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NONHEPARIN ANTICOAGULANTS
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Management of HIT requires immediate withdrawal of heparin, including cessation of heparin flushes and removal of heparin-coated catheters. However, discontinuation of heparin alone is insufficient to prevent thromboembolism. Historical studies of untreated patients document a 5 to 10 percent daily risk of thrombosis in the first 48 hours after heparin is stopped and a 30-day cumulative incidence of thrombosis of approximately 50 percent.57,94 Discontinuation of heparin must therefore be accompanied by initiation of a rapid-acting, parenteral, nonheparin anticoagulant.95 Table 118–4 summarizes the properties of nonheparin anticoagulants used to treat HIT.
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Argatroban and bivalirudin are direct thrombin inhibitors. Argatroban is the only FDA-approved drug for treatment of HIT available in the United States. Its approval was based on two open-label single-arm studies in which argatroban-treated subjects were compared with untreated historical controls.96,97 In a pooled analysis of these two studies, argatroban reduced the relative risk of new thrombosis by two-thirds. The incidence of major bleeding was approximately 1 percent per day.98 An important limitation of these studies was that serologic confirmation of HIT was not required for enrollment. Indeed, 36.4 percent of subjects were found to be anti-PF4–heparin antibody-negative on post hoc testing,99 suggesting that a sizable proportion of the study population did not have HIT.
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Bivalirudin is a hirudin analogue. It is approved for patients with and without HIT undergoing percutaneous vascular procedures. It is not approved for treatment of HIT, although it has been used off-label for this indication, particularly in patients with critical illness and multiorgan failure100 and those undergoing cardiac surgery.101 Published evidence supporting its use is limited to retrospective single-center cohort studies.100,102,103
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Two other direct thrombin inhibitors have been studied as treatments for HIT. Lepirudin, a recombinant hirudin, was shown to reduce the risk of thromboembolism compared with untreated historical controls, but is no longer available.94 A randomized clinical trial of desirudin closed because of poor accrual after only 16 subjects had been randomized.104
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Danaparoid and fondaparinux are indirect factor Xa inhibitors. Danaparoid is approved for treatment of HIT in multiple jurisdictions, but is no longer marketed in the United States and drug shortages have limited its availability elsewhere. In an open-label randomized trial, 42 patients with HIT complicated by thrombosis were allocated to receive either danaparoid or dextran 70. Significantly more subjects in the danaparoid arm were judged to have complete recovery from thrombosis at hospital discharge (56 percent vs. 14 percent; p = 0.02).105 In vitro crossreactivity of HIT antibodies with danaparoid occurs in some patients, although the clinical relevance of this phenomenon has not been established.106
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Fondaparinux in not approved for treatment of HIT, nor is it recommended in the 2012 American College of Chest Physicians Guidelines.95 Its use is supported by several small case series and retrospective cohort studies.107,108,109,110 In a pooled analysis involving 71 patients, no new thrombotic events were reported. Four patients suffered major hemorrhage.63 A small number of cases of HIT induced or exacerbated by fondaparinux have been reported, although the attribution to fondaparinux in at least some of these cases remains uncertain.111 Fondaparinux is more convenient to use than other agents given the ease of once-daily administration and a potential lack of need for monitoring (see Table 118–4). This may, in part, account for its increasing use. In a recent multicenter German registry of patients with suspected HIT, a greater proportion of patients were treated with fondaparinux (40 percent) than with danaparoid (23.6 percent) or argatroban (16.4 percent).112
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Oral direct inhibitors of thrombin (e.g., dabigatran) and factor Xa (e.g., rivaroxaban, apixaban, edoxaban) do not induce platelet aggregation or PF4 release in the presence of HIT-positive sera in vitro113 and constitute biologically rational approaches to the treatment of HIT. However, clinical evidence is limited to a small number of case reports114,115 and use of these agents for HIT cannot be recommended outside of a clinical trial. One such trial of rivaroxaban in patients with suspected HIT began enrollment in 2013 and is ongoing.116
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An important toxicity of anticoagulants used for treatment of HIT is major bleeding, a risk compounded by the absence of effective reversal agents. Novel therapeutic approaches that target pathways proximal to activation of coagulation may provide effective antithrombotic therapy without the degree of bleeding risk associated with anticoagulants. Candidate strategies include a desulfated form of heparin with minimal anticoagulant activity113 and small molecule PF4 antagonists,117 which interfere with formation of PF4–heparin complexes; inhibitors of FcγRIIA-mediated platelet activation by HIT immune complexes; and inhibitors of splenic tyrosine kinase and Ca2+118 and diacylglycerol-regulated guanine nucleotide exchange factor I,119 which disrupt intracellular transduction triggered by immune complex binding.
