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Stroke following Glenn anastomosis in a child with inherited thrombophilia
International Journal of Cardiology 111 (2006) 464 – 467 www.elsevier.com/locate/ijcard
Letter to the Editor
Stroke following Glenn anastomosis in a child with inherited thrombophilia Ioannis Germanakis a,*, Caterina Sfyridaki d, Eleftheria Papadopoulou b, Maria Raissaki c, Spyridon Rammos e, George Sarris f, Maria Kalmanti b a
Department of Pediatrics, Division of Pediatric Cardiology, University Hospital of Heraklion, 71201 Voutes - Heraklion, Crete, Greece b Department of Pediatrics, University Hospital Heraklion, Crete, Greece c Department of Radiology, University Hospital Heraklion, Crete, Greece d Blood Coagulation Laboratory, Venizelion Hospital, Heraklion, Crete, Greece e Department of Pediatric Cardiology, Onassis Cardiac Surgery Center, Athens, Greece f Department of Pediatric and Congenital Heart Surgery, Onassis Cardiac Surgery Center, Athens, Greece Received 18 March 2005; received in revised form 5 July 2005; accepted 24 July 2005 Available online 4 October 2005
Abstract The optimal anticoagulation following Fontan operation and its modifications remain controversial and it is even less well defined as regards patients with inherited thrombophilia. We present a case of a child with bidirectional Glenn anastomosis for double inlet left ventricle that suffered a stroke despite aspirin prophylaxis; the patient was combined homozygous for prothrombin G20210A mutation and for methylenetetrahydrofolate reductase C677T mutation as well. The family history was positive for fetal loss and premature cardiovascular disease. Large-scale studies are needed to evaluate whether carriers of thrombophilia mutations need more intense thromboprophylaxis. D 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Fontan operation; Thrombophilia; Stroke; Childhood; Congenital heart disease; Thrombosis
1. Introduction
2. Case report
The Fontan operation and its modifications divert systemic venous blood directly to pulmonary arterial circulation and offer the only surgical option in most cases of congenital heart disease where biventricular repair is not possible. However, they are often followed by thromboembolic complications associated with substantial morbidity and mortality [1]. In the pathogenesis of these thromboembolic events, acquired alternations of the haemostatic system might have a significant role [2] but the possible impact of inherited thrombophilia is not well studied and remains unclear. We report a child with a prior bidirectional cavopulmonary anastomosis, homozygous for two thrombophilia mutations, who suffered an ischemic stroke despite aspirin prophylaxis.
The patient, a 4-year-old boy, had undergone a bidirectional superior vena cava to pulmonary artery (Glenn) anastomosis with pulmonary artery ligation for double inlet left ventricle at the age of 6 months. His postoperative course was uneventful; he was asymptomatic without any clinical signs of heart failure and had an excellent weight gain and exercise capacity. Systemic oxygen saturation was 86% and his ventricular function was excellent without any atrioventricular or aortic valve regurgitation. He had a superior vena cava mean pressure of 10 mmHg (Sat 71%), mean right atrial pressure of 4 mmHg (Sat 68%) and a left ventricular end diastolic pressure of 8 mmHg. The child was placed on aspirin prophylaxis (6 mg/kg/day) and due to his excellent status the timing of the final total cavopulmonary anastomosis was under discussion with the family. The child was admitted in the hospital when he manifested an acute episode of dysarthria, focal seizures
* Corresponding author. Tel.: +30 3 2810 392035; fax: +30 3 2810 392778. E-mail address: [email protected] (I. Germanakis). 0167-5273/$ - see front matter D 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2005.07.013
I. Germanakis et al. / International Journal of Cardiology 111 (2006) 464 – 467
465
Labordiagnostika GmgH, Austria) showed that the child was a homozygous double carrier of prothrombin (PT) G20210A mutation and of methylenetetrahydrofolate reductase (MTHFR) C677T mutation as well. Both of his parents were heterozygous for the PT G20210A mutation, while for the MTHFR C677T mutation the father was heterozygous and the mother homozygous. Family history was positive for maternal fetal loss; the father manifested an acute heart infarct two months following the child’s admission. Following an initial course of heparin, the child is currently placed on secondary prophylaxis with warfarin (target INR of 2– 3) and his neurological status is gradually improving.
