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CARDIOVASCULAR ANESTHESIA

The Use of Lepirudin for Anticoagulation in Patients with Heparin-Induced Thrombocytopenia During Major Vascular Surgery

Departments of Anesthesiology & Pain Management and Surgery, University of Texas Southwestern Medical Center, Dallas, Texas

Address correspondence and reprint requests to Philip E. Greilich, MD, Anesthesiology and Pain Management Service (112A), Veterans Affairs North Texas Health Care System, 450. 0 South Lancaster Road, Dallas, TX 75216. Address e-mail to philip. greilich{at}email.swmed.edu

	Abstract

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IMPLICATIONS: The method of anticoagulation in patients undergoing major vascular surgery with a history of heparin-induced thrombocytopenia (HIT) is controversial. We present two cases in which a bolus only technique using recombinant hirudin (Lepirudin or Refludan) was used successfully in patients with HIT scheduled for vascular surgery.

	Introduction

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Heparin-induced thrombocytopenia (HIT) is one of the most common immune-mediated adverse drug reactions caused by immunoglobulin-G antibodies (1). Improved recognition of HIT and increased frequency of repeat heparin exposures in patients with cardiovascular disease has created a clinical dilemma when continued anticoagulation is necessary. Lepirudin (Refludan^TM Hoechst Marion Ronssel Inc., Kansas City, MO) is a recombinant hirudin derived from yeast cells and unlike heparin is a direct inhibitor of thrombin that acts independently of antithrombin-III (2). We present two cases in which bolus dosing of lepirudin was used intraoperatively in patients with HIT undergoing major vascular surgery.

	Case 1

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A 71 yr-old male with a history of hypertension, cerebrovascular accident, chronic obstructive pulmonary disease, and peripheral vascular disease presented for revision of a femoral to posterior tibial artery bypass placed 4 mo previously. The initial procedure was complicated by graft occlusion on postoperative Day 1 requiring emergent thrombectomy and anticoagulation with heparin. On postoperative Day 6, gangrene of his right first, second, and third toes developed that was also associated with a decrease in platelet count from 208,000 to 103,000/µL. A clinical diagnosis of HIT was confirmed by positive heparin-induced antibodies (heparin/platelet factor 4 enzyme-linked immunosorbent assay [ELISA]). The patient was treated for acute HIT with lepirudin (0.4 mg/kg bolus with continuous infusion at 0.15 mg/kg/hr) for 2 days.

Three months later, the patient was readmitted for a second revision of the bypass graft. All heparin-containing solutions were avoided and the patient received lepirudin 0.4 mg/kg bolus IV before vascular clamping, followed by 0.2 mg/kg every hour. The adequacy of anticoagulation was monitored (every 45 min) by using an activated partial thromboplastin time (aPTT) targeted at 2–2.5 times normal. The operation lasted 6 h and there was no evidence of clinically significant bleeding. At the conclusion of the procedure, lepirudin was not reversed and immediate postoperative laboratory studies included: prothrombin time 13.9 sec, aPTT 54.2 sec, and platelet count 226,000/µL. The patient was transferred to the surgical intensive care unit where lepirudin was infused for 4 days during which time he was transitioned to warfarin. There were no postoperative complications and he was discharged home 9 days after surgery.

	Case 2

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A 55 yr-old male with a history of coronary artery disease, diabetes mellitus, and hypertension developed HIT after coronary artery surgery while receiving subcutaneous heparin for deep vein thrombosis prophylaxis. His episode of HIT was associated with a decrease in platelet count from 198,000/µL to 51,000/µL and was complicated by extensive thrombosis resulting in bilateral above-the-knee amputations. The diagnosis of HIT was confirmed by heparin/PF4 ELISA. Because of nonhealing of the amputation wounds, the patient underwent aortoiliac thrombectomy with balloon angioplasty and stenting of bilateral iliac artery stenoses two days after all heparin was stopped. During surgery for thrombectomy and stent placement, he received lepirudin (0.4 mg/kg initial IV bolus) followed by 0.2 mg/kg boluses of lepirudin every hour for the duration of the procedure. The lepirudin was monitored to maintain aPTT levels of 2–2.5 times normal. There were no intra- or postoperative bleeding complications.

	Discussion

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The cases presented in this report demonstrate that bolus only dosing of lepirudin can be used to anticoagulate patients undergoing major vascular surgery with a history of HIT. Our clinical diagnosis was based on the presentation of moderate to severe thrombocytopenia and arterial thrombosis after several days of heparin exposure. The heparin-PF-4 ELISA was used to confirm the clinical diagnosis (1). Lepirudin, a Food and Drug Administration-approved drug for acute HIT, was used to anticoagulate the patients during arterial clamping (i.e., stasis) and surgical intervention. The selection of a dosing regimen and method of monitoring was based on existing literature, clinical context, and the pharmacokinetics of lepirudin.

The overall incidence of HIT after heparin therapy ranges from 1% to 30%, depending on the patient population, method, and criteria of diagnosis (1,3). Individuals with previous heparin exposures are generally considered at higher risk of HIT (1). Heparin-induced thrombocytopenia is generally divided into two subpopulations (Type I and II). Patients experiencing Type I HIT are asymptomatic and have mild thrombocytopenia that may resolve even if heparin is continued. Patients with Type II HIT have profound thrombocytopenia usually associated with arterial thrombosis. Failure to recognize this disorder can lead to further thrombotic complications, and mortality can reach 20%–30%, especially when heparin administration is not discontinued (1). Because it is unclear whether these two categories represent independent pathophysiologic mechanisms, it is recommended that patients with HIT I and II be treated similarly (1,4).

