Update on the Treatment of Heparin-Induced Thrombocytopenia

Heparin, a natural glycosaminoglycan, was first discovered in 1916 by Mclean and initially was used as an anticoagulant in 1935.1 Today, the use of unfractionated heparin and low-molecular-weight heparin remains widespread for the treatment and prevention of various thromboembolic disorders. Benefits of unfractionated heparin include its quick onset of action, short half-life, ease of monitoring, and reversibility.2 Low-molecular-weight heparin has the additional advantages of more predictable anticoagulant activity, less frequent monitoring, and potential use in the ambulatory setting.1 Heparin-induced thrombocytopenia (HIT) is a potentially life-threatening complication of heparin exposure associated with potential thrombosis, limb gangrene and amputation, and death.3,4 The incidence of HIT ranges from less than 0.1% to 5% of patients and varies according to patient factors.3 The risk is highest in patients receiving unfractionated heparin (as opposed to low-molecular-weight heparin), those undergoing cardiac surgery, and those receiving therapeutic doses.4–7The pathogenesis of HIT is complex, but understanding it is essential to comprehending why certain therapies are avoided, especially in the acute phase of disease progression. Heparin-induced thrombocytopenia begins with negatively charged heparin and positively charged platelet factor 4 (PF4) molecules.2–4 The PF4-heparin molecule forms an immunogenic complex that then binds to immunoglobulin G (IgG).3,4 The IgG, PF4, and heparin complex goes on to bind to platelet Fc receptors. The effect of this binding is a downstream reaction and release of procoagulant molecules, which in turn cause further platelet activation in a positive feedback loop.3,4 The end result is thrombin generation, thrombocytopenia, and an environment conducive to thrombotic complications.3 Because of the continuous nature of HIT, exposure to further heparin products in the acute setting must be immediately ceased because these would add more fuel to the reaction.Given the potential sequelae of failing to diagnose or misdiagnosing HIT, it is imperative that practitioners have an astute understanding of the clinical progression of the disease, including onset of initial presentation and resolution. The most recognizable feature of HIT is thrombocytopenia that is temporally associated with exposure to heparin.2–4 This thrombocytopenia typically occurs within 5 to 14 days after initial exposure. Certain patients may experience more rapid onset of thrombocytopenia (within a few hours of receiving heparin), possibly due to previous exposure to heparin and development of preexisting circulating HIT antibodies.Clinical manifestations of HIT are well documented and studied. A few predictive tools have been published, the most validated of which is the 4Ts score (Table 1). This tool uses 4 key characteristics of HIT (thrombocytopenia, timing of thrombocytopenia, thrombosis, and other causes of thrombocytopenia) to predict the likelihood that a patient has HIT. The tool is scored from 1 to 8, with a score of 1 to 3 indicating a low risk of HIT and a score of 6 to 8 indicating a high risk. Although the 4Ts score has a high negative predictive value (98%),7,9 scores that are intermediate to high are not confirmatory. Subsequent immunoassays, functional assays, and discontinuation of heparin-containing products are recommended for patients who have at least an intermediate clinical probability (4Ts score ≥ 4).7For patients with suspected HIT, guidelines recommend initial immunoassays followed by functional assays when able.7 Immunoassays such as an enzyme-linked immunoabsorbent assay can measure antibodies against the PF4-heparin complex. These assays are typically readily available in house at most institutions and are guideline recommended for first-line confirmatory testing because they usually have fast turnaround times. Immunoassays rule out HIT when results are negative. However, because of the limited specificity (40%-80%),9 a positive immunoassay result does not always mean that a patient truly has HIT even if the result is strongly positive (eg, optical density > 2.0 on enzyme-linked immunoabsorbent assay).7 Therefore, current guidelines recommend performing an additional functional assay for confirmatory diagnosis. Functional assays such as the serotonin release assay are considered the diagnostic standard for HIT, although these tests are technically difficult to conduct and also may not be available in house, depending on the institution. Therefore, initial