Concomitant heterozygous factor V Leiden mutation and homozygous prothrombin gene variant (G20210A) in patient with cerebral venous thrombosis

Transcription

1 Signature: Med Sci Monit, 2003; 9(5): PMID: Case Study Received: Accepted: Published: Concomitant heterozygous factor V Leiden mutation and homozygous prothrombin gene variant (G20210A) in patient with cerebral venous thrombosis Iwona Kurkowska-Jastrzębska 1, Wojciech Wicha 1, Anatol Dowżenko 2, Barbara Vertun-Baranowska 3, Andrzej Pytlewski 4, Romana Bogusławska 4, Anna Członkowska nd Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland 2 Department of Radiology, Hospital of the Ministry of Internal Affairs, Warsaw, Poland 3 Institute of Haematology and Blood Transfusion, Warsaw, Poland 4 Department of Neuroradiology, Institute of Psychiatry and Neurology, Warsaw, Poland Background: Case study: Conclusions: key words: Summary Factor V Leiden mutation represents the most common genetic risk factor of venous thrombosis in Caucasian population. A common mutation in prothrombin gene, which is due to GÆA transition at position 20210, is also associated with elevated prothrombin concentration and thrombosis. Both this mutations may constitute concomitant risk factors for deep venous thrombosis. A 29-years old woman was admitted in the Emergency Department because of severe headache with vomiting that she suffered for a few days without any neurological deficits. In the Emergency she presented first in her life tonic-clonic seizures followed by right hemiparesis and aphasia and than was admitted to hospital. CT and MR scan showed a large lesion in the left fronto-parietal region with extent edema, which was first diagnosed as tumor. Following MR showed more lesions and typical signs of sinus thrombosis. She improved quickly after stroke without any anticoagulant treatment. Genetic study revealed factor V Leiden mutation and homozygous mutation G20210A in prothrombin gene. Both mutations found in this case, alone, are not a high risk factors for venous thrombosis but together may increase 5 10 fold risk of venous thrombosis. Venous stroke must be considered always in acute neurological events with organic brain lesions, especially in young patients. venous stroke risk factors prothrombin factor V Leiden anticoagulant treatment Full-text PDF: Word count: 1711 Tables: Figures: 3 References: 26 Author s address: Anna Członkowska, 2nd Department of Neurology ul. Sobieskiego Warszawa, Poland 47

2 Case Study Med Sci Monit, 2003; 9(5): BACKGROUND We describe a patient with cerebral venous thrombosis and venous stroke who appeared to be heterozygous for factor V Leiden mutation and homozygous for prothrombin G20210A mutation. Factor V Leiden mutation represents the most common genetic risk factor of venous thrombosis in Caucasian population [1]. A common mutation in prothrombin gene, which is due to GÆA transition at position 20210, is also associated with elevated prothrombin concentration and thrombosis [2]. Concomitant inheritance of both, factor V Leiden and prothrombin mutations, has been shown to significantly elevate rates of deep venous thrombosis and may constitute additive risk factors [3]. However, the association of these mutations in cerebral venous thrombosis has not been reported. CASE REPORT A 29-years old woman was admitted to Emergency Department because of severe headache with nausea and vomiting, lasted for 4 days. She presented no other neurological deficits. For a few years she had been suffering from non frequent migrenic headaches, treated with common pain killers and for one year had been taking oral contraceptives. She did not smoke, and had neither personal history of venous thrombosis nor the familial predisposition. In the Emergency Department she was treated with ketoprofen and dimenhydrinate with only a slight effect and eventually she presented the first ever tonic-clonic seizures with short (20 30 seconds) focal beginning of shaking of right limbs. She was treated with diazepam 10 mg that stopped seizures and she was transferred immediately to Intensive Care Unit. On admission she was unconscious, blood pressure was 120/80 and temperature 37.1 C. She recovered after few minutes and was somnolent, but oriented to person and place. Blood count, biochemical tests and simple coagulation tests (APTT, PT, INR) were normal. Further examinations of the lungs, heart and abdomen revealed no significant abnormalities. She presented profound dysphasia, aggravated right hemiparesis, with brisk asymmetric tendom reflexes and right Babinski s reflex was present. Computed tomography and magnetic resonance showed one lesion in the left fronto-parietal region with extent edema, that was primary diagnosed as tumor (Figure 1). Patient was discharged for neurosurgery department, where next few days she