3. Discussion
Fig. 1. Intracardiac thrombus within the right atrium (between the cursors).
and acute right hemiparesis. Sonographic evaluation showed an intracardiac thrombus within the right atrium (Fig. 1) and an occlusion of the left internal carotid artery. A brain CT and MRI angiography revealed an ischemic stroke due to vascular occlusion of the left middle cerebral artery (Fig. 2). At admission, electrolytes, renal and liver function tests were normal and a secondary polycytemia was present (Hb = 15 g/dL). The activity of coagulation factors II, V, X, IX, XI, XII, VIII:c, vWFAG, protein C and S were within normal range, whereas the activity of factor VII was reduced (Table 1). There was a negative test for activated protein C resistance (STA\-Staclot\ APC-R, Diagnostica Stago, France). Anticardiolipin and antiphospholipid antibodies were negative. Molecular diagnosis using PCR (FV-PT-MTHFR strip assay\, Viennalab
Congenital heart disease is a leading known cause of stroke in children [3,4]. Chronic hypoxia resulting in secondary polycytemia, a low-blood-flow state, and the presence of right to left shunt allowing for paradoxical thromboembolism are well described risk factors in patients whose heart defect has not been completely surgically corrected. Patients with systemic to pulmonary vein anastomosis, either as bidirectional or total cavopulmonary anastomosis, are at a particularly increased risk for thromboembolism. Following the Fontan operation, the reported incidences of venous thromboembolic events and stroke range from 3% to 16% and 3% to 19%, respectively, and are associated with significant morbidity and mortality [1,4 – 7]. As regards their pathogenesis, aside from the well-described anatomic factors such as a history of pulmonary artery banding [7], the presence of a hypercoagulability state is under investigation. A disequilibrium in the haemostatic system favoring thrombosis
Fig. 2. Absence of flow in the left internal carotid, middle cerebral and proximal segment of the anterior cerebral artery on MRI angiography (left) and resulting hypodense area, suggestive of ischemic stroke on CT (right).
466
I. Germanakis et al. / International Journal of Cardiology 111 (2006) 464 – 467
Table 1 Coagulation profile of the patient Hematocrit (%) Hemoglobin (g/dL) Platelet count ( 103) PT (s) aPTT (s) APC-resistance Fibrinogen (mg/dL) INR Lupus anticoagulants Antiphospholipid Ab Lipoprotein A Total cholesterol (mg/dL) LDL cholesterol (mg/dL) Serum folate (nmol/L) (Normal 5th – 95th centile)22 Vitamin B12 (pmol/L) (Normal 5th – 95th centile)22 Total homocysteine(Amol/L) (Normal 10th – 90th centile)26 (Normal 5th – 95th centile)22 FII (%) FV (%) FVII (%) FX (%) FVIII:c (%) vWFAg (%) FIX (%) FXI (%) FXII (%) Protein C:c (%) Protein S:Ag (total) (%) Protein S:Ag (free) (%) Protein S:c (%) FV G1691A (FVL) mutation PT G20210A mutation MTHFR C677T mutation
46 15 225 14 32 Negative 250 1.1 Negative Negative 22 174 100 17.4 (10.2 – 27) 290 (162 – 570) 9 (3.3 – 5.8) (3.2 – 7.8) 108 133 45 80 119 152 92 98 92 97 97 102 132 Negative Homozygous Homozygous
over thrombolysis is present not only after the Fontan procedure and its modifications but also earlier prior to the initial bidirectional Glenn anastomosis [2]. The best described coagulation abnormalities are increased platelet reactivity [8], increased levels of factor VIII [9,10] and reduced levels of protein C, protein S and of coagulation factor VII [8 –12]. Although increased levels of factor VIII have been associated with elevated superior vena cava pressures [9] and reduced levels of antithrombin III with the presence of ventricular dysfunction [2], the hypothesis that the increased venous pressure interferes with the hepatic synthesis of procoagulant and anticoagulant factors is not supported by the recent evidence. The observed coagulation abnormalities cannot be attributed to a secondary hepatic dysfunction [3,8] and their pathogenesis remains unclear. The risk for thromboembolic complications and stroke might be further increased in patients who are carriers of thrombophilia mutations. The most significant inherited prothrombotic conditions are deficiencies of antithrombin III, protein C and S due to the large increase of the corresponding relative risk on individual patients. Never-