The diagnosis of HIT is based on the generation of antibodies directed against a heparin-platelet factor-4 (H-PF-4) complex (5). These antibodies bind platelet Fc receptors and cause platelet activation that can lead to thrombosis. Although most experts consider the platelet [¹⁴C]-serotonin release assay to be the most sensitive and specific (>95%) assay for diagnosing HIT, its technical complexity limits widespread use (1,3,4). Several related (i.e., aggregometric) and less complicated diagnostic assays include the heparin-induced platelet-activation assay, platelet-rich plasma aggregation (to small dose heparin), and an ELISA specific for the antibody to the H-PF-4 complexes. Although the sensitivity of platelet-rich plasma aggregation is quite low (50%), heparin-induced platelet-activation assay and heparin-PF-4 assays both have sensitivities and specificities of 90% or better (1,3).

As in our patients, the first step in the management of individuals suspected of HIT is to discontinue heparin administration (1,4). In some instances, this will be all that is required until a laboratory diagnosis of HIT is established. If the thrombocytopenia is severe and/or thrombosis ensues, immediate treatment based on a clinical diagnosis is indicated (1,4,6,7). Lepirudin is currently the only drug approved by the U. S. Food and Drug Administration (FDA) for the treatment of acute HIT. The current package insert recommends an initial dose of 0.4 mg/kg (not exceeding 110 kg) with an infusion of 0.15 mg/kg/hr (normal renal clearance) (8,9). Although there is no known reversal agent (including blood products) for lepirudin, its relatively short half-life (t_1/2 = 30–60 minutes) usually restores normal coagulation shortly after bolus doses are stopped (6,8). Topical fibrin sealant has been used to improve hemostasis when anticoagulation cannot be reversed (9). Other side effects include prolonged effects in patients with significant renal insufficiency, allergic skin reactions, airway edema, and very rarely anaphylaxis. Tachyphylaxis has not been reported (10).

When anticoagulation is required for either endovascular or surgical procedures, an emerging body of literature also supports the use of lepirudin in patients with a history of HIT (11–13). Historically, alternatives such as ancod and low molecular weight heparin have been used but were largely abandoned because of unacceptable difficulty in administration, bleeding, and/or extensive cross-reactivity with the H-PF-4 complexes (1,6,14). Although some centers currently advocate the use of the heparinoid, danaparoid sodium (limited cross-reactivity with H-PF-4 complexes), other centers have found its variable elimination half-life to result in unacceptable rates of complications associated with blood loss (6,15). The short-acting prostacyclin analog, Iloprost, has been used successfully in a few cases (16). Most recently, some centers have advocated the use of intraoperative heparin only in patients with a history of HIT that are currently antigen negative (17).

The optimal method for administering IV lepirudin in patients undergoing major vascular surgery has yet to be established. The largest studies using lepirudin for indications other than acute HIT involve patients undergoing coronary endovascular procedures (with and without unstable angina) and surgical coronary revascularization (with or without cardiopulmonary bypass) (11–13,18). Both bolus only and bolus plus infusion techniques have been safely used. Initial doses ranged from 0.2–0.6 mg/kg immediately before the intervention with subsequent doses between 0.05–0.2 mg/kg/hr administered as an infusion or as boluses throughout the duration of the procedure (6,11–13,18). Bolus doses and infusion were adjusted based on the aPTT or ecarin clotting times (ECT) (11–13,18). Our selection of a bolus only technique was based on familiarity (with heparin dosing) and simplicity in the face of a complex anesthetic. Given the slightly longer elimination half-life of lepirudin (compared with heparin), we felt that the selection of an initial dose (0.4 mg/kg) that would maintain therapeutic lepirudin levels for up to one hour was justified. We measured the aPTT every 45 minutes and continuously monitored the surgical field to ensure that the patients were not clinically under- or over-anticoagulated.

There is currently no consensus on the technique of choice for monitoring lepirudin levels. The aPTT is the method for monitoring lepirudin recommended in the manufacturer’s package insert and was also the method of choice in several large trials (7,11,12). Nonetheless, a significant interpatient variability in the doses required to maintain targeted lepirudin levels (because of fluctuations in renal clearance and thrombin generation) and poor correlation between lepirudin levels and the aPTT has prompted the development of alternate methodologies (19). In 1996, Nowak and Bucha (20) introduced the ECT, a method designed to improve the ability to accurately detect plasma lepirudin levels. The ECT uses a snake venom activator (ecarin) to convert prothrombin (factor II) to meizothrombin, which has moderate procoagulant activity (21). The ability of lepirudin to neutralize meizothrombin (and prolong the ECT) is concentration dependent. Potzsch et al. (21,22) have demonstrated the superiority of the ECT compared with the activated clotting time (no correlation) and aPTT in predicting ex vivo lepirudin levels in blood from healthy volunteers and patients with cardiovascular disease. Despite the potential advantages of using the ECT, our selection of the aPTT was based on the limited outcome data, lack of FDA-approval and the expense associated with maintaining the ECT system. Instead we adjusted our aPTT target to at least 2.5 times baseline to ensure that we achieved sufficient anticoagulation, especially during times of stasis (i.e., clamping).

In summary, the cases presented demonstrate that a bolus only technique can be safely used to anticoagulate patients with a history of HIT during major vascular surgery. The use of a lepirudin initial dose of 0.4 mg/kg followed by boluses of 0.2 mg/kg every hour were sufficient to maintain an aPTT more than 2.5 times control values. Although some clinicians may prefer to use an infusion technique and ECT to administer and monitor lepirudin therapy, we believe the same objectives can be achieved using a more familiar approach that uses readily available coagulation testing.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Sun, Y. Articles by Whitten, C. W. Search for Related Content PubMed PubMed Citation Articles by Sun, Y. Articles by Whitten, C. W. Related Collections Cardiovascular Heart Pharmacology