This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Reuner, K. H. Articles by Patscheke, H. Search for Related Content PubMed PubMed Citation Articles by Reuner, K. H. Articles by Patscheke, H.

(Stroke. 1998;29:1765-1769.)
© 1998 American Heart Association, Inc.

Original Contributions

Prothrombin Gene G₂₀₂₁₀A Transition Is a Risk Factor for Cerebral Venous Thrombosis

Karl H. Reuner, MD; Andreas Ruf, MD; Armin Grau, MD; Henning Rickmann, MD; Erwin Stolz, MD; Eric Jüttler, MD; Karl-F. Druschky, MD; Heinrich Patscheke, MD

From the Institute for Medical Laboratory Diagnostics, Klinikum Karlsruhe (K.H.R., A.R., H.P.), Department of Neurology, University of Heidelberg (A.G., E.J.), Department of Neurology, Klinikum Karlsruhe (H.R., K.-F.D.), and the Department of Neurology, University of Gießen (E.S.), Germany.

Correspondence to Dr Karl H. Reuner, Institute for Medical Laboratory Diagnostics, Klinikum Karlsruhe, Moltkestr 90, D-76133 Karlsruhe, Germany.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose—It has been recently reported that a GA transition at nucleotide position 20210 in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increased risk of deep venous thrombosis. To date, it is unknown whether this polymorphism also represents a risk factor for cerebral venous thrombosis (CVT).

Methods—Venous blood samples were collected from 45 patients with CVT and from 354 healthy blood donors as controls. A second control group consisted of 131 subjects with acute ischemic stroke or transient ischemic attack (TIA). Genomic DNA was isolated from peripheral blood leukocytes. Amplification of DNA was performed by polymerase chain reaction (PCR). The GA transition at nucleotide position 20210 of the prothrombin gene was detected by allele-specific restriction digestion.

Results—The G₂₀₂₁₀A transition in the prothrombin gene was found in a heterozygous form in 4 of 45 patients with CVT (8.9%) and in 8 of 354 healthy control subjects (2.3%). This difference was statistically significant (P=0.010). The G₂₀₂₁₀A transition increased the relative risk for CVT approximately 5-fold (age-adjusted odds ratio 5.7; 95% CI 1.5 to 21.5). In contrast, in the group of patients with acute cerebral ischemia, only 3 of 131 subjects (2.3%) were heterozygous for the G₂₀₂₁₀A transition, which corresponded to the prevalence in the group of healthy blood donors.

Conclusions—The recently described G₂₀₂₁₀A transition in the 3'-untranslated region of the prothrombin gene is an inherited risk factor for CVT but obviously not for acute ischemic stroke or TIA.

Key Words: coagulation • hereditary disease • thrombophilia • sinus thrombosis

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Cerebral venous thrombosis (CVT) is an infrequent disorder which can be caused by several infectious or noninfectious conditions such as surgery, pregnancy, puerperium, or tumors. Furthermore, hematologic or hemostaseologic risk factors have been described. They comprise leukemia, thrombocythemia, red blood cell disorders or coagulation abnormalities (such as factor V Leiden mutation), deficiencies of antithrombin III, protein C and protein S, or antiphospholipid syndromes. Moreover, recent studies have provided strong evidence that the intake of oral contraceptives is an independent risk factor for CVT. Despite the continuous description of new causes for CVT, to date, the fraction of cases with unknown cause is still more than 20%.^{1 2 3 4 5 6 7}

