Background Idiopathic cerebral-vein thrombosis can cause seriousneurologic disability. We evaluated risk factors for this disorder,including genetic risk factors (mutations in the genes encodingfactor V and prothrombin) and nongenetic risk factors (suchas the use of oral contraceptive agents).
Methods We compared the prevalence of these risk factors in40 patients with cerebral-vein thrombosis, 80 patients withdeep-vein thrombosis of the lower extremities, and 120 healthycontrols. The G1691A mutation in the factor V gene and the G20210Aprothrombin-gene mutation, which are established genetic riskfactors for venous thrombosis, were studied. We also assessedthe use of oral contraceptives and other risk factors for thrombosis.
Results The prevalence of the prothrombin-gene mutation washigher in patients with cerebral-vein thrombosis (20 percent)than in healthy controls (3 percent; odds ratio, 10.2; 95 percentconfidence interval, 2.3 to 31.0) and was similar to that inpatients with deep-vein thrombosis (18 percent). Similar resultswere obtained for the mutation in the factor V gene. The useof oral contraceptives was more frequent among women with cerebral-veinthrombosis (96 percent) than among controls (32 percent; oddsratio, 22.1; 95 percent confidence interval, 5.9 to 84.2) andamong those with deep-vein thrombosis (61 percent; odds ratio,4.4; 95 percent confidence interval, 1.1 to 17.8). For womenwho were taking oral contraceptives and who also had the prothrombin-genemutation (seven patients with cerebral-vein thrombosis but onlyone control), the odds ratio for cerebral-vein thrombosis roseto 149.3 (95 percent confidence interval, 31.0 to 711.0).
Conclusions Mutations in the prothrombin gene and the factorV gene are associated with cerebral-vein thrombosis. The useof oral contraceptives is also strongly and independently associatedwith the disorder. The presence of both the prothrombin-genemutation and oral-contraceptive use raises the risk of cerebral-veinthrombosis further.
The risk of venous thrombosis of the lower extremities is increasedby factors that cause hypercoagulability or venous stasis, suchas the use of oral contraceptives, pregnancy or the postpartumstate, surgery, trauma, and prolonged immobilization. The riskof venous thrombosis is also increased by hypercoagulable statesdue to inherited abnormalities of the coagulation system, suchas the G1691A mutation in the factor V gene, which causes resistanceto activated protein C, and deficiencies of antithrombin, proteinC, or protein S. Acquired abnormalities such as the presenceof antiphospholipid antibodies are also associated with an increasedrisk of venous thrombosis.1 The recent discovery of a transitionfrom guanine to adenine at position 20210 in the sequence ofthe 3' untranslated region of the prothrombin gene has widenedthe spectrum of inherited thrombophilia.2 Next to the mutationin the factor V gene,3,4 the prothrombin-gene mutation is themost common genetic determinant of deep-vein thrombosis of thelower extremities.2
Cerebral-vein thrombosis is a frightening event because of theseverity of the clinical manifestations and the high mortalityrate, estimated to be 5 to 30 percent.5,6,7 Clinically, cerebral-veinthrombosis presents with a wide range of symptoms, includingheadache, focal deficits (motor or sensory), dysphasia, seizures,and impaired consciousness. Idiopathic cerebral-vein thrombosis(i.e., that occurring in the absence of infection, trauma, tumors,or autoimmune disease) represents a large proportion of cases(approximately 30 percent).6 Although it is known that the mutationof the factor V gene,8,9,10,11,12,13 the use of oral contraceptives,and pregnancy6,8,10,11 are risk factors for cerebral-vein thrombosis,no information about the relation between the disorder and theprothrombin-gene mutation is yet available. The main objectiveof this study was to evaluate this risk factor and potentialinteractions with other risk factors for cerebral-vein thrombosis.
Methods
Patients with Cerebral-Vein Thrombosis
Forty unrelated patients with a first episode of idiopathiccerebral-vein thrombosis were studied retrospectively (9 menand 31 women; median age, 31 years; range, 15 to 64). They werereferred to our thrombosis center between April 1991 and May1997 for screening for abnormalities of the coagulation system.None of them had overt evidence of autoimmune or neoplasticdisease. Two additional patients were excluded from the studybecause cerebral-vein thrombosis was secondary to infection(acute otitis) or to a post-traumatic cerebral arteriovenousfistula. The clinical records and the objective documentationof cerebral-vein thrombosis were reviewed by a neurologist toconfirm the diagnosis. The diagnosis was made by intraarterialangiography in 20 cases, intravenous digital angiographic imagingin 2 cases, magnetic resonance imaging in 16 cases, and computedtomography showing the typical delta and cord signs in 2 cases.14
Twelve patients had symptoms of chronic isolated intracranialhypertension (headache and papilledema in all 12 and a sixth-nervepalsy in 2). The remaining 28 patients had various combinationsof focal neurologic deficits, seizures, and impaired consciousness.Nineteen patients had radiologic evidence of thrombosis in asingle dural sinus, and 21 had evidence of thromboses in twoor more sinuses. Six patients had concomitant cortical-veinthromboses (five with a single dural-sinus thrombosis and onewith multiple sinus thromboses).
