J Thromb Haemost. 2009 May;7(5):774-9. Epub 2009 Feb 24.
Major differences in bleeding symptoms between factor VII deficiency and hemophilia B.
Bernardi F, Dolce A, Pinotti M, Shapiro AD, Santagostino E, Peyvandi F, Batorova A, Lapecorella M, Schved JF, Ingerslev J, Mariani G; International Factor VII Deficiency Study Group.
Department of Biochemistry and Molecular Biology, University of Ferrara, Ferrara, Italy. ber@unife.it
Abstract
SUMMARY BACKGROUND: The autosomally-inherited factor VII (FVII) deficiency and X-linked hemophilia B offer an attractive model to investigate whether reduced levels of FVII and FIX, acting in the initiation and amplification of coagulation respectively, influence hemostasis to a different extent in relation to age and bleeding site.
METHODS: Hemophilia B patients (n = 296) and FVII-deficient males (n = 109) were compared for FVII/FIX clotting activity, F7/F9 genotypes and clinical phenotypes in a retrospective, multi-centre, cohort study.
RESULTS: Major clinical differences between diseases were observed. Bleeding occurred earlier in hemophilia B (median age 2.0 years, IR 0.9-5.0) than in FVII deficiency (5.2 years, IR 1.9-15.5) and the bleeding-free survival in FVII deficiency was similar to that observed in 'mild' hemophilia B (P = 0.96). The most frequent disease-presenting symptoms in hemophilia B (hematomas and oral bleeding) differed from those in FVII deficiency (epistaxis and central nervous system bleeding). Differences were confirmed by analysis of FVII-deficient women.
CONCLUSIONS: Our data support the notion that low FVII levels sustain hemostasis better than similarly reduced FIX levels. On the other hand, minute amounts of FVII, differently to FIX, are needed to prevent fatal bleeding, as indicated by the rarity of null mutations and the associated life-threatening symptoms in FVII deficiency, which contributes towards shaping clinical differences between diseases in the lowest factor level range. Differences between diseases are only partially explained by mutational patterns and could pertain to the specific roles of FVII and FIX in coagulation phases and to vascular bed-specific components.
PMID: 19245420
Clin Appl Thromb Hemost. 2010 Apr;16(2):221-3. Epub 2009 Jan 13.
Effective hemostasis during minor surgery in a case of hereditary combined deficiency of vitamin K-dependent clotting factors.
Lapecorella M, Napolitano M, Bernardi F, Pinotti M, Sbrighi PS, Marchetti G, Canella A, Caruso P, Orecchioni A, Mariani G.
Haemophilia and Thrombosis Centre, University of L'Aquila, Ospedale San Salvatore, Via Vetoio 1, Coppito, L'Aquila, Italy. emofilia.aq@cc.univaq.it
Abstract
Combined deficiency of the vitamin K-dependent clotting factors (VKCFD) is a rare bleeding disorder involving defective gamma-carboxylation of coagulation factors II , VII, IX and X as well as natural anticoagulants protein C and protein S. The disease is characterized by a cluster of different, often life threatening, bleeding symptoms occurring both spontaneously and in a surgical setting. In the present paper we describe two different treatment modalities to be used both in a programmed surgical procedure and in an emergency scenario. As this disease is a natural model that resembles oral anticoagulation, our experience discloses a possible rationale in the use of recombinant activated FVII for warfarin reversal.
PMID: 19144654 [PubMed - indexed for MEDLINE]
Clin Appl Thromb Hemost. 2010 Apr;16(2):221-3. Epub 2009 Jan 13.
Effective hemostasis during minor surgery in a case of hereditary combined deficiency of vitamin K-dependent clotting factors.
Lapecorella M, Napolitano M, Bernardi F, Pinotti M, Sbrighi PS, Marchetti G, Canella A, Caruso P, Orecchioni A, Mariani G.
Haemophilia and Thrombosis Centre, University of L'Aquila, Ospedale San Salvatore, Via Vetoio 1, Coppito, L'Aquila, Italy. emofilia.aq@cc.univaq.it
Abstract
Combined deficiency of the vitamin K-dependent clotting factors (VKCFD) is a rare bleeding disorder involving defective gamma-carboxylation of coagulation factors II , VII, IX and X as well as natural anticoagulants protein C and protein S. The disease is characterized by a cluster of different, often life threatening, bleeding symptoms occurring both spontaneously and in a surgical setting. In the present paper we describe two different treatment modalities to be used both in a programmed surgical procedure and in an emergency scenario. As this disease is a natural model that resembles oral anticoagulation, our experience discloses a possible rationale in the use of recombinant activated FVII for warfarin reversal.
