Eur J Cardiothorac Surg 2001;20:883-885
© 2001 Elsevier Science NL
Ischemic heart disease associated with protein C deficiency
Mikio Ninomiyaa,
Haruo Makuuchia,
Toshiya Ohtsukab,
Shinichi Takamotob
a Department of Cardiovascular Surgery, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo 105-8470, Japan
b Department of Cardiothoracic Surgery, Faculty of Medicine, University of Tokyo, Tokyo, Japan
Received 1 May 2001;
received in revised form 27 June 2001;
accepted 10 July 2001.
Corresponding author. Tel./fax: +81-3-3947-3210
e-mail: mikio-ninomiya{at}par.odn.ne.jp
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Abstract
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Three patients of ischemic heart disease associated with protein C deficiency are reported. Although delayed diagnosis of protein C deficiency resulted in the failure of repeated interventions, coronary artery bypass grafting performed after making the correct diagnosis has led to satisfactory mid-term results under strict anticoagulation therapy. The level of protein C should be measured more frequently in the field of ischemic heart disease and earlier diagnosis of its deficiency should be made, because measurement of protein C does not cost much.
Key Words: Protein C deficiency • Ischemic heart disease • Coronary artery bypass grafting
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1. Introduction
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We report three patients of ischemic heart disease associated with protein C deficiency that had adverse effects on the outcomes of the treatment.
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2. Case 1
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A 76-year-old man with three-vessel coronary artery disease underwent coronary artery bypass grafting (CABG) with vein grafts in 1989. Although the bypass procedure was uneventfully performed and 200 mg/day of ticlopidine had been administered, all the grafts became occluded within 3 months. Percutaneous transluminal coronary angioplasty (PTCA) was performed, but repeated thrombo-occlusion of the grafts required four additional PTCAs during the following 6 years. Since deep vein thrombosis occurred in 1997, protein C was measured and the diagnosis of hereditary protein C deficiency was made (Table 1). Although warfarin was started immediately, the graft to the left anterior descending artery (LAD) again became occluded, and the ejection fraction fell to 29%. Since further PTCA would have probably failed, the LAD was bypassed with the left internal thoracic artery (LITA) using a minimally invasive direct CABG technique. On postoperative day (POD) 1, 81 mg/day of aspirin, 150 mg/day of dipyridamole, and warfarin were started, maintaining an international normalized ratio of prothrombin time (INR) of between 2.0 and 2.5, and the graft remains patent 4 years after surgery.
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3. Case 2
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A 64-year-old man with acute myocardial infarction received PTCA for the LAD and subsequent heparin and anti-platelet therapy in January 1998. Six days later, soon after heparin was discontinued, re-occlusion of the LAD occurred and re-PTCA was performed. The same episode recurred three times during the following 7 weeks in spite of warfarin therapy, the ejection fraction fell to 36%, and the diagnosis of hereditary protein C deficiency was finally made (Table 1). CABG (LITA to the first diagonal branch, vein grafts to the LAD, the posterolateral branch (PL), and the second diagonal branch) was performed under cardiopulmonary bypass using mild hypothermia in March 1998. Since bleeding continued postoperatively, 81 mg/day of aspirin and 150 mg/day of dipyridamole were started only from POD4, and warfarin from POD10 to maintain an INR of between 2.0 and 2.5. All the grafts are patent 3 years after surgery.
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4. Case 3
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A 60-year-old woman underwent off-pump CABG for two-vessel coronary artery disease in August 2000. Although the activated coagulation time (ACT) had reached 307 s with 8000 U of heparin and the LAD was smoothly bypassed using the LITA within 20 min of coronary occlusion time, clot formation occurred during the subsequent revascularization of the PL, and 12,000 U of heparin were required to return the ACT to over 300 s. Although graft flow to the PL was 30 ml/min with a normal flow pattern and 81 mg/day of aspirin and warfarin were started from POD1, complete thrombo-occlusion of the graft was revealed on POD4, and the diagnosis of hereditary protein C deficiency was made. Warfarin has been continued in order to maintain an INR of between 2.0 and 2.5, and the LITA graft remains patent 10 months after surgery.
