By Kathryn Radigan, MD, MSc
Attending Physician, Division of Pulmonary and Critical Care, Stroger Hospital of Cook County, Chicago
Dr. Radigan reports no financial relationships relevant to this field of study.
Heparin-induced thrombocytopenia (HIT) is a life-threatening, heparin-mediated, prothrombotic disorder caused by antibodies directed to complexes containing heparin and an endogenous platelet protein, platelet factor 4 (PF4).1 Approximately 12 million patients are exposed to heparin each year in the United States.2 Depending on the type of heparin, the duration of exposure, and the patient population, the incidence of HIT among those exposed ranges from < 0.1% to 7%.3 Risk factors include surgical patients, exposure to unfractionated heparin (UFH) as opposed to low-molecular weight heparin (LMWH), use of therapeutic heparin as opposed to prophylactic heparin, and female sex.4 Although patients with HIT are thrombocytopenic, bleeding is rare, with some studies showing a bleeding incidence of 6%.5 Since the antibody that activates platelets can cause catastrophic arterial and venous thrombosis in one-third to one-half of cases, recognition, timely diagnosis, and treatment are crucial.6,7
An autoantibody against PF4, after complex formation with heparin, induces platelet activation by cross-linking FcγIIA receptors.6 Activated platelets increase both the release and surface expression of PF4, creating a positive feedback loop that stimulates further platelet activation. Thrombocytopenia occurs by way of removal of IgG-coated platelets by macrophages within the reticuloendothelial system and consumption of platelets caused by thrombosis. Platelet activation not only is accompanied by intense thrombin generation, but also occurs through intracellular signaling involving the spleen tyrosine kinase and the release of procoagulant microparticles, placing the patient at increased risk of thrombosis.
Types of HIT
Although there are two types of HIT, only HIT type II is of clinical significance with substantial clinical consequences.6 Differentiation between HIT types I and II is based on clinical parameters. Type I typically is described as a transient drop in platelet count within the first two days of heparin exposure due to non-immune platelet aggregation, and the platelet count recovers without discontinuation of heparin. The platelet count nadir typically is around 100,000 platelets per microliter. HIT type II typically presents with a more dramatic, persistent drop in platelet count due to antibodies that form in response to PF4 complexed to heparin. The “HIT antibodies” may cause thrombosis in addition to thrombocytopenia or the syndrome of heparin-induced thrombocytopenia and thrombosis (HITT). Other HIT variants include delayed-onset HIT (HIT occurring more than five days after heparin withdrawal), refractory HIT (persistent thrombocytopenia or thrombosis that lasts for weeks after heparin has been removed), and spontaneous HIT (HIT in the absence of heparin exposure).8 The exact cause of spontaneous HIT is unclear, but it may be related to exposure to a heparin-like proteoglycan, such as chondroitin sulfate, during surgery and/or it may be the result of proinflammatory events seen especially in postsurgical patients.9
Phases of HIT
HIT may be classified with respect to clinical presentation. Descriptors include suspected HIT, acute HIT, subacute HIT A and B, and remote HIT.10 Suspected HIT is appropriate nomenclature when suspicion is high and thrombocytopenia is noted but heparin-PF4 assays are not yet available. Acute HIT is appropriate when thrombocytopenia is present and testing for heparin-PF4 antibodies (either the functional assay and/or immunoassay) is positive. Subacute HIT A may be used when thrombocytopenia has resolved, but HIT antibodies remain (functional and immunoassays are positive). Subacute HIT B is appropriate when thrombocytopenia has resolved with a negative functional assay, but immunoassays continue to be positive. The term remote HIT may be used with a prior history of HIT, but current assays are negative and no thrombocytopenia is noted.
Screening of Asymptomatic Patients
The American Society of Hematology (ASH) guidelines have recommended regular screening of patients receiving heparin who are at intermediate (0.1-1.0%) or high (> 1.0%) risk of developing HIT.3 Surgical and trauma patients receiving postoperative UFH are high-risk patients.11 Medical and obstetrical patients receiving UFH and patients receiving LMWH after major surgery or trauma are intermediate-risk patients. Low-risk patients (those who do not need monitoring of platelets) include medical or obstetrical patients receiving LMWH, patients receiving LMWH after minor surgery or minor trauma, or those receiving fondaparinux. For patients with previous exposure to heparin within 30 days of reinitiating heparin, the ASH guidelines suggest screening for HIT on the day that heparin is initiated.3 For those with no previous exposure, screening should occur from day 4 until day 14 after initial heparin exposure or until discontinuation of the heparin product. Every-other-day screening is recommended in high-risk patients, and screening every two to three days is recommended in intermediate-risk patients.
