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Reducing Thrombotic Complications in the Perioperative Setting: An Update on Heparin-Induced Thrombocytopenia

Levy, Jerrold H. MD*; Tanaka, Kenichi A. MD*; Hursting, Marcie J. PhD, DABCC

doi: 10.1213/01.ane.0000277497.70701.47
Cardiovascular Anesthesia: Review Article

Heparins are widely used in the perioperative setting. Immune heparin-induced thrombocytopenia (HIT) is a serious, antibody-mediated complication of heparin therapy that occurs in approximately 0.5%–5% of patients treated with heparin for at least 5 days. An extremely prothrombotic disorder, HIT confers significant risks of thrombosis and devastating consequences on affected patients: approximately 38%–76% develop thrombosis, approximately 10% with thrombosis require limb amputation, and approximately 20%–30% die within a month. HIT antibodies are transient and typically disappear within 3 mo. In patients with lingering antibodies, however, re-exposure to heparin can be catastrophic. In the perioperative setting, heightened awareness is important for the prompt recognition, diagnosis, and treatment of HIT. HIT should be considered if the platelet count decreases 50% and/or thrombosis occurs 5–14 days after starting heparin, with other diagnoses excluded. On strong clinical suspicion of HIT, heparin should be discontinued and a parenteral alternative anticoagulant initiated, even before laboratory confirmation of HIT is obtained. Subsequent laboratory test results may help with the decision to continue with nonheparin therapy or switch back to heparin. Heparin avoidance in patients with current or previous HIT is feasible in most clinical situations, except perhaps in cardiovascular surgery. If the surgery cannot be delayed until HIT antibodies have disappeared, intraoperative alternative anticoagulation is recommended.

From the *Emory University School of Medicine, Atlanta, Georgia; and †Clinical Science Consulting, Austin, Texas.

Accepted for publication May 22, 2007.

J. Levy has received research support from the Medicines Company, is on the speakers’ bureau for GlaxoSmithKline, and is a consultant for Organon. M. Hursting is a consultant for GlaxoSmithKline.

Dr. Jerrold Levy, Section Editor for Hemostasis and Transfusion Medicine, was recused from all editorial decisions related to this manuscript.

Reprints will not be available from the author.

Address correspondence to Jerrold H. Levy, MD, Emory Hospital, 1364 Clifton Road, Atlanta, GA 30322.

Immune heparin-induced thrombocytopenia (HIT, sometimes called “HIT type II”) is an antibody-mediated, prothrombotic condition triggered by heparin therapy. HIT is characterized by an otherwise unexplained 50% or more decrease in the platelet count, often to <150 × 109/L and frequently accompanied by thrombosis, and the appearance of HIT antibodies (1,2). An estimated 600,000 new cases of HIT occur annually in the United States, with thromboembolic complications occurring in approximately 300,000 patients and death in approximately 90,000 patients (3). The annual health care cost of HIT complications in cardiac surgery alone is estimated to be $300 million (4). Heparin exposure is one of the strongest correlates with thrombocytopenia in the intensive care unit (5). In the perioperative setting, where heparin is widely used, an increased awareness of risk is necessary for prompt recognition of HIT. When HIT is strongly suspected, appropriate treatment should be initiated immediately, even before laboratory confirmation of HIT antibodies. We discuss the pathogenesis, frequency, complications, diagnosis, and treatment of HIT. Options for alternative anticoagulation before, during, and after surgery are described.

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PATHOGENESIS AND FREQUENCY

The pathogenesis of HIT is well studied, and thorough reviews have been published (6,7). Briefly, HIT is mediated by antibodies (sometimes called “HIT antibodies”) to a complex of heparin and platelet factor 4 (PF4). PF4 is a heparin-binding protein stored in platelets. HIT antibodies recognize epitopes newly exposed on PF4 when it is conformationally modified by binding to heparin. Immunoglobulin (Ig) G antibody binds heparin-PF4 complexes on the platelet surface to form immune complexes. The platelets, in turn, are activated by the Fc domain of the IgG in the immune complexes. Activated platelets release microparticles that promote thrombin formation which, in turn, fuels more platelet activation. Activated platelets also release PF4, which leads to more immune complex production. Thrombocytopenia, excessive thrombin generation, and a prothrombotic state ensue. Antibody-mediated endothelial injury and tissue factor production further increase the prothrombotic state.