therapy for HIT may be pursued until serotonin release assay results are obtained, especially when clinical suspicion based on 4Ts and immunoassay results is high.When HIT is clinically suspected, the first step is to calculate the 4Ts score to evaluate the probability.3 Patients with a 4Ts score indicating a low probability of HIT (≤ 3) need no further laboratory testing for HIT, and heparin products may be continued. For patients with a 4Ts score representing an intermediate to high probability, all heparin products should be discontinued, an immunoassay should be obtained, and a nonheparin anticoagulant should be initiated at therapeutic intensity.7 For patients with an intermediate-probability 4Ts score who have no indication for therapeutic anticoagulation, a nonheparin anticoagulant may be initiated at prophylactic intensity if the risk of bleeding is high. If the risk of bleeding is low, therapeutic intensity should be continued. If the immunoassay result is negative, HIT is unlikely and heparin products can be resumed as clinically indicated. If the immunoassay result is positive, cessation of heparin should continue and a functional assay should be obtained.7 If the functional assay result is positive, acute HIT is confirmed. If the functional assay result is negative, HIT is unlikely. False-negative results can occur, and the clinical picture along with a positive immunoassay result should be taken into consideration before resuming heparin.7Nonheparin anticoagulant options recommended in guidelines for acute HIT include argatroban, bivalirudin, fondaparinux, and direct oral anticoagulants.3,7 Nonheparin anticoagulant agent selection depends on the drug properties and patient characteristics.Argatroban is an anticoagulant in the class of direct thrombin inhibitors. Argatroban inhibits free, fibrin-bound, and clot-bound thrombin. Argatroban also inhibits platelet aggregation and thromboxane generation.10,11 It was approved by the US Food and Drug Administration (FDA) in 2000 for the treatment of HIT.10 It is administered as a continuous infusion and has a short duration of effect (Table 2). Argatroban is primarily metabolized via hepatic hydroxylation and aromatization and is excreted in the feces and urine. The typical starting dose in patients with normal hepatic function is 2 µg/kg/min. However, because argatroban relies on hepatic metabolism, caution must be exercised when initiating argatroban for patients who have hepatic dysfunction or are critically ill. In these patients, lower starting doses and tighter titrations are often warranted. Argatroban is most often titrated according to activated thromboplastin time (aPTT) but can be titrated according to activated clotting time or dilute thrombin time.12 Although some institutions may have a fixed aPTT goal, the therapeutic range that is typically targeted is 1.5 to 3 times a patient’s baseline aPTT.Current literature and guidelines support the use of argatroban for patients with acute HIT. Because of its short half-life, argatroban may also be advantageous for patients requiring urgent procedures.7,13,14 Argatroban may increase values on the the prothrombin time (PT) and international normalized ratio (INR) assay. This interaction with the PT/INR assay is significant because patients with HIT are typically transitioned to oral therapy, for which warfarin is an option. In patients being bridged with argatroban to therapeutic warfarin, the PT/INR may be elevated partly because of argatroban, making it difficult to ascertain whether an elevation in PT/INR is due to warfarin dosing. A few methods can be used to estimate PT/INR changes attributed to warfarin doses.15 In general, once the INR is greater than 4, argatroban can be stopped and the INR measurement can be repeated in 4 to 6 hours to allow argatroban-related effects on the PT/INR to subside.Although not FDA approved for the treatment of acute HIT, bivalirudin is another direct thrombin inhibitor commonly used and recognized in guidelines as a management option.7 In contrast to argatroban, bivalirudin is primarily eliminated via enzymatic processes, with about 20% renal elimination.12 Compared with argatroban, bivalirudin has a shorter half-life (approximately 25 minutes), so it may reach steady-state concentrations more quickly.12,16 However, the half-life may be prolonged in patients with renal impairment. The infusion is typically started at a rate of 0.15 mg/kg/h and titrated to a goal aPTT of 1.5 to 2.5 times the patient’s baseline (Table 2).7,12 Bivalirudin also has the potential to cause