A modified Blalock-Taussig shunt had been implanted 3 times to treat cyanosis to a patient who has uncorrectable congenital cardiac deformity. We repaired the entire pulmonary artery, from one hilus to the other, to prevent future stenosis while making cardiac transplant. Our patient was also heterozygous for 2 thrombophilic mutations: methylene tetrahydrofolate reductase C677T and Factor V A4070G. Congenital risk factors should be evaluated in patients who have experienced a thromboembolic event before cardiac surery.

Key words : Factor V A4070G, Methylene tetrahydrofolate reductase C677T, Thrombosis

Introduction

Cardiac surgery presents a unique hemostatic paradox. Little attention has been paid to the thrombophilic disorders that (in contrast to a bleeding diathesis) lead to the perioperative thromboembolic complications associated with significant morbidity and mortality in cardiac surgical patients (1). Such patients often demonstrate hypercoagulation (which results from the stress response to surgery and the contact of circulating blood with the cardiopulmonary bypass circuit) and a strong anticoagulant and/or fibrinolytic response (which is associated with the inflammatory response to cardiopulmonary bypass). An imbalance between those 2 competing responses often increases the risk for either hemorrhage or a thromboembolic event during the postoperative period (2, 3).

An additional factor for thromboembolic complications may be a known or unknown pre-existing coagulopathic condition in patients admitted for cardiac surgery. Obtaining the detailed medical history of a patient scheduled to undergo cardiac surgery helps to identify those who have experienced a prior thromboembolic event or are prone to thrombosis. In those patients, a more elaborate work-up is necessary to identify underlying genetic or acquired disorders (1).

In this report, we describe a successful cardiac transplant in a patient in whom thrombosis due to thrombophilic mutations had developed 3 times in a modified Blalock-Taussig shunt.

Case Report

A 12-year-old boy with congenital heart disease who was experiencing cyanosis, dyspnea, and fatigue was admitted to Baskent University Hospital. He was first admitted to our hospital at the age of 16 months when he exhibited signs of cyanosis. At that time, he was diagnosed as having a complex congenital cardiac disorder consisting of a double inlet left ventricle, a double outlet left ventricle, a rudimentary right ventricle, a complete atrioventricular septal defect, valvular and sub¬valvular pulmonary stenosis, and severe right and left atrioventricular valvular insufficiencies. This patient’s medical history was remarkable for 3 occlusions (all of which were due to thromboses) of his modified Blalock-Taussig shunt. All shunt procedures had been performed with synthetic polytetrafluoroethylene grafts; 1 via a left-sided thoracotomy, 1 via a right-sided thoracotomy, and 1 via a median sternotomy.

Since his first shunt operation in 1997, this patient had been treated with acetylsalicylic acid (5 mg/kg/d). The results of laboratory evaluation for thrombosis at the time of the first occlusion of graft showed that his levels of protein C, protein S, and antithrombin were within the normal range, and lupus anticoagulant and anticardiolipin antibodies were not detected. However, his plasma homocysteine levels were moderately high (range, 29-34 µmol/L; normal range, 4.45-15 µmol/L). To identify the cause of high homocysteine level, we assessed vitamin B12 and vitamin B6 levels and screen the thrombophilic mutations as C677T, A1298C, and T1317C in methylene tetrahydrofolate reductase (MTHFR) gene, Leiden, A1090G, A4070G in Factor V gene, Prothrombin G20210A, and the Plasminogen Activator Inhibitor-1 (PAI-1) 4G/5G polymorphism. All genotyping analyses were performed as previously described (4-9).

Mutation screening revealed that this patient was heterozygous for 2 thrombophilic mutations: methylene tetrahydrofolate reductase C677T and Factor V A4070G. The plasminogen activator inhibitor-1 4G/5G polymorphism revealed a 5G/5G genotype that is not associated with thrombo¬embolic events. The patient’s levels of vitamin B12 and B6 were within the normal range.

According to the genetyping results, treatment with warfarin (to maintain an international normalized ratio (INR) between 2.0 and 2.5) in addition to low-dose aspirin was initiated. In 2005, although that anticoagulant therapy was effective and the patient’s INR was 2.48, he was admitted to the hospital with the diagnosis of an occluded polytetrafluoroethylene graft for the last time. Oxygen saturation was 69% as determined by pulse oximetry. Because it was not possible to correct the patient’s pathologic cardiac condition, a successful cardiac transplant was performed in 2007, at which time his weight was 28 kg. After he had received an infusion of fresh frozen plasma, heparin was administered intraoperatively to maintain an activated clotting time of longer than 500 seconds, and reversal was done by protamine. Aprotinin (30 000 U/kg) was added to the prime of the cardiopulmonary bypass to perform operation without perioperative hemorrhage or thrombosis.