Recently, it has been reported that a GA transition at nucleotide position 20210 in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and deep venous thrombosis.⁸ The G₂₀₂₁₀A transition was found in a heterozygous form in 6.2% of 471 unselected consecutive patients with the first episode of deep venous thrombosis, but in only 2.3% of 474 healthy control subjects. It was concluded that the G₂₀₂₁₀A transition in the prothrombin gene represents a risk factor for venous thrombosis (odds ratio, 2.8),⁸ which was more recently confirmed by other groups.^{9 10 11 12 13} Moreover, the G₂₀₂₁₀A transition was reported to increase the risk of myocardial infarction in young women.¹⁴ On the other hand, 2 recent studies have indicated that the mutation is not a risk factor for cerebral ischemia.^{15 16} It was the aim of this study to investigate whether the G₂₀₂₁₀A transition in the prothrombin gene represents a risk factor for CVT.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Study Population
Forty-five unrelated patients with CVT were recruited from 3 Neurology departments in Southern and Middle Germany. For this purpose, 96 patients who had suffered from CVT between 1967 and 1997 were contacted for possible participation in this study. Eleven patients had died, most from carcinoma. Forty-five subjects agreed to participate in the study. All patients were examined for the following risk factors for CVT¹ : (1) inherited risk factors such as deficiency of antithrombin III, protein C and protein S, factor V Leiden, and (2) acquired risk factors such as local and general infections, AV fistula, head injury, cerebral infarction and hemorrhages, general and local surgery, tumors, pregnancy and puerperium, oral contraceptives, heart diseases, red blood cell disorders, thrombocythemia, lupus anticoagulants, heparin-induced thrombocytopenia, dehydration, liver cirrhosis, Crohn's disease and ulcerative colitis, connective tissue diseases, venous thromboembolism, Behçet's disease, sarcoidosis, and nephrotic syndrome. Forty-two of the participating 45 subjects (93%) had suffered from CVT during the last 10 years. Eleven subjects were male (mean age 47 years, median age 53 years, range 3 to 65 years) and 34 were female (mean age 34 years, median age 33 years, range 17 to 69 years). CVT was diagnosed by angiography (n=12), cranial CT (n=3), MR imaging techniques including MR angiography (n=19), or by a combination of 2 or 3 of these methods (n=11).

Patients with acute ischemic stroke or transient ischemic attack (TIA) (n=131) were recruited consecutively from one of the Neurology departments in Southern Germany from 1996 to 1997. Seventy-six were male and 55 were female, they were between 21 and 78 years old (mean age 51 years). Ischemic cerebral disease was diagnosed by cranial MRI/CT scan, cervical and transcranial ultrasonography, and cardiologically by ECG and echocardiography. Because the G₂₀₂₁₀A transition in the prothrombin gene has already been described not to be a risk factor for cerebral ischemia,^{15 16} this group of patients was used as a second control group without further characterization.

The group of healthy control subjects included 354 blood donors (aged 18 to 65 years) from Southern Germany. One hundred seventy-six subjects were male (mean age 43 years, median age 43 years, range 20 to 65 years) and 178 were female (mean age 35 years, median age 33 years, range 18 to 63 years). All blood donors were routinely asked about drug intake. All patients and control subjects gave informed consent.

Laboratory Tests
Preparation of genomic DNA from peripheral blood leukocytes and determination of factor V Leiden mutation were performed as described previously.¹⁷ For detection of the G₂₀₂₁₀A transition in the 3'-untranslated region of the prothrombin gene, amplification of genomic DNA was performed by polymerase chain reaction (PCR), essentially as described.⁸ PCR products (345 bp) were restricted with HindIII for 2 hours at 37°C, separated by 2% agarose gel electrophoresis, and visualized by ethidium bromide staining. The GA substitution at nucleotide position 20210 generates a HindIII restriction site leading to restriction products of 322 and 23 bp in length, whereas amplification of wild-type alleles lacks the restriction site.⁸

Blood samples of all participating patients with CVT were collected within the last 12 months. Citrated plasma samples (venous blood: 0.1 mol/L trisodium citrate=10:1) were used for determination of protein C, protein S, antithrombin III, and lupus anticoagulants. Platelet-poor plasma was obtained by centrifugation at 2000g at room temperature. The plasma was collected carefully, strictly avoiding contamination with platelets. Aliquots were frozen at -25°C. Determination of protein C, protein S, antithrombin III, and lupus anticoagulants was carried out on a coagulation analyzer Amga (Sigma-Amelung) using the test kits Protein C reagent,¹⁸ Protein S clotting test,¹⁹ Antithrombin, and Staclot PNP²⁰ (Boehringer Mannheim). Lupus anticoagulants were determined as a rule when CVT occurred because of the possibility of a transient antiphospholipid syndrome. Cases deviating from this rule are indicated in Table 1.