theless, factor V G1619A (FV Leiden), prothrombin G20210A and the MTHFR C677T mutation while having less impact on individual risk are significant because of their frequencies in certain populations [13]. A limited number of studies have addressed the impact of inherited thrombophilia on thromboembolic complications of children with congenital heart disease. In a study of children with a stroke of cardiac origin, 4 out of 38 children were carriers of combined thrombophilia defects (FV Leiden and PT G20210A mutation) [14]. A further study reports that 6 out of 28 children with thromboembolism and congenital heart disease or cardiomyopathy were carriers of FV Leiden and PT G20210A mutation; two of the patients with Fontan operation and thrombotic complications were heterozygous carriers of FVL [15]. In otherwise healthy adults, the presence of the PT G20210A and MTHFR C677T mutation is associated with a moderate increased risk for stroke (O.R 1.3 and 1.46, respectively) [16]. Although the role of thrombophilia mutations in pediatric stroke remains controversial [17,18], children carriers of the PT G20210A mutation do show a striking predilection for cerebral ischemic events [19]. The expected number of homozygous individuals for PT G20210A mutation in the general population is 1.3 per 10,000 [20]. Children homozygous for PT G20210A mutation are very rarely described (2 out of 38 children in the largest series today) [19] and our patient is the only described pediatric patient homozygous double carrier for prothrombin G20210A mutation and for MTHFR C677T mutation. The impact of MTHFR C677T mutation on thromboembolic events in adults and children is less clear. MTHFR catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5 methyltetrahydrofolate, a major methyl donor in the remethylation of homocysteine to methionine by methionine synthase. The common variant of the MTHFR gene (677CT), observed in 40% of the alleles in Caucasian populations, is associated with reduced activity and moderate hyperhomocysteinemia especially in states of folate deficiency in young adults [21] and children older than 10 years homozygous for the mutation [22,23]. Hyperhomocysteinemia is associated with a 4.4 O.R for stroke during childhood [24] and the interpretation of total homocysteine levels in children should take into account the normal increase of its levels with age [25,26]. Our patient had a modest increase of total homocysteine compared with reported age-specific values, which was not attributed either to folate or vitamin B12 deficiency (Table 1). Thrombophilia mutations show a geographical distribution and therefore an increased prevalence of PT G20210A and MTHFR C677T mutation in the general population of the Mediterranean island of Crete could account for the presence of a patient double homozygous for both of the mutations [27,28]. The observation that the patient suffered a stroke despite aspirin prophylaxis could be an indication of the negative impact of inherited thrombophilia on the
I. Germanakis et al. / International Journal of Cardiology 111 (2006) 464 – 467
final outcome and of the necessity of a more intense thromboprophylaxis in patient carriers of combined thrombophilia defects. Although most patients following cavopulmonary anastomosis receive aspirin [29] or warfarin [30] prophylaxis, there is no consensus in the literature as to the optimal type or duration of anticoagulation following the Fontan operation and its modifications due to the lack of large-scale prospective studies [1,13]. Cerebrovascular events are reported despite aspirin or warfarin prophylaxis [1,7] although a systemic evaluation of these patients for inherited thrombophilia is not performed. In patients with documented acquired alternations of the haemostatic system, who are considered at increased risk for thromboembolic complications, anticoagulation prophylaxis is recommended by several authors [9,11]. Anticoagulant rather than platelet-directed therapy may be preferable in adult patients without congenital heart disease who are experiencing acute arterial events and are carriers of factor V Leiden, prothrombin G20210A or MTHFR C677T mutations [16]. Given the rarity of inherited thrombophilia defects and particularly of their combined forms, except among certain ethnic groups, large-scale studies are needed to evaluate whether screening for thrombophilia mutations is cost effective and whether carriers of these mutations require a more intense thromboprophylaxis following cavopulmonary anastomosis for congenital heart disease.