started to improve. Second MR scan (after 7 days) showed disseminated, partially hemorrhagic lesions, and the cerebrospinal fluid examination exposed slightly increased white blood count (24 cells/mm 2 ) (Figure 2). Patients was diagnosed as viral encephalitis and treated with aciclovir, dexamethasone, anti-emetic and nonsteroid anti-inflammatory drugs. After two weeks she was transferred again to our neurological department. Another MR scan showed the same lesions but magnetic resonance angiography (MRA) demonstrated no signal in the central part of the superior saggittal sinus indicating thrombosis. MRA finding was verified by classical angiography of the cerebral veins (Figure 3). A diagnosis of venous sinus thrombosis was made after 4 weeks from the beginning of the disease. The patient however starts to improve during hospitalization without any anticoagulant treatment. The weakness of the limbs, as well as dysphasia diminished. After establishing diagnosis, she was treated with enoxaparine followed by acenocumarol. She got better constantly and was discharged after 8 weeks from the admission with only slight right hemiparesis and without speech disturbances. The 3 months follow-up showed further neurological improvement and no epileptic seizures. After a year from a stroke, she presented no right limb weak- Figure 1. MR scan taken on admission to the hospital showed one lesion in the left fronto-parietal region with extent edema, that was primary diagnosed as a tumor. Figure 2. MR scan taken on the 7 th day after clinical onset showing disseminated partially hemorrhagic lesions in both hemispheres. 48

3 Med Sci Monit, 2003; 9(5): Kurkowska-Jastrzębska I et al Concomitant heterozygous factor V Figure 3A. Angio-MR showing less blood flow in the anterior and posterior part and no signal indecentral part of the superior saggittal sinus indicating thrombosis. ness, only asymmetric tendom reflexes, no epileptic seizures. Coagulation studies including antinuclear and anticardiolipin antibodies, protein S and antithrombin were normal. Protein C resistance ratio was decreased and PCR analysis revealed factor V Leiden mutation. Additionally the patients occurred to be homozygous for prothrombin G20210A mutation. DISCUSSION Many studies have showed that hereditary coagulation disorders may increase risk of venous sinus thrombosis. Association of factor V Leiden mutation with venous thrombosis is clearly documented and the pathomechanism of this trombophilic mutation discovered. Factor V Leiden is a single point mutation resulting in a change of factor V molecule that makes it resistant to activated protein C, which normally cleaves and partially inactivates factor V [4]. Lack of factor V cleavage leads in consequence to increased plasma prothrombotic properties. Factor V Leiden mutation is relatively common with 3 5% prevalence of heterozygous carriers. It has been shown to increase prevalence of cerebral venous thrombosis in heterozygous and homozygous patients [5,6], however, usually with another additive risk factor. No correlation of this genetic factor with ischemic arterial stroke has been found [7]. The pathomechanism related to prothrombin G20210A mutation is currently not understood. Prothrombin, the precursor of thrombin, plays a central role in blood coagulation participating in the process of clotting and platelet activation. It also plays a role in other physiologic mechanism, e.g. in the central nervous system it acts on cell proliferation and differentiation [8]. The mutation of the prothrombin gene G20210A is quite Figure 3B. Latero venous phase cerebral angiogram of right internal carotid artery. There is absence of filling of the posterior and middle part of superior saggittal sinus. The findings are consistent with thrombosis of this sinus. common and the prevalence is 1% up to 3% in population [9]. In carriers of G20210A mutation, there has been found a significant higher plasma prothrombin activity and level than in wild type carriers [10]. The concentration of prothrombin however has not been always elevated in mutation carriers, and there has been no correlation between prothrombin activity and concentration. Dysfunctional variants of prothrombin may be responsible for this phenomenon, and may explain the higher activity of enzyme, that may provide to thrombosis. However, there is no ongoing thrombin generation even in patients homozygous for this mutation [11] and the genotype-phenotype connection of this prothrombin gene polymorphism is not clear. Several studies have been able to confirm an association of prothrombin G20210A mutation with arterial or thrombosis event [1,3,12]. Prothrombin mutation has been found to be connected with myocardial infarction but not with ischemic stroke [7,13]. Case-control studies performed in the Netherlands