Ann Thorac Surg 2006;82:2187-2191
© 2006 The Society of Thoracic Surgeons
Original Articles: Cardiovascular
Thrombophilia in Cardiac Surgery—Patients With Protein S Deficiency
Parwis Massoudy, MDa,*,
Matthias Thielmann, MDa,
Hannes Müller-Beißenhirtz, MDb,
Ivan Aleksic, MDa,
Günter Marggraf, MDa,
Wulf Dietrich, MDc,
Heinz Jakob, MDa
a Department of Thoracic and Cardiovascular Surgery, West German Heart Center, Essen
b Department of Hematology and Oncology, University Hospital, Essen
c Department of Anesthesiology, German Heart Center, Munich, Germany
Accepted for publication June 27, 2006.
* Address correspondence to Dr Massoudy, Klinik für Thorax- und Kardiovaskuläre Chirurgie, Universitätsklinikum Essen, Hufelandstr. 55, 45147 Essen, Germany (Email: parwis.massoudy{at}uni-essen.de).
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Abstract
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BACKGROUND: Thrombophilic diathesis may cause severe problems in cardiac surgical patients. Among these, protein S deficiency is a coagulation disorder associated with recurrent thromboembolic events. We analyzed our experience with 7 patients with protein S deficiency who underwent cardiac surgery.
METHODS: We retrospectively reviewed the clinical data, operative and postoperative courses, and the long-term results of 7 patients who were diagnosed to have protein S deficiency. Six of them were operated on using cardiopulmonary bypass, one was operated on with an off-pump procedure.
RESULTS: Procedures performed were emergent pulmonary embolectomy (patient 1), aortic valve replacement and coronary artery bypass grafting (CABG, patient 2), re-CABG (patients 3 and 7), and CABG (patients 4, 5, and 6). In patients 1, 2, 3, and 7, the diagnosis was made perioperatively. Patients 4, 5, and 6 were treated with a modified regimen of warfarin or protamine. All of the latter 3 patients had an uneventful perioperative course without thromboembolic complication. At follow-up, all but 1 of the 7 patients were on continuous warfarin, and were well and without any further thromboembolic events.
CONCLUSIONS: In patients with a past medical history of thromboembolic events or with a perioperative thromboembolic complication, elaborate laboratory investigation should lead to a definite diagnosis. For instance, patients with protein S deficiency undergoing cardiac surgery belong to a high-risk subgroup. Although rare, this and other coagulation disorders can be a critical issue in cardiac surgery. In such patients, we suggest perioperative warfarin therapy with a target international normalized ratio of 2.0 and incomplete protamine antagonism to minimize the risk of a perioperative thromboembolic event.
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Introduction
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In contrast to a bleeding diathesis leading to increased perioperative blood loss in cardiac surgical patients, little attention has been paid to the presence of thrombophilic disorders potentially leading to perioperative thromboembolic complications causing increased mortality and significant morbidity [1]. The reason for thromboembolic complications may be preexisting coagulopathy, known or unknown when the patient is admitted for cardiac surgery [1, 2]. A thorough past medical history examination of any patient due for cardiac surgery helps to identify those with prior thromboembolic events such as deep venous thrombosis, pulmonary embolism, unexpected graft occlusion, and others. In this subpopulation of patients with prior thromboembolic events, a more elaborate laboratory workup is necessary to identify the underlying disorder. This may be antiphospholipid syndrome [1], antithrombin III deficiency, factor V Leyden mutation, protein C or protein S deficiency, and others. The incidence of protein S deficiency in cardiac surgical patients has been described to be 0.03% to 0.13% [2]. Protein S is a vitamin K–dependent protein, which is a cofactor of activated protein C. The latter inactivates factors Va and VIIIa. Both protein S and protein C are produced in the liver. Patients with heterozygous protein S deficiency have a ninefold increased incidence of thromboembolic events compared with the normal population [3]. Homozygous protein S deficiency is extremely rare and not compatible with life. Interestingly, in asymptomatic carriers of a deficiency of protein S, the use of continuous anticoagulant prophylaxis does not seem to be warranted because the incidence of thromboembolic events was not increased in a large prospective cohort study [4]. However, for any patient who is a carrier of a thrombophilic disorder, surgery and immobilization represent periods of increased risk for the occurrence of venous thromboembolism [4].
In the present study, we report on 7 patients with hereditary heterozygous and symptomatic protein S deficiency undergoing cardiac surgery. A concept of a thorough past medical history, laboratory workup, and of perioperative anticoagulant treatment to reduce the risk of thromboembolic events is introduced.