References [1] Monagle P, Cochrane A, McCrindle B, Lee Benson L, Williams W, Andrew M. Thromboembolic complications after Fontan procedures—the role of prophylactic anticoagulation. J Thorac Cardiovasc Surg 1998;115:493 – 8. [2] Odegard KC, McGowan Jr FX, DiNardo JA, et al. Coagulation abnormalities in patients with single-ventricle physiology precede the Fontan procedure. J Thorac Cardiovasc Surg 2002;123:459 – 65. [3] Barnes C, Newall F, Furmedge J, Mackay M, Monagle P. Arterial ischaemic stroke in children. J Paediatr Child Health 2004;40:384 – 7. [4] du Plessis A, Chang A, Wessel D, et al. Cerebrovascular accidents following the Fontan operation. Pediatr Neurol 1995;12:230 – 6. [5] Rosenthal DN, Friedman AH, Kleinman CS, Kopf GS, Rosenfeld LE, Hellenbrand WE. Thromboembolic complications after Fontan operations. Circulation 1995;92S:287 – 93. [6] Mathews K, Bale Jr JF, Clark EB, Marvin Jr WJ, Doty DB. Cerebral infarction complicating Fontan surgery for cyanotic congenital heart disease. Pediatr Cardiol 1986;7:161 – 6. [7] Chun DS, Schamberger MS, Flaspohler T, et al. Incidence, outcome, and risk factors for stroke after the Fontan procedure. Am J Cardiol 2004;93:117 – 9. [8] Ravn HB, Hjortdal VE, Stenbog EV, et al. Increased platelet reactivity and significant changes in coagulation markers after cavopulmonary connection. Heart 2001;85:61 – 5. [9] Odegard KC, McGowan FX, Zurakowski D, et al. Procoagulant and anticoagulant factor abnormalities following the Fontan procedure: increased factor VIII may predispose to thrombosis. J Thorac Cardiovasc Surg 2003;125:1260 – 7. [10] Jahangiri M, Kreutzer J, Zurakowski D, et al. Evaluation of hemostatic and coagulation factor abnormalities in patients undergoing the Fontan operation. J Thorac Cardiovasc Surg 2000;120:778 – 82.