View this table: [in this window] [in a new window]   Table 1. Main Characteristics of 45 Patients With CVT

Statistics
Fisher's exact test was done by the GraphPad Prism software (Version 2.0, GraphPad Software Inc.) in cases of nonage- and sex-adjusted statistical evaluation. Age- and sex-adjusted statistical evaluation was done by including interaction terms into the logistic model. These algorithms are an integral part of the SAS (Statistic Analyzing System) software package (Version 6.11 for Windows, SAS Institute Inc.). P values<0.05 were considered significant.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Four of 45 patients (8.9%) with CVT were heterozygous for the G₂₀₂₁₀A transition in the prothrombin gene, whereas 41 subjects (91.1%) did not carry the 20210 A allele. Among the 354 healthy blood donors, 346 (97.7%) did not carry the G₂₀₂₁₀A transition in the prothrombin gene, whereas 8 subjects (2.3%) were heterozygous for the 20210 A allele. This difference was statistically significant (P=0.010). The G₂₀₂₁₀A transition was associated with an approximately 5-fold increased risk for CVT (age-adjusted odds ratio, 5.7; Table 2). In the subgroup of female patients with CVT, 3 of 34 subjects (8.8%) were heterozygous for the G₂₀₂₁₀A transition in the prothrombin gene, compared with 2 of 178 female blood donors (1.1%), resulting in an approximately 8-fold increased risk for CVT (age-adjusted odds ratio, 8.5; P=0.022; Table 2). In the subgroup of 11 male patients with CVT, 1 (9.1%) subject was heterozygous compared with 6 of 176 male blood donors (3.4%). Because of the small number of male patients, this difference lacked significance (age-adjusted odds ratio, 3.5; P=0.28; Table 2). Furthermore, the difference between both genders was not significant (P=0.53).

View this table: [in this window] [in a new window]   Table 2. Prothrombin Genotypes and Estimated Risk for CVT

In the group of patients with acute cerebral ischemia, only 3 of 131 subjects (2.3%) were heterozygous for the G₂₀₂₁₀A transition, which corresponded to the prevalence in the group of healthy blood donors. None of the 530 individuals investigated in this study was homozygous for the G₂₀₂₁₀A transition.

Because intake of oral contraceptives is reported to be a strong risk factor for CVT,^{6 7} we have further investigated this association in our study. Eighteen of 31 women (58%) aged 50 took oral contraceptives when CVT occurred, compared with 13 of 148 (9%) age- and sex- matched healthy blood donors who declared intake of the pill. Thus, use of oral contraceptives was associated with an approximately 14-fold increased risk of CVT in the subgroup of women <51 years (odds ratio, 14.4; 95% CI 5.8 to 35.8; P<0.0001).

Major characteristics of the patients with CVT are given in Table 1. Thirty-four subjects (76%) were female and 11 (24%) were male; the mean ages at the time of CVT were 34 and 47 years, respectively. Inherited and/or acquired risk factors could be detected in 31 of 45 cases (69%). Protein C- and protein S activities could not be investigated in 5 patients because of treatment with oral anticoagulants. Lupus anticoagulants were not determined at the time of CVT in 9 cases. The G₂₀₂₁₀A transition in the prothrombin gene was the sole risk factor in 1 patient (patient 27), whereas it was associated with oral contraceptives, lupus anticoagulants, or Crohn's disease in the remaining 3 cases (patients 4, 13, and 34). CVT was the sole thrombotic event in 39 patients (87%); the remaining 6 subjects had additionally suffered from pulmonary embolism (patients 13, 21, and 33), deep venous thrombosis of the lower limbs (patients 17, 21, 30, and 35), or deep venous thrombosis of the pelvis and upper limbs (patient 35). Of these 6 patients, 3 (patients 13, 30, and 35) had suffered from CVT as the first thromboembolic episode. The main established inherited risk factors in our group of patients with CVT were factor V Leiden mutation in 5 cases (11.1%), protein C deficiency in 2 cases (4.4%), and protein S deficiency in 2 cases (4.4%). No coincidence existed between these inherited risk factors and the 4 cases (8.9%) of the G₂₀₂₁₀A transition in the prothrombin gene.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
To the best of our knowledge, this is the first study providing strong evidence that the G₂₀₂₁₀A transition in the 3'-untranslated region of the prothrombin gene is a significant risk factor for CVT. No difference in the frequencies of the G₂₀₂₁₀A transition was found in the subgroups of female (8.8%) and male (9.1%) patients. The fact that the G₂₀₂₁₀A transition in the prothrombin gene lacked significance as a risk factor for men with CVT may thus be due to the small number of male patients.