PMID: 19144654
Reduced factor VII and factor VIII levels and prolonged thrombin-generation times during a healthy diet in middle-aged women with mild to moderate cardiovascular disease risk.Passaro A,
Calzavarini S,
Volpato S,
Caruso P,
Poli A,
Fellin R,
Bernardi F.
Department of Clinical and Experimental Medicine, University of Ferrara, Ferrara, Italy.
BACKGROUND: No experimental study has investigated the effect of whole-diet therapies on a wide range of hemostatic parameters, and their relationship with metabolic and inflammatory markers. Such information was sought in middle-aged women with moderate cardiovascular disease (CVD) risk subjected to an integrated healthy diet. METHODS: Forty-nine premenopausal women were screened for C-reactive protein levels > or =1 mg L(-1) and at least one additional CVD risk factor. Sixteen women (age: 43-54 years) were selected and received a 12-week diet (four phases) integrating National Cholesterol Education Program-Adult Treatment Panel-III recommendations with components of a Mediterranean-style diet. RESULTS: We observed a reduction in body mass index (BMI) (P = 0.001), waist circumference (P = 0.005), total (P = 0.011) and low-density lipoprotein (LDL) cholesterol levels (P = 0.035). Antigen levels of coagulation factor (F)VII (P = 0.003) and FVIII (P = 0.005) were clearly reduced by dietary intervention, which also appeared to decrease circulating tissue factor but not fibrinogen and von Willebrand factor (VWF) antigen levels. Levels of FVIII and tumor necrosis factor-alpha, among the inflammation markers, showed the highest correlation, particularly before the intervention (r = 0.55, P = 0.032). Only this cytokine influenced FVIII variation over time, thus highlighting new relations between coagulation and cellular components of inflammation. The functional effect of diet on coagulation was indicated by markedly prolonged thrombin generation initiation and propagation times (lag time, P = 0.002; time to peak, P = 0.005). CONCLUSIONS: The changes observed in coagulation initiation and amplification phases, body composition and lipid profile could translate into a remarkable decrease in the risk for cardiovascular disease. Our observations suggest novel relationships between coagulation and inflammatory components.
PMID: 18823339 [PubMed - indexed for MEDLINE]
Vitamin K-induced modification of coagulation phenotype in VKORC1 homozygous deficiency.Marchetti G,
Caruso P,
Lunghi B,
Pinotti M,
Lapecorella M,
Napolitano M,
Canella A,
Mariani G,
Bernardi F.
Department of Biochemistry and Molecular Biology, University of Ferrara, Ferrara, Italy.
BACKGROUND: Combined vitamin K-dependent clotting factor (VKCF) deficiency type 2 (VKCFD2) is a rare bleeding disorder caused by mutated vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1) gene. METHODS AND RESULTS: An Italian patient with moderate to severe bleeding tendency was genotyped, and found to be homozygous for the unique VKORC1 mutation (Arg98Trp) so far detected in VKCFD2. The activity levels of VKCFs were differentially reduced, and inversely related to the previously estimated affinity of procoagulant factor propeptides for the gamma-carboxylase. The normal (factor IX) or reduced antigen levels (other VKCFs) produced a gradient in specific activities. Vitamin K supplementations resulted in reproducible, fast and sustained normalization of PT and APTT. At 24 h the activity/antigen ratios of VKCFs were close to normal, and activity levels were completely (factor VII and IX), virtually (prothrombin, factor X and protein C) or partially (protein S) restored. Thrombin generation assays showed a markedly shortened lag time. The time to peak observed at low tissue factor concentration, potentially mimicking the physiological trigger and able to highlight the effect of reduced protein S levels, was shorter than that in pooled normal plasma. At 72 h the thrombin generation times were normal, and the decrease in activity of procoagulant VKCFs was inversely related to their half-life in plasma. The improved coagulation phenotype permitted the uneventful clinical course after invasive diagnostic procedures. CONCLUSIONS: Modification of coagulation phenotypes in VKCFD2 after vitamin K supplementation was clinically beneficial, and provided valuable patterns of factor specific biosynthesis, half-life and decay.
PMID: 18315553 [PubMed - indexed for MEDLINE]
Blood. 2003 Dec 1;102(12):4014-20. Epub 2003 Jul 24.