Patients with Deep-Vein Thrombosis of the Lower Extremities
Four hundred eighty-nine patients with first documented episodesof proximal deep-vein thrombosis of the lower extremities werereferred to our thrombosis center for the same screening forabnormalities of the coagulation system during the same periodas the patients with cerebral-vein thrombosis. We randomly selected80 of these patients (18 men and 62 women; median age, 30 years;range, 13 to 62) who were matched to the patients with cerebral-veinthrombosis according to sex, age (±5 years), geographicorigin, and level of education (less than high school, highschool, or college). They had no evidence of cancer or autoimmunedisease.
Healthy Controls
One hundred twenty healthy persons (27 men and 93 women; medianage, 32 years; range, 18 to 64) were matched to the patientswith cerebral-vein thrombosis according to sex, age, geographicorigin, and level of education. These controls came from a populationof biologically unrelated friends or partners of the patientswho agreed to accompany the patients to the thrombosis centerand to participate in the study. Persons who had had thrombosiswere excluded with use of a structured questionnaire validatedfor the retrospective diagnosis of thrombosis.15,16
The presence of known risk factors for thrombosis, such as theuse of oral contraceptives, pregnancy or the postpartum state(the three months after childbirth), surgery, trauma, and prolongedimmobilization, was recorded. The period of oral-contraceptiveuse was recorded. Women were considered to be using oral contraceptivesif they had taken them during the two weeks preceding the episodeof thrombosis. Since smoking may increase the risk of thrombosisin carriers of genetic coagulation defects,17,18 informationon smoking was also recorded. Persons who smoked at least fivecigarettes daily were considered smokers.
Laboratory Tests
Blood was collected in vacuum tubes containing 3.8 percent (wt/vol)sodium citrate as an anticoagulant. DNA analysis to identifya transition from guanine to adenine at position 20210 in the3' untranslated region of the prothrombin gene was carried outaccording to the method of Poort et al.19 DNA analysis to identifya transition from guanine to adenine at position 1691 in thecoagulation factor V gene was carried out as described by deRonde and Bertina.20 Heparin cofactor activity, an indicatorof the antithrombin level, was measured by an amidolytic assay(Coamate AT, Chromogenix, Mölndal, Sweden). When antithrombinlevels were low, the defect was further characterized by measuringantigen levels by immunoelectrophoresis with a polyclonal antibody(Stago, Asnieres, France), measuring functional activity inthe absence of heparin, and performing crossed immunoelectrophoresiswith and without heparin.21
Protein C activity was assayed by a clotting assay (ProClot,Instrumentation Laboratory, Milan, Italy). When plasma levelsof protein C activity were low, antigen levels were also measuredby enzyme-linked immunosorbent assay (ELISA) with polyclonalantibodies (Dako, Glostrup, Denmark). Total protein S antigenwas measured by ELISA with polyclonal antibodies (Dako). Freeprotein S was measured in the same way after precipitation ofthe C4b-binding protein–protein S complex with polyethyleneglycol 6000 (final concentration, 3.5 percent)22 or directlyby ELISA with a commercial kit that uses a specific monoclonalantibody (Asserachrom Free Protein S, Stago). The diagnosisof antiphospholipid-antibody syndrome was made when lupus anticoagulant,anticardiolipin antibodies, or both were present. Protein Cand protein S levels and lupus anticoagulant could not be evaluatedin one patient with cerebral-vein thrombosis and in seven patientswith deep-vein thrombosis who were receiving oral anticoagulanttherapy at the time of blood sampling, since measurements ofvitamin K–dependent proteins are unreliable during suchtherapy.
Statistical Analysis
We compared patients with cerebral-vein thrombosis with thosewith deep-vein thrombosis with respect to the listed risk factors.Because patients with deep-vein thrombosis were matched withpatients with cerebral-vein thrombosis, they could not be directlycompared with healthy controls. The estimated risks for patientswith cerebral-vein thrombosis are given as odds ratios and 95percent confidence intervals, with the approximation of Woolf.23Because using oral contraceptives is incompatible with beingpregnant or in the postpartum state, the proportion of womentaking oral contraceptives was calculated after excluding pregnantor postpartum women, and the proportion of pregnant women wascalculated after excluding women taking oral contraceptives.These proportions were also calculated after the exclusion ofpostmenopausal women (two with cerebral-vein thrombosis, threewith deep-vein thrombosis, and six controls). Adjustment formatching factors and potential confounding factors was performedby unconditional logistic-regression analysis with the SAS softwarepackage.24
Results
Coagulation Abnormalities
The main characteristics of the patients and the prevalenceof coagulation defects are listed in Table 1. Twenty percentof the patients with cerebral-vein thrombosis (7 women and 1man), 18 percent of those with deep-vein thrombosis (11 womenand 3 men), and 3 percent of the controls (2 women and 1 man)were carriers of the prothrombin-gene mutation. The prevalenceof the defect was significantly higher in patients with cerebral-veinthrombosis than in controls (odds ratio, 10.2; 95 percent confidenceinterval, 2.3 to 31.0) and was similar to that found in patientswith deep-vein thrombosis (18 percent) (Table 2). Similarly,the prevalence of the factor V mutation was significantly higherin patients with cerebral-vein thrombosis (15 percent) thanin controls (3 percent; odds ratio, 7.8; 95 percent confidenceinterval, 1.8 to 34.1) (Table 2). In one patient with cerebral-veinthrombosis and in two with deep-vein thrombosis, both the prothrombin-genemutation and the factor V mutation were present.
