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(Stroke. 2000;31:543.)
© 2000 American Heart Association, Inc.

Letters to the Editor

Cerebral Venous Thrombosis and the G20210A Mutation of Factor II

Pieter Jan Simons, MD Geert Vanhooren, MD

Stroke Unit, Department of Neurology, St Janshospitaal, Bruges, Belgium

To the Editor:

In addition to the article of Longstreth et al¹ recently published in Stroke, we describe 2 cases of stroke due to cerebral venous thrombosis with the G20210A mutation as only risk factor.

After sequencing of the gene for human prothrombin (factor II) by Degen and Davie² in 1987, a new mutation of prothrombin (G20210A) was described by Poort et al³ in 1996. It is a common mutation of this factor associated with an increased risk of venous (and possible arterial) thrombosis, as stated by Martinelli et al.⁴ The mutation can be detected by a polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) method, as described by Poort.³ Our laboratory uses this method.

Recently, we saw 2 patients with a definite diagnosis of cerebral venous thrombosis. No other known risk factor for cerebral venous thrombosis could be found. The finding of the abnormal mutation (G20210A) of factor II gene (both patients had a heterozygous state for the mutation) suggested this as etiology.

Patient 1 was a 42-year-old employee and moderate smoker. In his early thirties he had an arterial thrombectomy in a peripheral artery. In his family only his father had suffered a "stroke." He was admitted to our hospital with a first epileptic seizure, focal in origin. There was a venous infarction in the right frontal lobe. MR angiography (including venous phase) showed a typical stop in the frontal superior sagittal sinus, with loss of draining veins. None of the other tests associated with venous hypercoagulability showed a hypercoagulable state (no activated protein C resistance, proteins C or S deficiency, detectable antinuclear factors, lupus anticoagulants, or antithrombin III). The G20210A mutation was found, showing a heterozygous genotype for this mutation in this patient.

Patient 2 was a 63-year-old farmer who was admitted to our hospital 3 days after being missed by his family. He didn’t return home after market day and was disorientated in place, time, and person. A few days earlier, his family had found him to be a little distracted. CT and MRI showed a bithalamic venous infarction. On MR angiography and arteriography there was total obliteration of deep intracerebral venous structures. Anticoagulation was started. He remained with disinhibited frontal behavior. None of the classical risk factors of hypercoagulation were present. He did not smoke. By PCR-RFLP (as described above), he proved to be heterozygous for the G20210A mutation.

Besides being a well-known and relatively frequent risk factor for venous thrombosis in general, this mutation must be looked for in the less-frequent cerebral venous thrombosis patients. Testing for this mutation is important because people with this genotype should be strongly advised to avoid other risk factors, such as oral contraceptive use⁵ and smoking.

References

1. Longstreth WT Jr, Rosendaal FR, Siscovick DS, Vos HL, Schwartz SM, Psaty BM, Raghunathan TE, Koepsell TD, Reitsma PH. Risk of stroke in young women and two prothrombotic mutations: factor V Leiden and prothrombin gene variant (G20210A). Stroke. 1998;29:577–580.
2. Degen SJF, Davie EW. Nucleotide sequence of the gene for human prothrombin. Biochemistry. 1987;26:6165–6177.
3. Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood. 1996;88:3698–3703.
4. Martinelli I, Sacchi E, Landi G, Taioli E, Duca F, Mannucci PM. High risk of cerebral-vein thrombosis in carriers of a prothrombin-gene mutation and in users of oral contraceptives. N Engl J Med. 1998;338:1793–1797.
5. Van Krimpen J, Leebeek FWG, Dippel DWJ, Gomez Garcia E. Prothrombin gene variant (G20210A) in a patient with cerebral venous sinus thrombosis. Clin Neurol Neurosurg. 1999;101:53–55.

Response

W.T. Longstreth, Jr, MD, MPH

Department of Neurology

Roy M. Colven, MD

Department of Medicine, Division of Dermatology, University of Washington, Harborview Medical Center, Seattle, Washington

Key Words: prothrombin • mutation • factor V

Many thanks to Drs Simons and Vanhooren for sharing their interesting patients. Since the initial description by Bloem and colleagues^R1 of a patient with sagittal sinus thrombosis and the prothrombin gene variant (G20210A), others have described similarly affected patients.^{R2 R3 R4 R5 R6} In addition to the prothrombin gene mutation, these patients often have other condition that promote thrombosis, such as use of oral contraceptives. We saw such a patient recently with the mutation and a well-recognized but unusual prothrombotic condition.