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[11] Jahangiri M, Shore D, Kakkar V, Lincoln C, Shinebourne E. Coagulation factor abnormalities after the Fontan procedure and its modifications. J Thorac Cardiovasc Surg 1997;113:989 – 93. [12] Cromme-Dijkhuis AH, Henkens CM, Bijleveld CM, Hillege HL, Bom VJ, van der Meer J. Coagulation factor abnormalities as possible thrombotic risk factors after Fontan operations. Lancet 1990;336: 1087 – 90. [13] Monagle P, Michelson AD, Bovill E, Andrew M. Antithrombotic therapy in children. Chest 2001;119S:344 – 70. [14] Strater R, Vielhaber H, Kassenbohmer R, von Kries R, Gobel U, Nowak-Gottl U. Genetic risk factors of thrombophilia in ischaemic childhood stroke of cardiac origin. A prospective ESPED survey. Eur J Pediatr 1999;158S:122 – 5. [15] Gurgey A, Ozyurek E, Gumruk F, et al. Thrombosis in children with cardiac pathology: frequency of factor V Leiden and prothrombin G20210A mutations. Pediatr Cardiol 2003;24:244 – 8. [16] Kim RJ, Becker RC. Association between factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations and events of the arterial circulatory system: a meta-analysis of published studies. Am Heart J 2003;146:948 – 57. [17] Zenz W, Bodo Z, Plotho J, et al. Factor V Leiden and prothrombin gene G20210A variant in children with ischemic stroke. Thromb Haemost 1998;80:763 – 6. [18] Nowak-Gottl U, Strater R, Heinecke A, et al. Lipoprotein (a) and genetic polymorphisms of clotting factor V, prothrombin, and methylenetetrahydrofolate reductase are risk factors of spontaneous ischemic stroke in childhood. Blood 1999;94:3678 – 82. [19] Young G, Manco-Johnson M, Gill JC, et al. Clinical manifestations of the prothrombin G20210A mutation in children: a pediatric coagulation consortium study. J Thromb Haemost 2003;1:958 – 62. [20] Nguyen A. Prothrombin G20210A polymorphism and thrombophilia. Mayo Clin Proc 2000;75:595 – 604. [21] Spotila LD, Jacques PF, Berger PB, Ballman KV, Ellison RS, Rozen R. Age dependence of the influence of methylenetetrahydrofolate reductase genotype on plasma homocysteine level. Am J Epidemiol 2003;158:871 – 7. [22] Delvin EE, Rozen R, Merouani A, Genest Jr J, Lambert M. Influence of methylenetetrahydrofolate reductase genotype, age, vitamin B-12, and folate status on plasma homocysteine in children. Am J Clin Nutr 2000;72:1469 – 73. [23] Papoutsakis C, Yiannakouris N, Manios Y, et al. Plasma homocysteine concentrations in Greek children are influenced by an interaction between the methylenetetrahydrofolate reductase C677T genotype and folate status. J Nutr 2005;135:383 – 8. [24] van Beynum IM, Smeitink JA, den Heijer M, te Poele Pothoff MT, Blom HJ. Hyperhomocysteinemia: a risk factor for ischemic stroke in children. Circulation 1999;99:2070 – 2. [25] Vilaseca MA, Moyano D, Ferrer I, Artuch R. Total homocysteine in pediatric patients. Clin Chem 1997;43:690 – 2. [26] Must A, Jacques PF, Rogers G, Rosenberg IH, Selhub J. Serum total homocysteine concentrations in children and adolescents: results from the third National Health and Nutrition Examination Survey (NHANES III). J Nutr 2003;133:2643 – 9. [27] Stiakaki E, Germanakis I, Sfyridaki C, Katzilakis N, Danilatou V, Kalmanti M. Prevalence of factor V Leiden and other thrombophilic traits among Cretan children with malignancy. Pediatr Blood Cancer 2005;44:386 – 9. [28] Germanakis I, Stiakaki E, Sfyridaki C, Karampekios S, Danilatou V, Kalmanti M. Stroke in an infant heterozygous carrier of both factor V G1691A and the G20210A prothrombin mutation. Thromb Haemost 2003;90:760 – 3. [29] Jacobs ML, Pourmoghadam KK, Geary EM, et al. Fontan’s operation: is aspirin enough? Is coumadin too much? Ann Thorac Surg 2002; 73:64 – 8. [30] Seipelt RG, Franke A, Vazquez-Jimenez JF, et al. Thromboembolic complications after Fontan procedures: comparison of different therapeutic approaches. Ann Thorac Surg 2002;74:556 – 62.
