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Case Reports  |   September 2004
Perioperative Hemorrhage and Combined Clopidogrel and Aspirin Therapy
Author Affiliations & Notes
  • Michael Moore, M.B., F.R.C.A.R.S.I.
    *
  • Michael Power, M.B., F.F.A.R.C.S.I., F.A.C.P.
  • *Specialist Registrar, †Consultant Anesthetist and Intensivist, Department of Anesthesia and Intensive Care, Beaumont Hospital, Dublin, Ireland.
Article Information
Case Reports
Case Reports   |   September 2004
Perioperative Hemorrhage and Combined Clopidogrel and Aspirin Therapy
Anesthesiology 9 2004, Vol.101, 792-794. doi:
Anesthesiology 9 2004, Vol.101, 792-794. doi:
CLOPIDOGREL has been introduced as another antiplatelet drug in combination with aspirin to decrease thrombotic events in patients with cerebrovascular and coronary artery disease. Patients are presenting for surgery taking a combination of both aspirin and clopidogrel. We report two cases of surgery and anesthesia complicated by bleeding associated with the combination of aspirin and clopidogrel.
Case Reports
Case 1
An 83-yr-old woman with known atherosclerotic cerebrovascular disease presented with a transient ischemic attack. Her medications included aspirin 300 mg once daily and bendrofluazide, lisinopril, and pravastatin for concomitant hypertension and ischemic heart disease.
Twenty-four hours after admission the patient, while receiving intravenous heparin, had another transient ischemic attack. Computerized tomography brain scan revealed a small new area of infarction near her right internal capsule. For this reason clopidogrel 75 mg daily was added and heparin was stopped. Magnetic resonance imaging of the brain revealed right parietal/temporal/frontal deep matter changes consistent with watershed infarction. Over the next 2 days she had fluctuating neurologic signs with periods of recovery. A carotid duplex scan showed a 70–80% stenosis of her right internal carotid artery. She was therefore scheduled for a right carotid endarterectomy. Preoperative platelet count was 258 × 109/L (150–400 × 109/L), activated partial thromboplastin time 36 s (normal range 23–35 s), and prothrombin time 14 s (normal range10–14 s). Bleeding time was not performed.
Intraoperatively received 5,000 units of intravenous heparin before shunt insertion. The neck incision was noted to be “oozy,” and a drain was inserted before wound closure. A coagulation screen revealed an activated partial thromboplastin time of >300 s that was corrected to normal with protamine. Anesthesia was discontinued and the endotracheal tube was removed uneventfully and the patient was transferred to the recovery room.
Over the next 2 h the patient had persistent bleeding from her neck wound despite a normal activated partial thromboplastin time. A hematoma developed that required evacuation under general anesthesia. She then returned to the recovery area, where she developed stridor with cyanosis. She was again transferred to the operating theater and underwent emergency intubation after inhalation induction. She was subsequently transferred to the intensive care unit. Wound hemostasis remained satisfactory.
The patient received ventilatory support for 3 days as a result of glottic edema. She also received 2 units of erythrocyte concentrate. On the third day, the endotracheal tube was removed uneventfully with minimal residual stridor. She made a successful recovery and was transferred to the ward for further management
Case 2
A 74-yr-old woman presented to the outpatient clinic with a history of hoarseness for 2–3 yr and dyspnea on exertion. Examination revealed a large multinodular goiter with tracheal compression. The patient was scheduled for subtotal thyroidectomy.
She had a background history of coronary artery disease with a myocardial infarction, coronary angioplasty, and stenting and subsequent therapy with clopidogrel 75 mg daily. The patient was advised to discontinue clopidogrel and aspirin for 1 week before surgery. The date of surgery was changed twice. Ultimately, on the day of surgery the patient remained on clopidogrel 75 mg once daily, aspirin 75 mg once daily, atorvastatin, isosorbide mononitrate, and sotalol hydrochloride.
Preoperative platelet count was 225 × 109/L (150–400 × 109/L), activated partial thromboplastin time 30 s (normal range 23–35 s), prothrombin time 12 s (normal range10–14 s). Bleeding time was not performed.
Anesthesia and surgery were uneventful. The endotracheal tube was removed uneventfully and the patient was transferred to the recovery area.
In the recovery room, bleeding was noted from her wound, and approximately 45 mins after surgery she developed respiratory distress. As clips were being removed she developed cyanosis and asystole. After successful placement of the endotracheal tube with cardiopulmonary resuscitation and intravenous adrenaline, circulation was returned. In the operating theater, on clip removal, fresh blood and clots were removed from the neck wound. Several bleeding sites received diathermy. No bleeding vessel was seen. After hemostasis was secured two drains were inserted and the wound was closed. The patient was transferred to intensive care.
She required two units of packed cells because of her blood loss. On the third day the endotracheal tube was successfully removed. Four days later the drains and clips were removed.
Discussion
Clopidogrel hydrogen sulfate is a platelet aggregation inhibitor that was introduced as a secondary prevention therapy in patients at high risk of thrombotic events as a result of recent myocardial infarction or stroke or established vascular disease. A single daily dose of 75 mg is effective.1 
Platelets are activated by adenosine diphosphate. Clopidogrel selectively and irreversibly inhibits adenosine diphosphate induced binding of fibrinogen to platelets by causing a major reduction in the adenosine diphosphate induced activation of the membrane glycoprotein IIb/IIIa complex. It also inhibits platelet aggregation in response to collagen, thrombin, and shear stress and has a synergistic effect when combined with aspirin.2 Clopidogrel thus prolongs bleeding time, inhibits platelet aggregation, and delays clot retraction. Bleeding time is significantly prolonged with both agents and reaches a maximum of 1.5-fold to twofold of baseline after 3 to 7 days.3 Platelets are inhibited for their lifespan.
