Ann Thorac Surg 2005;79:1388-1390
© 2005 The Society of Thoracic Surgeons
Case report
Heparin-Induced Thrombocytopenia Associated With Bilateral Adrenal Hemorrhage After Coronary Artery Bypass Surgery
Faisal G. Bakaeen, MB, BChira,
Jon-Cecil M. Walkes, MDa,
Michael J. Reardon, MD*,a
a Department of Surgery, The Methodist Hospital, Houston, Texas, USA
Accepted for publication September 22, 2003.
* Address reprint requests to Dr Reardon, 6560 Fannin St, #1002, Houston, TX 77030-2761, USA
mreardon{at}tmh.tmc.edu
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Abstract
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Heparin-induced thrombocytopenia (HIT) is a well-recognized syndrome associated with thrombosis and multiple potential clinical sequelae. We report a case of bilateral adrenal hemorrhage, a known but rare complication of heparin-induced thrombocytopenia complicating a routine coronary artery bypass surgery. Thrombocytopenia, abdominal pain, and signs of adrenal insufficiency in the context of heparin treatment should raise suspicion of this unusual complication.
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Introduction
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Heparin-induced thrombocytopenia (HIT) is the most common cause of immune thrombocytopenia. The incidence of HIT in patients undergoing cardiac surgery is relatively rare, but it is a well-documented complication related to frequent heparin exposure in this group of patients. An important component of HIT is the development of thrombotic lesions that are associated with significant morbidity and mortality. We describe HIT with venous thrombosis resulting in adrenal venous obstruction and hemorrhagic infarction after coronary artery bypass.
A 51-year-old man with a history of hypertension and hyperlipidemia presented with angina and a stress test that was positive for ischemia. Coronary angiogram identified severe proximal left anterior descending artery, ramus, circumflex disease, and a good ejection fraction of 45%. He underwent cardiopulmonary bypass and received a triple coronary bypass (left internal mammary artery to the left anterior descending artery, saphenous vein graft to the obtuse marginal and ramus vessels).
The operative course was unremarkable. Intravenous amino caproic acid (Amicar, 10 g) (Xanodyne Pharmaceuticals, Florence, KY) was administered after induction of anesthesia. The patient received 3 units of cell saver blood, 1 unit of fresh frozen plasma, and 2 units of platelets to secure hemostasis before closure. The patient was on aspirin and had received 3,000 units of heparin intravenously during coronary angiography 6 days before the surgery. He received 26,000 units of heparin in the operating room pre-bypass and was reversed with protamine.
The next day the patient was transferred from the intensive care unit to a monitored floor bed after removal of his chest tubes, and aspirin was restarted. An echocardiogram obtained on postoperative day (POD) 4 for a pericardial rub identified no significant pericardial effusion, but there was apical hypokinesis and a possible apical thrombus for which he was started on enoxaparin (Lovenox; Aventis Pharmaceuticals, Kansas City, MO) (1 mg/kg) and sodium warfarin (Coumadin; Bristol-Meyers Squibb, Princeton, NJ). The patient had a fever of 40°C on POD 6 and diffuse abdominal pain with diarrhea. Coumadin was withheld, but Lovenox was continued.
A computed tomographi scan of the abdomen demonstrated mildly enlarged adrenal glands (Fig 1). The patient continued to spike fevers despite negative cultures. His white cell count was normal. However he was noted to have mild thrombocytopenia with a platelet count of 115 x 109 on POD 7 compared with a preoperative platelet count of 266 x 109 and a prior postoperative count of 180 x 109 on POD 1. His platelet count reached a nadir of 40 x 109 on POD 9. At that point Lovenox was stopped, and the patient tested positive for heparin antibodies with a strongly positive enzyme-linked immunoadsorbent assay test. Argatroban (GlaxoSmithKline, Research Triangle Park, NC) drip was initiated at 1 µg/kg/min and was titrated to a target activated partial thromboplastin time of 60 to 75.
A follow-up echocardiogram on POD 11 showed no apical thrombus, but a large pericardial effusion was identified, which required surgical drainage and creation of a pericardial window. The Argatroban infusion was briefly interrupted for the surgery. Later that day the patient's abdominal pain worsened and a repeat computed tomographic scan on POD 12 identified bilateral adrenal lesions consistent with bilateral adrenal hemorrhage (Fig 2). The patient had mild tachycardia and orthostatic hypotension. His serum electrolytes were normal.
Biochemical confirmation of adrenal insufficiency was made including a corticotropin (adrenocorticotropic hormone) stimulation test, and the patient was started on steroid replacement therapy. The platelet count had gradually risen since starting the Argatroban infusion, and it normalized 5 days later. The patient was started on Coumadin on POD 20 and Argatroban was continued throughout the remainder of his hospitalization. He was discharged home on POD 29 (after his initial surgery), and he has been doing well on Coumadin for 3 months. In addition, hydrocortisone was continued with endocrinology follow-up to assess the continued need for hormone replacement therapy.