Letter to the Editor
Stroke following Glenn anastomosis in a child with inherited thrombophilia Ioannis Germanakis a,*, Caterina Sfyridaki d, Eleftheria Papadopoulou b, Maria Raissaki c, Spyridon Rammos e, George Sarris f, Maria Kalmanti b a
Department of Pediatrics, Division of Pediatric Cardiology, University Hospital of Heraklion, 71201 Voutes - Heraklion, Crete, Greece b Department of Pediatrics, University Hospital Heraklion, Crete, Greece c Department of Radiology, University Hospital Heraklion, Crete, Greece d Blood Coagulation Laboratory, Venizelion Hospital, Heraklion, Crete, Greece e Department of Pediatric Cardiology, Onassis Cardiac Surgery Center, Athens, Greece f Department of Pediatric and Congenital Heart Surgery, Onassis Cardiac Surgery Center, Athens, Greece Received 18 March 2005; received in revised form 5 July 2005; accepted 24 July 2005 Available online 4 October 2005
Abstract The optimal anticoagulation following Fontan operation and its modifications remain controversial and it is even less well defined as regards patients with inherited thrombophilia. We present a case of a child with bidirectional Glenn anastomosis for double inlet left ventricle that suffered a stroke despite aspirin prophylaxis; the patient was combined homozygous for prothrombin G20210A mutation and for methylenetetrahydrofolate reductase C677T mutation as well. The family history was positive for fetal loss and premature cardiovascular disease. Large-scale studies are needed to evaluate whether carriers of thrombophilia mutations need more intense thromboprophylaxis. D 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Fontan operation; Thrombophilia; Stroke; Childhood; Congenital heart disease; Thrombosis
1. Introduction
2. Case report
The Fontan operation and its modifications divert systemic venous blood directly to pulmonary arterial circulation and offer the only surgical option in most cases of congenital heart disease where biventricular repair is not possible. However, they are often followed by thromboembolic complications associated with substantial morbidity and mortality [1]. In the pathogenesis of these thromboembolic events, acquired alternations of the haemostatic system might have a significant role [2] but the possible impact of inherited thrombophilia is not well studied and remains unclear. We report a child with a prior bidirectional cavopulmonary anastomosis, homozygous for two thrombophilia mutations, who suffered an ischemic stroke despite aspirin prophylaxis.
The patient, a 4-year-old boy, had undergone a bidirectional superior vena cava to pulmonary artery (Glenn) anastomosis with pulmonary artery ligation for double inlet left ventricle at the age of 6 months. His postoperative course was uneventful; he was asymptomatic without any clinical signs of heart failure and had an excellent weight gain and exercise capacity. Systemic oxygen saturation was 86% and his ventricular function was excellent without any atrioventricular or aortic valve regurgitation. He had a superior vena cava mean pressure of 10 mmHg (Sat 71%), mean right atrial pressure of 4 mmHg (Sat 68%) and a left ventricular end diastolic pressure of 8 mmHg. The child was placed on aspirin prophylaxis (6 mg/kg/day) and due to his excellent status the timing of the final total cavopulmonary anastomosis was under discussion with the family. The child was admitted in the hospital when he manifested an acute episode of dysarthria, focal seizures
* Corresponding author. Tel.: +30 3 2810 392035; fax: +30 3 2810 392778. E-mail address: [email protected] (I. Germanakis). 0167-5273/$ - see front matter D 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2005.07.013
I. Germanakis et al. / International Journal of Cardiology 111 (2006) 464 – 467
465
Labordiagnostika GmgH, Austria) showed that the child was a homozygous double carrier of prothrombin (PT) G20210A mutation and of methylenetetrahydrofolate reductase (MTHFR) C677T mutation as well. Both of his parents were heterozygous for the PT G20210A mutation, while for the MTHFR C677T mutation the father was heterozygous and the mother homozygous. Family history was positive for maternal fetal loss; the father manifested an acute heart infarct two months following the child’s admission. Following an initial course of heparin, the child is currently placed on secondary prophylaxis with warfarin (target INR of 2– 3) and his neurological status is gradually improving.
