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(Stroke. 1998;29:1739-1740.)
© 1998 American Heart Association, Inc.

Letters to the Editor

Coincidence of Factor V Leiden Mutation and a Mutation in the Prothrombin Gene at Position 20210 in a Patient With Puerperal Cerebral Venous Thrombosis

M. Weih; MD S. Mehraein; MD J. M. Valdueza; MD K. M. Einhäupl, MD

Department of Neurology

B. Vetter; PhD A. E. Kulozik, MD, PhD

Department of Pediatrics, Charité Hospital, Humboldt University, Berlin, Germany

To the Editor:

Cerebral venous thrombosis (CVT) is a rare cause of stroke with a variable clinical picture. A search for underlying disorders may be successful in 65% to 80% of cases.^1,2 Over the past few years, activated protein C (APC) resistance has been identified as the most common hereditary thrombophilic factor in CVT.^3,4 More recently, a mutation in the prothrombin gene at position 20210 has been found in pedigrees with venous thrombosis.⁵ We report the case of a patient with puerperal CVT with hereditary APC resistance, who in addition showed a heterozygous mutation in the prothrombin gene at position 20210.

A 30-year-old, previously healthy woman suffered a generalized seizure after a 10-day-long headache episode 5 weeks after she had given birth to her first child. After the ictus she was confused and disoriented for several days. A cranial CT showed a 2x3-cm hypodense area in the right temporal lobe. A cranial MRI revealed a 3-cm lesion in the right parietal lobe that was hyperintense in T2-weighted images and hypointense in T1-weighted images and showed no contrast enhancement. MR angiography subsequently showed no flow signal in the right lateral sinus. An EEG showed a right parietotemporal focus with delta and theta waves. The family history was negative for epilepsy, cerebrovascular events, and thromboembolic events, except for an occurrence of deep venous thrombosis in the patient's grandmother. The patient was treated with unfractionated heparin IV (partial thromboplastin time adjusted) during the acute phase, followed by oral anticoagulation with phenprocoumon (international normalized ratio adjusted to 2.5 to 3.0) for 2 years by her private physician. Due to persistent sharp waves during the patient's follow-up EEGs, phenytoin treatment was continued for 2o years. During this time she recovered completely and showed no signs of relapse. Two years 3 months after the thrombosis she was referred to our clinic for assessment of future treatment, particularly during a desired pregnancy. A workup for thrombophilic factors showed normal values for thrombocytes, prothrombin time, plasma thromboplastin time, antithrombin, fibrinogen, protein S, protein C, antinuclear, double-stranded DNA antibodies, and antiphospholipid IgG. Antiphospholipid IgM levels were markedly elevated but normalized after control. In contrast, the APC resistance ratio (assay by Chromogenix) was markedly decreased to 1.5 (normal, >2.0). Prothrombin activity was found to be in the upper normal range (108%). Restriction analysis with Mnl I of a 267-bp fragment spanning the exon 10 fragment of the factor V gene with Mnl I revealed a heterozygous point mutation at position 1691 from G to A within the factor V Leiden gene as described.⁶ Restriction analysis with Hind III of a 345-bp fragment in the 3'-UT region in the prothrombin gene showed a heterozygous point mutation at position 20210 from G to A, as described previously.⁵ To date, no family screening for both mutations has been performed.

It has been shown that the presence of more than one thrombophilic factor increases the penetrance of a thrombotic event.^7–9 In addition, approximately 50% of thrombotic episodes occur in association with circumstantial factors such as immobilization or pregnancy, suggesting that multiple risk factors might be necessary before clinically evident thrombosis is likely to develop. To our knowledge, this is the first report of factor V Leiden mutation in coincidence with a mutation in the prothrombin gene at position 20210 in CVT. More recently, a similar combination has been reported in a female with pregnancy-associated deep-vein thrombosis.¹⁰

In general we recommend testing for inherited thrombophilia in CVT in addition to a complete workup for other possible thrombotic factors. In our case we recommended primary prophylaxis with heparin during immobilization, pregnancy, and puerperium. However, the question of whether patients with combined thrombophilia benefit from long-term anticoagulation after the first incidence of CVT cannot be answered. The decision on treatment of hereditary thrombophilia after CVT must be made on a case-by-case basis as long as prospective studies are lacking.

(We would like to thank Dr Schulz, Department of Neurology, Ernst v. Bergman Hospital Potsdam, for the EEG description, and Mrs S. Ziemer, Department of Pathologic and Clinical Biochemistry, for the coagulation tests.)

References

1. Einhäupl KM, Masuhr F. Cerebral venous and sinus thrombosis: an update. Eur J Neuro. 1994;1:109–126.

2. Bousser MG, Russell RR. Cerebral Venous Thrombosis. London, UK: WB Saunders Co; 1997.

3. Martinelli I, Landi G, Maerati G, Cella R, Tosetto A, Mannuci PM. Factor V gene mutation is a risk factor for cerebral venous thrombosis. Thromb Haemost.. 1996;75:393–394.[Medline] [Order article via Infotrieve]

4. Deschiens MA, Conard J, Horellou MH, Ameri A, Preter M, Chedru F, Samama MM, Bousser MG. Coagulation studies, factor V Leiden, and anticardiolipin antibodies in 40 cases of cerebral venous thrombosis. Stroke. 1996;27:1724–1730.[Abstract/Free Full Text]

5. 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.[Abstract/Free Full Text]

6. Bertina RM, Koeleman BP, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, van der Velden PA, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature. 1994;369:64–67.[Medline] [Order article via Infotrieve]

7. Koeleman BP, van Rumpt D, Hamulyak K, Reitsma PH, Bertina RM. Factor V Leiden: an additional risk factor for thrombosis in protein S deficient families? Thromb Haemost. 1995;74:580–583.[Medline] [Order article via Infotrieve]

8. Koeleman BP, Reitsma PH, Allaart CF, Bertina RM. Activated protein C resistance as an additional risk factor for thrombosis in protein C-deficient families. Blood. 1994;84:1031–1035.[Abstract/Free Full Text]

9. Mandel H, Brenner B, Berant M, Rosenberg N, Lanir N, Jakobs C, Fowler B, Seligsohn U. Coexistence of hereditary homocystinuria and factor V Leiden: effect on thrombosis. N Engl J Med. 1996;334:763–768.[Abstract/Free Full Text]

10. Conard J, Mabileau-Brouzes C, Horellou MH, Elalamy I, Samama MM. Multigenic thrombophilia: genetic anomaly of factor II and mutation of factor V Leiden: study in a French family. Presse Med. 1997;26:951–953.

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