Heparin-Induced Thrombocytopenia


Heparin-induced thrombocytopenia (HIT) is a complication of heparin therapy. [1]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. [23]

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. [2]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.[4]

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.


Factors that increase the risk for heparin-induced thrombocytopenia (HIT) are as follows:

  • Use of unfractionated heparin (UFH) rather than low molecular weight heparin (LMWH)
  • Intravenous rather than subcutaneous administration of heparin
  • Longer duration of heparin use
  • Surgical (especially cardiac or orthopedic surgery) rather than medical patient
  • Female sex

Clinical features that help distinguish HIT from other forms of thrombocytopenia include the timing of onset and the presence of thrombosis (eg, venous thromboembolism) or other sequelae. In contrast to other drug-induced immune thrombocytopenia syndromes, HIT is generally not associated with bleeding. [34]

Onset of HIT usually occurs 5-14 days after the start of heparin therapy. However, in patients with recent prior heparin exposure (within the past 100 days), persistence of circulating HIT antibodies may result in rapid-onset HIT, in which the platelet count falls within 24 hours of starting heparin. [2]

Onset of HIT may also occur after heparin cessation. Delayed-onset HIT should be considered when a patient presents with thrombosis and unexplained thrombocytopenia up to 3 weeks after the end of heparin therapy. [35]

Physical Examination

Patients with heparin-induced thrombocytopenia (HIT) may present with unusual characteristic sequelae, including the following:

  • Venous limb gangrene
  • Bilateral adrenal hemorrhagic infarction
  • Skin lesions at injection sites
  • Acute systemic reactions following an intravenous heparin bolus

Acute systemic reactions include chills, fever, dyspnea, chest pain, and flushing. [36]Patients with HIT can also present with deep venous thrombosis (DVT) or pulmonary embolism. In patients with DVT who are started on warfarin, severe protein C depletion can develop, leading to warfarin-induced venous limb gangrene and likely loss of the limb. [37Less often, patients may present with arterial thromboembolism (eg, stroke, myocardial infarction)

Heparin-Induced Thrombocytopenia Differential Diagnoses

Diagnostic Considerations4Ts scoreHIT expert probability scoreOther problems to be considered

Diagnosis of heparin-induced thrombocytopenia (HIT) can be challenging, and both underdiagnosis and overdiagnosis pose potential dangers. Failure to diagnose HIT increases the risk of thrombosis, amputation, or death, while misdiagnosis can result in major hemorrhage (in thrombocytopenic patients treated with alternative anticoagulants) or thrombosis (if heparin treatment is suspended unnecessarily). [38]Consequently, pretest scoring systems have been devised to guide diagnosis of HIT.

The 4Ts is a pretest clinical scoring system for HIT that is widely used in clinical practice. [38See the Table below. The title refers to four characteristics of HIT:

  • Thrombocytopenia
  • Timing of thrombocytopenia relative to heparin exposure
  • Thrombosis or other sequelae of HIT
  • Likelihood of other (oTher) causes of thrombocytopenia

A systematic review and meta-analysis by Cuker and colleagues found that a low-probability 4Ts score was a robust means of excluding HIT, with a negative predictive value of 0.998 (95% confidence interval [CI], 0.970-1.000). These researchers proposed that in patients with a low-probability 4Ts score, it may be possible to exclude HIT without further laboratory testing and continue heparin. 

Cuker and colleagues reported that the positive predictive value of an intermediate 4Ts score was 0.14 (95% CI, 0.09-0.22) and that of a high-probability score was 0.64 (95% CI, 0.40-0.82). [38In other studies, the 4Ts model has demonstrated a positive predictive value of 9%–17%. 