an elevation in INR, although to a lesser extent than argatroban.12 Lower initial starting doses are considered in patients with renal impairment.7 Although few studies have been conducted, evidence demonstrates that bivalirudin is a safe and effective therapeutic option for HIT.16,17Fondaparinux is a synthetic pentasaccharide that is identical in structure to the antithrombin binding domain of heparin. It exerts its pharmacologic effect through selective factor Xa inhibition. Although fondaparinux resembles a portion of the heparin molecule, it does not bind to PF4 and does not pose a risk for cross-reaction with HIT antibodies in the way that heparin and low-molecular-weight heparin do.18,19 Because of its long half-life (17-21 hours), it is given once a day with dosing based on the patient’s weight (Table 2). Caution must be used in patients with renal dysfunction due to the propensity for delayed elimination.Warfarin exerts its anticoagulant activity by inhibiting vitamin K–dependent clotting factors (II, VII, IX, and X) and anticoagulant factors (proteins C and S). The half-life of anticoagulant factor protein C is shorter than most of the procoagulant factors, leading to a possible hypercoagulable state in early therapy.20 Case reports have described skin necrosis and limb gangrene in patients receiving warfarin in the setting of HIT.20 In patients with HIT, guidelines recommend reversal of warfarin with intravenous vitamin K and concomitant administration of an alternative nonheparin anticoagulant to prevent this potential complication.21 If warfarin administration is required for short- or long-term anticoagulation, the patient’s platelet count should fully recover (platelet count of ≥ 150×103/µL) before therapy is resumed.7,16 Transition to therapeutic warfarin requires a bridge with a parenteral anticoagulant for a minimum of 5 days and until the INR is in the therapeutic range.21 Argatroban and bivalirudin may be used as bridge options, and both may elevate the INR.12,21Direct oral anticoagulants include the factor Xa inhibitors apixaban, rivaroxaban, and edoxaban and the direct thrombin inhibitor dabigatran. These agents, although previously considered novel, have been FDA approved for more than a decade and data for their use other than for initial approved indications continue to grow. Although none of these agents are approved for the treatment of HIT, current literature and guidelines support their off-label use for this purpose.7,22,23 The 2018 American Society of Hematology guidelines endorse the use of direct oral anticoagulants instead of vitamin K antagonists such as warfarin to treat HIT.7 Direct oral anticoagulants have an advantage over vitamin K antagonists in that they do not require any formal laboratory monitoring. Although no recommendation for a specific direct oral anticoagulant is offered,7 most published studies to date have been of rivaroxaban.22–24 Because of the need for prolonged anticoagulant therapy, patients may need to be discharged with oral anticoagulation. Selection of appropriate oral therapy should take into account patient-specific factors such as renal and hepatic function, drug-drug interactions, insurance coverage, and other disease states that require anticoagulation.The optimal duration of anticoagulation in patients with acute isolated HIT without thrombosis remains uncertain.7 In a cohort of patients with untreated acute isolated HIT, the incidence of 30-day thromboembolic events was 52%.25 The risk of an event occurring was highest in the first 10 days during platelet recovery.25 Guidelines suggest continuing a non-heparin anticoagulant at minimum until the platelet count has recovered (platelet count of ≥ 150×103/µL).7,21 Given the 30-day risk, treatment continuation could be considered for 4 weeks21 but for no more than 3 months.7 In patients with acute HIT complicated by thrombosis, treatment with a nonheparin anticoagulant should be continued for 3 months because HIT is considered a reversible risk factor.21,26Heparin-induced thrombocytopenia has the potential to cause thromboembolic events and life-threatening complications and requires prompt recognition and treatment. Clinical suspicion along with appropriate laboratory tests can aid in its diagnosis. Cessation of all heparin products is key in the initial treatment of a patient with suspected HIT. Various nonheparin anticoagulant options exist, each with a unique profile. Use of a nonheparin anticoagulant should be continued depending on the clinical picture of the patient and evaluation of laboratory test results.