3. Discussion
Fig. 1. Intracardiac thrombus within the right atrium (between the cursors).
and acute right hemiparesis. Sonographic evaluation showed an intracardiac thrombus within the right atrium (Fig. 1) and an occlusion of the left internal carotid artery. A brain CT and MRI angiography revealed an ischemic stroke due to vascular occlusion of the left middle cerebral artery (Fig. 2). At admission, electrolytes, renal and liver function tests were normal and a secondary polycytemia was present (Hb = 15 g/dL). The activity of coagulation factors II, V, X, IX, XI, XII, VIII:c, vWFAG, protein C and S were within normal range, whereas the activity of factor VII was reduced (Table 1). There was a negative test for activated protein C resistance (STA\-Staclot\ APC-R, Diagnostica Stago, France). Anticardiolipin and antiphospholipid antibodies were negative. Molecular diagnosis using PCR (FV-PT-MTHFR strip assay\, Viennalab
Congenital heart disease is a leading known cause of stroke in children [3,4]. Chronic hypoxia resulting in secondary polycytemia, a low-blood-flow state, and the presence of right to left shunt allowing for paradoxical thromboembolism are well described risk factors in patients whose heart defect has not been completely surgically corrected. Patients with systemic to pulmonary vein anastomosis, either as bidirectional or total cavopulmonary anastomosis, are at a particularly increased risk for thromboembolism. Following the Fontan operation, the reported incidences of venous thromboembolic events and stroke range from 3% to 16% and 3% to 19%, respectively, and are associated with significant morbidity and mortality [1,4 – 7]. As regards their pathogenesis, aside from the well-described anatomic factors such as a history of pulmonary artery banding [7], the presence of a hypercoagulability state is under investigation. A disequilibrium in the haemostatic system favoring thrombosis
Fig. 2. Absence of flow in the left internal carotid, middle cerebral and proximal segment of the anterior cerebral artery on MRI angiography (left) and resulting hypodense area, suggestive of ischemic stroke on CT (right).
466
I. Germanakis et al. / International Journal of Cardiology 111 (2006) 464 – 467
Table 1 Coagulation profile of the patient Hematocrit (%) Hemoglobin (g/dL) Platelet count ( 103) PT (s) aPTT (s) APC-resistance Fibrinogen (mg/dL) INR Lupus anticoagulants Antiphospholipid Ab Lipoprotein A Total cholesterol (mg/dL) LDL cholesterol (mg/dL) Serum folate (nmol/L) (Normal 5th – 95th centile)22 Vitamin B12 (pmol/L) (Normal 5th – 95th centile)22 Total homocysteine(Amol/L) (Normal 10th – 90th centile)26 (Normal 5th – 95th centile)22 FII (%) FV (%) FVII (%) FX (%) FVIII:c (%) vWFAg (%) FIX (%) FXI (%) FXII (%) Protein C:c (%) Protein S:Ag (total) (%) Protein S:Ag (free) (%) Protein S:c (%) FV G1691A (FVL) mutation PT G20210A mutation MTHFR C677T mutation
46 15 225 14 32 Negative 250 1.1 Negative Negative 22 174 100 17.4 (10.2 – 27) 290 (162 – 570) 9 (3.3 – 5.8) (3.2 – 7.8) 108 133 45 80 119 152 92 98 92 97 97 102 132 Negative Homozygous Homozygous
over thrombolysis is present not only after the Fontan procedure and its modifications but also earlier prior to the initial bidirectional Glenn anastomosis [2]. The best described coagulation abnormalities are increased platelet reactivity [8], increased levels of factor VIII [9,10] and reduced levels of protein C, protein S and of coagulation factor VII [8 –12]. Although increased levels of factor VIII have been associated with elevated superior vena cava pressures [9] and reduced levels of antithrombin III with the presence of ventricular dysfunction [2], the hypothesis that the increased venous pressure interferes with the hepatic synthesis of procoagulant and anticoagulant factors is not supported by the recent evidence. The observed coagulation abnormalities cannot be attributed to a secondary hepatic dysfunction [3,8] and their pathogenesis remains unclear. The risk for thromboembolic complications and stroke might be further increased in patients who are carriers of thrombophilia mutations. The most significant inherited prothrombotic conditions are deficiencies of antithrombin III, protein C and S due to the large increase of the corresponding relative risk on individual patients. Never-