showed that the risk of cerebral sinus thrombosis is increased threefold to fourfold in carriers of Factor V Leiden, prothrombin mutation or other hereditary prothrombotic condition and is more augmented by oral contraceptives [14,15]. Carriers of two prothrombotic mutations (also factor V Leiden and prothrombin G20210A) have 5 10 fold more increased risk of venous thrombosis [6,16]. In Polish population, concomitant inheritance of these mutation about 4 times increased risk for venous thrombosis [17]. It is evident that neither factor V Leiden nor the prothrombin mutations alone are the major risk factors for stroke, ischemic or venous, unless accompanied by other classical risk factors [17,18]. It was showed that among 40 women with cerebral venous thrombosis 85% (versus 45% of control group) used oral contraceptives and 19% (versus 7%) 49

4 Case Study Med Sci Monit, 2003; 9(5): had various prothrombotic deficiency [14]. In our patient there were coincidence of homozygous mutation in prothrombin gene, factor V Leiden mutation and long use of oral contraceptives. All these factors together may eventually provide to sinus thrombosis and stroke. Venous stroke is often misdiagnosed because of various course and no typical signs of the disease. It is also relatively rare disease. Some clinical studies showed that only about 1% of stroke events are caused by venous thrombosis [7]. The average mortality from sinus thrombosis in Great Britain according to the British registrar was 0.4/10 6 /year. Because mortality rate in sinus thrombosis in more recent reviews was about 10% [19], that made an incidence about 4/10 6 /year [20]. The main risk factors for sinus venous thrombosis are oral contraceptives use, pregnancy, puerperium and thrombofilia. Many other risk factors have been reported in retrospective studies but a significant association with sinus thrombosis has not been demonstrated [14,21]. As in the presented case, clinical manifestation of sinus thrombosis starts frequently with headache, vomiting and seizures and cerebral infarct leading to other neurological symptoms or death. However, patients with sinus thrombosis may recover completely [21]. The long-term outlook of patient showed that 86% had no neurological symptoms, 12% developed second episode of thrombosis and 14% had recurrent seizures [19]. Difficulties with diagnosis of venous stroke had been diminished by MR imaging, which is able to show thrombosis of cerebral veins and sinuses, nevertheless in many cases, patients are waiting long for a proper diagnosis. In our case patient has been treated for viral encephalitis and observed as brain tumor. However venous stroke should be always taken under attention in the cases of partially hemorrhagic, diffused lesions in a brain with clinical acute onset, especially in young person [7]. Our patient had not been treated with anticoagulant agents for a long period during which she presented gradual improvement. The management of patient with cerebral venous thrombosis usually is intravenous heparin followed by oral anticoagulant, however, results of clinical trials are controversial. Einhaupl et al randomizing 20 patient with sinus thrombosis to placebo or intravenous heparin, showed significant better outcome in heparin treated patients [22]. A double-blind randomized trial of low molecular-weight-heparin, nadroparin, and placebo showed no significant difference in outcome in 60 patients [23]. Meta analysis of available randomized trials (very limited) with anti-coagulants in cerebral sinus thrombosis showed that anticoagulant treatment in the acute phase of stroke is quite safe and reduces the risk of death or dependency [24]. Recently intra-sinus infusion of rt-pa was reported in a few cases of deep cerebral venous thrombosis with a very good effect [25]. Oral anticoagulant treatment after stroke is even more controversial. A one year observation of cognition and functional health of 57 patients showed that outcome was not significantly influenced by treatment after stroke [26]. However, there is not a clear indication for anti-coagulant treatment in cerebral venous thrombosis, intravenous heparin followed by prolonged oral anti-coagulants seems to be a choice. CONCLUSIONS In the present study we showed a case of the young woman with good recovery of venous stroke, which was a carrier of two prothrombotic mutation factor V Leiden mutation and prothrombin gene G20210A homozygous mutation. These two mutation constitute contributory risk factors for venous thrombosis. Additive administration of oral contraceptives, taken for a year before onset of the disease probably eventually lead to sinus thrombosis. Our patient was misdiagnosed as brain tumor and viral encephalitis, and has no sign of sinus thrombosis in standard MR scan. Although rare, venous stoke should