Heparin-Induced Thrombocytopenia

Updated: Nov 22, 2016
  • Author: Sancar Eke, MD, FASN; Chief Editor: Srikanth Nagalla, MBBS, MS, FACP  more...
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Overview

Practice Essentials

Heparin-induced thrombocytopenia (HIT) is a complication of heparin therapy. There are two types of HIT. Type 1 HIT presents within the first 2 days after exposure to heparin, and the platelet count normalizes with continued heparin therapy. Type 1 HIT is a nonimmune disorder that results from the direct effect of heparin on platelet activation. [1, 2]

Type 2 HIT is an immune-mediated disorder that typically occurs 4-10 days after exposure to heparin and has life- and limb-threatening thrombotic complications. [1] In general medical practice, the term HIT refers to type 2 HIT.

HIT must be suspected when a patient who is receiving heparin has a decrease in the platelet count, particularly if the fall is over 50% of the baseline count, even if the platelet count nadir remains above 150 x 109/L. Clinically, HIT may manifest as skin lesions at heparin injection sites or by acute systemic reactions (eg, chills, fever, dyspnea, chest pain) after administration of an intravenous bolus of heparin. [3]

Unlike other forms of thrombocytopenia, HIT is generally not marked by bleeding; instead, venous thromboembolism (eg, deep venous thrombosis, pulmonary embolism) is the most common complication. Less often, arterial thrombosis (eg, myocardial infarction) may occur. For that reason, the disorder is sometimes termed heparin-induced thrombocytopenia and thrombosis (HITT).

Diagnosis of HIT is based on the combination of clinical findings, thrombocytopenia characteristics, and laboratory studies of HIT antibodies. See Workup. Treatment of HIT begins with discontinuation of all heparin products (including heparin flushes of intravenous catheters). The patient should then be started on an alternative anticoagulant. See Treatment and Medication.

For patient education information, see Deep Vein Thrombosis (Blood Clot in the Leg, DVT), Pulmonary Embolism, and Thrombocytopenia.

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Pathophysiology

Heparin-induced thrombocytopenia (HIT) is a prothrombotic disorder caused by antibodies to complexes of platelet factor 4 (PF4) and heparin. [4] Rauova and colleagues reported that heparin and PF4 form stable, ultralarge (>670 kDa) complexes (ULCs) composed of multiple PF4 tetramers arrayed in a lattice with several molecules of unfractionated heparin. Far fewer ULCs were formed when low-molecular weight heparin was used, and none were formed with the factor Xa inhibitor fondaparinux. [5]

Zheng and colleagues reported that healthy humans possess preexisting inactive/tolerant PF4/heparin-specific B cells, and that breakdown of tolerance can lead to production of PF4/heparin-specific antibodies. [4] These HIT antibodies can be found in plasma in more than 90% of patients with the clinical diagnosis of HIT. [4] However, HIT antibodies are also present in many patients (especially patients undergoing cardiac procedures) who have been exposed to heparin but who do not have clinical manifestations of HIT.

The antibodies bind to the PF4-heparin complexes on the platelet surface and induce platelet activation by cross-linking FcγIIA receptors. [6, 7, 8] The activated platelets increase the release and surface expression of PF4, creating a positive feedback loop in which further release of PF4 promotes further platelet activation. [9]

Alternatively, HIT antibodies may recognize PF4 bound to platelet chondroitin sulfate. These antibodies activate platelets even in the absence of heparin, thus explaining delayed-onset HIT, persistent HIT (in which recovery takes several weeks), spontaneous HIT syndrome (which resembles HIT clinically and serologically but occurs without proximate heparin exposure), and fondaparinux-associated HIT. [10]

Platelet activation results in the release of procoagulant platelet microparticles, platelet consumption, and thrombocytopenia. Marked generation of thrombin, activation of monocytes and other inflammatory cells, and endothelial injury and activation follow, producing the characteristic venous and arterial thromboses of HIT.

