrast with fibrin-rich clots (which are red due to trapped red blood cells). Most thrombotic events are in the lower limbs, skin lesions and necrosis may also occur at the site of the heparin infusion

The most important enzyme in type II HIT is thrombin, the generation of which is increased following platelet activation. Platelet activation follows the binding of heparin to PF4 and the cross linking of receptors on the platelet surface. Genetic risk factors for thrombosis such as factor V Leiden, prothrombin gene mutation, methylenetetrahydrofolate reductase (MTHFR) polymorphism and platelet-receptor polymorphisms do not increase the risk of developing HIT associated thrombosis.

Treatment

Treatment is by prompt withdrawal of heparin and replacement with a suitable alternative anticoagulant. Protamine sulfate, the normal antidote for heparin, is not effective as the antibodies react with platelets independent of heparin. To block the thrombotic state, lepirudin (Refludan®), bivalirudin, argatroban, danaparoid or other direct thrombin inhibitors are used. Low molecular weight heparin is contraindicated in HIT.

External links

• Cleveland clinic page on HIT
• HIT page

Reference

• Kumar, Vinay, Abul Abbas, and Nelson Fausto. Robbins and Cotran Pathologic Basis of Disease, 7th ed. (2005). ISBN 0-7216-0187-1

Hematology

Heparin-induzierte Thrombozytopenie