CASE REPORT JIACM 2005; 6(3): 244-7 Thrombophilia due to Activated Protein C Resistance Kamal S Saini*, Mrinal M Patnaik*, Vidya S Nagar**, Alaka K Deshpande*** Abstract Thrombophilia is a hereditary or acquired condition that predisposes individuals to thrombo-embolic events. In patients with a positive family history, or young patients without clear-cut risk factors for thrombosis, it is a relatively easy decision to recommend a thrombophilia profile. The problem arises when these risk factors are camouflaged under the presence of other known and relatively common factors like hyperlipidaemia, cigarette smoking, etc. Here we describe the case of an elderly male who was a chronic smoker and a hypertensive, who presented to us with a neuro-deficit secondary to a pontine infarct. He had suffered in the past from deep vein thrombosis and claudication due to arterial obstruction. Investigations revealed that he had an underlying Activated protein C resistance due to factor V Leiden mutation. Keywords: Thrombophilia, Activated protein C resistance, Factor V Leiden mutation, Deep vein thrombosis, Arterial thrombosis. Introduction Thrombophilia is defined as a hereditary or acquired condition that predisposes individuals to thromboembolic events like myocardial infarction, stroke, deep vein thrombosis, pulmonary embolism, and recurrent miscarriages. The most common cause of hereditary thrombophilia is Activated protein C resistance 1, which is usually caused by the factor V Leiden mutation. Thrombophilic factors generally predispose young individuals to either arterial and/or venous thrombosis, depending on their type and nature. The problem arises when these factors are camouflaged under common acquired prothrombotic conditions like smoking, hypertension, and hyperlipidaemia. In this case report we describe a middle-aged male who had presented to us with repeated episodes of arterial and venous thrombosis. He was a heavy smoker and had poorly controlled hypertension. It was thought all along that these risk factors were responsible for the thrombotic events. He presented to us with a neuro-deficit due to a catastrophic pontine infarct. It was then that we detected that he also had an underlying genetic defect, producing a prothrombotic state, which was then getting accentuated by the acquired risk factors. This defect was identified as the Activated protein C resistance due to the factor V Leiden mutation. Case report A 52-year-old Muslim male was referred to our centre for the management of a catastrophic neuro-deficit. The deficit was acute in onset, and was associated with complete loss of sensorium and generalised tonic clonic convulsions. The patient was unresponsive and had a deviation of the angle of the mouth towards the right side. On examination, his blood pressure was 190/110 mm Hg. He had loss of horizontal conjugate gaze with left facial and bulbar palsy. An urgent CT scan of the brain revealed a large pontine infarct with significant peri-lesional oedema. Within a few hours of admission, the patient developed raised intracranial tension, and went into respiratory failure for which he had to receive assisted mechanical ventilation. The patient then had a stormy course in the critical care unit. He developed ventilatoracquired pneumonia, which then evolved into sepsis with renal failure. It took five weeks before he could be weaned off all artificial life supporting devices and was finally shifted to the medical ward. A detailed history and review of his medical records revealed that in the past, the patient had suffered from several episodes of arterial and venous thrombosis. In 1991, at the age of 44, he suffered from inferior wall myocardial infarction, following which coronary angiography was done which revealed the presence of significant triple vessel disease. He * Chief Resident, ** Associate Professor, *** Professor, Department of Medicine, Grant Medical College and Sir JJ Group of Hospitals, Mumbai, Maharashtra.
was advised to undergo CABG, which was carried out in December, 1991. In 1995, the patient was readmitted to the hospital for complaints of acute right hypochondriac pain associated with severe nausea and vomiting. A diagnosis of acute calculous cholecystitis was made, and the patient underwent cholecystectomy. During the fifth post-operative day, the patient noticed an acute painful swelling of the left lower limb, which on colour doppler studies proved to be an extensive thrombosis of left internal and external iliac veins. The thrombosis was attributed to be due to the postoperative immobilisation alongwith prevalent atherosclerotic risk factors. The patient was started on heparin cover and was administered warfarin for three months. After three months, repeat studies showed a partial recanalisation of the veins with perforator incompetence. In 1996, the patient developed acute pain in his left lower limb with blackish discoloration of his toes. Except for the left femoral pulse no other pulses were felt in the left lower limb. A colour doppler of the lower limbs showed obstruction of left popliteal artery with poor collateral run-off and a thrombus occluding the left popliteal vein. He was again anticoagulated, this time for six months. He was advised to give up smoking and started on aspirin with dipyridamole alongwith his anti-hypertensive medications. In 1998, he developed severe bilious vomiting with abdominal colic. Within a few hours, the patient had severe abdominal distention and was rushed to the hospital. An urgent exploratory laparotomy was done which revealed a distal small intestinal infarction with gangrene, probably due to thrombosis of the mesenteric artery. The patient then underwent a resection anastomosis and was discharged after nearly three months. From 1998 to 2002, the patient s condition stabilised considerably. He gave-up alcohol completely, significantly reduced his smoking, and ensured strict compliance with his medications. He was on his way to the city of Mumbai when he suffered a severe pontine infarct for which he was admitted in our hospital for the first time. An MRI brain with angiography was subsequently performed, which confirmed a pontine infarct due to an occlusion of the basilar artery. Going through his entire history made us feel that although this patient had