Approximately 7%–50% of heparin-treated patients generate heparin-PF4 antibodies (8). Cardiovascular surgery patients are particularly at risk of generating the antibodies (8–10). HIT antibodies circulate only temporarily, with a median half-life of 85 days by antigenic assay (11). These antibodies may be clinically significant even in the absence of thrombocytopenia. The presence (12–17) and the level (14,15) of the antibodies, regardless of thrombocytopenia, are associated with increased morbidity or mortality in various clinical settings, such as acute coronary syndromes (12,13), hemodialysis (14), and cardiovascular (15,16) or orthopedic (17) surgery.

A minority of patients with heparin-PF4 antibodies also develops thrombocytopenia (with or without thrombosis). HIT occurs in approximately 1%–5% of patients administered unfractionated heparin and <1% of patients administered low-molecular-weight heparin (8,18,19). Cardiac transplant and neurosurgery patients are at increased risk of HIT (11% and 15%, respectively) (20,21). However, for individuals receiving postoperative heparin therapy, orthopedic patients develop HIT more often than cardiac patients (8). Other risk factors for HIT include high-titer, IgG HIT antibodies (8,22), and female gender (23).

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HIT AS A PROTHROMBOTIC DISEASE

HIT carries a substantial risk of new or recurrent thrombosis (odds ratio, 37; 95% CI, 5–1638) (24). Examples of thrombotic events are deep venous thrombosis, pulmonary embolism, myocardial infarction, stroke, and limb artery occlusion requiring amputation (25). Venous events predominate over arterial events in most patients (26), although arterial events predominate in cardiac (27) and postcardiac surgery (28) patients. The overall risk for thrombosis in patients with HIT is 38%–76% (29). The risk for thrombosis is greatest during the first days to week after the recognition of thrombocytopenia (26,30). In one report (30), the combined event rate of death, amputation, or new thromboembolic complications per patient day was 6.1% during the interval between when HIT was clinically suspected and the time alternative anticoagulation was initiated (mean interval = 1.7 days). In many patients, thrombosis appears coincident with, or slightly before, the decline in platelet count (31). The platelet count typically normalizes within a week of heparin discontinuation in a HIT patient, but the thrombotic risk remains increased. In HIT patients initially presenting without thrombosis, 19%–52% suffer thrombosis within a month of heparin cessation (29).

Localized vascular injury predisposes to some thrombotic events in HIT, e.g., venous thrombosis in the arms usually happens at the site of a central catheter (32). Patients with HIT after coronary artery bypass grafting are at increased risk for occlusion of saphenous vein grafts, but not for occlusion of arterial grafts (33). Other risk factors for HIT-related thrombosis include female gender (34–36), orthopedic surgery (31,37), malignancy (38), higher titer heparin-PF4 antibodies (37,39), and more severe thrombocytopenia (31,36,37,40).

Other complications include skin lesions at heparin injection sites, disseminated intravascular coagulation, warfarin-associated venous limb ischemia, and acute systemic reactions after heparin bolus (41). Bleeding is rare, even in the presence of severe thrombocytopenia. Approximately 10% of patients with HIT and thrombosis requires a limb amputation (42,43). Mortality is approximately 20%–30% (42,43).

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DIAGNOSIS

HIT should be suspected whenever the platelet count decreases by 50%, or when new thrombosis occurs in a patient 5–14 days after the start of heparin therapy (1,2). Other causes of thrombocytopenia, e.g., sepsis, mechanical destruction with an intraaortic balloon pump, or another drug-induced thrombocytopenia, should be excluded. Cardiopulmonary bypass (CPB) causes a 40%–60% reduction in platelet count that lasts 3–4 days and is due to dilution and consumption (44). Patients who develop HIT after CPB typically have a decrease in platelet count that follows correction of the routine dilutional CPB-related thrombocytopenia (biphasic pattern) or else a persistently low or worsening platelet count for >4 days after bypass (45,46).

“Rapid onset” HIT has also been described (11,47,48). In this presentation of HIT, the platelet count begins to decrease within minutes to hours of heparin exposure. Affected patients have heparin-PF4 antibodies from a previous heparin exposure usually, but not always (47), within the prior 3 mo (11,48). HIT should also be suspected if acute systemic reactions, e.g., hypotension, pulmonary hypertension, and/or tachycardia, occur 2–30 min after IV heparin bolus. This may be observed intraoperatively, and often presents as an immediate hypersensitivity reaction (49,50). These reactions are usually accompanied by an abrupt decrease in platelet count. Platelet count should be determined immediately for comparison with a prebolus count.