Table 2. Risk of Cerebral-Vein Thrombosis in the Presence of Genetic Coagulation Defects and Nongenetic Risk Factors.
The risk of cerebral-vein thrombosis associated with the prothrombin-genemutation was independent of the presence of the factor V mutation,since the exclusion of carriers of both mutations did not appreciablychange the results (odds ratio, 10.0; 95 percent confidenceinterval, 2.4 to 42.1). All carriers of the prothrombin-genemutation were heterozygous, whereas four patients with deep-veinthrombosis were homozygous for the factor V mutation. The resultsdid not substantially change after exclusion of the four homozygotesfrom the analysis.
The prevalence of other causes of thrombophilia (deficiencyof antithrombin, protein C, or protein S or the presence ofantiphospholipid antibodies) was 3 percent both in patientswith cerebral-vein thrombosis and in controls, lower than theprevalence in patients with deep-vein thrombosis (16 percent).One patient with cerebral-vein thrombosis had both the mutationin the factor V gene and antithrombin deficiency. Of the patientswith deep-vein thrombosis, two (2 percent) had antithrombindeficiency, three (4 percent) had protein C deficiency, one(1 percent) had protein S deficiency, and seven (9 percent)had antiphospholipid antibodies. Four controls (3 percent) hadcoagulation defects other than prothrombin and factor V mutations(three had antithrombin deficiency, and one had protein S deficiency).
Other Risk Factors for Thrombosis
The prevalence of other risk factors for thrombosis is shownin Table 1. Apart from the use of oral contraceptives, noneof the controls had had any of the risk factors for thrombosisin the month before the visit. A smaller proportion of patientswith cerebral-vein thrombosis than of patients with deep-veinthrombosis had had surgery, trauma, or prolonged immobilization(3 percent vs. 18 percent). Pregnancy or the postpartum statewas frequently associated with both disorders (80 percent ofpatients with cerebral-vein thrombosis and 34 percent of thosewith deep-vein thrombosis). The most prevalent nongenetic riskfactor for both disorders was oral-contraceptive use. Eightpatients with cerebral-vein thrombosis (20 percent), 20 withdeep-vein thrombosis (25 percent), and 35 controls (29 percent)were smokers. Smoking was not associated with an increased riskof cerebral-vein thrombosis, either alone or in combinationwith the prothrombin-gene mutation or the factor V mutation(data not shown). Because of the high frequency of oral-contraceptiveuse among the female patients, we analyzed in detail the effectof oral contraceptives and their interaction with the mutationsin the prothrombin and factor V genes in determining the riskof thrombosis.
Oral Contraceptives and Thrombosis
The proportion of oral-contraceptive users was higher amongwomen with cerebral-vein thrombosis (96 percent) than amongcontrols (32 percent; odds ratio, 22.1; 95 percent confidenceinterval, 5.9 to 84.2) (Table 2) and among patients with deep-veinthrombosis (61 percent; odds ratio, 4.4; 95 percent confidenceinterval, 1.1 to 17.8). The median period of oral-contraceptiveuse was 15 months for women with either cerebral-vein thrombosisor deep-vein thrombosis (range, 1 to 161 and 1 to 168, respectively)and 26 months for controls (range, 1 to 189).
The odds ratio for cerebral-vein thrombosis according to thecombined presence of the prothrombin-gene mutation or the factorV mutation and the use of oral contraceptives at the time ofthrombosis (or at the time of blood sampling, for controls)is shown in Table 3. Women using oral contraceptives who didnot have the prothrombin-gene mutation had a higher risk ofcerebral-vein thrombosis than controls (63 percent of the womenwith cerebral-vein thrombosis had these characteristics, ascompared with 29 percent of the controls; odds ratio, 13.4;95 percent confidence interval, 3.5 to 51.3). This odds ratiowas similar to that calculated for oral-contraceptive userswho did not have the factor V mutation (78 percent of the womenwith cerebral-vein thrombosis had these characteristics, ascompared with 30 percent of the controls; odds ratio, 15.8;95 percent confidence interval, 4.3 to 57.2). For women whowere taking oral contraceptives and who also had the prothrombin-genemutation (seven patients with cerebral-vein thrombosis but onlyone control), the odds ratio for cerebral-vein thrombosis increasedto nearly 150. The combined effect of the use of oral contraceptivesand the factor V mutation could not be evaluated because noneof the controls had both risk factors.
Table 3. Risk of Cerebral-Vein Thrombosis in Women According to Whether They Had the G20210A Prothrombin-Gene Mutation or the G1691A Factor V Mutation and Used Oral Contraceptives.