Very recently, a case report was published which describes a superior sagittal sinus thrombosis in a 21-year-old woman heterozygous for the mutation.²¹ Moreover, in a more recent abstract, the authors found the G₂₀₂₁₀A transition in 5.7% of 35 patients with CVT.²² Prevalences of the G₂₀₂₁₀A transition in the prothrombin gene in our control subjects and patients with CVT are in a similar range, as has been reported for both healthy controls and patients with deep venous thrombosis. In these studies, the prevalence of the G₂₀₂₁₀A transition was between 0.7¹³ and 2.6%¹¹ in control subjects and between 4.3¹³ and 7.1%⁹ in unselected patients with deep venous thrombosis. Odds ratios for the risk of thrombosis between 2.0 and 6.6% were reported.^{8 9 10 11 12 13} A probable reason for the increased risk is the significantly increased plasma prothrombin level in the presence of the 20210 A allele.^{8 12}

In contrast to the fact that the G₂₀₂₁₀A transition in the prothrombin gene represents a risk factor for CVT, the mutation obviously does not increase the risk for acute ischemic stroke or TIA. The prevalence in a group of 131 patients (2.3%) did not differ from that observed in the group of 354 healthy controls (2.3%). Thus, our data confirm 2 recent studies which demonstrated that the G₂₀₂₁₀A transition in the prothrombin gene is not a risk factor for cerebral ischemia.^{15 16}

During the last few years, many of the predisposing factors for the occurrence of CVT have been described, including inherited factors (deficiencies of protein C, protein S, and antithrombin III, or factor V Leiden mutation) and acquired conditions (infections, tumors, pregnancy, puerperium, or lupus anticoagulants). Moreover, intake of oral contraceptives is reported to be a strong risk factor for CVT, which may lead to an over-representation of young women in CVT-collectives.^{6 7} The present study confirms this observation. Eighteen of 31 (58%) women 50 years took oral contraceptives when CVT occurred, compared with 13 of 148 (9%) age-matched healthy female blood donors who declared intake of the pill. Thus, use of oral contraceptives was associated with an approximately 14-fold increased risk of CVT in the subgroup of women <51 years (odds ratio, 14.4; 95% CI 5.8 to 35.8; P<0.0001). One might argue that the number of users of oral contraceptives in the group of female blood donors is smaller than one would expect. However, the healthy blood donors declared by signature that all drugs used were declared. Moreover, even if among female blood donors a portion of 30% of users of the pill was assumed, the risk for CVT remained significant (P<0.05).

It is likely that a combination of an inherited predisposition to thrombosis (eg, factor V Leiden mutation) and an acquired thrombogenic stimulus (eg, use of oral contraceptives) finally leads to thrombosis.^{1 2 3 4 5 6 7 23 24 25 26} In our study, inherited and/or acquired risk factors were present in 31 of 45 cases with CVT (69%). The most frequently established inherited risk factor was factor V Leiden mutation in 11.1% of the cases. Interestingly, the frequency of the G₂₀₂₁₀A transition in the prothrombin gene (8.9%) was nearly as high as the frequency of factor V Leiden mutation in the group of patients with CVT. No coincidence between both mutations could be observed. Thus, it is likely that the newly detected G₂₀₂₁₀A transition in the 3'-untranslated region of the prothrombin gene is of equal importance for CVT as the factor V Leiden mutation. Because we could not observe risk factors other than the G₂₀₂₁₀A transition in 1 patient with CVT (patient 27), this mutation might be an independent risk factor for CVT in some cases. This hypothesis has to be proven in further studies.