HIT sometimes manifests days to weeks after heparin has been stopped (51,52). This scenario, known as “delayed onset HIT,” is less common than the more rapid presentations of HIT. Affected patients often have been discharged from the hospital and return with thrombosis (and typically high-titer antibody). HIT should be considered if a recently hospitalized, heparin-treated patient presents with thrombosis (51–54). Because heparin-treated patients may also develop thrombosis due to other causes, i.e., inadequate anticoagulation, Levine et al. (55) conducted a meta-analysis to determine the risk of a patient having HIT when venous thromboembolism follows heparin therapy. This risk is distinct from the risk of developing HIT with heparin therapy, which is approximately <1%–5%, depending on the patient population and type of heparin (1,8), and also distinct from the risk of a patient with HIT developing thrombosis, which is 38%–76% in the absence of alternative anticoagulation (29). According to the meta-analysis of studies of patients administered heparin for thromboprophylaxis or treatment, and in which frequency data on venous thromboembolism (in-hospital or follow-up to 90 days) and HIT were available, an estimated one in eight unfractionated heparin-treated patients with new or recurrent venous thromboembolism has HIT (55). It has been suggested that this risk estimate might have been greater if data only on symptomatic events, rather than on symptomatic and asymptomatic events, had been available for analysis (56).

Routine platelet count monitoring, including a preheparin value, is recommended for most heparin-treated patients (1,2,57). For patients with suspected HIT, laboratory testing for heparin-PF4 antibody is recommended (57). Because of the high-thrombotic risk early in HIT (30), treatment (discussed below) for patients with strongly suspected HIT should not be withheld while waiting for laboratory results (58). Clinical scoring systems such as the “Four T’s” (for Timing, Thrombocytopenia, Thrombosis, and oTher sequelae) support estimation of pretest probability of HIT (59). The four T’s “scoring system” numbers are assigned for patient risk classification and are useful for excluding HIT (60).

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LABORATORY CONFIRMATION

The use of antigenic and functional testing for HIT antibody is important for patient management (61). Antigenic tests, such as the enzyme-linked immunosorbent assay (ELISA) (57) and rapid particle gel immunoassay (62), detect antibodies to complexes of PF4 and heparin or complexes of PF4 and other polyanions. Commercial ELISAs, which detect IgG, IgM, and IgA, are sensitive for antibody, but are not specific for HIT. Measurement of only IgG antibodies enhances clinical specificity (63). Although ELISA results can be reported as positive or negative, the actual optical density and/or antibody titer based on the optical density is more informative (2). Many patients with “high-titer negative” ELISA results (i.e., 66.7%–99.9% of the threshold for a positive test) become positive upon retesting several days later as titer increases (64). Higher titer antibodies are associated with increased thrombotic risk (37,39). Antibody titers by gel particle immunoassay correlate with clinical likelihood scores in suspected HIT (62).

Functional tests, such as the 14C-serotonin release assay and platelet aggregation test, detect heparin-dependent, platelet-activating antibodies (57). The serotonin release assay has high sensitivity and specificity for HIT. Its drawbacks include radioactive reagents and high technical demands, and it is typically only performed at larger research centers. The platelet aggregation test is less sensitive, yet simpler to perform and more widely available. Its sensitivity improves when washed platelets are used, although this in turn increases the technical difficulty.

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TREATMENT

The recommended treatment for patients with strongly suspected or confirmed HIT, with or without complicating thrombosis, is the cessation of heparin and initiation of a fast-acting, nonheparin, alternative anticoagulant such as a direct thrombin inhibitor (e.g., lepirudin, argatroban, and bivalirudin) or danaparoid (1,2). Vigilance is required to identify and eliminate heparin sources including, but not limited to, IV and subcutaneous injections, line or port flushes, and heparin-coated devices. A visible sign on the patient’s bed and/or chart stating “No heparin: HIT” may help prevent inadvertent heparin exposure (65).

Different direct thrombin inhibitors are approved in the United States for use in HIT patients without initial thrombosis (argatroban), HIT patients with thrombosis (lepirudin, argatroban), and patients with or at risk of HIT undergoing percutaneous coronary intervention (PCI) (argatroban, bivalirudin). Lepirudin and argatroban are also available in some other countries for use in HIT patients in the noninterventional setting. The direct thrombin inhibitors do not resemble heparin, do not cross-react with heparin-PF4 antibodies, and cannot propagate HIT (66).