Discussion
This study shows that there is a hypercoagulable state in 35percent of patients with idiopathic cerebral-vein thrombosis.The most frequent coagulation abnormality is the G20210A mutationin the prothrombin gene, which increases the risk of the disorderby a factor of 10. This relation was not affected by the concomitantpresence of the G1691A mutation in the factor V gene, whichis known to increase the risk of cerebral-vein thrombosis.8,9,10,11,12,13This study also indicates that oral contraceptives are stronglyassociated with cerebral-vein thrombosis, increasing the riskby a factor of approximately 20. Although the number of womenwith both risk factors was small, the combined effect of theprothrombin-gene mutation and the use of oral contraceptivesgreatly increased the risk of cerebral-vein thrombosis. Sinceboth the prothrombin-gene mutation and the use of oral contraceptivescause hypercoagulability,2,25 their combination probably enhancestheir individual effects on coagulation. In particular, bothincrease plasma levels of prothrombin,2,25 the zymogen responsiblefor thrombin formation in the coagulation system.
It has previously been observed that cerebral-vein thrombosisis associated with the factor V mutation and occurs more frequentlyin young women who are taking oral contraceptives or who arepregnant or in the postpartum state.6,8,10 In a recent smallstudy, the relative risk associated with the use of oral contraceptiveswas estimated to be 4.2.26 In the current study of twice asmany women, there was an association between oral-contraceptiveuse and cerebral-vein thrombosis, but the magnitude of the risk,especially when oral-contraceptive use and the prothrombin-genemutation were both present, was unexpected.
This finding raises two questions. One question is whether screeningfor the prothrombin-gene mutation in young women before theyare prescribed oral contraceptives would be useful. The otherquestion is whether withholding oral contraceptives from carriersof the prothrombin-gene mutation would be worthwhile. Indiscriminatescreening for the prothrombin-gene mutation would probably notbe useful, since cerebral-vein thrombosis is a rare condition.The incidence of cerebral-vein thrombosis is not precisely known,but it is likely to be lower than the incidence of approximately1 per 1000 persons per year reported for deep-vein thrombosis.27Vandenbroucke et al.28,29 suggested that indiscriminate screeningwould not be cost effective, even though the risk of deep-veinthrombosis in oral-contraceptive users who have the factor Vmutation is greater than the risk in those with only one ofthese risk factors. Likewise, since the prevalence of the prothrombin-genemutation is similar to or lower than that of the factor V mutationin the general population, one can reasonably draw the sameconclusion for cerebral-vein thrombosis, even though its mortalityrate is higher than that of deep-vein thrombosis.
With respect to the second question, withholding the most effectivemode of contraception might lead to more pregnancies, whichwould also increase the risk of venous thromboembolism. Therefore,we recommend that carriers of the prothrombin-gene mutationwho have had an episode of thrombosis discontinue taking oralcontraceptives. For asymptomatic carriers, who are usually identifiedin family studies, counseling about alternative methods of contraceptionshould be considered, taking into account whether other riskfactors for thrombosis are present.
Another unresolved issue is the indication for anticoagulanttreatment in patients with cerebral-vein thrombosis.5,6,30 Becauseof the design of our study, no definite opinion can be givenabout the efficacy and safety of this treatment. In the absenceof objective evidence of cerebral hemorrhage, we give oral anticoagulanttherapy for at least three months after the occurrence of cerebral-veinthrombosis to patients without coagulation defects, for up toone year to those with a coagulation defect, and for life tothose who have had more than one thrombotic episode.
Source Information
From the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center (I.M., E.S., F.D., P.M.M.), Neurology Department (G.L.), and Epidemiology Unit (E.T.), Istituto di Ricovero e Cura a Carattere Scientifico Maggiore Hospital, University of Milan, Milan, Italy.
Address reprint requests to Dr. Martinelli at the Hemophilia and Thrombosis Center, IRCCS Maggiore Hospital, Via Pace 9, 20122 Milan, Italy.
References
De Stefano V, Finazzi G, Mannucci PM. Inherited thrombophilia: pathogenesis, clinical syndromes, and management. Blood 1996;87:3531-3544. [Free Full Text]
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. [Free Full Text]
Bertina RM, Koeleman BPC, Koster T, et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994;369:64-67. [CrossRef][Medline]
Koster T, Rosendaal FR, de Ronde H, Briët E, Vandenbroucke JP, Bertina RM. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. Lancet 1993;342:1503-1506. [CrossRef][Medline]
Bousser MG, Chiras J, Bories J, Castaigne P. Cerebral venous thrombosis -- a review of 38 cases. Stroke 1985;16:199-213. [Free Full Text]