In a recent study Serebruany et al.  examined the antiplatelet properties of clopidogrel and aspirin versus  aspirin alone in patients with congestive heart failure with heightened platelet activity. Platelet studies were performed at baseline and after 30 days of therapy. After 30 days of monotherapy with aspirin 325 mg there were no changes in platelet characteristics as compared to baseline. However, the addition of clopidogrel 75 mg resulted in significant inhibition of platelet activity.4 
The Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events trial found that long-term administration of clopidogrel 75 mg alone in patients with atherosclerotic vascular disease was more effective than aspirin alone in reducing the combined risk of ischemic stroke, myocardial infarction, or vascular death. The overall safety profile of clopidogrel appears to be as least as good as that of medium-dose aspirin with an added benefit of fewer gastrointestinal side effects than aspirin.5 
The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators trial demonstrated an impressive benefit from combined clopidogrel and aspirin in reduction of mortality and Q wave myocardial infarction. However, discontinuation of clopidogrel and aspirin for less than 5 days resulted in an increased tendency of perioperative bleeding in patients undergoing coronary artery bypass graft compared with patients receiving aspirin alone.6 
In reply to correspondence concerning the Clopidogrel in Unstable Angina to Prevent Recurrent Events trial, the authors state that for elective surgery, combined clopidogrel and aspirin therapy “may be stopped a few days before surgery to minimize the risks of bleeding.”7 
The increased morbidity associated with combined aspirin and clopidogrel therapy has also been reported in a recent study by Yende et al.  8 They demonstrated that the combination of clopidogrel and aspirin before coronary artery bypass graft is associated with increased frequency of reexploration for bleeding and an increased need for erythrocyte transfusion. The authors recommend platelet transfusion for bleeding in patients who have received clopidogrel before coronary artery bypass graft and that the discontinuation of these agents before surgery may reduce postoperative bleeding.
Furthermore, Chapman et al.  described an elective abdominal aortic aneurysm repair complicated by diffuse hemorrhage resulting from combined therapy.9 The editor of the journal in which this was published replied with the knowledge of at least two other cases where combined therapy caused excessive blood loss during carotid endarterectomy.10 
Recently, a study by Payne et al.  investigating the effect of combined clopidogrel and aspirin on bleeding times in healthy volunteers found after 2 days treatment with clopidogrel 75 mg and 150 mg aspirin per day there was a significant 3.4-fold increase in bleeding time relative to baseline. The authors suggest that combination clopidogrel and aspirin therapy in major cardiovascular or general surgical patients may carry a significantly increased risk of bleeding.11 
Surgeons and anesthetists are now increasingly likely to encounter patients on combined clopidogrel and aspirin therapy presenting for elective and emergency surgery. These two cases demonstrate perioperative bleeding associated with continued combined aspirin and clopidogrel therapy. In both cases the bleeding was delayed in that it was not obvious until the end of surgery. As a result both patients required unanticipated emergency intubation and intensive care admission and needed unanticipated surgical reexploration and increased blood product transfusion.
The increased risk of intraoperative and postoperative bleeding should be of concern. Timely discontinuation of these agents before surgery to reduce perioperative bleeding must be balanced against the benefit of combined antiplatelet therapy in the prevention of thrombotic events.
References
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Calvin JE, Klein LW: The use of antiplatelet agents in acute cardiac care. Crit Care Clin 2001; 17:365–77Calvin, JE Klein, LW
Quinn MJ, Fitzgerald DJ: Ticlopidine and clopidogrel. Circulation 1999; 100:1667–72Quinn, MJ Fitzgerald, DJ
Serebruany VL, Malinin AI, Jerome SD, Lowry DR, Morgan AW, Sane DC Tanguay JF, Steinhubl SR, O’Connor CM: Effects of clopidogrel and aspirin combination versus aspirin alone on platelet aggregation and major receptor expression in patients with heart failure: The Plavix Use for Treatment of Congestive Heart Failure (PLUTO-CHF) Trial. Am Heart J 2003; 146:713–20Serebruany, VL Malinin, AI Jerome, SD Lowry, DR Morgan, AW Sane, DC
Clopidogrel Versus Aspirin in Patients at Risk of Ischaemic Events Steering Committee: A randomized, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348:1329–39
Yusuf S, Phil D, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK, The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators: Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345:494–502Yusuf, S Phil, D Zhao, F Mehta, SR Chrolavicius, S Tognoni, G Fox, KK
Yusuf S, Mehta S: Treatment of acute coronary syndromes. N Engl J Med 2002; 346:206–8Yusuf, S Mehta, S
Yende S, Wunderlink RG: Effect of clopidogrel on bleeding after coronary artery bypass surgery. Crit Care Med 2001; 29:2271–5Yende, S Wunderlink, RG
Chapman TW, Bowley DM, Lambert AW, Walker AJ, Ashley SA, Wilkins DC: Haemorrhage associated with combined clopidogrel and aspirin therapy. Eur J Vasc Endovasc Surg 2001; 22:478–9Chapman, TW Bowley, DM Lambert, AW Walker, AJ Ashley, SA Wilkins, DC
Beard JD: Haemorrhage associated with combined clopidogrel and aspirin therapy. Eur J Vasc Endovasc Surg 2001; 22:478–9Beard, JD
Payne DA, Hayes PD, Jones CI, Belham P, Naylor AR, Goodall AH: Combined therapy with clopidogrel and aspirin significantly increases the bleeding time through a synergistic antiplatelet action. J Vasc Surg 2002;Payne, DA Hayes, PD Jones, CI Belham, P Naylor, AR Goodall, AH