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Ann Thorac Surg 2009;87:629-631. doi:10.1016/j.athoracsur.2008.06.040
© 2009 The Society of Thoracic Surgeons
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Case Reports

Acute Profound Thrombocytopenia After Treatment With Tirofiban and Off-Pump Coronary Artery Bypass Grafting

Andres Beiras-Fernandez, MDa,*,*, Anke Kowert, MDa,*, Pascale Jiru, MDb, Marion Weis, MDb, Michael Spannagl, MDc, Bruno Reichart, MDa, Michael Schmoeckel, MDa

a Department of Cardiac Surgery, University Hospital Grosshadern, Ludwig-Maximilians-University, Munich, Germany
b Department of Anesthesiology, University Hospital Grosshadern, Ludwig-Maximilians-University, Munich, Germany
c Department of Transfusion Medicine, University Hospital Grosshadern, Ludwig-Maximilians-University, Munich, Germany

Accepted for publication June 10, 2008.

* Address correspondence to Dr Beiras-Fernandez, Department of Cardiac Surgery, University Hospital Grosshadern, Ludwig-Maximilians-University, Munich, 81377, Germany (Email: andres.beiras{at}med.uni-muenchen.de).


   Abstract
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The glycoprotein IIb/IIIa (GP IIb/IIIa) receptor antagonists prevent platelet aggregation and thrombus formation, improving outcomes of patients with acute coronary syndrome. Therapy with these agents may lead to bleeding complications and thrombocytopenia, challenging the perioperative management of patients undergoing coronary surgery. We report the successful management of an acute profound thrombocytopenia after urgent off-pump coronary surgery in a patient treated with tirofiban for unstable angina and acute coronary syndrome.


   Introduction
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GPIIb/IIIa receptor antagonists prevent platelet aggregation and thrombus formation, improving outcomes after acute coronary syndrome [1]. However, they may lead to bleeding complications and thrombocytopenia [2], challenging the management of patients after coronary surgery.

A 63-year-old man patient presented with acute coronary syndrome (anterior ST-segment elevation depression; negative myocardial laboratory markers) after a 6-day period of unstable angina. Cardiac catheterization showed a two-vessel coronary disease involving the left main, the left anterior descending, and the left circumflex coronary arteries. The patient was scheduled for coronary artery bypass grafting and infusion with heparin (1,000 IU/h) and tirofiban (initial infusion of 0.4 mg/h for 30 minutes followed by 0.1 mg/h) was started. Initial laboratory results revealed no remarkable findings (Table 1). The baseline platelet count was 223 x 109/L. Treatment with tirofiban and heparin was continued until surgery, which occurred 8 hours later. At this time, the platelet count was 226 x 109/L. The patient underwent off-pump coronary artery bypass grafting by using the left internal thoracic artery to the left anterior descending artery and a single saphenous vein graft to the medial portion of the left circumflex artery. Anticoagulation was initially performed with 10,000 IU of unfractioned heparin and was carefully monitored with activated clotting time (>300 sec). Heparin was conventionally antagonized with protamine after the aortic anastomosis. However, the patient showed a severe diffuse bleeding. Intraoperative blood loss was 1,700 mL. Nine units of frozen fresh plasma, 1 unit of erythrocytes, and 1 unit of platelets were administered. The patient was transferred to the intensive care unit in stable condition with low pharmacologic support with norepinephrine (0.2 mg/h) and milrinone (0.4 mg/h).


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  		Table 1 Laboratory Values of the Patient After Tirofiban Infusion and Transfusion of Thrombocytes
 
At admission, the platelet count was 77 x 109/L. The myocardial laboratory measurements were slightly increased, and the plasmatic coagulation laboratory findings were unremarkable (Table 1). Postoperative blood loss was less than 50 mL/h in the first 8 hours and less than 20 mL/h after that time. Six hours after intervention, the laboratory analyses showed a platelet count of 1 x 109/L. No clinical signs of bleeding were observed. Severe thrombocytopenia (1 x 109/L) was reconfirmed 30 minutes later, and pseudothrombocytopenia was excluded by using an alternate anticoagulant (citrate). Heparin-induced thrombocytopenia could be also excluded after negative enzyme-linked immunosorbent assay test for antibodies to platelet factor 4/heparin. The patient was transfused with 3 units of platelets with a rise in the platelet count from 1 x 109/L to 16 x 109/L after the first unit and 52 x 109/L after all of them. No thromboembolic or bleeding phenomena were observed. Six hours later (12 hours postoperatively) the platelet count was again severely reduced to 18 x 109/L, and a new transfusion of 2 thrombocyte units was necessary. The plasmatic coagulation laboratory values were not remarkable. Two hours later, the platelet count increased to 56 x 109/L and another thrombocyte unit was transfused. In the following 12 hours, the count of platelets increased slowly without transfusion and remained stable (Table 1). The patient was discharged from the intensive care unit 4 days after surgery without thromboembolic or bleeding complications with a platelet count of 179 x 109/L.