Preter MP, Tzourio C, Ameri A, Bousser MG. Long-term prognosis in cerebral venous thrombosis: follow-up of 77 patients. Stroke 1996;27:243-246. [Free Full Text]
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 Haemost 1996;75:393-394. [Medline]
Dulli DA, Luzzio CC, Williams EC, Schutta HS. Cerebral venous thrombosis and activated protein C resistance. Stroke 1996;27:1731-1733. [Free Full Text]
Deschiens MA, Conard J, Horellou MH, et al. Coagulation studies, factor V Leiden, and anticardiolipin antibodies in 40 cases of cerebral venous thrombosis. Stroke 1996;27:1724-1730. [Free Full Text]
de Bruijn SF, Stam J, Koopman MM, Vandenbroucke JP. Case-control study of risk of cerebral sinus thrombosis in oral contraceptive users who are carriers of hereditary prothrombotic conditions. BMJ 1998;316:589-592. [Free Full Text]
Zuber M, Toulon P, Marnet L, Mas JL. Factor V Leiden mutation in cerebral venous thrombosis. Stroke 1996;27:1721-1723. [Free Full Text]
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]
Frezzato M, Tosetto A, Rodeghiero F. Validated questionnaire for the identification of previous personal or familial venous thromboembolism. Am J Epidemiol 1996;143:1257-1265. [Free Full Text]
Taioli E, Martinelli I, Rossi V, Crosti F, Mannucci PM. Re: "Validated questionnaire for the identification of previous personal or familial venous thromboembolism." Am J Epidemiol 1998;147:605-606. [Free Full Text]
Rosendaal FR, Siscovick DS, Schwartz SM, et al. Factor V Leiden (resistance to activated protein C) increases the risk of myocardial infarction in young women. Blood 1997;89:2817-2821. [Free Full Text]
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. [Free Full Text]
Poort SR, Bertina RM, Vos HL. Rapid detection of the prothrombin 20210 A variation by allele specific PCR. Thromb Haemost 1997;78:1157-1158. [Medline]
de Ronde H, Bertina RM. Laboratory diagnosis of APC-resistance: a critical evaluation of the test and the development of diagnostic criteria. Thromb Haemost 1994;72:880-886. [Medline]
Sas G, Pepper DS, Cash JD. Plasma and serum antithrombin III: differentiation by crossed immunoelectrophoresis. Thromb Res 1975;6:87-91. [CrossRef][Medline]
Comp PC, Doray D, Patton D, Esmon CT. An abnormal plasma distribution of protein S occurs in functional protein S deficiency. Blood 1986;67:504-508. [Free Full Text]
Woolf B. On estimating the relation between blood group and disease. Ann Hum Genet 1955;19:251-253. [Medline]
SAS user's guide, version 6, 4th ed. Cary, N.C.: SAS Institute, 1990.
Kluft C, Lansink M. Effect of oral contraceptives on haemostatic variables. Thromb Haemost 1997;78:315-326. [Medline]
Martinelli I, Rosendaal FR, Vandenbroucke JP, Mannucci PM. Oral contraceptives are a risk factor for cerebral vein thrombosis. Thromb Haemost 1996;76:477-478. [Medline]
Kierkegaard A. Incidence of acute deep vein thrombosis in two districts: a phlebographic study. Acta Chir Scand 1980;146:267-269. [Medline]
Vandenbroucke JP, Koster T, Briët 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. [CrossRef][Medline]
Vandenbroucke JP, van der Meer FJM, Helmerhorst FM, Rosendaal FR. Factor V Leiden: should we screen oral contraceptive users and pregnant women? BMJ 1996;313:1127-1130. [Free Full Text]
Einhäupl KM, Villringer A, Meister W, et al. Heparin treatment in sinus venous thrombosis. Lancet 1991;338:597-600. [Erratum, Lancet 1991;338:958.] [CrossRef][Medline]
Santoro, R.
(2009). A Woman With Rectal Sinus and Left Transversal Sinus Thrombosis After Ovarian Stimulation: Case Report. CLIN APPL THROMB HEMOST
15: 711-713
[Abstract]
Dangal, G., Thapa, L. B.
(2009). Cerebral venous sinus thrombosis presenting in pregnancy and puerperium. BMJ Case Reports
2009: bcr0620092045-bcr0620092045
[Abstract][Full Text]
Coutinho, J. M., Ferro, J. M., Canhao, P., Barinagarrementeria, F., Cantu, C., Bousser, M.-G., Stam, J.
(2009). Cerebral Venous and Sinus Thrombosis in Women. Stroke
40: 2356-2361
[Abstract][Full Text]
Martinelli, I., Franchini, M., Mannucci, P. M.
(2008). How I treat rare venous thromboses. Blood
112: 4818-4823
[Abstract][Full Text]
Rathbun, S.
(2008). Venous thromboembolism in women. Vasc Med
13: 255-266
[Abstract]
Albers, G. W., Amarenco, P., Easton, J. D., Sacco, R. L., Teal, P.
(2008). Antithrombotic and Thrombolytic Therapy for Ischemic Stroke: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest
133: 630S-669S
[Abstract][Full Text]
Wysokinska, E. M., Wysokinski, W. E., Brown, R. D., Karnicki, K., Gosk-Beirska, I., Grill, D., McBane, R. D. II
(2008). Thrombophilia differences in cerebral venous sinus and lower extremity deep venous thrombosis. Neurology
70: 627-633
[Abstract][Full Text]
Voetsch, B., Jin, R. C., Bierl, C., Deus-Silva, L., Camargo, E. C.S., Annichino-Bizacchi, J. M., Handy, D. E., Loscalzo, J.
(2008). Role of Promoter Polymorphisms in the Plasma Glutathione Peroxidase (GPx-3) Gene as a Risk Factor for Cerebral Venous Thrombosis. Stroke
39: 303-307
[Abstract][Full Text]
Goldstein, L. B., Adams, R., Alberts, M. J., Appel, L. J., Brass, L. M., Bushnell, C. D., Culebras, A., DeGraba, T. J., Gorelick, P. B., Guyton, J. R., Hart, R. G., Howard, G., Kelly-Hayes, M., Nixon, J.V., Sacco, R. L.