Danaparoid, a heparinoid with minimal cross-reactivity with heparin-PF4 antibodies, is approved for use in HIT in many countries outside the United States. Danaparoid is unavailable in the United States. The selective factor Xa inhibitor fondaparinux has been suggested for use in HIT (56,61). Fondaparinux has not been prospectively studied in HIT, and hence data are limited.

Table 1 summarizes the salient features of these alternative anticoagulants. Each drug is discussed in the following pages. Prospective, randomized comparisons among these drugs have not been conducted in HIT. The anticoagulants vary in their regional availability, labeled indication(s), associated benefits and risks in the intended use, and clinical pharmacology (e.g., primary mode of elimination). These features as well as patient factors should be considered when drug therapy is individualized for a patient (19). For example, because argatroban is predominantly hepatically metabolized, it is a preferred anticoagulant for treating patients with HIT and renal dysfunction. Table 1 also presents the evidence-based guidelines from the American College of Chest Physicians for the use of these alternative anticoagulants in patients with HIT in noninterventional and interventional settings (1). American College of Chest Physicians Grade 1 recommendations indicate that the benefits do, or do not, outweigh risks, burden, and cost. Grade 2 recommendations suggest that the best choice among available alternatives requires consideration of the individual patient’s medical condition. Consistent results from randomized controlled trials support a Grade A for the quality of the evidence. Inconsistent results from randomized controlled trials support a Grade B for the quality of the evidence. Observational studies with very strong effects, or logical generalizations from randomized controlled trials support a Grade C+. Observational studies alone support a Grade C.

Table 1

Table 1

The management of HIT should include not only heparin cessation but also continued alternative anticoagulant coverage to prevent thrombotic complications (1,2,29). However, the risk of excessive, life-threatening bleeding after cardiac surgery from direct thrombin inhibition (67–71) should be carefully considered, especially in patients who have had surgery within 24–48 h and have a lower pretest probability of HIT. Low-molecular-weight heparins should be avoided because they cross-react with heparin-PF4 antibodies and exacerbate HIT (1,2). Warfarin should be avoided as the initial, sole anticoagulant therapy because of its slow onset of action and risk of inducing venous limb gangrene or skin necrosis (1,2,72,73). Warfarin has sometimes already been started when HIT is recognized, and the American College of Chest Physicians suggests (Grade 2C) that vitamin K should be given to such patients (1). This is needed to reverse the effects of warfarin and to minimize the risk of warfarin-induced limb gangrene or skin necrosis (1). Prophylactic platelet transfusions may contribute to the thrombotic risk, and are not recommended (1,2).

Nonheparin anticoagulation should be maintained for at least a month, reflecting the time course of thrombotic risk in HIT (61,74). A longer duration, e.g., 3–6 mo, is warranted if HIT-associated thrombosis occurred (65,75). Warfarin or other vitamin K antagonists can be carefully introduced provided alternative parenteral anticoagulation is adequate and stable, and that platelet counts have recovered substantially, preferably to 150 × 109/L (1). The parenteral and oral anticoagulants should overlap for at least 5 days, with a therapeutic international normalized ratio (INR) achieved for at least 2 days before the parenteral anticoagulant is stopped (1,2).

Heparin should be avoided, if possible, at least as long as heparin-PF4 antibody testing is positive (1,2). A longer, perhaps indefinite, heparin-free period is often preferred owing to the availability of safe, effective alternative anticoagulants, and uncertainty regarding the risk of recurrence on heparin re-exposure (47,76–78). The British Committee for Standards in Hematology recommends the use of a heparin alternative for most patients requiring anticoagulation with previous HIT (2). Avoiding heparin is generally feasible in many patients, but may be challenging in a few clinical situations, e.g., cardiovascular surgery (discussed subsequently). For patients with current or previous HIT who require cardiac surgery, the surgery should be delayed, if possible, until heparin-PF4 antibodies are negative (1,2). If heparin use is unavoidable or planned, the heparin exposure should be limited to the surgery itself, with alternative anticoagulation used pre- and postoperatively as needed (1,2,28).

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PRE- AND POSTOPERATIVE ALTERNATIVE ANTICOAGULATION THERAPIES

Lepirudin

Lepirudin is a recombinant derivative of the leech protein hirudin. It is primarily eliminated via renal clearance. Lepirudin was evaluated in three historical controlled studies in HIT (43,79,80) and was the first direct thrombin inhibitor approved for use in HIT. In a combined study analysis (80), the composite end-point of death, amputation, and thromboembolic complications within 35 days of HIT confirmation occurred in 29.7% of 403 lepirudin-treated patients and 52.1% of 120 controls (P = 0.047). New thrombosis was reduced from 32.1% to 11.9% (P < 0.001).