	Acknowledgments

 
The excellent technical assistance of Frank Litfin and Stefan Kreft is gratefully acknowledged.

Received March 2, 1998; revision received June 9, 1998; accepted June 9, 1998.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 
1. Ameri A, Bousser MG. Cerebral venous thrombosis. Neurol Clin. 1992;10:87–111.[Medline] [Order article via Infotrieve]

2. Heistinger M, Rumpl E, Illiasch H, Türck H, Kyrle PA, Lechner K, Pabinger I. Cerebral sinus thrombosis in a patient with hereditary protein S deficiency: case report and review of the literature. Ann Hematol. 1992;64:105–109.[Medline] [Order article via Infotrieve]

3. Cantù C, Barinagarrementeria F. Cerebral venous thrombosis associated with pregnancy and puerperium. Stroke. 1993;24:1880–1884.[Abstract/Free Full Text]

4. Brey RL, Coull BM. Cerebral venous thrombosis: role of activated protein C resistance and factor V gene mutation. Stroke. 1996;27:1719–1720.[Free Full Text]

5. 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]

6. Martinelli I, Rosendaal FR, Vandenbroucke JP, Mannucci PM. Oral contraceptives are a risk factor for cerebral vein thrombosis. Thromb Haemostasis. 1996;76:477–478. Letter.[Medline] [Order article via Infotrieve]

7. De Bruijn SFTM, Stam J, Koopman MMW, Vandenbroucke JP. Case-control study of risk of cerebral sinus thrombosis in oral contraceptive users who are carriers of hereditary prothrombotic conditions. Br Med J. 1998;316:589–592.[Abstract/Free Full Text]

8. 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]

9. Hillarp A, Zöller B, Svensson PJ, Dahlbäck B. The 20210 A allele of the prothrombin gene is a common risk factor among Swedish outpatients with verified deep venous thrombosis. Thromb Haemost. 1997;78:990–992.[Medline] [Order article via Infotrieve]

10. Cumming AM, Keeney S, Salden A, Bhavnani M, Shwe KH, Hay CRM. The prothrombin gene G20210A variant: prevalence in a U. K. anticoagulant clinic population. Br J Haematol. 1997;98:353–355.[Medline] [Order article via Infotrieve]

11. Brown K, Luddington R, Williamson D, Baker P, Baglin T. Risk of venous thromboembolism associated with a G to A transition at position 20210 in the 3'-untranslated region of the prothrombin gene. Br J Haematol. 1997;98:907–909.[Medline] [Order article via Infotrieve]

12. Makris M, Preston FE, Beauchamp NJ, Cooper PC, Daly ME, Hampton KK, Bayliss P, Peake IR, Miller GJ. Co-inheritance of the 20210A allele of the prothrombin gene increases the risk of thrombosis in subjects with familial thrombophilia. Thromb Haemostasis. 1997;78:1426–1429.[Medline] [Order article via Infotrieve]

13. Arruda VR, Annichino-Bizzacchi JM, Goncalves MS, Costa FF. Prevalence of the prothrombin gene variant (nt20210A) in venous thrombosis and arterial disease. Thromb Haemostasis. 1997;78:1430–1433.[Medline] [Order article via Infotrieve]

14. Rosendaal FR, Siscovick DS, Schwartz SM, Psaty BM, Raghunathan TE, Vos HL. A common prothrombin variant (20210 G to A) increases the risk of myocardial infarction in young women. Blood. 1997;90:1747–1750.[Abstract/Free Full Text]

15. Bentolila S, Ripoll L, Dronet L, Mazoyer E, Woimant F. Thrombophilia due to 20210 GA prothrombin polymorphism and cerebral ischemia in the young. Stroke. 1997;28:1846–1847. Letter.

