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Ann Thorac Surg 2004;78:e89-e91
© 2004 The Society of Thoracic Surgeons

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Case report

Severe Argatroban-Induced Coagulopathy in a Patient With a History of Heparin-Induced Thrombocytopenia

^a Division of Cardiac Surgery, Boston, Massachusetts, USA
^b Division of Anesthesia, Brigham and Women's Hospital, Boston, Massachusetts, USA

Accepted for publication April 12, 2004.

^* Address reprint requests to Dr Aranki, Division of Cardiac Surgery, Brigham and Women's Hospital, 75 Francis St, Boston, MA, 02115 USA
saranki{at}partners.org

	Abstract

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Heparin-induced thrombocytopenia is a serious complication of heparin therapy, and it remains a therapeutic challenge in the subset of patients requiring cardiopulmonary bypass. Alternative anticoagulation strategies include lepirudin, danaparoid, bivalirudin, and argatroban, or a combination of unfractionated heparin with a platelet antagonist. Argatroban is eliminated by a hepatic route, making it a practical option for patients with renal insufficiency. However, the lack of an effective antidote poses a significant problem. We present a patient with a history of heparin-induced thrombocytopenia with thrombosis who underwent a redo aortic valve replacement. Although the level of anticoagulation achieved with argatroban was initially adequate, its persistence after the completion of cardiopulmonary bypass proved to be life threatening.

	Introduction

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Adequate anticoagulation is of paramount importance in the institution of dependable extracorporeal circulation. Argatroban is a synthetic direct thrombin (Factor IIa) inhibitor (derived from L-arginine) that harbors several potentially useful characteristics. Argatroban clearance is dependent on hepatic metabolism. Its short half life and simplicity of monitoring with activated partial thromboplastin time make it an attractive alternative anticoagulant [1]. The elimination time is 39 to 53 minutes with normalization of the activated partial thromboplastin time occurring within 2 to 4 hours [1]. The disadvantage of argatroban in comparison with heparin is the lack of an effective reversal agent.

We present an 82-year-old man with aortic stenosis who was referred to our institution for aortic valve replacement. He underwent coronary revascularization 13 years ago. The postoperative course at that time was complicated by a heparin-induced thrombocytopenia with thrombosis that developed, which led to amputation below the knee of his left lower extremity. His relevant medical history also included repair of his abdominal aortic aneurysm 9 years ago, transurethral prostate resection, right iliac artery stenting, and right carotid endarterectomy. No heparin had been administered during his vascular surgery procedure, nor was any other anticoagulant used in that setting. His preoperative echocardiogram revealed an ejection fraction of 55% and a heavily calcified aortic valve with an aortic valve area of 0.9 cm² and a peak gradient of 61 mm Hg. In addition to aortic stenosis, mild aortic regurgitation was also observed, as well as trace tricuspid and mild mitral insufficiency. His coronary angiogram showed a left anterior descending artery and a left circumflex artery disease, with a patent left internal mammary artery to the left anterior descending artery, and a patent saphenous vein graft to the obtuse marginal branch. Right heart catheterization demonstrated a pulmonary artery pressure of 70/16 and a pulmonary vascular resistance of 425. His Fick cardiac index was 2.1 L/min/m² and his systemic vascular resistance was 1,699. He complained of progressive dyspnea on exertion. As part of his preoperative workup, we found that the patient did not currently have any demonstrable heparin-platelet factor 4 antibodies. However, the patient adamantly refused heparin as an anticoagulant due to his history of heparin-induced thrombocytopenia with thrombosis. In consultation with our hematological team, we opted for argatroban as the alternative anticoagulant. The patient's hepatic function was normal.

Our initial surgical strategy was to institute cardiopulmonary bypass (CPB) through a peripheral route, but after the femoral vessels were exposed we found them to be diseased and opted to cannulate the aorta and right atrium. After the reoperative sternotomy and adhesiolysis, the argatroban infusion was started at 10 µg/kg/min.

Once the activated clotting time reached 350 seconds, we cannulated the aorta and right atrium and instituted CPB. The activated clotting time during CPB was closely monitored, and the argatroban dose was adjusted as needed. The schematic interpretation of the activated clotting time dynamics during CPB is depicted in Figure 1. As demonstrated, the argatroban infusion on CPB was initially reduced to 5 µg/kg/min, then to 3 µg/kg/min, and then it was turned off. The surgical procedure itself was quite uneventful. The aorta was cross clamped and cold blood cardioplegia was administered. After a transverse aortotomy the native aortic valve was excised and the aortic annulus was meticulously debrided. A 21-mm Mosaic valve (Medtronic, Minneapolis, MN) was then sutured in place, and the aortotomy was closed, followed by routine air removal maneuvers and weaning from CPB. The aortic cross-clamp time was 89 minutes. The total CPB time was 169 minutes. A prolonged and arduous attempt at achieving adequate hemostasis ensued. Even though the argatroban infusion was stopped while the cross clamp was still on, more than 8 hours had passed before we were able to control the coagulopathy (Table 1). Once this was achieved, the patient was then transferred to the intensive care unit with an open chest. Intraoperatively the patient received 34 U of cell saver blood, 26 U of packed red blood cells, 24 U of fresh frozen plasma, 7 U of cryoprecipitate, as well as 15 bags (approximately 60 U) of platelets. In the ensuing 24 hours of postoperative care, the patient received an additional 8 U of packed red blood cells, 8 U of fresh frozen plasma, and 1 U of cryoprecipitate.