Safety concerns with lepirudin include an 18% incidence of major bleeding (80), formation of antilepirudin antibodies (81,82), and anaphylactic reactions on re-exposure (83). The major bleeding risk directly relates to serum creatinine levels (2). If serum creatinine is >1.6 mg/dL, a reduced dose or discontinuation of lepirudin is necessary. Approximately 50% of lepirudin-treated patients form antilepirudin antibodies. These antibodies can prolong the drug’s elimination half-life, and careful monitoring and dose adjustment are required to avoid bleeding in affected patients (81,82). An estimated 0.2% of patients re-exposed to lepirudin have anaphylactic reactions, which have led to some fatal outcomes (83). According to its prescribing information, lepirudin should be administered as a 0.4 mg/ kg initial bolus, followed by a 0.15 mg · kg−1 · h−1 infusion (reduced in renal impairment). The infusion is then adjusted to maintain activated partial thromboplastin time (aPTT) ratios of 1.5 to 2.5 (Table 2). A lower initial infusion of 0.1 mg · kg−1 · h−1 (80,84) without a bolus (83) may reduce the bleeding risk. Avoidance of lepirudin re-exposure has been suggested (74).

Table 2

Table 2

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Argatroban

Argatroban is a hepatically metabolized, small molecule derived from l-arginine. Argatroban is the only anticoagulant approved for use in HIT in both noninterventional and interventional settings. Two historical controlled studies, Argatroban-911 (42) and Argatroban-915 (85), evaluated argatroban therapy in clinically suspected HIT. In a combined study analysis with 697 argatroban-treated patients and 185 controls (36), argatroban significantly reduced the risk for the thrombotic composite end-point of death due to thrombosis, amputation secondary to HIT, or new thrombosis in patients presenting without or with thrombosis. There were also significant risk reductions in the individual end-points of new thrombosis and death due to thrombosis. Major bleeding rates with argatroban and control were similar (6% vs 7%). The recommended initial dose is an infusion of 2 μg · kg−1 · min−1 (0.5 μg · kg−1 · min−1 if hepatic impairment), adjusted to achieve aPTTs 1.5–3 times baseline (Table 2). A conservative initial dose, such as that recommended for patients with hepatic impairment, may be prudent after cardiac surgery (86,87) and in patients with heart failure, multiple organ system failure, severe anasarca (88–90), or other conditions associated with possible hepatic congestion or excessive intravascular volume. Patients require no argatroban dose adjustment for renal failure Argatroban clearance during dialysis is clinically insignificant (91,92).

Argatroban is also approved for use in patients with or at risk of HIT undergoing PCI (Table 2). Across three open-label prospective studies in which 91 patients underwent 112 procedures using argatroban, outcomes were comparable with those reported for heparin (93). Patients with hepatic impairment were excluded from the studies. On the basis of the study results, the recommended argatroban dose during PCI is a 350-μg/kg initial bolus given over 3–5 min and a continuous infusion of 25 μg · kg−1 · min−1 adjusted to achieve activated clotting time (ACT)s of 300–450 s. Lower doses, e.g., an initial 250- or 300-μg/kg bolus administered over 2 min followed by a continuous infusion of 15 μg · kg−1 · min−1, may be adequate when argatroban is used in combination with glycoprotein IIb/IIIa inhibitors (94).

Direct thrombin inhibitors, particularly argatroban, prolong the INR (95). INRs >5, without bleeding, are common during argatroban or argatroban–warfarin therapy (96). Published methods for monitoring the argatroban-to-coumarin transition using the INR (97,98) or chromogenic factor Xa assay (99) should be followed. Argatroban does not induce antibody formation (100) and has been used safely in patients with antilepirudin antibodies (101).

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Bivalirudin

Bivalirudin is a polypeptide with sequence homology to hirudin. It is cleared by renal elimination and by circulating proteases. Bivalirudin is approved in the United States for use in patients with or at risk of HIT during PCI (Table 2). and was evaluated in an open-label, prospective study of 52 patients with or at risk of HIT (102). The primary end-point of major bleeding occurred in one (2%) patient. Clinical success, defined as survival, emergency bypass surgery, or Q-wave infarction, occurred in 48 (96%) of 50 evaluable patients. The recommended dose is a 0.75-mg/kg initial bolus followed by an infusion of 1.75 mg · kg−1 · h−1 (reduced in renal impairment). There is considerable additional experience with this drug in non-HIT patients who have undergone interventional procedures using bivalirudin anticoagulation with provisional glycoprotein IIb/IIIa inhibition (103).