Typically, the platelet count falls more than half, with a nadir between 50 to 80 × 109/L and may occur with catastrophic arterial and venous thrombosis.12 In one study that examined the timing in greater detail, 70% of HIT patients experienced a fall in platelets four or more days after the start of heparin therapy.13 In these patients, a history of previous heparin exposure did not influence the timing of the thrombocytopenia. In 30% of patients, the onset of the thrombo-cytopenia was rapid, with a median time of onset approximately 10.5 hours after the start of heparin. All of these patients had been treated with heparin within the prior 100 days.
The probability of HIT in an ICU patient should be estimated using the 4Ts score (Thrombocytopenia, Timing, Thrombosis, and oThers).14 Guidelines recommend against using a gestalt approach to the diagnosis.3 A presumptive diagnosis of HIT is based solely on clinical findings and platelet counts until laboratory results are available. It is imperative to obtain accurate and complete information for the 4Ts score; incomplete information may lead to an inaccurate assessment of risk. If information is missing, it is recommended to err on the side of a higher 4Ts scores. In patients with suspected HIT and a low-probability 4Ts score, the ASH guidelines recommend against both further laboratory testing and empiric treatment.3 In patients with intermediate- or high-risk 4Ts scores, discontinuation of heparin and treatment with non-heparin anticoagulants is important while a further workup proceeds.
Immunoassays, which detect PF4/heparin IgG antibodies, are quite sensitive (> 95%) and often are available within most institutions for a rapid turnaround time, but they have poor specificity.15 The solid-phase ELISA is the most widely available test. If a patient has an intermediate or high probability 4Ts score, the ASH guidelines recommend an immunoassay with a follow-up functional assay if the immunoassay is positive and a functional assay is available.3 Often the ELISA is reported as positive or negative, but it is important to know the optical density (OD) as well. A higher OD represents a higher titer of antibody in the patient’s serum.
If an ELISA OD is less than 0.60, HIT typically is excluded.16 In this setting, functional HIT antibody testing is not necessary unless the clinical picture changes or the clinical picture is discordant. This caveat may be especially important in patients with high-probability 4Ts score in the rare case of lab error or if the pathologic antigen involves a complex of heparin and a molecule other than PF4. Unless there is a special caveat, it is appropriate to discontinue non-heparin anticoagulation and resume heparin if clinically indicated. An ELISA OD > 2.00 or OD ≥ 1.5 and a high-probability 4Ts score confirms HIT. Although functional HIT antibody testing typically is not pursued in the setting of a high OD, some centers will send off the functional assay with the immunoassay to optimize efficiency and ensure quality. One of the most common functional assays, the serotonin release assay (SRA), has high specificity and positive predictive values. Another functional assay that is used commonly, especially in Europe, is the heparin-induced platelet activation (HIPA) assay.17 An ELISA OD between 0.60 and 1.99 or OD between 0.60 and 1.49 with a high-probability 4Ts score is indeterminate. Assuming that heparin already has been discontinued, non-heparin anticoagulants are continued while functional assays are pending.3 A positive functional assay in the appropriate clinical setting typically confirms a diagnosis of HIT, and a negative functional assay excludes it.
Management of the Acute Phase
In patients with acute HIT without thrombosis (isolated HIT) or acute HIT complicated by thrombosis (HITT), ensure that all heparin has been stopped and that a non-heparin anticoagulant, such as argatroban, bivalirudin, danaparoid, fondaparinux, or a direct oral anticoagulant (DOAC) already has been started at a therapeutic dose.3 Vitamin K antagonists should not be initiated. In critically ill patients, it is important to consider argatroban or bivalirudin in light of their short half-life, especially if there is a potential for invasive procedures and a risk of bleeding that may necessitate temporary discontinuation. Fondaparinux and DOACs may be an option in patients who are stable and not at increased risk of bleeding, but experience with DOACs in patients with HIT complicated by life- or limb-threatening thromboembolism is limited.
In cases of non-life-threatening or non-limb-threatening disease, rivaroxaban has been the DOAC with the most published literature.3 Patients with acute HITT typically are started on rivaroxaban 15 mg twice daily for three weeks, followed by 20 mg daily. Patients with acute isolated HIT should be started at 15 mg twice daily until platelet recovery, followed by 20 mg daily if there is an indication for continued anticoagulation. In acute HITT or acute isolated HIT, the ASH guidelines recommend against an inferior vena cava (IVC) filter. Platelets should not be transfused in HIT unless the patient has active bleeding or a high risk of bleeding.
In patients with acute isolated HIT and no deep vein thrombosis (DVT) identified by compression ultrasound, the ASH guidelines suggest that anticoagulation be continued until proven platelet recovery. The guidelines suggest three months of therapy unless HIT persists without recovery of platelets. For 90% of patients, platelets will recover within seven days of the HIT diagnosis.18 Among those with HITT, there are no specific recommendations regarding length of therapy. In patients with subacute HIT, treatment with DOACs, as opposed to vitamin K antagonists, is preferred. An emergency identifier with information including the allergy to heparin, the reaction of HIT, and the date of diagnosis is recommended for patients diagnosed with remote HIT.