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Material and Methods
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Patients
Of 7,606 patients who underwent cardiac surgery at our institution from March 1999 to October 2005, 3 patients were admitted with a diagnosis of protein S deficiency. These 3 patients had a past medical history of pulmonary embolism, deep venous thrombosis, and coronary artery thrombus. In an additional 4 patients the diagnosis of protein S deficiency was made after a perioperative thromboembolic event leading to laboratory screening for the underlying disorder. Two of the latter had perioperative pulmonary embolism, 1 had perioperative coronary artery bypass graft occlusion, and 1 had intraluminal thrombosis of his left internal thoracic artery graft to the left anterior descending coronary artery. In case of the presence of such events, an elaborate laboratory screening including activated protein C resistance, protein C and S deficiencies, the presence of antiphospholipid antibodies, and lupus anticoagulans is initiated.
The local ethics committee approved this retrospective study and waived the need for patient consent. The study is in compliance with the Declaration of Helsinki.
Anesthesia and Surgery
In the patients in whom protein S deficiency had not been diagnosed before surgery, half the dose of aprotinin (Trasylol; Bayer, Leverkusen, Germany) defined by the Hammersmith protocol (reduced dose of 3 million KIU) was applied. After systemic heparinization, the target activated clotting time (celite before and kaolin after protamine) was 400 seconds. We added 5,000 IU of heparin (Ratiopharm, Ulm, Germany) and 2 million KIU of aprotinin to the priming solution. Additional heparin was applied when control activated clotting time, which was obtained every half hour, fell below 400 seconds. Conventional cardiopulmonary bypass roller pumps (Stöckert, Munich, Germany) and a disposable membrane oxygenator (Jostra, Hirrlingen, Germany) were used after priming with 1,600 mL (1,030 mL of lactated Ringer’s solution; 445 mL of hydroxy-ethyl-starch, 6%; 90 mL of mannitol; and 35 mL of sodium bicarbonate). The patients were cooled (32°C), and 1,500 ml of cold Bretschneider cardioplegic solution (Custodiol; Köhler Chemie, Alsbach-Hähnlein, Germany) was infused into the aortic root after cross-clamping (except in the patient receiving a heart-lung transplant).
Laboratory Determinations
In all but 1 patient protein S determination was conducted in one laboratory. In those patients who had perioperative thromboembolic events, aliquots of routinely preserved preoperative patient plasma were taken for investigation. Protein S was measured as protein S activity using a clotting assay (STA Protein S Clotting; Diagnostika Stago Roche, Basel, Switzerland). Results are presented as percentage of standard normal plasma.
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Results
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Preoperative patient data are given in Table 1. Mean patient age at the time of surgery was 49 ± 7 years. All patients were male.
Pathologic coagulation data and past medical history of thromboembolic events are given in Table 2. Only in 3 of 7 patients, had the diagnosis been made before surgery.
Intraoperative data are shown in Table 3. Patient 5, in whom the diagnosis of protein S deficiency had been established only very shortly before surgery, underwent urgent coronary artery bypass grafting (CABG) and could not wait for warfarin to reach therapeutic range. In the other 2 patients with known protein S deficiency (patients 5 and 6), warfarin therapy was never stopped, and they underwent CABG under therapeutic anticoagulation at an international normalized ratio of 2.2 (target international normalized ratio of 2.0 to 2.3).
Postoperative patient data are shown in Table 4. The 4 patients in whom the diagnosis of a protein S deficiency was made perioperatively (Table 2) were treated with intravenous heparin and thereafter started on oral warfarin.
Patient 7 is still in the intensive care unit and is receiving intravenous heparin with a partial thromboplastin time in the therapeutic range.
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Comment
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In patients with a coagulation disorder, the overall incidence of a thromboembolic event is increased when compared with the normal population. The risk was reported to be eightfold in patients with antithrombin deficiency, sevenfold in patients with protein C deficiency, ninefold in patients with protein S deficiency, and twofold in patients with activated protein C resistance [3]. Surgery and immobilization are periods of increased risk that may trigger the occurrence of thromboembolic events in otherwise healthy persons with thrombophilic diathesis [4]. Indeed, in patients with a thrombophilic diathesis, a predisposing factor was reported to be present at the time of the thromboembolic event in 50% of cases [3]. The potentially devastating thromboembolic events in patients with thrombophilic diathesis occurring in cardiac surgery include deep venous thrombosis, pulmonary embolism, graft occlusion, coagulation of the extracorporeal circuit, and others [1].
In the present study we report on our experience with 7 patients with protein S deficiency undergoing cardiac surgery. In 4 patients with previously unknown protein S deficiency, the diagnosis was established after the occurrence of a perioperative thromboembolic event leading to a laboratory search for an underlying coagulation disorder. The extended coagulopathy investigation includes protein C and protein S levels, activated protein C resistance, and the presence of cardiolipin antibodies and lupus anticoagulans. In the other 3 patients, in whom the diagnosis had been established before surgery, we describe our strategy to perform perioperative anticoagulation to prevent further thromboembolic events. The observed incidence of 7 of 7,607 patients having protein S deficiency is in accordance with the literature [2].
One of the patients with previously unknown protein S deficiency underwent reoperative CABG. He suffered from perioperative occlusion of two bypass grafts, which followed the occlusion of three bypass grafts implanted at the occasion of his first CABG 6 months earlier. Whereas the first incidence of bypass occlusion had not prompted the referring cardiologist to investigate for a possible coagulation disorder, the second incidence was so unexpected that a thorough laboratory investigation was initiated.