(2006). Primary Prevention of Ischemic Stroke: A Guideline From the American Heart Association/American Stroke Association Stroke Council: Cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: The American Academy of Neurology affirms the value of this guideline.. Circulation
113: e873-e923
[Abstract][Full Text]
Goldstein, L. B., Adams, R., Alberts, M. J., Appel, L. J., Brass, L. M., Bushnell, C. D., Culebras, A., DeGraba, T. J., Gorelick, P. B., Guyton, J. R., Hart, R. G., Howard, G., Kelly-Hayes, M., Nixon, J.V., Sacco, R. L.
(2006). Primary Prevention of Ischemic Stroke: A Guideline From the American Heart Association/American Stroke Association Stroke Council: Cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: The American Academy of Neurology affirms the value of this guideline.. Stroke
37: 1583-1633
[Abstract][Full Text]
Morcos, Z., van den Bergh, W. M., van der Schaaf, I., van Gijn, J.
(2006). The spectrum of presentations of venous infarction caused by deep cerebral vein thrombosis. Neurology
66: 1284-1284
[Full Text]
Bick, R. L.
(2006). Hereditary and Acquired Thrombophilic Disorders. CLIN APPL THROMB HEMOST
12: 125-135
Dentali, F., Crowther, M., Ageno, W.
(2006). Thrombophilic abnormalities, oral contraceptives, and risk of cerebral vein thrombosis: a meta-analysis. Blood
107: 2766-2773
[Abstract][Full Text]
van den Bergh, W. M., van der Schaaf, I., van Gijn, J.
(2005). The spectrum of presentations of venous infarction caused by deep cerebral vein thrombosis. Neurology
65: 192-196
[Abstract][Full Text]
Stam, J.
(2005). Thrombosis of the Cerebral Veins and Sinuses. NEJM
352: 1791-1798
[Full Text]
Meschia, J. F., Brott, T. G., Brown, R. D. Jr
(2005). Genetics of Cerebrovascular Disorders. Mayo Clin Proc.
80: 122-132
[Abstract]
Gomes, M. P. V., Deitcher, S. R.
(2004). Risk of Venous Thromboembolic Disease Associated With Hormonal Contraceptives and Hormone Replacement Therapy: A Clinical Review. Arch Intern Med
164: 1965-1976
[Abstract][Full Text]
Albers, G. W., Amarenco, P., Easton, J. D., Sacco, R. L., Teal, P.
(2004). Antithrombotic and Thrombolytic Therapy for Ischemic Stroke: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest
126: 483S-512S
[Abstract][Full Text]
Martinelli, I., Battaglioli, T., Bucciarelli, P., Passamonti, S. M., Mannucci, P. M.
(2004). Risk Factors and Recurrence Rate of Primary Deep Vein Thrombosis of the Upper Extremities. Circulation
110: 566-570
[Abstract][Full Text]
Kovalevsky, G., Gracia, C. R., Berlin, J. A., Sammel, M. D., Barnhart, K. T.
(2004). Evaluation of the Association Between Hereditary Thrombophilias and Recurrent Pregnancy Loss: A Meta-analysis. Arch Intern Med
164: 558-563
[Abstract][Full Text]
Dunkley, S., Johnston, I.
(2004). Thrombophilia as a common predisposing factor in pseudotumor cerebri. Blood
103: 1972-1973
[Full Text]
Ou, Y.-C., Kao, Y.-L., Lai, S.-L., Kung, F.-T., Huang, F.-J., Chang, S.-Y., ChangChien, C.-C.
(2003). Thromboembolism after ovarian stimulation: successful management of a woman with superior sagittal sinus thrombosis after IVF and embryo transfer: Case report. Hum Reprod
18: 2375-2381
[Abstract][Full Text]
Petitti, D. B.
(2003). Combination Estrogen-Progestin Oral Contraceptives. NEJM
349: 1443-1450
[Full Text]
Heller, C., Heinecke, A., Junker, R., Knofler, R., Kosch, A., Kurnik, K., Schobess, R., von Eckardstein, A., Strater, R., Zieger, B., Nowak-Gottl, U.
(2003). Cerebral Venous Thrombosis in Children: A Multifactorial Origin. Circulation
108: 1362-1367
[Abstract][Full Text]
Martinelli, I., Battaglioli, T., Pedotti, P., Cattaneo, M., Mannucci, P. M.
(2003). Hyperhomocysteinemia in cerebral vein thrombosis. Blood
102: 1363-1366
[Abstract][Full Text]
Cosmi, B., Legnani, C., Bernardi, F., Coccheri, S., Palareti, G.
(2003). Role of Family History in Identifying Women With Thrombophilia and Higher Risk of Venous Thromboembolism During Oral Contraception. Arch Intern Med
163: 1105-1109
[Abstract][Full Text]
Cakmak, S., Derex, L., Berruyer, M., Nighoghossian, N., Philippeau, F., Adeleine, P., Hermier, M., Froment, J.C., Trouillas, P.
(2003). Cerebral venous thrombosis: Clinical outcome and systematic screening of prothrombotic factors. Neurology
60: 1175-1178
[Abstract][Full Text]
Evans, W. E., McLeod, H. L.