DVT Screening and Prevention
Thrombosis occurs in up to 50% of individuals with HIT who are not treated appropriately, and it is the presenting finding in 25% of patients.19 The sequelae of thrombosis can be life-threatening and can include skin necrosis, limb gangrene, and organ infarction, including stroke, myocardial infarction, bowel infarction, and renal infarction. Per ASH guidelines, all patients with acute HIT should receive a bilateral lower extremity compression ultrasound to screen for asymptomatic DVT.3 All patients with upper extremity catheters should receive an upper extremity compression ultrasound. In patients with a history of HIT who require venous thromboembolism treatment or prophylaxis, administration of a non-heparin anticoagulant (e.g., apixaban, dabigatran, danaparoid, edoxaban, fondaparinux, rivaroxaban, or vitamin K antagonist), rather than UFH or LMWH, is recommended.3
HIT is an iatrogenic, potentially life-threatening complication that occurs after exposure to heparin therapy in hospitalized patients. Even though the diagnosis ideally is established based on both clinical and laboratory findings, a presumptive clinical diagnosis using the 4Ts score often is necessary while awaiting laboratory confirmation. Early recognition and timely initiation of treatment are critical for improved prognosis. In addition to the typical non-heparin anticoagulant options, fondaparinux or DOACs may be options in patients who are stable without life-threatening or limb-threatening thromboembolism and not at increased risk of bleeding. Screening for asymptomatic DVT also is recommended for newly diagnosed HIT patients.
- Amiral J, Bridey F, Dreyfus M, et al. Platelet factor 4 complexed to heparin is the target for antibodies generated in heparin-induced thrombocytopenia. Thromb Haemost 1992;68:95-96.
- Rice L. Heparin-induced thrombocytopenia: Myths and misconceptions (that will cause trouble for you and your patient). Arch Intern Med 2004;164:1961-1964.
- Cuker A, Arepally GM, Chong BH, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: Heparin-induced thrombocytopenia. Blood Adv 2018;2:3360-3392.
- Salter BS, Weiner MM, Trinh MA, et al. Heparin-induced thrombocytopenia: A comprehensive clinical review. J Am Coll Cardiol 2016;67:2519-2532.
- Goel R, Ness PM, Takemoto CM, et al. Platelet transfusions in platelet consumptive disorders are associated with arterial thrombosis and in-hospital mortality. Blood 2015;125:1470-1476.
- Arepally GM. Heparin-induced thrombocytopenia. Blood 2017;129:2864-2872.
- Nand S, Wong W, Yuen B, et al. Heparin-induced thrombocytopenia with thrombosis: Incidence, analysis of risk factors, and clinical outcomes in 108 consecutive patients treated at a single institution. Am J Hematol 1997;56:12-16.
- Greinacher A, Selleng K, Warkentin TE. Autoimmune heparin-induced thrombocytopenia. J Thromb Haemost 2017;15:2099-2114.
- Mallik A, Carlson KB, DeSancho MT. A patient with ‘spontaneous’ heparin-induced thrombocytopenia and thrombosis after undergoing knee replacement. Blood Coagul Fibrinolysis 2011;22:73-75.
- Cuker A. Management of the multiple phases of heparin-induced thrombocytopenia. Thromb Haemost 2016;116:835-842.
- Martel N, Lee J, Wells PS. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: A meta-analysis. Blood 2005;106:2710-2715.
- Warkentin TE. Heparin-induced thrombocytopenia: A clinicopathologic syndrome. Thromb Haemost 1999;82:439-447.
- Warkentin TE, Kelton JG. Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med 2001;344:1286-1292.
- Lo GK, Juhl D, Warkentin TE, et al. Evaluation of pretest clinical score (4 T’s) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost 2006;4:759-765.
- Nagler M, Bachmann LM, ten Cate H, ten Cate-Hoek A. Diagnostic value of immunoassays for heparin-induced thrombocytopenia: A systematic review and meta-analysis. Blood 2016;127:546-57.
- Raschke RA, Curry SC, Warkentin TE, Gerkin RD. Improving clinical interpretation of the anti-platelet factor 4/heparin enzyme-linked immunosorbent assay for the diagnosis of heparin-induced thrombocytopenia through the use of receiver operating characteristic analysis, stratum-specific likelihood ratios, and Bayes theorem. Chest 2013;144:1269-1275.
- Leo A, Winteroll S. Laboratory diagnosis of heparin-induced thrombocytopenia and monitoring of alternative anticoagulants. Clin Diagn Lab Immunol 2003;10:731-740.
- Pon TK, Mahajan A, Rosenberg A, et al. Platelet response to direct thrombin inhibitor or fondaparinux treatment in patients with suspected heparin-induced thrombocytopenia. J Thromb Thrombolysis 2018;45:536-542.
- Linkins LA, Dans AL, Moores LK, et al. Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e495S-e530S.