multiple risk factors for thrombosis, these were not enough to explain the recurrent episodes of arterial and venous thrombosis. Most of these evident risk factors had been modulated by either lifestyle changes or appropriate medications and still he developed a major basilar artery occlusion. It was at this point of time that we decided to investigate this patient for an underlying thrombophilia. Table I shows the results of the investigations performed on the patient. The patient was then started on warfarin, which he was advised to take life-long. He was asked to follow-up in the out-patients department with regular monitoring of his PT/INR. Discussion Thrombophilic factors predispose an individual for arterial and/or venous thrombosis. Depending on the nature of the factor and the underlying predisposing condition in the patient, the arteries and or the veins can be involved. Table II enlists the different thrombophilic factors and their relative predisposition to involve arteries and/or veins. Activated Protein C (APC) resistance, first reported by Dahlback et al in 1993, is the most common cause of inherited thrombophilia 1. It is said to be present when a patient s plasma fails to demonstrate significant prolongation of the APTT on addition of APC. Bertina and colleagues at the University of Leiden explained this observation in 1994 2. A single point mutation results in the substitution of arginine at position 506 by glutamine. Arg506 is one of several cleavage sites in factor V for the anticoagulant action of APC and the mutation results in loss of the cleavage site. This has been termed the factor V Leiden mutation. Activated protein C is a natural anticoagulant that cleaves two activated coagulant factors factor VIIIa and factor Va. This cleavage inhibits the conversion of factor X to factor Xa and of prothrombin to thrombin. The Arg 506 Gln mutation in the factor V Leiden molecule renders factor Va resistant to breakdown by activated protein C. Population genetics and linkage studies revealed that this mutation was found to be present in about 4-7 per cent of the general Caucasian population. It was subsequently proven to be a common causative factor in venous thrombosis. Recent evidence implicates APC resistance as an important factor in arterial thrombosis as well 2,3. Journal, Indian Academy of Clinical Medicine Vol. 6, No. 3 July-September, 2005 245
Table I: Laboratory investigations and results. Investigation Haemoglobin WBC Count Result 10.8 gm% 6,800 (P-85%, L-15%) Bleeding profile BT/CT 4 minutes/6 minutes PT/APTT PT- 13 (C-12), APTT- 35 (C-32) Absolute platelet count 2,30,000/cmm Renal function Serum lipid profile Lipoprotein (a) Serum homocysteine Fasting blood glucose Anti-cardiolipin antibodies (IgM, IgG) BUN - 60 mg/dl, Creatinine - 2.1 mg/dl Cholesterol- 210 mg/dl, LDL 160 mg/dl, HDL 45 mg/dl. Triglyceride - 240 mg/dl 23 mg/dl (normal < 30 mg/dl) 16 mg/dl (normal) 100 mg/dl Negative Protein C activity 62% (N = 70% - 130%) Protein S activity 58.5% (N = 70% - 123%) Activated protein C resistance PCR for factor V Leiden MRI brain Present Positive Pontine infarct with basilar artery obstruction Table II: Thrombophilic factors. Causes of venous Causes of arterial Causes of arterial and thrombosis thrombosis venous thrombosis Protein C deficiency. Atherosclerosis (High serum Activated protein C resistance Protein S deficiency. LDL cholesterol and triglycerides) (Factor V Leiden mutation) Antithrombin III deficiency. Cigarette smoking Antiphospholipid antibody syndrome Prothrombin mutation Hypertension Protein S deficiency (Prothrombin G 20210A). Diabetes Mellitus Oral Contraceptive Pills Oral contraceptives High serum lipoprotein a levels Hyperhomocysteinaemia Malignancy Factor VIII polymorphism (MTHFR enzyme mutation) Immobilisation Infection (Chlamydia, CMV) Surgeries Obesity APC resistance may cause thrombosis, pre-eclampsia, placental abruption, intrauterine growth retardation, and stillbirth 4,5. Females with factor V Leiden who are on oral contraception have considerably higher relative risk of thrombosis. In a study performed in north India, Ahmed et al tested 68 patients who presented with arterial or venous thrombosis for the factor V mutation. 7.3% of patients with venous thrombosis, and 3% of patients with arterial thrombosis tested positive for this molecular defect. In our patient, recurrent episodes of arterial and venous thromboses were repeatedly blamed on prevalent and easily identified risk factors like cigarette smoking, hypertension, and chronic alcoholism. He was Contd. at page 253 246 Journal, Indian Academy of Clinical Medicine Vol. 6, No. 3 July-September, 2005
Contd. from page 246 anticoagulated for short durations of time, after which he would again present with a thrombotic occlusion. Had the underlying genetic predisposition been identified earlier, this patient could have been put on life-long warfarin therapy, saving him all the trouble, which he and his family had to endure. The take home message from this article is that in a case of recurrent thromboses an underlying thrombophilic factor must be pursued, because if identified and treated properly it can significantly reduce mortality and morbidity. References 1. Dahlback B, Carlson M, Svesson PJ. Familial thrombophilia due to previously unrecognised mechanism characterised by poor anticoagulant response to activated protein C: prediction of a co factor to activated protein C. Proc Natl Acad Sci USA 1993; 90: 1004-8. 2. Bertina RM, Koeleman BP, Koster T et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-7. 3. Ahmed RP, Gupta PK, Kannan M, Choudhry VP, Saxena R, Factor V Leiden-the commonest molecular defect in arterial and venous thrombophilia in India. Thromb Res 2003; 110 (1): 19-21. 4. Seligsohn U, Lubetsky A. Medical progress: genetic susceptibility to venous thrombosis. N Engl J Med 2001; 344: 1222-31. 5. Middeldorp S, Meinardi JR, Koopman MM et al. A prospective study of asymptomatic carriers of the factor V Leiden mutation to determine the incidence of venous thromboembolism. Ann Intern Med 2001; 135 (5): 322-7. 6. Prandoni P, Bilora F, Marchiori A. An association between atherosclerosis and venous thrombosis. N Engl J Med 2003; 348: 1435-41. Journal, Indian Academy of Clinical Medicine Vol. 6, No. 3 July-September, 2005 253