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Comment
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Heparin-induced thrombocytopenia is a distinct clinicopathologic syndrome caused by platelet-activating antibodies that recognize complexes of platelet factor four (PF4) and heparin [1]. Platelets carry PF4 in their alpha granules and when platelets are activated, PF4 is released, and some of it binds to the platelet surfaces. Heparin binds to the PF4 resulting in conformational changes that expose determinants in PF4 to act as an immunogen. In patients at risk for HIT, IgG antibodies form against and bind to the heparin-PF4 units. The resulting immune complex binds to and activates platelets through their constant fragment receptors. In addition, the immune complex may activate the coagulation cascade leading to thrombin generation and induction of vascular endothelial thrombogenic effects.
Thrombocytopenia (platelet count less than 150 x 109/L) or a 50% decrease from the pre-treatment platelet count, or a combination of these, is the most common clinical effect of HIT. The thrombocytopenia is typically moderately severe (40 to 80 x 109/L) and bleeding is seldom an issue. Of far greater importance are the thrombotic complications seen in HIT [2]. The platelet count typically begins to fall between 5 and 10 days after heparin exposure (with our patient, day 7). In a different scenario, also known as rapid onset (type II) HIT, a patient who had been exposed and sensitized to heparin within the past 100 days has a precipitous drop in platelet count develop after re-exposure. This in turn is due to residual circulating HIT antibodies rather than newly generated antibodies.
Heparin-induced thrombocytopenia is associated with a high frequency of thrombosis, despite the discontinuation of heparin therapy. The initial rate of thrombosis is about 5% to 10% per day for the first 1 to 2 days, and the 30-day cumulative risk is about 50% [1].
The frequency of HIT in patients undergoing cardiac surgery is about 2% [3]. In this setting, HIT is associated with an overall mortality of 18% to 43%. The predominant thrombotic event appears to be arterial in keeping with the arterial disease in these patients in contrast with the predominance of venous thrombosis in other patient groups. In the case at hand, the nature of the thrombosis was venous resulting in adrenal venous obstruction and hemorrhagic infarct.
The diagnosis of HIT starts with a high index of clinical suspicion. A variety of assays are available, including the platelet aggregation test, serotonin release assay, and enzyme immunoassay. Only a subset of patients who had HIT develop also had thrombocytopenia develop and then subsequent thrombotic complications. Thus the iceberg model of HIT was proposed [1].
Once a diagnosis of HIT is entertained, all heparin products including low molecular weight heparin administration should be immediately stopped and an anticoagulant substitute including hirudin (Lepirudin, Berlex Laboratories, Montville, NJ) and Argatroban should be started. Argatroban is a small synthetic molecule derived from L-arginine that inactivates clot-bound and free thrombin. Argatroban has an advantage of achieving a steady state rapidly, with a predictable dose-response effect. Its anticoagulant effects are reversible with a hepatic elimination half life of 40 to 50 minutes. In a study using historical controls, Argatroban was shown to improve clinical outcomes in patients who have HIT without increasing the risk of bleeding [4].
Coumadin results in a rapid decline in the level of protein C, a natural anticoagulant that precedes the reduction in other pro-coagulant factors. Also, Coumadin does not have antithrombin activity and therefore should be introduced only after starting an antithrombin agent and recovery of the platelet count. Inappropriate timing of Coumadin administration can result in progression of thrombosis.
Bilateral adrenal hemorrhagic infarct should be suspected when thrombocytopenic patients have abdominal pain and hypotension develop in association with heparin treatment [5]. In general, the role of HIT in the incidence of adrenal hemorrhage is likely underestimated because heparin exposure may have not been reported and HIT testing may have not been uniformly performed.
We describe a unique case of adrenal insufficiency related to HIT after a coronary artery bypass surgery and its treatment.
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References
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- Warkentin TE. Clinical picture of heparin-induced thrombocytopenia. Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia. 2nd ed. : New York: Marcel-Deckker, Inc; 2001. p. 43–86
- Kelton JG. Heparin-induced thrombocytopenia: an overview. Blood Rev. 2002;16:77–80[Medline]
- Lee DH, Warkentin TE. Frequency of heparin-induced thrombocytopenia. Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia. 2nd ed. : New York: Marcel-Deckker, Inc; 2001. p. 87–121
- Lewis BE, Wallis DE, Berkowitz SD, et al. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation. 2001;103:1838–1843[Abstract/Free Full Text]
- Ernest D, Fisher MM. Heparin-induced thrombocytopenia complicated by bilateral adrenal hemorrhage. Intens Care Med. 1991;17:238–240[Medline]
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Abstract
Introduction