16. Martinelli I, Franchi F, Akwan S, Bettini P, Merati G, Mannucci PM. The transition G to A at position 20210 in the 3'-untranslated region of the prothrombin gene is not associated with cerebral ischemia. Blood. 1997;90:3806. Letter.[Free Full Text]

17. Reuner KH, Litfin F, Patscheke H. Discrimination between normal wildtype and carriers of coagulation factor V Leiden mutation by the activated protein C resistance test in the presence of factor V deficient plasma. Eur J Clin Chem Clin Biochem. 1997;35:41–45.[Medline] [Order article via Infotrieve]

18. Martolini JL, Stocker K. Functional protein C assay using protac, a novel protein C activator. Thromb Res. 1986;43:253–259.[Medline] [Order article via Infotrieve]

19. Wolf M, Boyer-Neumann C, Martolini JL, Amiral J, Meyer D, Larieu MJ. A new functional assay for human protein S using activated factor V as substrate. Thromb Haemostasis. 1989;62:1144–1145.[Medline] [Order article via Infotrieve]

20. Triplet DA, Brandt JT, Kaczor D, Schaeffer J. Laboratory diagnosis of lupus inhibitors: a comparison of the tissue thromboplastin inhibition procedure with a new platelet neutralization procedure. Am J Clin Pathol. 1983;79:678–682.[Medline] [Order article via Infotrieve]

21. Bloem BR, van Putten MJAM, vd Meer FJM, van Hilten JJ, Bertina RM. Superior sagittal sinus thrombosis in a patient heterozygous for the novel 20210 A allele of the prothrombin gene. Thromb Haemostasis. 1998;79:235. Letter.[Medline] [Order article via Infotrieve]

22. Conard J, Brouzes C, Biousse V, Horellou MH, Elalamy I, Chedru F, Ameri A, Samama MM, Bousser MG. Frequency of the 20210 GA mutation in the 3'-untranslated region of the prothrombin gene in 35 patients with cerebral venous thrombosis. Stroke. 1998;29:319. Abstract.

23. Vandenbroucke JP, Koster T, Briet E, Reitsma PH, Bertina RM, Rosendaal FR. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet. 1994;344:1453–1457.[Medline] [Order article via Infotrieve]

24. Schafer AI. Hypercoagulable states: molecular genetics to clinical practice. Lancet. 1994;344:1739–1742.[Medline] [Order article via Infotrieve]

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

26. Zuber M, Toulon P, Marnet L, Mas JL. Factor V Leiden mutation in cerebral venous thrombosis. Stroke. 1996;27:1721–1723.[Abstract/Free Full Text]

This article has been cited by other articles:

				E. S. Roach, M. R. Golomb, R. Adams, J. Biller, S. Daniels, G. deVeber, D. Ferriero, B. V. Jones, F. J. Kirkham, R. M. Scott, et al. Management of Stroke in Infants and Children: A Scientific Statement From a Special Writing Group of the American Heart Association Stroke Council and the Council on Cardiovascular Disease in the Young Stroke, September 1, 2008; 39(9): 2644 - 2691. [Abstract] [Full Text] [PDF]

				E. M. Wysokinska, W. E. Wysokinski, R. D. Brown, K. Karnicki, I. Gosk-Beirska, D. Grill, and R. D. McBane II Thrombophilia differences in cerebral venous sinus and lower extremity deep venous thrombosis Neurology, February 19, 2008; 70(8): 627 - 633. [Abstract] [Full Text] [PDF]

				B. Voetsch, R. C. Jin, C. Bierl, L. Deus-Silva, E. C.S. Camargo, J. M. Annichino-Bizacchi, D. E. Handy, and J. Loscalzo Role of Promoter Polymorphisms in the Plasma Glutathione Peroxidase (GPx-3) Gene as a Risk Factor for Cerebral Venous Thrombosis Stroke, February 1, 2008; 39(2): 303 - 307. [Abstract] [Full Text] [PDF]

				K. H. Reuner, E. Jenetzky, A. Aleu, F. Litfin, P. Mellado, M. Kloss, E. Juttler, A. J. Grau, H. Rickmann, H. Patscheke, et al. Factor XII C46T gene polymorphism and the risk of cerebral venous thrombosis Neurology, January 8, 2008; 70(2): 129 - 132. [Abstract] [Full Text] [PDF]