(2003). Pharmacogenomics -- Drug Disposition, Drug Targets, and Side Effects. NEJM
348: 538-549
[Full Text]
Deitcher, S. R, Gomes, M. P.
(2003). Hypercoagulable state testing and malignancy screening following venous thromboembolic events. Vasc Med
8: 33-46
[Abstract]
Seibert, C., Barbouche, E., Fagan, J., Myint, E., Wetterneck, T., Wittemyer, M.
(2003). Prescribing Oral Contraceptives for Women Older Than 35 Years of Age. ANN INTERN MED
138: 54-64
[Abstract][Full Text]
Schafer, A. I., Levine, M. N., Konkle, B. A., Kearon, C.
(2003). Thrombotic Disorders: Diagnosis and Treatment. ASH Education Book
2003: 520-539
[Abstract][Full Text]
Bates, S. M., Ginsberg, J. S.
(2002). How we manage venous thromboembolism during pregnancy. Blood
100: 3470-3478
[Abstract][Full Text]
Pollak, E. S., Lam, H.-S., Russell, J. E.
(2002). The G20210A mutation does not affect the stability of prothrombin mRNA in vivo. Blood
100: 359-362
[Abstract][Full Text]
Thaler, D. E., Frosch, M. P.
(2002). Case 16-2002 - A 41-Year-Old Woman with Global Headache and an Intracranial Mass. NEJM
346: 1651-1658
[Full Text]
Joffe, H. V, Goldhaber, S. Z
(2002). Laboratory thrombophilias and venous thromboembolism. Vasc Med
7: 93-102
[Abstract]
Madonna, P., de Stefano, V., Coppola, A., Cirillo, F., Cerbone, A. M., Orefice, G., Di Minno, G.
(2002). Hyperhomocysteinemia and Other Inherited Prothrombotic Conditions in Young Adults With a History of Ischemic Stroke. Stroke
33: 51-56
[Abstract][Full Text]
Herrington, D. M., Klein, K. P.
(2001). Genome and Hormones: Gender Differences in Physiology: Invited Review: Pharmacogenetics of estrogen replacement therapy. J. Appl. Physiol.
91: 2776-2784
[Abstract][Full Text]
Lynch, J. K., Nelson, K. B., Curry, C. J., Grether, J. K.
(2001). Cerebrovascular Disorders in Children With the Factor V Leiden Mutation. J Child Neurol
16: 735-744
[Abstract]
Bauer, K. A.
(2001). The Thrombophilias: Well-Defined Risk Factors with Uncertain Therapeutic Implications. ANN INTERN MED
135: 367-373
[Abstract][Full Text]
deVeber, G., Andrew, M., Adams, C., Bjornson, B., Booth, F., Buckley, D. J., Camfield, C. S., David, M., Humphreys, P., Langevin, P., MacDonald, E. A., Meaney, B., Shevell, M., Sinclair, D. B., Yager, J., Gillett, J., the Canadian Pediatric Ischemic Stroke Study Group,
(2001). Cerebral Sinovenous Thrombosis in Children. NEJM
345: 417-423
[Abstract][Full Text]
KOMAJDA, M., CHARRON, P.
(2001). How will the human genome project change cardiovascular medicine?. Heart
86: 123-124
[Full Text]
Hankey, G. J., Eikelboom, J. W., van Bockxmeer, F. M., Lofthouse, E., Staples, N., Baker, R. I.
(2001). Inherited Thrombophilia in Ischemic Stroke and Its Pathogenic Subtypes. Stroke
32: 1793-1799
[Abstract][Full Text]
Edelberg, J. M., Christie, P. D., Rosenberg, R. D.
(2001). Regulation of Vascular Bed-Specific Prothrombotic Potential. Circ. Res.
89: 117-124
[Abstract][Full Text]
CHAK, M, WALLACE, G R, GRAHAM, E M, STANFORD, M R
(2001). Thrombophilia: genetic polymorphisms and their association with retinal vascular occlusive disease. Br J Ophthalmol
85: 883-886
[Full Text]
Federman, D. G., Kirsner, R. S.
(2001). An Update on Hypercoagulable Disorders. Arch Intern Med
161: 1051-1056
[Abstract][Full Text]
Seligsohn, U., Lubetsky, A.
(2001). Genetic Susceptibility to Venous Thrombosis. NEJM
344: 1222-1231
[Full Text]
Macik, B. G., Rand, J. H., Konkle, B. A.
(2001). Thrombophilia: What's a Practitioner to Do?. ASH Education Book
2001: 322-338
[Abstract][Full Text]
Albers, G. W., Amarenco, P., Easton, J. D., Sacco, R. L., Teal, P.
(2001). Antithrombotic and Thrombolytic Therapy for Ischemic Stroke. Chest
119
: 300S-320S
[Full Text]
Holtzman, N. A., Marteau, T. M.
(2000). Will Genetics Revolutionize Medicine?. NEJM
343: 141-144
[Full Text]
Gillum, L. A., Mamidipudi, S. K., Johnston, S. C.