Graft occlusion in a patient with protein S deficiency has been reported earlier. In this patient three veins and the mammary artery were found to be occluded 1 month after surgery. After the event, the patient was found to have protein S deficiency. After re-CABG he was treated with intravenous heparin to maintain a partial thromboplastin time twice the normal value. Warfarin was started on the first postoperative day [5].
Thus, when an unexpected graft occlusion event occurs, it is important to diagnose a possibly underlying coagulation disorder early. It may save the patient from a second event of graft occlusion when protective measures such as anticoagulation are started. In the case of our patient, the second thromboembolic event, which was associated with a considerable deterioration of his left ventricular ejection fraction, could possibly have been avoided.
In the 3 patients in whom the diagnosis of the coagulation disorder had been established before surgery, a different regimen of perioperative anticoagulation was applied. One of these patients only received half the dose of protamine calculated to reverse the effect of intraoperative heparin. He had unstable angina and was diagnosed to have protein S deficiency a few days before surgery, which did not allow time to treat him with warfarin to produce sufficient anticoagulation. The other 2 patients were left on warfarin with a target international normalized ratio of 2.0 to 2.3. They underwent CABG (1 off-pump and 1 on-pump) under the protection of both warfarin and heparin.
The performance of cardiac surgery with warfarin has been reported earlier. Postoperative bleeding tendency was not increased in 125 patients operated on with a mean international normalized ratio of 2.4 as compared with 115 control patients who were operated on with a mean international normalized ratio of 1.1 [6].
Alternatively, perioperative heparinization was described in a CABG patient with known protein S deficiency and a past medical history of recurrent thromboembolic events. In this patient, warfarin was discontinued 6 days before surgery, and in-hospital intravenous heparin was started to maintain a partial thromboplastin time of 70 to 90 seconds. Heparin was again started 14 hours after CABG with a target partial thromboplastin time of 60 to 75 seconds, and warfarin was resumed on day 4 after surgery [7].
However, application of warfarin and heparin, theoretically, confers double protection. Heparin is an activator of the physiologic thrombin inhibitor antithrombin, whereas warfarin inhibits the vitamin K–dependent generation of coagulation factors II, VII, IX, and X.
Clinical Implications
Thorough preoperative screening for thromboembolic events in the patient’s past medical history is of utmost importance to identify patients at risk. Surgery itself and immobilization represent triggers for thromboembolic events in otherwise healthy and asymptomatic patients with a thrombophilic diathesis. However, in the present small population of patients with protein S deficiency, fewer than half of the patients had been diagnosed before surgery.
When a patient’s past medical history indicates thrombophilic diathesis, determination of protein C and protein S levels, activated protein C resistance, and the presence of cardiolipin antibodies and lupus anticoagulins should additionally be performed.
Conclusions
Protein S deficiency is a coagulation disorder associated with the occurrence of potentially devastating perioperative thromboembolic events. When the disorder is known before surgery, we suggest to continue the patient’s routine oral anticoagulant treatment and to perform cardiac surgery under the double protection of warfarin and heparin.
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Acknowledgments
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The authors acknowledge the excellent laboratory work by Ms. Kaiser and colleagues, as well as the dedicated work of the perfusionists Ruth Staab, Ingo Wiese, Joerg von Manstein, Markus Deus, Frank Schön, and Josef Graban.
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References
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- Massoudy P, Cetin SM, Thielmann M, et al. Antiphospholipid syndrome in cardiac surgery—an underestimated coagulation disorder? Eur J Cardiothorac Surg 2005;28:133-137.[Abstract/Free Full Text]
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- Martinelli I, Manucci PM, De Stefano V, et al. Different risks of thrombosis in four coagulation defects associated with inherited thrombophilia: a study of 150 families Blood 1998;92:2353-2358.[Abstract/Free Full Text]
- Sanson B-J, Simioni P, Tormene D, et al. The incidence of venous thromboembolism in asymptomatic carriers of a deficiency of antithrombin, protein C, or protein S: a propective cohort study Blood 1999;94:3702-3706.[Abstract/Free Full Text]
- De Pauils R, Bognolo G, Tomai F, Bassano C, Tracey M, Chiariello L. Early coronary artery bypass graft thrombosis in a patient with protein S deficiency Eur J Cardiothorac Surg 1996;10:470-472.[Abstract]
- Dietrich W, Dilthey G, Spannagl M, Richter JA. Warfarin pretreatment does not lead to increased bleeding tendency during cardiac surgery J Cardiothorac Vasc Anesth 1995;9:250-254.[Medline]
- Grocott HP, Clements F, Landolfo K. Coronary artery bypass graft surgery in a patient with hereditary protein S deficiency J Cardiothorac Vasc Anesth 1996;10:915-917.[Medline]
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Abstract
Introduction