View larger version (24K): [in this window] [in a new window]   Fig 1. The correlation of activated clotting time (ACT) with the argatroban (ARG) infusion during cardiopulmonary bypass. (X-clamp = aortic cross-clamp time; CPB = cardiopulmonary bypass.)

	Comment

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Heparin-induced thrombocytopenia with thrombosis is the most severe complication attributed to heparin. In its origin is the heparin induced IgG antibody directed at the heparin-platelet factor 4 complex [2]. The incidence of heparin-induced thrombocytopenia after cardiac surgery is 1% to 3%, whereas as many as 27% to 50% of patients have heparin-induced antibodies develop [3]. Argatoban is a direct, reversible inhibitor of both free and clot-bound thrombin. The reports on using argatroban for institution of CPB in the setting of contraindications to the use of heparin are quite limited [4]. Argatroban has been used successfully in the experimental model, but a definitive dose that is safe and effective is yet to be determined [5]. The effectiveness of argatroban can be ascertained by monitoring the activated partial thromboplastin time. Higher levels of anticoagulation achieved with argatroban are monitored by the activated clotting time; however this also prolongs the prothrombin and thrombin time, as well as the ecarin clotting time [5]. The complexity of the affect argatroban has on the coagulation process should make us cognizant that the level of anticoagulation achieved by it may require more sophisticated monitoring methods. One should not assume that the same activated clotting time measurements are equivalent in value when defining the level of anticoagulation achieved with heparin and argatroban [6].

A remote history of heparin-induced thrombocytopenia with thrombosis with a currently negative assay for heparin-platelet factor 4 antibodies should not disqualify the patient from anticoagulation with heparin [5]. However, in the setting of our patient's refusal to proceed with this anticoagulation strategy, we decided to use argatroban as a substitute. The level of anticoagulation achieved was disproportionate to our goal and was also quite prolonged. In the absence of an adequate antidote to argatroban, our management consisted of supportive measures. We have found that the prolongation of the induced hypocoagulable state did not correspond to the expected short half life of the agent. We hypothesize that there was a consumptive component to the observed coagulopathy. However, one must also acknowledge the complex role of CPB in the initiation of hematologic derangements, which include platelet activation, reduction in coagulation factors, fibrinogen and plasminogen, as well as fibrinolytic activation. Previous reports in the literature have pointed to exaggerated argatroban anticoagulation in the setting of heparin-induced thrombocytopenia [7]. One must be aware of inconsistencies in the level of anticoagulation achieved with argatroban [6, 7]. Various modes of anticoagulation in the setting of CPB are available and the choice should be tailored to the individual patient. Ideally patients with heparin-induced thrombocytopenia requiring cardiac surgery should be delayed for 12 weeks, provided that their conditions allow for such a delay. During that period the antibodies will typically disappear [8]. Should their condition bear the burden of urgency, we believe that a lower starting dose of argatroban then used in this case is indicated.

	References

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1. Kathiseran S, Shiomura J, Jang IK. Argatroban. J Thromb Thrombolysis. 2002;13:41–47[Medline]
2. Sakai K, Oda H, Honsako A, Takahashi K, Miida T, Higuma N. Obstinate thrombosis during percutanous coronary intervention in a case with HITTS successfully treated by argatroban anticoagulant therapy. Cath Cardiovasc Interv. 2003;59:351–354
3. Warkentin TE, Greinacher A. Heparin induced thrombocytopenia and cardiac surgery. Ann Thorac Surg. 2003;76:2121–2131[Abstract/Free Full Text]
4. Edwards JT, Hamby JK, Worrall NK. Successful use of argatroban as a heparin substitute during cardiopulmonary bypass: heparin-induced thrombocytopenia in a high-risk cardiac surgical patient. Ann Thorac Surg. 2003;75:1622–1624[Abstract/Free Full Text]
5. Lewis BE, Hursting MJ. Argatroban therapy in heparin induced thrombocytopenia. Warkentin TE, Greinacher A. Heparin induced thrombocytopenia. New York: Dekker; 2001. p. 385–394
6. Cannon MA, Butterworth J, Riley RD, Hyland JM. Failure of argatroban anticoagulation during off-pump coronary artery bypass surgery. Ann Thorac Surg. 2004;77:711–713[Abstract/Free Full Text]
7. Reichert MG, MacGregor DA, Kincaid EH, Dolinski SY. Excessive argatroban anticoagulation for heparin-induced thrombocytopenia. Ann Pharmacother. 2003;37:652–654[Abstract/Free Full Text]
8. Lubenow N, Selleng S, Wollert HG, Eichler P, Mullejans B, Greinacher A. Heparin-induced thrombocytopenia and cardiopulmonary bypass: perioperative argatroban use. Ann Thorac Surg. 2003;75:577–579[Abstract/Free Full Text]

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Hrvoje Gasparovic Sary F. Aranki Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gasparovic, H. Articles by Aranki, S. F. Search for Related Content PubMed PubMed Citation Articles by Gasparovic, H. Articles by Aranki, S. F. Related Collections Extracorporeal circulation