(2000). Ischemic Stroke Risk With Oral Contraceptives: A Meta-analysis. JAMA
284: 72-78
[Abstract][Full Text]
Mira, Y., Aznar, J., Estelles, A., Vaya, A., Villa, P., Ferrando, F.
(2000). State-of-the-Art Review : Congenital and Acquired Thrombotic Risk Factors in Women Using Oral Contraceptives: Clinical Aspects. CLIN APPL THROMB HEMOST
6: 162-168
[Abstract]
Madonna, P., De Stefano, V., Coppola, A., Albisinni, R., Cerbone, A. M.
(2000). G20210A PRTH Gene Mutation and Other Trombophilic Polymorphisms in Patients With Cerebral Vein Thrombosis. Stroke
31
: 1785-1790
[Full Text]
Kupferminc, M. J., Yair, D., Bornstein, N. M., Lessing, J. B., Eldor, A.
(2000). Transient Focal Neurological Deficits During Pregnancy in Carriers of Inherited Thrombophilia. Stroke
31: 892-895
[Abstract][Full Text]
Lane, D. A., Grant, P. J.
(2000). Role of hemostatic gene polymorphisms in venous and arterial thrombotic disease. Blood
95: 1517-1532
[Full Text]
Gerhardt, A., Scharf, R. E., Beckmann, M. W., Struve, S., Bender, H. G., Pillny, M., Sandmann, W., Zotz, R. B.
(2000). Prothrombin and Factor V Mutations in Women with a History of Thrombosis during Pregnancy and the Puerperium. NEJM
342: 374-380
[Abstract][Full Text]
Lanthier, S., Carmant, L., David, M., Larbrisseau, A., de Veber, G.
(2000). Stroke in children: The coexistence of multiple risk factors predicts poor outcome. Neurology
54: 371-371
[Abstract][Full Text]
Lenfant, C.
(1999). Conquering Cardiovascular Disease: Progress and Promise. JAMA
282: 2068-2070
[Full Text]
Nowak-Gottl, U., Strater, R., Heinecke, A., Junker, R., Koch, H.-G., Schuierer, G., von Eckardstein, A.
(1999). Lipoprotein (a) and Genetic Polymorphisms of Clotting Factor V, Prothrombin, and Methylenetetrahydrofolate Reductase Are Risk Factors of Spontaneous Ischemic Stroke in Childhood. Blood
94: 3678-3682
[Abstract][Full Text]
Gul, A., Aslantas, A. B., Tekinay, T., Konice, M., Ozcelik, T.
(1999). Procoagulant mutations and venous thrombosis in Behcet's disease. Rheumatology (Oxford)
38: 1298-1299
[Full Text]
Irish, A.
(1999). Renal allograft thrombosis: can thrombophilia explain the inexplicable?. Nephrol Dial Transplant
14: 2297-2303
[Full Text]
Collins, F. S.
(1999). Medical and Societal Consequences of the Human Genome Project. NEJM
341: 28-37
[Full Text]
Speroff, L.
(1999). Modern Low-Dose Oral Contraceptives Are Very Safe. J. Clin. Endocrinol. Metab.
84: 1823-1825
[Full Text]
Rosenberg, R. D., Aird, W. C.
(1999). Vascular-Bed-Specific Hemostasis and Hypercoagulable States. NEJM
340: 1555-1564
[Full Text]
Kianmanesh Rad, N. A., Helmerhorst, F. M.
(1999). OHSS and cerebrovascular thrombosis. Hum Reprod
14: 1138a-1138a
[Full Text]
Yang, Y., Algazy, K. M.
(1999). Warfarin-Induced Skin Necrosis in a Patient with a Mutation of the Prothrombin Gene. NEJM
340: 735-735
[Full Text]
Martinelli, I., Taioli, E., Bucciarelli, P., Akhavan, S., Mannucci, P. M.
(1999). Interaction Between the G20210A Mutation of the Prothrombin Gene and Oral Contraceptive Use in Deep Vein Thrombosis. Arterioscler. Thromb. Vasc. Bio.
19: 700-703
[Abstract][Full Text]
Kupferminc, M. J., Eldor, A., Steinman, N., Many, A., Bar-Am, A., Jaffa, A., Fait, G., Lessing, J. B.
(1999). Increased Frequency of Genetic Thrombophilia in Women with Complications of Pregnancy. NEJM
340: 9-13
[Abstract][Full Text]
Ludemann, P., Nabavi, D. G., Junker, R., Wolff, E., Papke, K., Buchner, H., Assmann, G., Ringelstein, E. B.
(1998). Factor V Leiden Mutation Is a Risk Factor for Cerebral Venous Thrombosis : A Case-Control Study of 55 Patients. Stroke
29: 2507-2510
[Abstract][Full Text]
BROWN, M. M, BEVAN, D.
(1998). Is inherited thrombophilia a risk factor for arterial stroke?. J. Neurol. Neurosurg. Psychiatry
65: 617-617
[Full Text]
Vandenbroucke, J. P
(1998). Cerebral sinus thrombosis and oral contraceptives. BMJ
317: 483-484
[Full Text]
Bertina, R.M., Rosendaal, F.R.
(1998). Venous Thrombosis -- The Interaction of Genes and Environment. NEJM
338: 1839-1841
[Full Text]
Previous