The patient was a 20-year-old man who developed headaches and deep-vein thrombosis in the right lower extremity following orthopedic surgery on his right knee. The headaches worsened, and he developed diplopia. He had a history of recurrent aphthous ulcers of the mouth but had otherwise been healthy and very athletic. On neurological examination, he had papilledema and a right sixth nerve palsy. His C-reactive protein was markedly elevated at 20.8 mg/dL (normal range being from 0 to 1.0 mg/dL). His venogram on cranial MRI showed a superior sagittal sinus thrombosis. During his hospitalization, he developed ulcers on his scrotum and thighs, from which bacterial and viral cultures were negative. He also demonstrated pathergy. Based on these observations, the dermatologists diagnosed Behçet’s disease.^R7 Although he was found to be negative for factor V Leiden, he was heterozygous for the prothrombin gene variant (G20210A). He improved with anticoagulation and pentoxifylline^R8 but eventually required prednisone and colchicine to control recurrent skin lesions and fever.

Behçet’s disease is known to be associated with cerebral venous thrombosis,^R9 and factor V Leiden has been reported to increase the risk of venous thrombosis in patients with Behçet’s disease.^R10 We are not aware of previous patients with cerebral venous thrombosis, Behçet’s disease, and the prothrombin gene variant. Given the combined prothrombotic effects of Behçet’s disease and the prothrombin gene variant, the association is not unexpected.

References

1. Bloem BR, van Putten MJ, van der Meer FJ, van Hilten JJ, Bertina RM. Superior sagittal sinus thrombosis in a patient heterozygous for the novel 20210 A allele of the prothrombin gene. Thromb Haemost. 1998;79:235. Letter.
2. Longstreth WT Jr, Rosendaal FR, Siscovick DS, Vos HL, Schwartz SM, Psaty BM, Raghunathan TE, Koepsell TD, Reitsma PH. Risk of stroke in young women and two prothrombotic mutations: factor V Leiden and prothrombin gene variant (G20210A). Stroke. 1998;29:577–580.
3. Martinelli I, Sacchi E, Landi G, Taioli E, Duca F, Mannucci PM. High risk of cerebral-vein thrombosis in carriers of a prothrombin-gene mutation and in users of oral contraceptives. N Engl J Med. 1998;338:1793–1797.
4. Biousse V, Conard J, Brouzes C, Horellou MH, Ameri A, Bousser MG. Frequency of the 20210 GA mutation in the 3'-untranslated region of the prothrombin gene in 35 cases of cerebral venous thrombosis. Stroke. 1998;29:1398–1400.
5. Reuner KH, Ruf A, Grau A, Rickmann H, Stolz E, Juttler E, Druschky KF, Patscheke H. Prothrombin gene G20210A transition is a risk factor for cerebral venous thrombosis. Stroke. 1998;29:1765–1769.
6. Weih M, Mehraein S, Valdueza JM, Einhaupl KM, Vetter B, Kulozik AE. Coincidence of factor V Leiden mutation and a mutation in the prothrombin gene at position 20210 in a patient with puerperal cerebral venous thrombosis. Stroke. 1998;29:1739–1740.
7. International Study Group for Behçet’s Disease. Criteria for diagnosis of Behçet’s disease. Lancet. 1990;335:1078–1080.
8. Yasui K, Ohta K, Kobayashi M, Aizawa T, Komiyama A. Successful treatment of Behçet disease with pentoxifylline. Ann Intern Med. 1996;124:891–893.
9. Wechsler B, Vidailhet M, Piette JC, Bousser MG, Dell Isola B, Bletry O, Godeau P. Cerebral venous thrombosis in Behçet’s disease: clinical study and long-term follow-up of 25 cases. Neurology. 1992;42:614–618.
10. Gul A, Ozbek U, Ozturk C, Inanc M, Konice M, Ozcelik T. Coagulation factor V gene mutation increases the risk of venous thrombosis in Behçet’s disease. Br J Rheumatol. 1996;35:1178–1180.

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