Overdiagnosis of HIT in surgical patients with critical illness has been reported. [41A retrospective study in surgical intensive care unit patients by Berry and colleagues found that 8.6 % of patients with low-probability 4Ts scores were positive for HIT on laboratory testing, and 57% of patients with high-probability scores of 6-8 were HIT negative. These researchers concluded that testing or treatment for HIT should not depend on the 4Ts score alone. [42]

The HIT expert probability score (HEP) is a more detailed system developed to improve on the diagnostic utility of the 4Ts score. Testing in a validation cohort showed that the HEP model was 100% sensitive and 60% specific for determining the presence of HIT, and demonstrated better correlation with serologic HIT testing and better interobserver agreement than the 4Ts score. Nevertheless, the researchers cautioned that prospective multicenter validation is warranted

Heparin-Induced Thrombocytopenia Workup

Heparin-induced thrombocytopenia (HIT) has three characteristic features that can distinguish it from other causes of thrombocytopenia. [34First is the timing of the onset of thrombocytopenia; in most patients with HIT, the platelet count decrease begins from days 5 to 14 of heparin treatment. Second, the severity of the thrombocytopenia is usually mild to moderate, with platelet counts only rarely less than 15 x 109/L.

Third is the occurrence of large-vessel venous or arterial thrombosis in association with thrombocytopenia. Thrombosis precedes thrombocytopenia in up to 25% of patients with HIT. [43]

All patients should have baseline platelet counts measured before heparin treatment is started. Guidelines from the American College of Chest Physicians (ACCP) suggest basing further platelet counts on the patient’s risk of HIT. For patients whose risk is considered to be greater than 1% (eg, patients receiving unfractionated heparin after cardiac or orthopedic surgery), the ACCP suggests monitoring the platelet count every 2 or 3 days from days 4-14 of heparin therapy (or until heparin is stopped, whichever comes first). [43]

The ACCP suggests that platelet counts need not be monitored in patients receiving heparin whose risk of HIT is considered to be less than 1%. These include medical patients receiving low molecular weight heparin.

If the platelet count falls by over 50% of the baseline count, even if the nadir remains above 150 x 109/L, and/or a thrombotic event occurs, diagnostic tests should be performed. [43Diagnostic tests for HIT consist of immunoassays and functional assays.

Immunoassays identify antibodies against heparin/platelet factor 4 (PF4) complexes. Functional assays measure the platelet-activating capacity of PF4/heparin-antibody complexes. Functional assays have greater specificity than immunoassays but are time-consuming and not widely available; many institutions offer only immunoassays.

Heparin-Induced Thrombocytopenia Treatment & Management

If heparin-induced thrombocytopenia (HIT) is suspected, the first step is to discontinue all heparin products immediately and avoid any further exposure. An order to simply “discontinue heparin” may not necessarily prevent heparin exposure, because unfractionated heparin (UFH) is commonly used to flush catheters.

Warfarin may cause microthrombosis in patients with HIT. These patients typically present with an international normalized ratio (INR) greater than 4, which corresponds to severe protein C depletion. Initiation of warfarin should be postponed until substantial platelet recovery. Preferably, warfarin should not started before the platelet count exceeds 150 x 109/L. [255If warfarin has already been started, vitamin K should be given. [43]

Platelet transfusions should be avoided in HIT, as they may increase the thrombogenic effect. [55Guidelines from the American College of Chest Physicians (ACCP) suggest limiting platelet transfusions to patients with severe thrombocytopenia who are experiencing bleeding or undergoing an invasive procedure with a high risk of bleeding. [43]

Patients with HIT are at high risk for thrombotic events and should be treated with alternative anticoagulants, typically a direct thrombin inhibitor (DTI). The US Food and Drug Administration (FDA) has approved the DTI argatroban (Acova) for prophylaxis and treatment of thrombosis in patients with HIT. The DTI bivalirudin is approved for use in patients who are undergoing percutaneous coronary intervention (PCI) and have, or are at risk for, HIT or HIT with thrombosis (HITT). The DTI lepirudin was discontinued by the manufacturer in May 2012.

The indirect factor Xa inhibitor fondaparinux (Arixtra) is not approved for use in HIT, but some experts consider it an important treatment option, especially in stable, non–critically ill patients. [5356

Another indirect factor Xa inhibitor, danaparoid, is no longer available in the United States but is used in Canada, Europe, and Australia. The ACCP recommends the use of fondaparinux in pregnant patients with HIT if danaparoid is not available, as this agent does not cross the placenta. [43]

Several novel oral anticoagulants exist (eg, rivaroxaban,dabigatran,apixaban), and preliminary evidence suggests that they may be beneficial for HIT, particularly in cases refractory to standard therapies. [575859However, these agents have not been fully assessed for treatment of patients with HIT and none have FDA approval for use in HIT.

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