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5. Discussion
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Although protein C deficiency is a well-known disorder associated with thromboembolism, making its diagnosis is difficult unless remarkable past or family history exists. To our regret, PTCA or CABG failed several times before protein C deficiency was diagnosed, resulting in low cardiac function or incomplete revascularization. The prevalence of hereditary protein C deficiency is reported to be 1 in 200 to 300 according to Miletich [1] and 1 in 620 according to Sakata [2]. We think that this prevalence is not very low and that it is worth measuring the level of protein C more frequently in the early stages of treatment for ischemic heart disease, thus enabling proper anticoagulation therapy. At our institution, protein C antigen is measured by a latex photometric immunoassay method using LPIA-ACE PC kit from IATRON Laboratories (Tokyo, Japan) and its activity is measured by a coagulation time method using Protein C Reagent Coagulometric Combipack from Dade Behring (Marburg, Germany), each costing only 1750 yen (about $15).
Several methods of diagnosing deficiency of protein C under warfarin therapy have been advocated. Linn et al. [3] reported that the protein C activity to coagulation factor II activity ratio was less than 3.57 and its ratio to factor X activity was less than 4.56 in protein C deficient patients. We utilized this criterion.
Few reports have been available about the influence of protein C deficiency on CABG. During the operation, protein C deficiency may lead to unexpected clot formation as in Case 3. In this regard, off-pump rather than on-pump CABG seems to be more dangerous because a reduced dose of heparin is usually used during off-pump CABG. Care should be taken to maintain the proper level of ACT (above 300 s during on-pump CABG from our experience). The use of antifibrinolytic agents such as epsilon aminocaproic acid is ill advised, because they inhibit plasmin and increase the risk of thrombosis. Although aprotinin may have some theoretical benefit because of its inhibitory effect on thrombin and Spanier [4] reported a successful cardiac transplantation in a patient with protein S deficiency using aprotinin, we do not recommend its use in conventional CABG, because it is unknown which of the two effects of aprotinin, plasmin inhibition or thrombin inhibition, would predominate, as Grocott [5] asserted. As for the outcome of CABG, satisfactory mid-term results have been obtained in Cases 2 and 3, in which protein C deficiency had been diagnosed before surgery. Although postoperative warfarin therapy is thought to be indispensable, it must be started carefully because the blood level of protein C falls faster by warfarin than that of factors II, IX, and X, leading to temporal hypercoagulable status, and possibly resulting in graft occlusion. Although a definite protocol of anticoagulation therapy after CABG could not be determined from our experiences alone, starting heparin as soon as possible and subsequent life-long warfarin administration to maintain an INR above 2.0 are recommended. Zauber et al. [6] also reported that heparin should precede warfarin.
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References
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Miletich J., Sherman L., Bronze G., Jr Absence of thrombosis in subjects with heterozygous protein C deficiency. N Engl J Med 1987;317:991-996.[Abstract]
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Sakata T., Kario K., Katayama Y., Matsuyama T., Kato H., Miyata T. Studies on congenital protein C deficiency in Japanese: prevalence, genetic analysis, and relevance to the onset of arterial occlusive diseases. Semin Thromb Hemost 2000;26:11-16.[Medline]
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Linn Y.C., Tien S.L. Detection of protein C or protein S deficiency in patients on warfarin therapy — a study of nine patients. Ann Acad Med Singapore 1994;23:775-780.[Medline]
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Spanier T.B., Chen J.M., Mancini D.M., Smith C.R., Edwards N.M. Cardiac transplantation in a patient with protein S deficiency. Ann Thorac Surg 1999;68:1078-1080.[Abstract/Free Full Text]
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Grocott H.P., Clements F., Landolfo K. Coronary artery bypass graft surgery in a patient with hereditary protein S deficiency. J Cardio-thorac Vasc Anesth 1996;10:915-917.[Medline]
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Zauber N.P., Stark M.W. Successful warfarin anticoagulation despite protein C deficiency and a history of warfarin necrosis. Ann Intern Med 1986;104:659-660.
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Abstract
1. Introduction