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Different GPIIb/IIIa receptor inhibitors, abciximab, tirofiban, and eptifibatide, have been approved for clinical use in patients with acute coronary syndrome [3]. Abciximab has been reported to increase the incidence of thrombocytopenia in comparison with placebo, tirofiban, and eptifibatide [4]. In the RESTORE trial [5], severe thrombocytopenia (< 50 x 109/L) was observed in 0.2% of the patients treated with tirofiban. Drug-induced acute thrombocytopenia is defined as a decrease of the thrombocyte count to less than 20 x 109/L within 24 hours of exposure [6]. In our patient, the platelet counts were lower than 1 x 109/L at 6 hours after an exposure time of 14 hours.

Differential diagnosis with other entities in patients receiving GPIIb/IIIa receptor inhibitors and heparin is mandatory. Pseudo-thrombocytopenia is defined as an artifactual miscalculation of platelets because of clumping platelets in blood samples anti-coagulated with ethylenediaminetetraacetic acid (EDTA). In our case, pseudo-thrombocytopenia could be excluded after repeated platelet counts in blood anti-coagulated with citrate. Heparin-induced thrombocytopenia could be excluded after a negative enzyme-linked immunosorbent assay test for antibodies to platelet factor 4/heparin. Furthermore, heparin-induced thrombocytopenia type I is associated with mild thrombocytopenia, and heparin-induced thrombocytopenia type II typically occurs 4 to 10 days after starting a therapy with heparin.

The profound thrombocytopenia observed in our patient was then most likely associated with tirofiban, considering the duration of the therapy (less than 24 h), the severity of the thrombocytopenia (1 x 109/L 6 hours after exposure), and the negative enzyme-linked immunosorbent assay heparin-induced thrombocytopenia test. However, the mechanism of GPIIb/IIIa receptor antagonists associated with severe thrombocytopenia is not fully understood. One hypothesis suggests the induction of conformational changes in the thrombocyte receptors after therapy, which could react with pre-existing circulating antibodies [7].

Shanmugam and colleagues [8] reported that surgical revascularization could be safely performed in patients within a few hours of receiving tirofiban with little bleeding risk. However, acute profound thrombocytopenia after tirofiban can be life threatening in patients who will undergo coronary surgery, as it may increase the incidence of perioperative bleeding, thus potentially leading to reintervention. In our patient, acute thrombocytopenia presented 6 hours after off-pump coronary artery bypass grafting, and increased thrombocyte substitution therapy was needed to obtain sufficient hemostasis. We believe that no data regarding acute profound thrombocytopenia after off-pump coronary artery bypass grafting have been published.

In our opinion, the thrombocyte count should be strictly monitored in patients presenting with an acute coronary syndrome needing coronary surgery, especially after administration of a GPIIb/IIIa receptor inhibitor. Furthermore, platelet's transfusion should be considered if presentation of the thrombocytopenia occurs in the early postoperative period, to reduce the bleeding risk.


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* Both authors contributed equally to this work. Back


   References
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  1. Boersma E, Harrington RA, Moliterno DJ, et al. Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: a meta-analysis of all major randomised clinical trials Lancet 2002;359:189-198.[Medline]
  2. Demirkan B, Guray Y, Guray U, Korkmaz S. Differential diagnosis and management of acute profound thrombocytopenia by tirofiban: a case report J Thromb Thrombolysis 2006;22:77-78.[Medline]
  3. Karvouni E, Katritsis DG, Ioannidis JP. Intravenous glycoprotein IIb/IIIa receptor antagonists reduce mortality after percutaneous coronary interventions J Am Coll Cardiol 2003;41:26-32.[Abstract/Free Full Text]
  4. Dasgupta H, Blankenship JC, Wood GC, Frey CM, Demko SL, Menapace FJ. Thrombocytopenia complicating treatment with intravenous glycoprotein IIb/IIIa receptor inhibitors: a pooled analysis Am Heart J 2000;140206–1.
  5. RESTORE Investigators Effects of platelet glycoprotein IIb/IIIa blockade with tirofiban on adverse cardiac events in patients with unstable angina or acute myocardial infarction undergoing coronary angioplasty. Randomized Efficacy Study of Tirofiban for Outcomes and REstenosis. Circulation 1997;96:1445-1453.[Abstract/Free Full Text]
  6. Berkowitz SD, Harrington RA, Rund MM, Tcheng JE. Acute profound thrombocytopenia after C7E3 Fab (abciximab) therapy Circulation 1997;95:809-813.[Abstract/Free Full Text]
  7. Bougie DW, Wilker PR, Wuitschick ED, et al. Acute thrombocytopenia after treatment with tirofiban or eptifibatide is associated with antibodies specific for ligand-occupied GPIIb/IIIa Blood 2002;100:2071-2076.[Abstract/Free Full Text]
  8. Shanmugam G. Tirofiban and emergency coronary surgery Eur J Cardiothorac Surg 2005;28:546-550.[Abstract/Free Full Text]



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F. Bizzarri and G. Frati
Acute Profound Thrombocytopenia After Treatment With Tirofiban and Off-Pump Coronary Artery Bypass Grafting: Is There a Paradox?
Ann. Thorac. Surg., September 1, 2009; 88(3): 1048 - 1048.
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 Ann. Thorac. Surg.Home page
A. Beiras-Fernandez, M. Weis, and M. Schmoeckel
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Ann. Thorac. Surg., September 1, 2009; 88(3): 1048 - 1048.
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