theless, factor V G1619A (FV Leiden), prothrombin G20210A and the MTHFR C677T mutation while having less impact on individual risk are significant because of their frequencies in certain populations [13]. A limited number of studies have addressed the impact of inherited thrombophilia on thromboembolic complications of children with congenital heart disease. In a study of children with a stroke of cardiac origin, 4 out of 38 children were carriers of combined thrombophilia defects (FV Leiden and PT G20210A mutation) [14]. A further study reports that 6 out of 28 children with thromboembolism and congenital heart disease or cardiomyopathy were carriers of FV Leiden and PT G20210A mutation; two of the patients with Fontan operation and thrombotic complications were heterozygous carriers of FVL [15]. In otherwise healthy adults, the presence of the PT G20210A and MTHFR C677T mutation is associated with a moderate increased risk for stroke (O.R 1.3 and 1.46, respectively) [16]. Although the role of thrombophilia mutations in pediatric stroke remains controversial [17,18], children carriers of the PT G20210A mutation do show a striking predilection for cerebral ischemic events [19]. The expected number of homozygous individuals for PT G20210A mutation in the general population is 1.3 per 10,000 [20]. Children homozygous for PT G20210A mutation are very rarely described (2 out of 38 children in the largest series today) [19] and our patient is the only described pediatric patient homozygous double carrier for prothrombin G20210A mutation and for MTHFR C677T mutation. The impact of MTHFR C677T mutation on thromboembolic events in adults and children is less clear. MTHFR catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5 methyltetrahydrofolate, a major methyl donor in the remethylation of homocysteine to methionine by methionine synthase. The common variant of the MTHFR gene (677CT), observed in 40% of the alleles in Caucasian populations, is associated with reduced activity and moderate hyperhomocysteinemia especially in states of folate deficiency in young adults [21] and children older than 10 years homozygous for the mutation [22,23]. Hyperhomocysteinemia is associated with a 4.4 O.R for stroke during childhood [24] and the interpretation of total homocysteine levels in children should take into account the normal increase of its levels with age [25,26]. Our patient had a modest increase of total homocysteine compared with reported age-specific values, which was not attributed either to folate or vitamin B12 deficiency (Table 1). Thrombophilia mutations show a geographical distribution and therefore an increased prevalence of PT G20210A and MTHFR C677T mutation in the general population of the Mediterranean island of Crete could account for the presence of a patient double homozygous for both of the mutations [27,28]. The observation that the patient suffered a stroke despite aspirin prophylaxis could be an indication of the negative impact of inherited thrombophilia on the
I. Germanakis et al. / International Journal of Cardiology 111 (2006) 464 – 467
final outcome and of the necessity of a more intense thromboprophylaxis in patient carriers of combined thrombophilia defects. Although most patients following cavopulmonary anastomosis receive aspirin [29] or warfarin [30] prophylaxis, there is no consensus in the literature as to the optimal type or duration of anticoagulation following the Fontan operation and its modifications due to the lack of large-scale prospective studies [1,13]. Cerebrovascular events are reported despite aspirin or warfarin prophylaxis [1,7] although a systemic evaluation of these patients for inherited thrombophilia is not performed. In patients with documented acquired alternations of the haemostatic system, who are considered at increased risk for thromboembolic complications, anticoagulation prophylaxis is recommended by several authors [9,11]. Anticoagulant rather than platelet-directed therapy may be preferable in adult patients without congenital heart disease who are experiencing acute arterial events and are carriers of factor V Leiden, prothrombin G20210A or MTHFR C677T mutations [16]. Given the rarity of inherited thrombophilia defects and particularly of their combined forms, except among certain ethnic groups, large-scale studies are needed to evaluate whether screening for thrombophilia mutations is cost effective and whether carriers of these mutations require a more intense thromboprophylaxis following cavopulmonary anastomosis for congenital heart disease.
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