Cardiac transplant was successfully performed by means of the bicaval technique. The left pulmonary artery was distorted because of previous operations, and the right pulmonary artery was hypoplastic. We repaired the entire pulmonary artery from one hilus to the other to prevent future stenosis and the need for reoperation. Protamine was administered after cardiopulmonary bypass had been performed and 2 additional units of fresh frozen plasma were administered at that time to hasten hemostasis. Aortic cross-clamp time, cardiopulmonary bypass time and total ischemic time were 78 minutes, 145 minutes, and 285 minutes, respectively. Postoperatively, the patient received 1 U of packed red blood cells and 1 U of fresh frozen plasma. Systemic anticoagulation with intravenous heparin (10-20 mg/kg/h) to maintain an activated partial thromboplastin time between 60 and 85 seconds was resumed uneventfully on postoperative day 1 with no additional need for blood products. Treatment with warfarin (2.5 mg/d) and acetyl¬salicylic acid (5 mg/kg/d) was initiated on the fourth post-operative day as outpatient anti¬coagulant therapy; the INR target was 2.5 to 3.5. To facilitate routine surveillance consisting of endomyocardial biopsies, enoxaparin (1 mg/kg/d) was substituted for warfarin for short periods. No thrombotic or hemorrhagic events were noted during the perioperative period. The patient was discharged uneventfully from hospital on the 17th postoperative day. He has been well for the last 10 months.

Discussion

In patients with a coagulation disorder, the overall incidence of a thromboembolic event is greater than that in the healthy population. Surgery and immobilization are periods of increased risk for thromboembolic events in otherwise healthy persons with a thrombophilic diathesis. Multiple prothrombotic and proinflammatory stimuli converge during cardiopulmonary bypass to effect a balance of procoagulant and profibrinolytic activity (2). In patients with a thrombophilic diathesis, thromboembolic events that develop during cardiac surgery include deep venous thrombosis, pulmonary embolism, graft occlusion, coagulation of the extracorporeal circuit, and, as in our patient, the occlusion of artificial vascular grafts. As a result of careful anticoagulation, our patient did not experience a thromboembolic event during the perioperative or postoperative period.

Hyperhomocysteinemia caused by point mutation that affect homocysteine metabolism may increase the risk for thrombosis and therefore the risk for coronary and peripheral vascular diseases (10, 11). C677T, A1298C and T1317C are the 3 common point mutations in the methylene tetrahydrofolate reductase gene associated with increased plasma homocysteine level. A C>T substitution at nucleotide 677 of the methylene tetrahydrofolate reductase gene reduces 50% of the activity of that enzyme, even in heterozygous or homozygous patients. Activated protein C resistance is another significant risk factor for venous thromboembolism. The Leiden mutation in the Factor V gene accounts for most cases of inherited activated protein C resistance. However, A4074G is an additional Factor V gene mutation that has been shown to increase venous thromboembolic risk by reducing circulating Factor V concentration and activity and thus contributing to the activated protein C resistance phenotype (12, 13). Recently, Factor V mutation at A4070G was identified as an independent prothrombotic factor that may be clinically relevant when associated with other inherited and acquired prothrombotic defects (14).

We previously reported that both point mutations and the single-nucleotide polymorphisms of genes that encode proteins involved in coagulation and anticoagulation cascades are important risk factors for thrombosis during the perioperative period in children who undergo cardiac surgery to correct a congenital defect (15). In a recent study, we also showed that cardiac defects are common risk factors for thromboses in children (16). Our patient, who had a complex congenital cardiac condition, was heterozygous for 2 thrombophilic mutations (methylene tetrahydrofolate reductase C677T and Factor V A4070G); this may explain the 3 prior thromboses that occluded his shunts. Because our patient experienced 3 thrombotic events before cardiac transplant, synthetic material polytetrafluoroethylene from which his shunt was made, may have contributed to those episodes of thrombosis.

The serine protease inhibitor aprotinin inhibits thrombin generation and exerts a direct antifibrinolytic effect via plasmin inhibition. Cardiac transplant, especially in patients who have undergone prior cardiac surgery can be a more complicated procedure, as a documented increased risk of hemorrhagic complications and the need for antifibrinolytic agents such as aprotinin (3). In the setting of reoperative cardiac transplant, aprotinin was safely used without producing hemorrhage or a thromboembolism during the perioperative period in a patient with a methylene tetrahydrofolate reductase C677T mutation (17). We prefer aprotinin because it has been shown that in pediatric patients undergoing cardiac surgery, that agent reduced only thrombomodulin plasma levels and did not alter the homocysteine plasma concentration (17).

In conclusion, patients who have experienced a thromboembolic event before cardiac surgery should be carefully evaluated for congenital risk factors. If such risk factors are identified, we suggest continuing to carefully administer the patient’s routine anticoagulant therapy during the perioperative and postoperative periods.

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