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Because of the frequency of heparin use and thrombocytopenia among hospitalized patients, the modest specificity of immunologic assays, and clinicians’ fears of missing a case of HIT, overdiagnosis and unnecessary treatment with nonheparin anticoagulants of patients without HIT is common.120 Inappropriate use of these agents is associated with increased costs and bleeding risk.121 In light of the very-high negative predictive value (99.8 percent) of a low-probability 4T score,65 a reasonable first step toward reducing unnecessary treatment is to avoid use of nonheparin anticoagulants in patients with a low-probability 4T score. Heparin should be discontinued and a nonheparin anticoagulant initiated in patients with an intermediate- or high-probability 4T score until the results of HIT laboratory testing become available.65,95,122
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TRANSITIONING TO A VITAMIN K ANTAGONIST
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Warfarin and other vitamin K antagonists should not be prescribed as the initial anticoagulant in patients with acute HIT because their use increases the risk of venous limb gangrene as a result of rapid lowering of protein C activity.123 For patients receiving a vitamin K antagonist at the time HIT is diagnosed, the vitamin K antagonist should be discontinued and its effects reversed with vitamin K. A vitamin K antagonist may be initiated once the platelet count has recovered to a stable plateau. Large loading doses (e.g., warfarin >5 mg/day) should be avoided. The vitamin K antagonist should be overlapped with a parenteral nonheparin anticoagulant for at least 5 days and until the international normalized ratio (INR) has reached its intended target.63,95 If the patient is being transitioned from argatroban to warfarin, guidelines regarding the appropriate INR target should be followed,124 because both argatroban and warfarin increase the INR. This target will vary according to the sensitivity of the prothrombin time reagent to argatroban used in each institution.
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DURATION OF ANTICOAGULATION
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Patients with HIT-associated thromboembolism are typically treated with therapeutic anticoagulation for 3 to 6 months. The optimal duration of anticoagulation in patients with HIT without thrombosis (i.e., isolated HIT) is unknown. In a historical series of untreated patients with isolated HIT, the cumulative incidence of thromboembolism at 30 days was 53 percent.57 Most events occurred within 10 days of heparin cessation, corresponding to the platelet recovery phase. It is therefore generally accepted that anticoagulation be continued in patients with isolated HIT until platelet count recovery. Some authorities recommend longer courses (e.g., 4 weeks).122
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There is a long-held concern that platelet transfusion may precipitate thrombosis in HIT by “adding fuel to the fire.” Two case series challenge this dogma. Collectively, these series included 41 patients with suspected HIT who underwent platelet transfusion. None developed thrombosis during extended followup.125,126 Nevertheless, because HIT is characteristically prothrombotic rather than prohemorrhagic, prophylactic platelet transfusion is rarely indicated. Transfusion may be considered in the setting of clinically significant bleeding, high bleeding risk, or diagnostic uncertainty.
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HEPARIN REEXPOSURE IN PATIENTS WITH A HISTORY OF HEPARIN-INDUCED THROMBOCYTOPENIA
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In general, heparin reexposure should be avoided in patients with a history of HIT because of the risk of reoccurrence.127 An exception to this rule is the use of intraoperative heparin in patients with a history of HIT who are undergoing cardiovascular surgery. The HIT immune response wanes over time. Functional assays become negative at a median of 50 days after heparin cessation, whereas anti-PF4–heparin antibody titers decline more slowly and are no longer detectable in 60 percent of patients by day 100.23 HIT laboratory testing can be used to determine the safety of heparin reexposure during cardiovascular surgery. Patients with a negative immunologic and functional assay may safely receive UFH during surgery. This was first demonstrated in 10 patients with a history of HIT undergoing cardiac surgery, none of whom developed clinical reoccurrence.128 In a newer report, 11 of 17 such patients developed recrudescence of anti-PF4–heparin antibodies, but only one developed HIT.129 Heparin should be strictly avoided in patients with a positive functional assay. If possible, surgery should be delayed in these individuals until functional and immunologic assays become negative. If surgery cannot be delayed, a nonheparin anticoagulant (e.g., bivalirudin) should be used.101 Appropriate intraoperative anticoagulation of patients with a functional assay that has become negative, but an immunologic assay that remains positive is uncertain. The 2012 American College of Chest Physicians Guidelines recommend a nonheparin anticoagulant in this setting.95 However, intraoperative heparin was used uneventfully in three such patients undergoing urgent heart transplantation.130 When heparin is administered to patients with HIT, it should be limited to the intraoperative setting. Pre- and postoperative exposure should be scrupulously avoided, though patients with a history of HIT who are (inadvertently) reexposed to longer courses of heparin do not always develop recurrent HIT.129
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In light of its documented efficacy and safety in large coronary angiography trials, bivalirudin is recommended over heparin in patients with a history of HIT who require percutaneous vascular procedures, irrespective of the results of HIT laboratory testing.95
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Although approximately 10 percent of patients on chronic hemodialysis develop circulating anti-PF4–heparin antibodies,131 the incidence of HIT in this population is less than 1 percent.132 Ongoing heparin exposure during dialysis in patients with a history of HIT is contraindicated. Alternative strategies including regional citrate, saline flushing, danaparoid, argatroban, and vitamin K antagonists use have been reported.95
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HIT is rare (<0.1 percent) in pregnant women exposed to heparin.11,12 When it does occur, initiation of a nonheparin anticoagulant is warranted. The largest published experience is with danaparoid. A retrospective cohort of 30 women with acute HIT received danaparoid during pregnancy.133 Five patients developed thrombosis and three developed major bleeding. Danaparoid does not cross the placenta and there was no measurable anti-Xa activity in the cord blood of six neonates who were tested after delivery. If danaparoid is unavailable, fondaparinux may be considered though evidence supporting its use in pregnant women with HIT is limited to case reports134,135 and partial transplacental passage has been demonstrated.136