Prospective, controlled studies in the noninterventional setting have not been conducted with bivalirudin in HIT, although limited retrospective data appear promising (104). In a study of patients with suspected or confirmed HIT who were administered bivalirudin (n = 24), argatroban (n = 13), or lepirudin (n = 5) (105), clinical outcomes were similar among groups. In a retrospective study of 18 bivalirudin-treated patients with suspected or confirmed HIT (106), no patient experienced thrombosis and one (6%) patient had major bleeding. Typically, bivalirudin was started at 0.14 mg · kg−1 · h−1 (reduced to 0.03–0.05 mg · kg−1 · h−1 in renal dysfunction), and then titrated to achieve aPTTs of 1.5–2.5 times baseline.

In approximately half of patients with antilepirudin antibodies, the patient sera also contain antibodies that recognize bivalirudin in vitro (107). The clinical implications of exposing previously lepirudin-treated patients to bivalirudin are unknown.

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Danaparoid

Danaparoid is a glycosaminoglycan isolated from porcine intestine. It has been used since 1982 for treating patients with HIT and is the only alternative anticoagulant evaluated in a randomized controlled trial in HIT (108). In the randomized study, the comparator was dextran 70, which is now considered inappropriate therapy. None of the 42 study patients had major bleeding. In a recent compilation of 1478 clinical experiences with danaparoid in HIT (109), event rates were 16.2% for mortality, 9.7% for thrombosis, and 8.1% for major bleeding. In vitro cross-reactivity between danaparoid and heparin-PF4 antibodies occurred in 3.2% of the patients. In a retrospective comparison of danaparoid and lepirudin therapy in HIT (110), major bleeding was less with danaparoid. High-dose danaparoid (e.g., 2,500 anti-Xa U bolus followed by 400 U/h for 4 h, then 300 U/h for 4 h, then 200 U/h as a maintenance dose) is preferred over a lower, prophylactic dose for patients with HIT (2,110,111). Danaparoid does not affect the INR, can be administered IV or subcutaneously, and does not cross the placenta. The use of danaparoid in critically ill patients with HIT was found to be safe and effective (112).

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Fondaparinux

Fondaparinux is modeled after the antithrombin-binding pentasaccharide region of heparin and has negligible in vitro cross-reactivity with HIT sera (113). It is approved in the United States and elsewhere for prophylaxis and treatment of venous thromboembolism. Prospective, controlled studies in HIT have not been conducted. Data on fondaparinux in HIT are limited. A review of literature available before February 2006 identified 37 patients (114). Thrombotic and hemorrhagic event rates in this small sample were low. Fondaparinux is contraindicated in renal failure and must be used with caution in patients with renal impairment.

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Reversal of Anticoagulation

The direct thrombin inhibitors and fondaparinux have no direct reversal drug. Protamine sulfate negligibly reverses danaparoid. If excessive levels of anticoagulation occur, with or without bleeding, the drug should be stopped or its dose decreased. The rapid elimination half-lives of the direct thrombin inhibitors (argatroban, 39–51 min; lepirudin, 1.7 h; bivalirudin, 36 min), but not antithrombin-dependent drugs (danaparoid, 7 h; fondaparinux, 15 h), support normalization of anticoagulant effects within hours of drug cessation. Normalization would take longer in lepirudin- or bivalirudin-treated patients with renal impairment and argatroban-treated patients with hepatic impairment due to systemic overdose from impaired elimination.

Recombinant factor VIIa has been used off-label to treat severe bleeding in HIT patients administered direct thrombin inhibitors (68–70) and healthy subjects administered fondaparinux (115). Fresh frozen plasma has been used to treat a patient after an overdose of argatroban (116).

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CARDIOVASCULAR SURGERY

Antibody Positive

If HIT or persisting heparin-PF4 antibodies are present, and if cardiac surgery cannot be delayed, nonheparin anticoagulation during the surgery is recommended (1,2) (Table 3). In acute HIT patients undergoing cardiac surgery, direct thrombin inhibition is preferred over heparin or danaparoid (1). Of the direct thrombin inhibitors, bivalirudin is preferred over lepirudin (1). Safe, effective doses of the direct thrombin inhibitors during cardiac surgery in HIT have not been established in prospective studies, and no direct thrombin inhibitor is approved for use in this setting. However, clinical experiences with direct thrombin inhibition during cardiac surgery in patients with HIT or antibodies are reported, and results from the larger patient series are described subsequently. Clinical experiences are also reported for danaparoid (109) and for heparin, together with the short-acting platelet inhibitors epoprostenol (117), iloprost (118), or tirofiban (119). Antifactor Xa monitoring is needed if danaparoid is used during the surgery. Protocols for the dosing and monitoring of these anticoagulants during cardiac surgery have been proposed (28,120,121).