				F. Dentali, M. Crowther, and W. Ageno Thrombophilic abnormalities, oral contraceptives, and risk of cerebral vein thrombosis: a meta-analysis Blood, April 1, 2006; 107(7): 2766 - 2773. [Abstract] [Full Text] [PDF]

				J. Stam Thrombosis of the Cerebral Veins and Sinuses N. Engl. J. Med., April 28, 2005; 352(17): 1791 - 1798. [Full Text] [PDF]

				G. Sebire, B. Tabarki, D. E. Saunders, I. Leroy, R. Liesner, C. Saint-Martin, B. Husson, A. N. Williams, A. Wade, and F. J. Kirkham Cerebral venous sinus thrombosis in children: risk factors, presentation, diagnosis and outcome Brain, March 1, 2005; 128(3): 477 - 489. [Abstract] [Full Text] [PDF]

				J. P. Casas, A. D. Hingorani, L. E. Bautista, and P. Sharma Meta-analysis of Genetic Studies in Ischemic Stroke: Thirty-two Genes Involving Approximately 18 000 Cases and 58 000 Controls Arch Neurol, November 1, 2004; 61(11): 1652 - 1661. [Abstract] [Full Text] [PDF]

				C. Heller, A. Heinecke, R. Junker, R. Knofler, A. Kosch, K. Kurnik, R. Schobess, A. von Eckardstein, R. Strater, B. Zieger, et al. Cerebral Venous Thrombosis in Children: A Multifactorial Origin Circulation, September 16, 2003; 108(11): 1362 - 1367. [Abstract] [Full Text] [PDF]

				F. L Ruberg and J. Loscalzo Prothrombotic determinants of coronary atherothrombosis Vascular Medicine, November 1, 2002; 7(4): 289 - 299. [Abstract] [PDF]

				T. G. DeLoughery Thrombocytopenia in Critical Care Patients J Intensive Care Med, November 1, 2002; 17(6): 267 - 282. [Abstract] [PDF]

				B. Rizzato, F. Ferrante, A. Pisani, M. Diomedi, J. N. Fink, and D. L. McAuley Recurrent Cerebral Venous Thrombosis in a 24-Year-Old Puerperal Woman * Response Stroke, September 1, 2002; 33(9): 2148 - 2149. [Full Text] [PDF]

				A. Kao, D. Dlugos, J. V. Hunter, P. Mamula, and O. Thorarensen Anticoagulation Therapy in Cerebral Sinovenous Thrombosis and Ulcerative Colitis in Children J Child Neurol, July 1, 2002; 17(7): 479 - 482. [Abstract] [PDF]

				P. Madonna, V. de Stefano, A. Coppola, F. Cirillo, A. M. Cerbone, G. Orefice, and G. Di Minno Hyperhomocysteinemia and Other Inherited Prothrombotic Conditions in Young Adults With a History of Ischemic Stroke Stroke, January 1, 2002; 33(1): 51 - 56. [Abstract] [Full Text] [PDF]

				A. J. Catto Genetic aspects of the hemostatic system in cerebrovascular disease Neurology, September 1, 2001; 57(90002): S24 - 30. [Abstract] [Full Text]

				P. Madonna, V. De Stefano, A. Coppola, R. Albisinni, and A. M. Cerbone G20210A PRTH Gene Mutation and Other Trombophilic Polymorphisms in Patients With Cerebral Vein Thrombosis Stroke, July 1, 2000; 31 (7): 1785 - 1790. [Full Text] [PDF]

				M. J. Kupferminc, D. Yair, N. M. Bornstein, J. B. Lessing, and A. Eldor Transient Focal Neurological Deficits During Pregnancy in Carriers of Inherited Thrombophilia Stroke, April 1, 2000; 31(4): 892 - 895. [Abstract] [Full Text] [PDF]

				R. D. Rosenberg and W. C. Aird Vascular-Bed-Specific Hemostasis and Hypercoagulable States N. Engl. J. Med., May 20, 1999; 340(20): 1555 - 1564. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Reuner, K. H. Articles by Patscheke, H. Search for Related Content PubMed PubMed Citation Articles by Reuner, K. H. Articles by Patscheke, H.