Coinheritance of Factor V (FV) Leiden enhances thrombin formation and is associated with a mild bleeding phenotype in patients homozygous for the FVII 9726+5G>A (FVII Lazio) mutation.Castoldi E,
Govers-Riemslag JW,
Pinotti M,
Bindini D,
Tans G,
Berrettini M,
Mazzucconi MG,
Bernardi F,
Rosing J.
Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, PO Box 616, 6200 MD Maastricht, the Netherlands. e.castoldi@bioch.unimaas.nl
We investigated the role of thrombophilic mutations as possible modifiers of the clinical phenotype in severe factor VII (FVII) deficiency. Among 7 patients homozygous for a cross-reacting material-negative (CRM-) FVII defect (9726+5G>A, FVII Lazio), the only asymptomatic individual carried FV Leiden. Differential modulation of FVII levels by intragenic polymorphisms was excluded by a FVII to factor X (FX) gene haplotype analysis. The coagulation efficiency in the FV Leiden carrier and a noncarrier was evaluated by measuring FXa, FVa, and thrombin generation after extrinsic activation of plasma in the absence and presence of activated protein C (APC). In both patients coagulation factor activation was much slower and resulted in significantly lower amounts of FXa and thrombin than in a normal control. However, more FXa and thrombin were formed in the plasma of the patient carrying FV Leiden than in the noncarrier, especially in the presence of APC. These results were confirmed in FV-FVII doubly deficient plasma reconstituted with purified normal FV or FV Leiden. The difference in thrombin generation between plasmas reconstituted with normal FV or FV Leiden gradually decreased at increasing FVII concentration. We conclude that coinheritance of FV Leiden increases thrombin formation and can improve the clinical phenotype in patients with severe FVII deficiency.
PMID: 12881304 [PubMed - indexed for MEDLINE]
Predictive value of D-dimer test for recurrent venous thromboembolism after anticoagulation withdrawal in subjects with a previous idiopathic event and in carriers of congenital thrombophilia.Palareti G,
Legnani C,
Cosmi B,
Valdré L,
Lunghi B,
Bernardi F,
Coccheri S.
Dipartimento di Angiologia, Unità Ricerca Clinica sulla Trombofilia Marino Golinelli, University Hospital S Orsola-Malpighi, Bologna, Italy. palareti@tin.it
BACKGROUND: We have shown that normal D-dimer levels obtained after the discontinuation of oral anticoagulant treatment (OAT) has a high negative predictive value for recurrent venous thromboembolism (VTE). The aim of the present study was to assess the predictive value of D-dimer for recurrent VTE in subjects with a previous unprovoked event who are either carriers of inherited thrombophilia or not. METHODS AND RESULTS: We prospectively evaluated 599 patients (301 males) with a previous VTE episode. They were repeatedly examined for D-dimer levels after OAT withdrawal and were screened for inherited thrombophilic alterations. Alterations were detected in 130 patients (21.7%), factor V Leiden (70 patients; 2 of whom were homozygotes) and prothrombin mutation (38 patients) were the most prevalent ones. Recurrent events were recorded in 58 subjects (9.7%) during a follow-up of 870.7 patient-years. Altered D-dimer levels at 1 month after OAT withdrawal were associated with a higher rate of subsequent recurrence in all subjects investigated, especially in those with an unprovoked qualifying VTE event (hazard ratio, 2.43; 95% confidence interval, 1.18 to 4.61) and in those with thrombophilia (hazard ratio, 8.34; 95% confidence interval, 2.72 to 17.43). The higher relative risk for recurrence of altered D-dimer was confirmed by multivariate analysis after adjustment for other risk factors. The negative predictive value of D-dimer was 92.9% and 95.8% in subjects with an unprovoked qualifying event or with thrombophilia, respectively. CONCLUSIONS: D-dimer levels measured 1 month after OAT withdrawal have a high negative predictive value for recurrence in subjects with unprovoked VTE who are either carriers or not carriers of congenital thrombophilia.
PMID: 12847064 [PubMed - indexed for MEDLINE]
Asymptomatic carriership of factor V Leiden and genotypes of the fibrinogen gene cluster.Marchetti G,
Ferraresi P,
Legnani C,
Pinotti M,
Lunghi B,
Scapoli C,
Gemmati D,
Coccheri S,
Palareti G,
Bernardi F.
Dipartimento di Biochimica e Biologia Molecolare, Università di Ferrara, Unità di Ricerca Clinica sulla Trombofilia 'Marino Golinelli', Divisione di Angiologia, Azienda Ospedaliera di Bologna, Policlinico S.Orsola-Malpighi, Bologna, Italia.