Table 3

Table 3

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Lepirudin

A retrospective analysis evaluated 57 patients with HIT who underwent cardiovascular surgery with CPB using lepirudin anticoagulation (122). Lepirudin 0.20 mg/kg was added to the priming solution. A 0.25-mg/kg IV bolus followed by continuous infusion of 0.5 mg/min was started before cannulation. During CPB, lepirudin was monitored using the ecarin clotting time. Target values were 350–400 s. Fifty-four (95%) patients fully recovered without evidence of thromboembolism. Four (7%) patients, each with renal impairment, had excessive bleeding associated with prolonged lepirudin elimination. Significant bleeding has been reported in smaller case series (67).

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Argatroban

Dosing guidelines for argatroban during cardiac surgery have been proposed based on retrospective analysis of 21 published adult cases (121). The patients had HIT, a history of HIT, heparin allergy, or antithrombin deficiency. The guidelines suggest an initial argatroban dose of 5 μg · kg−1 · min−1 (plus a 100-μg/kg bolus if CPB), adjusted to target ACTs of 300–500 s for surgery without CPB or 400–600 s for CPB, with the ACT checked every 15 min. The investigators indicated the upper limits of the ACT ranges were arbitrary levels proposed to prevent severe coagulopathy. The proposed initial dose, which remains to be prospectively evaluated, is less than the initial argatroban doses that were evaluated during PCI in clinical studies (93,94).

Lesser argatroban doses and target ACTs have been used in Japan in patients requiring a heparin substitute during cardiovascular surgery (123). Among 15 patients with percutaneous cardiopulmonary support and one patient who underwent aortic replacement with left heart assist, argatroban doses of 0.05–3.9 μg · kg−1 · min−1 achieved target ACTs of 180–200 s. In 16 patients who underwent vascular surgery, argatroban 2 μg · kg−1 · min−1 (initial bolus, 100 μg/kg) supported a target ACT of approximately 150 s. No patient had a postoperative bleeding complication.

In a literature analysis of argatroban use in pediatrics, four patients, each <1 yr old, were identified who underwent CPB using argatroban anticoagulation (124). Each patient had HIT, a history of HIT, or HIT antibodies. There was no consistent approach regarding argatroban dosing or monitoring, with the exception that the target ACT was at least 400 s. No thrombosis occurred. Three infants had major bleeding in association with ACTs >999 s.

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Bivalirudin

A case series reported four patients with suspected HIT who underwent coronary artery bypass grafting using CPB and bivalirudin anticoagulation (125). Patients received a 1.5 mg/kg initial loading dose before cannulation and continuous 2.5 mg · kg−1 · min−1 infusion during CPB. Anticoagulation was monitored using ACTs with a target of 500 s. Anticoagulation during CPB was effective, and total operating times were acceptable. One patient experienced excessive postoperative bleeding.

Prospective studies have evaluated bivalirudin (versus heparin) in non-HIT patients undergoing cardiac surgery using CPB (126) or undergoing coronary artery bypass grafting without CPB (127). Across the studies, bivalirudin was administered to 206 patients and provided effective anticoagulation with a safety profile similar to that of heparin. Bivalirudin dosing in surgery without CPB is similar to that used in PCI.

Surgical techniques that allow blood to stay stagnant should be avoided when using bivalirudin, which is metabolized by enzymes present in blood exposed to wound or foreign surfaces (28). Accordingly, direct retransfusion of shed pericardial/ mediastinal blood into the cardiotomy container should be avoided with the use of bivalirudin to avoid systemic activation and circulation of thromboemboli. Alternatively, shed pericardial blood can be processed via cell salvage systems when using bivalirudin.

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Other Considerations

Direct thrombin inhibitors exert some antiplatelet activity by reducing the thrombin-mediated activation of platelets (128). However, these drugs at clinically relevant concentrations are not potent antiplatelet drugs, and this may be a shortcoming during cardiac surgery. Although data are available on the use of heparin plus short-acting platelet inhibitors in HIT patients undergoing cardiac surgery (117–119), the combined use of direct thrombin inhibitors and platelet inhibitors in this setting remains to be characterized in humans.