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Etiology

Heparin-induced thrombocytopenia (HIT) is caused by antibodies that bind to complexes of heparin and platelet factor 4 (PF4), activating the platelets and promoting a prothrombotic state. HIT is more frequently encountered with unfractionated heparin (UFH) than with low molecular weight heparin (LMWH). [11]

The risk of HIT is highest with prolonged use of heparin for postoperative thrombophylaxis. However, case studies have also demonstrated the possibility of developing HIT with minimal heparin exposure via intravascular flushes to maintain the patency of indwelling arterial or venous catheters. [12, 13, 14, 15, 16]

Fondaparinux is a synthetic pentasaccharide that catalyzes the inhibition of factor Xa (but not thrombin) by antithrombin, and thus inhibits thrombin generation. A study suggested that fondaparinux may be associated with formation of anti–PF4/heparin antibodies but, in contrast to LMWH, is unlikely to cause HIT because of the poor reactivity of antibodies against PF4/fondaparinux. [17]

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Epidemiology

In the United States, approximately 12 million individuals, or one third of hospitalized patients, have some heparin exposure yearly. A study by Smythe and colleagues estimated the frequency of heparin-induced thrombocytopenia (HIT) to be 0.76% in patients receiving therapeutic doses of intravenous unfractionated heparin (UFH) and less than 0.1% in patients receiving antithrombotic prophylaxis with subcutaneous UFH, with an overall risk of HIT of about 0.2% in all heparin-exposed patients. [18]

Other studies in the literature quote frequencies as high as 1-5%. [19, 20, 21] High frequencies of HIT are especially common in surgical patients receiving prolonged postoperative thromboprophylaxis (eg, for 10-14 days following orthopedic surgery [22] or after coronary artery bypass and/or valve replacement surgery [18] ).

Mortality/Morbidity

HIT is a severe prothrombotic condition, with affected individuals having a greater than 50% risk of developing new thromboembolic events. [23] The mortality rate is approximately 20%, and approximately 10% of patients require amputations or suffer other major morbidity. [11, 24, 25]

A consecutive study with 108 hospitalized patients diagnosed with HIT showed that thrombotic complications occurred in about 29%. Early, severe falls in platelet counts in elderly patients receiving heparin appear to be associated with the development of thrombotic complications. [24]

Thrombosis associated with HIT can involve the arterial system, the venous system, or both. Thrombotic complications may include deep venous thrombosis, stroke, myocardial infarction, limb ischemia, and, rarely, ischemia of other organs. The thrombotic complications are fatal in about 29% of patients, and an additional 21% have to undergo limb amputations. [26]

Race

A study by Lewis et al reported that white patients had significantly less risk than nonwhite patients for thrombotic events, irrespective of the heparin-induced thrombocytopenia (HIT) presentation. [27] This study showed that nonwhites are approximately 2-3 times more likely than whites to progress to a HIT-associated thrombotic outcome, particularly with regard to new thromboses. [27]

Sex- and age-related differences in risk

Men have significantly less risk than women for thrombotic manifestations in HIT. Women diagnosed with HIT and thrombosis are 1.7 times more likely than men to have a new HIT-associated thrombotic event. [27]

The higher frequency of HIT in females was found most strikingly in patients treated with UHF. There was no relationship between sex and the risk for HIT in patients treated with low molecular weight heparin (LMWH). [28] LMWH in prevention of HIT may have the greatest absolute benefit in females undergoing surgical thromboprophylaxis. [28]

In a retrospective study of 408 patients diagnosed with HIT, 66% of patients were older than 60 years. [29]  Obeng and colleagues, in a retrospective cohort study of 155 patients under 21 years old with sufficient data for 4Ts scoring for HIT, found that the prevalence of HIT was significantly lower in these patients than in adults. [30]

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Prognosis

Until recently, the mortality rate in heparin-induced thrombocytopenia (HIT) has been reported as high as 20%, and a similar percentage of patients survived with major complications, including limb loss or stroke. Recent improvements in early diagnosis and treatment have resulted in a better prognosis, but rates of mortality and major complications of HIT are still as high as 6-10%. [31]

Complications

Possible complications of HIT include the following:

  • Deep venous thrombosis
  • Pulmonary embolism
  • Myocardial infarction
  • Occlusion of limb arteries (possibly resulting in amputation)
  • Transient ischemic attack and stroke
  • Skin necrosis
  • End-organ damage (eg, adrenal, bowel, spleen, gallbladder, or hepatic infarction; renal failure)
  • Death
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