Heparin-induced thrombocytopenia

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 unfractionated heparin (UFH), it can also occur with exposure 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. Of note, the rate of DVT (Deep Venous Thrombosis) is roughly 4 times that of arterial thrombosis, and while thrombocytopenia is the most common "event" in HIT, DVT is in fact the most common complication.

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.

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Type I

Patients have a transient decrease in platelet count (down to 50% normal) without any further symptoms. Platelet counts recover even if heparin continues to be administered. Platelet counts rarely fall below 100,000. It occurs in 10-20% of all patients on heparin. Type I HIT is not due to an auto-immune disorder (as Type II is).

Type II

This form is due to an autoimmune reaction where antibodies form against platelet factor 4 (PF4), neutrophil-activating peptide 2 (NAP-2) and/or interleukin 8 (IL-8). These reactive complexes then bind with heparin (heparin-PF4 complex being the most common). Research suggests that when heparin complexes with platelet factor 4, the heparin molecule undergoes a conformational change that renders it antigenic and different antibodies then clear the heparin from the bloodstream. IgG class antibodies are the most commonly found, reactive against heparin, whereas IgM and IgA class antibodies may or may not form. IgM and IgA are rarely found without IgG antibodies. Type II HIT develops in 3-5% of all patients on unfractionated heparin (UFH), and only 0.1% of patients on low molecular weight heparin (LMWH). Arterial and venous thromboses occur in 30% to 40% of patients with type II HIT. The remaining patients seem able to compensate for the activation of hemostasis 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.

Risk for HIT is higher in women than in men, and HIT occurs more commonly in surgical settings rather than non-surgical settings.^[1]

Diagnosis

The sensitivity and specificity of Enzyme Immunoassay-Serotonin Release assay (EIA-SRA) was 100% and 97.4%, respectively and for 14C-SRA was 100% and 92.9% in HITS patients. No false positive results were found in patients receiving heparin (n=28), in patients with elevated levels of bilirubin (n=5), in patients w/ Antiphospholipid Antibody Syndrome (n=10), or in non-HIT patients (n=78) w/ both assays. ^[2]

Treatment

Treatment is by prompt withdrawal of heparin and replacement with a suitable alternative anticoagulant. To block the thrombotic state, lepirudin, fondaparinux, bivalirudin, argatroban, danaparoid or other direct thrombin inhibitors are used. Low molecular weight heparin is contraindicated in HIT.

According to systematic review, patients treated with lepirudin for heparin-induced thrombocytopenia showed a relative risk reduction of clinical outcome (death, amputation, etc.) to be 0.52 and 0.42 when compared to patient controls. In addition, patients treated with argatroban for HIT showed a relative risk reduction of the above clinical outcomes to be 0.20 and 0.18. ^[3]

References

1. ^ Warkentin TE, Sheppard JA, Sigouin CS, Kohlmann T, Eichler P, Greinacher A. Gender imbalance and risk factor interactions in heparin-induced thrombocytopenia. Blood 2006;108:2937-41. PMID 16857993.
2. ^ Harenberg J, Huhle G, Giese C, Wang L, Feuring M, Song X, Hoffmann U (2000). "Determination of serotonin release from platelets by enzyme immunoassay in the diagnosis of heparin-induced thrombocytopenia". Br J Haematol 109 (1): 182-6. PMID 10848798. .
3. ^ Hirsh J, Heddle N, Kelton J (2004). "Treatment of heparin-induced thrombocytopenia: a critical review". Arch Intern Med 164 (4): 361-9. PMID 14980986. .

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