Larger volumes of blood products and severe coagulopathy have been described when ACTs >600 s occurred during bypass surgery using argatroban anticoagulation (121). However, intraoperative thrombosis in the CPB circuit of an argatroban-treated patient with HIT and an ACT >800 s has also been described (129). A possible mechanism for the thrombotic event in the face of the prolonged ACT was suggested by subsequent in vitro, thrombelastographic studies on the effects of different anticoagulants on clot dynamics (129). The investigators found that, at clinically relevant concentrations, direct thrombin inhibitors delay clot initiation and propagation, but in contrast with heparin, only minimally affect clot strength in vitro in human plasma. Similar findings have been demonstrated in vitro in human whole blood (130), where the direct thrombin inhibitors were associated with slow formation of strong clots in vitro. It is possible that the combination of a direct thrombin inhibitor with a clot strength-reducing drug, such as hydroxyethyl starch, would provide greater safety than direct thrombin inhibition alone during CPB (131).

Laboratory monitoring of direct thrombin inhibition during cardiac surgery is critical to avoid under- or over-anticoagulation. However, there are limitations with available assays. Functional tests such as the ACT do not reliably assess the degree of anticoagulation with direct thrombin inhibitors. This is partly due to the effects of hemodilution, CPB-related reductions in procoagulant proteins, and/or hypothermia on the ACT (132). Correlation is weak between the standard ACT and plasma levels of lepirudin or bivalirudin (120,132). Modified ACT tests have been described that partially correct the preanalytical effects of CPB on the test, and that extend the linear monitoring range for the direct thrombin inhibitors (132,133). ACT values may also be misleading with respect to anticoagulation status and clot dynamics with direct thrombin inhibitors when compared with heparin (129,130). Monitoring of both clot initiation and clot strength (using thrombelastography) during cardiac surgery with direct thrombin inhibition may be useful (134,135). The ecarin clotting time has been recommended for monitoring lepirudin and bivalirudin during cardiac surgery (120). Modified versions of the ecarin clotting time have been described that are designed to improve accuracy in monitoring (136,137). However, the ecarin clotting time is not a commercially available test in the United States. As monitoring approaches continue to be refined, and perhaps alternative means become available for rapid assessment of antithrombin activity (chromogenic or otherwise), complications associated with excessive or inadequate levels of direct thrombin inhibition during cardiac surgery may be reduced.

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Antibody Negative

If heparin-PF4 antibodies are negative after a HIT episode, guidelines recommend heparin over nonheparin anticoagulants during cardiac surgery (1,2) (Table 3). The risk of complications, particularly bleeding, associated with nonheparin anticoagulants during cardiac surgery is believed to outweigh the risk of recurrence of HIT with brief heparin re-exposure (1). Additional concerns with alternative anticoagulants for cardiac surgery include limited experience and the lack of a reversal drug (1,2). Heparin use should be confined to the intraoperative period, with alternative anticoagulation used pre- and postoperatively as needed (1,2,28). As previously discussed, heparin-PF4 antibodies are transient. In one study of 144 HIT patients, the median time to a negative antibody result after an initial positive result was 50 days by activation assay and 85 days by antigenic assay (11). Patients in whom antibodies have fully waned have briefly tolerated heparin during cardiac or vascular surgery, without recurrence of HIT (11,67,138). This recommendation may evolve as experience grows with direct thrombin inhibition during cardiac surgery.

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CONCLUSIONS

HIT is a prothrombotic disorder that is mediated by immunospecific antibodies and associated with significant risks of thrombosis. Perioperatively, heightened awareness is important for the prompt recognition, diagnosis, and treatment of HIT. HIT should be considered if a patient experiences a platelet count decrease of 50% or if thrombosis occurs 5–14 days after the start of heparin, with other diagnoses excluded. When HIT is strongly suspected or confirmed in a patient, heparin should be discontinued and parenteral alternative anticoagulation should be initiated. HIT antibodies are transient, and heparin should be avoided as long as the antibody test is positive. Many experts prefer a longer, perhaps indefinite, heparin-free period in patients with previous HIT because safe, effective alternative anticoagulants are available and because uncertainty remains regarding the risk of recurrence on heparin re-exposure. In patients with HIT who require cardiac surgery, the surgery should be delayed, if possible, until HIT testing is negative.Alternative anticoagulation should be used perioperatively as needed. HIT is a prothrombotic disease that, even with alternative anticoagulation, is associated with a significant risk for life-threatening morbidity and death.

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