be thus considered, especially in young person, with clinical acute onset of headache, seizures and/or hemiparesis, and if MR examination shows the partially hemorrhagic, diffused lesions in a brain. However diagnostic delay constitute one of the factors of poor outcome, our patient recovered without any anticoagulant treatment. The treatment of cerebral venous thrombosis is not yet established, however, and need randomized multicenter studies to showed the proper management. REFERENCES: 1. De Moerloose P, Reber G, Perrier A et al: Prevalence of factor V Leiden and prothrombin G20210A mutations in unselected patients with venous thrombosis and metabolism. Br J Haematol, 2000; 110: Poort SR, Rosendaal FR, Reitsma PR, Bertina RM: A common genetic variant in the 3 -untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood, 1996; 88: Corral J, Zuazu-Jausoro I, Rivera J et al: Clinical and analytical relevance of the combination of prothrombin 20210A/A and factor V Leiden: results from a large family. Br J Haematol, 1999; 105: Bertina RM, Koeleman BPC, Koster T et al: Mutation in blood coagulation factor V associated with resostance to activated protein C. Nature, 1994; 369: Bridey F, Wolff M, Laissy JP et al: Fatal cerebral venous sinus thrombosis associated with the factor V Leiden mutation and the use of oral contraceptives. Thromb Haemost, 1995; 74: Emmerich J, Rosendaal FR, Cattaneo M et al: Combined effect of factor V Leiden and prothrombin A on the risk of venou thromboembolism-pooled analysis of 8 case-control studies including 2310 cases and 3404 controls. Study Group for Pooled Analysis of Venous Thromboembolism. Thromb Haemost, 2001; 86: Longstreth WT, Rosendaal FR, Siscovick DS et al: Risk of stroke in young women and two prothrombotic mutation: factor VLeiden and prothrombin gene variant G20210A. Stroke, 1998; 29: Weinstein JR, Gold SJ, Cunningham DD, Gall CM: Cellular localisation of thrombin receptor mrna in rat brain: expression by mesencephalic dopaminergic neurons and codistribution with prothrombin mrna. J Neurosci, 1995; 15: Rosendaal FR, Doggen CJ, Zivelin A et al: Geographic distribution of the G to A prothrombin variant. Thromb Haemost, 1998; 79: Ahsen N, Lewczuk P, Schutz E et al: Prothrombin activity and concentration in healthy subjects with and without prothrombin G20210A mutation. Thrombosis Res, 2000; 99:

5 Med Sci Monit, 2003; 9(5): Kurkowska-Jastrzębska I et al Concomitant heterozygous factor V 11. Kyrle PA, Mannhalter C, Beguin S et al: Clinical studies and thrombin generation in patients homozygous and heterozygous for the G20210A mutation in the prothrombin gene. Arterioscler Thromb Vasc Biol, 1998; 18: De Stefano V, Martinelli I, Mannucci PM et al: The risk of reccurent deep venous thrombosis among heterozygous carriers of both factor Leiden and the G20210A prothrombin mutation. N engl J Med, 1999; 341: Rosendaal FR, Siscovick DS, Schwartz SM et al: A common prothrombin variant (20210 GtoA) increases the risk of myocardial infarction in young women. Blood, 1997; 90: De Bruijn SF, Stam J, Koopman MM, Vandenbroucke JP: Case control study of risk of cerebral sinus thrombosis in oral contraceptives users and in carriers of hereditary prothrombotic conditions. BMJ, 1998; 16: Rosendaal FR, Vessey, Rumley A et al: Hormonal replacement therapy, prothrombotic mutations and the riskof venous thrombosis. Br J Haematol, 2002; 116: van Boven HH, Vandenbroucke JP, Briet E, Rosendaal FR: Genegene and gene-envirenment interactions determine risk of thrombosis in families with inherited antithrombin deficiency. Blood, 1999; 94: Bykowska K, Vertun-Baranowska B, Windyga J, Lopaciuk S: Prevalence of G20210A prothrombin gene mutation in Poland. Pol Arch Med Wewn, 2000; 104: Huisman MV, Rosendaal F: Thrombophilia. Curr Opin Hematol, 1999; 6: Preter M, Tzourio C, Ameri A, Bousser MG: Long-term prognosis in cerebral venous thrombosis. Follow-up of 77 patients. Stroke, 1996, 27: Kalbag RM, Woolf AL: Cerebral venous thrombosis. London: Oxford University Press, Bousser M, Chiras J, Castaigne P: Cerebral venous thrombosis: a review of 38 cases. Stroke, 1985; 16: Einhaupl KM, Villringer A, Meister W et al: Heparin treatment in sinous venous thrombosis. Lancet, 1991; 338: De Bruijn SF, Stam J: Randomized, placebo controlled trial of anticoagulant treatment with low-molecular weight heparin for cerebral sinus thrombosis. Stroke, 1999; 30: Stam J, De Bruijn SF, De Veber G: Anticoagulation for cerebral sinus thrombosis. Cochrane Database Syst Rev 2002; 4: CD Yamini B, Macdonald RL, Rosenblum J: Treetment of deep cerebral venous thrombosis by local infusion of tissue plasminogen activator. Surg Neurol, 2001; 55: de Bruijn SF, Budde M, Teunisse S et al: Long-term outcome of cognition and functional health after cerebral venous sinus thrombosis. Neurology, 2000; 54: