Heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia


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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 vein 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.

Type I

Occurring in approximately 15% of patients receiving heparin, type I HIT manifests as a transient decrease in platelet count (down to 50% normal) without any further symptoms secondary to platelet sequesteration. Platelet counts recover even if heparin continues to be administered. Platelet counts rarely fall below 100,000. Unlike type II HIT, type I HIT is not due to an auto-immune disorder.

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. [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.]


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 with Antiphospholipid Antibody Syndrome (n=10), or in non-HIT patients (n=78) with both assays. [cite journal |author=Harenberg J, Huhle G, Giese C, Wang L, Feuring M, Song X, Hoffmann U |title=Determination of serotonin release from platelets by enzyme immunoassay in the diagnosis of heparin-induced thrombocytopenia |journal=Br J Haematol |volume=109 |issue=1 |pages=182–6 |year=2000 |pmid=10848798 |doi=10.1046/j.1365-2141.2000.01966.x.]


Treatment is by prompt withdrawal of heparin and replacement with a suitable alternative anticoagulant. To block the thrombotic state, lepirudin, fondaparinux, bivalirudin, argatroban or other direct thrombin inhibitors are used. Danaparoid, a past alternative, is no longer manufactured. 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. [cite journal |author=Hirsh J, Heddle N, Kelton J |title=Treatment of heparin-induced thrombocytopenia: a critical review |journal=Arch Intern Med |volume=164 |issue=4 |pages=361–9 |year=2004 |pmid=14980986 |doi=10.1001/archinte.164.4.361.]


While heparin was introduced for clinical use in the late 1930s, new thrombosis in people treated with heparin was not described until 1957, when vascular surgeons reported the association. [cite journal |author=Weismann RE, Tobin RW |title=Arterial embolism occurring during systemic heparin therapy |journal=AMA Arch Surg |volume=76 |issue=2 |pages=219–25; discussion 225–7 |year=1958 |month=February |pmid=13497418] cite journal |author=Kelton JG, Warkentin TE |title=Heparin-induced thrombocytopenia: a historical perspective |journal=Blood |volume=112 |issue=7 |pages=2607–16 |year=2008 |month=October |pmid=18809774 |doi=10.1182/blood-2008-02-078014 |url=http://bloodjournal.hematologylibrary.org/cgi/content/full/112/7/2607] The fact that this phenomenon occurred together with thrombocytopenia was reported in 1969; prior to this time, platelet counts were not routinely performed. A 1973 report established HIT as a diagnosis, as well as suggesting that its features were the result of an immune process. [cite journal |author=Rhodes GR, Dixon RH, Silver D |title=Heparin induced thrombocytopenia with thrombotic and hemorrhagic manifestations |journal=Surg Gynecol Obstet |volume=136 |issue=3 |pages=409–16 |year=1973 |month=March |pmid=4688805]

Initially, various theories existed about the exact cause of the low platelets in HIT. Gradually, evidence accumulated on the exact underlying mechanism, and diagnostic tests for the condition emerged in the 1980s. Treatment was initially limited to aspirin and warfarin, but the 1990s saw the introduction of a number of agents that could provide anticoagulation without a risk of recurrent HIT.


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