We investigated the role of frequent fibrinogen polymorphisms in venous thromboembolic disease in conjunction with inherited thrombophilia. Two hundred unrelated subjects, all carriers of the factor V R506Q mutation (FV Leiden), were genotyped at the fibrinogen gene cluster. Among these subjects, 100 had experienced previous venous thromboembolism (VTE) and 100 were still asymptomatic for VTE. Significant differences were observed between the groups for the BclI polymorphism (P = 0.004). Scanning, by sequencing the DNA regions flanking the BclI marker, revealed new polymorphisms, a C to T transition and a G to T transversion at 1520 and 3369 base pairs 3' to the beta gene stop codon respectively. These markers showed less association with the clinical phenotype than BclI itself. A combined genotype including 10 markers was more frequent among the asymptomatic subjects (17%) than among patients (3%), and was associated with a reduction in fibrinogen antigen level (2.42 +/- 0.35 vs 2.69 +/- 0.41 g/l, P = 0.028) among the asymptomatic subjects. Our data suggest that, in the presence of inherited thrombophilia, frequent fibrinogen polymorphisms may interact to modulate the risk of venous thromboembolism.
PMID: 12752105 [PubMed - indexed for MEDLINE]
Venous thromboembolism, oral contraceptives and high prothrombin levels.
Legnani C, Cosmi B, Valdrè L, Boggian O, Bernardi F, Coccheri S, Palareti G.
Unità di Ricerca Clinica sulla Trombofilia Marino Golinelli, Dipartimento Cardiovascolare, Divisione di Angiologia, Azienda Ospedaliera di Bologna, Policlinico S. Orsola-Malpighi, Bologna, Italy. legnanic@tin.it
The G20210A prothrombin mutation, associated with elevated prothrombin levels, is a risk factor for venous thromboembolism (VTE) and displays a strong interaction with oral contraceptives (OC). No data are available on VTE risk of OC use in women with high prothrombin levels, either associated or not with the mutation. The aim of this study was to evaluate the risk of VTE in OC users with high prothrombin levels, either including or excluding carriers of the prothrombin mutation. Prothrombin levels were measured by a chromogenic assay in 152 women who suffered from VTE in reproductive age and in 296 healthy women. Subjects carrying thrombophilic alterations other than the G20210A prothrombin mutation were excluded. Prothrombin levels were stratified into quartiles. The OR of subjects in the upper quartile were 3.10 [95% confidence interval (CI) 1.73-5.55] and 2.07 (95% CI 1.11-3.85) in all women and in those not carrying the prothrombin mutation, respectively. Among the 152 patients, 88 had experienced VTE during OC; in the control group we considered as OC users the women who had used OC for at least 6 months in the 2 years before presentation but had stopped the treatment at least 3 months before the time of blood sampling (n = 127). For the interaction between OC and prothrombin levels only the two extreme strata of prothrombin were considered. Women with the lowest prothrombin levels and who did not use OC were used as reference category. The VTE risk of using OC in subjects with prothrombin levels in the upper quartile was increased 5.4-fold (95% CI 2.38-12.3) and 3.5-fold (95% CI 1.48-8.22) in all women and in those not carrying the prothrombin mutation, respectively. We conclude that elevated prothrombin levels, even in women without the G20210A prothrombin mutation, are associated with an increased risk for venous thromboembolism and that oral contraceptive use potentiates such association.
PMID: 12871547 [PubMed - indexed for MEDLINE]
Venous thromboembolism in young women; role of thrombophilic mutations and oral contraceptive use.Legnani C,
Palareti G,
Guazzaloca G,
Cosmi B,
Lunghi B,
Bernardi F,
Coccheri S.
Unità di Ricerca Clinica sulla Trombofilia Marino Golinelli - Dipartimento Cardiovascolare, Divisione di Angiologia, Azienda Ospedaliera di Bologna, Policlinico S. Orsola-Malpighi, Bologna, Italy.
