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Ann Thorac Surg 2006;81:2308-2310
© 2006 The Society of Thoracic Surgeons
a Department of Anesthesiology, Virginia Commonwealth University Medical Center, Richmond, Virginia, USA
b Division of Cardiothoracic Surgery, Virginia Commonwealth University Medical Center, Richmond, Virginia
Accepted for publication August 22, 2005.
* Address correspondence to Dr Cain, Virginia Commonwealth University Medical Center, Department of Anesthesiology, 1200 E Broad St, Box 980695, Richmond, VA 23298-0695 (Email: rebeccs13{at}aol.com).
| Dr Spiess discloses that he has a financial relationship with The Medicines Company, Parsippany, NJ.
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Abstract |
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Unfractionated heparin (UFH) has been a near universal anticoagulant for cardiac surgery; however it is contraindicated in patients with heparin-induced thrombocytopenia type II (HIT type II). Antibodies to platelet factor four heparin complexes (PF4-H) are present in 6% to 17% of patients prior to cardiac surgery, and 1% to 3% of all patients exhibit thrombocytopenia after administration of UFH [1]. After cardiopulmonary bypass (CPB), 30% to 50% express platelet factor four heparin complexes antibodies [1]. This immune-mediated reaction and its consequences are bringing routine use of UFH into question.
Anticoagulation strategies for patients needing CPB with HIT type II have been numerous, but none have been approved. Direct thrombin inhibitors act directly without antithrombin III. Hirudin (a leech protein) is a parent compound for this drug class. Bivalirudin (an analog of hirudin) is approved for primary anticoagulation in percutaneous angioplasty interventions [2]. It is presently undergoing Food and Drug Administration trials for patients with HIT type II undergoing heart surgery. We present a successful case using bivalirudin anticoagulation for a woman requiring mitral valve surgery with HIT type II, past thromboses, systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), and dialysis-dependent renal failure.
A 25-year-old black female with systemic lupus erythematosus presented to cardiac surgery with worsening congestive heart failure. For dialysis she had been receiving UFH with unexplained episodes of sudden and prolonged thrombocytopenia. She was on chronic warfarin therapy as a consequence of her APS and previous thrombotic events. The APS antibodies were thought to be contributory to both her past thrombocytopenia and thromboses. The possibility of HIT type II was raised due to the episodic nature of her thrombocytopenia after UFH administration.
An enzyme-linked immunoassay for platelet factor four heparin complexes antibodies was performed, which was negative. A transesophageal echocardiogram demonstrated severe mitral regurgitation, severe pulmonary hypertension, and an ejection fraction of 40% to 45%. Mitral valve surgery was recommended.
Prior to surgery her platelet count was 106,000/mm3, and she received UFH per dialysis protocol. The next morning her platelet count was 47,000/mm3. Surgery was postponed and an enzyme-linked immunoassay for platelet factor four heparin complexes antibodies was positive. Within a week her platelets increased to 98,000/mm3 and it was decided to proceed with surgery. Bivalirudin was chosen for anticoagulation. Unknown to us, UFH was placed in her dialysis catheter overnight. After induction of anesthesia and the start of surgery, pre-bypass coagulation testing revealed a platelet count of 65,000/mm3. Surgery continued, and as planned, no further heparin would be administered.
A bolus of 1.0 mg/kg and an infusion of 2.5 mg/kg/h of bivalirudin were utilized, and 50 mg was added to the pump prime. A baseline activated clotting time (ACT) was elevated (337 seconds), which was probably due to residual warfarin that had been discontinued 4 days before surgery or due to the APS antibodies. After bolusing bivalirudin, the ACT was 507 seconds (Table 1).
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Bivalirudin utilizes the amino acid sequences of the two active sites of hirudin connected with a tetra-glycine spacer [1, 4]. With the shortest half-life (ie, 25 minutes), it is cleaved directly by thrombin (80%) and has no known antidote. Bivalirudin is dialyzable and can be removed post-bypass via hemofiltration [5]. In renal failure there is modest prolongation of its half-life [2].
Bivalirudin has been utilized in large percutaneous angioplasty intervention studies with improved outcome compared with heparin and protamine or heparin and protamine plus IIb/IIIa blocking agents [2]. In a trial comparing bivalirudin with heparin and protamine for off-pump CABG, the bivalirudin group showed no difference in overall outcome or bleeding [6].
Antiphospholipid syndrome is an autoimmune disorder often associated with systemic lupus erythematosus [7]. It is the most common of the hypercoagulability syndromes [7]. The APS antibodies compete with anticoagulant proteins (ie, protein C, S, tissue plasminogen activator, and annexin V) for platelet binding activation sites, creating a prothrombotic state [7]. Unfractionated heparin or heparan assists in the binding of annexin V to platelets; however, no cross-reactivity to HIT type II has been described [7, 8]. The APS antibody increases the endothelial expression and creation of tissue factor, a leading cause of thrombin generation during CPB [7].
Antiphospholipid syndrome has been studied in cardiac surgery with several series reported [7]. Thrombotic events were common, and in one series of 19 patients, 16 had major postoperative complications [7]. Twelve of the 19 patients died. Heparin was used in all of these patients and the possibility of HIT type II was never examined.
With APS, the ACT is elevated at baseline because the antibody interferes with sample activation. Patients who have APS requiring cardiac surgery are often managed with high-dose heparin to maintain elevated ACTs. However, there remains a high incidence of thrombotic events and anticoagulants, such as direct thrombin inhibitors may be indicated. Our patient had an elevated baseline ACT. After receiving bivalirudin, the ACT behaved as expected for patients without APS, yet never normalized after stopping the infusion. The chest was closed with minimal bleeding and there was no subsequent hemorrhage. The APS antibodies may have been responsible for the prolonged ACT post-CPB.
Unfractionated heparin markedly increases expression of PF4 and the platelet factor four heparin complex is highly antigenic. Our patient received UFH regularly, producing repeated antigenic challenges, perhaps with increased platelet factor four heparin complex antibodies. The high incidences of thrombotic complications in patients with APS who receive UFH for CPB may represent unrecognized HIT type II. No investigation exists in the literature of increased risk of HIT type II in patients with APS.
Our patient did not have thrombotic or bleeding complications. We cannot claim these results were solely due to bivalirudin, but with the question unexplored regarding cross-reactivity between HIT type II and APS, it seems possible. The only recommendation regarding APS patients undergoing heart surgery has been to give large doses of UFH, which have often been catastrophic. Bivalirudin worked well in this complex case. We believe that patients undergoing cardiac surgery with APS should be tested for HIT type II and administered an alternative to UFH.
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This article has been cited by other articles:
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  Q. A Czosnowski, S. W Finks, and K. C Rogers Bivalirudin for Patients with Heparin-Induced Thrombocytopenia Undergoing Cardiovascular Surgery Ann. Pharmacother., September 1, 2008; 42(9): 1304 - 1309. [Abstract] [Full Text] [PDF]
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 H. Gorki, V. Malinovski, and R. D.L. Stanbridge The antiphospholipid syndrome and heart valve surgery Eur. J. Cardiothorac. Surg., February 1, 2008; 33(2): 168 - 181. [Abstract] [Full Text] [PDF]
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