AIMS: The interaction between the R506Q mutation of factor V and the G20210A mutation of prothrombin with oral contraceptives on venous thromboembolism was evaluated. METHODS AND RESULTS: Three hundred and one women of reproductive age who had venous thromboembolism (140 while using oral contraceptives) and 650 healthy women (173 on oral contraceptives at presentation) were examined. Of the patients, 19.3% were carriers of R506Q (two homozygotes) and 9.6% were heterozygous carriers of G20210A; eight patients (2.7%) were heterozygous for both mutations. Among controls, 2.9% were carriers of R506Q, 3.1% of G20210A, while one case was a heterozygous carrier of both mutations. The relative risk (odds ratio) associated with carriership of R506Q or G20210A mutations was 10.3 and 4.7, respectively; it was 45.6 in carriers of both mutations. The odds ratio of using oral contraceptives in the absence of both mutations was 2.4. The odds ratios according to oral contraceptives use and the presence of R506Q or G20210A or both mutations were 41.0, 58.6 and 86.5, respectively. While the odds ratio for R506Q remains elevated (8.9) in non-oral contraceptive users, the odds ratio for G20210A was 2.0 and did not reach statistical significance. CONCLUSIONS: Our data showed a strong interaction between oral contraceptive use and the presence of either R506Q or G20210A mutations. In non-oral contraceptive users the risk of venous thromboembolism was significantly increased in carriers of R506Q but not in those with the G20210A mutation. Copyright 2002 The European Society of Cardiology.
PMID: 12069454 [PubMed - indexed for MEDLINE]
Blood. 2000 Aug 15;96(4):1443-8.
Combinations of 4 mutations (FV R506Q, FV H1299R, FV Y1702C, PT 20210G/A) affecting the prothrombinase complex in a thrombophilic family.Castoldi E,
Simioni P,
Kalafatis M,
Lunghi B,
Tormene D,
Girelli D,
Girolami A,
Bernardi F.
Department of Biochemistry and Molecular Biology, Ferrara University, Ferrara, Italy.
The study of the molecular bases of thrombophilia in a large family with 4 symptomatic members is reported. Three thrombophilic genetic components (FV R506Q, FV H1299R, and PT 20210G/A), all affecting the activity of the prothrombinase complex, were detected alone and in combination in various family members. In addition, a newly identified missense mutation (factor V [FV] Y1702C), causing FV deficiency, was also present in the family and appeared to enhance activated protein C (APC) resistance in carriers of FV R506Q or FV H1299R by abolishing the expression of the counterpart FV allele. The relationships between complex genotypes, coagulation laboratory findings, and clinical phenotypes were analyzed in the family. All symptomatic family members were carriers of combined defects and showed APC resistance and elevated F1 + 2 values. Evidence for the causative role of the FV Y1702C mutation, which affects a residue absolutely conserved in all 3 A domains of FV, factor VIII, and ceruloplasmin, relies on (1) the absolute cosegregation between the mutation and FV deficiency, both in the family and in the general population; (2) FV antigen and immunoblot studies indicating the absence of Y1702C FV molecules in plasma of carriers of the mutation, despite normal levels of the FV Y1702C messenger RNA; and (3) molecular modeling data that support a crucial role of the mutated residue in the A domain structure. These findings help to interpret the variable penetrance of thrombosis in thrombophilic families and to define the molecular bases of FV deficiency. (Blood. 2000;96:1443-1448)
PMID: 10942390 [PubMed - indexed for MEDLINE]
Hyperhomocyst(e)inemia and a common methylenetetrahydrofolate reductase mutation (Ala223Val MTHFR) in patients with inherited thrombophilic coagulation defects.Legnani C,
Palareti G,
Grauso F,
Sassi S,
Grossi G,
Piazzi S,
Bernardi F,
Marchetti G,
Ferraresi P,
Coccheri S.
Department of Angiology and Blood Coagulation, University Hospital S. Orsola-Malpighi, Bologna, Italy.
To assess whether certain abnormalities of the sulfated amino acid metabolism are associated with the occurrence of thromboembolic events in patients with inherited thrombophilic conditions, the levels of homocyst(e)ine, before or after methionine load, and the presence of the Ala223Val substitution in the 5,10-methylenetetrahydrofolate reductase (MTHFR) were evaluated in 119 subjects with a congenital single thrombophilic condition (type I deficiency of antithrombin n = 10, protein C n = 24, protein S n = 16; activated protein C resistance due to factor V Leiden mutation n = 69). Sixty-three subjects had experienced at least one documented thrombotic event, while the remaining 56 subjects were still free from any thrombotic symptom. Our results show that (1) high homocyst(e)ine levels, either in fasting condition or after methionine load, were not more frequent in subjects with inherited thrombophilic alterations (14.4%) than in normal control subjects (10% by definition) and (2) the frequency of hyperhomocyst(e)inemia was similar in thrombophilic subjects, who already have (14.3%) or have not (14.6%) experienced thrombotic events. As regards the MTHFR mutation, the homozygous condition was present in 23.2% of the thrombophilic patients versus 17.5% in the control subjects, a nonsignificant difference. The mutation was slightly more frequent in those thrombophilic subjects who had suffered a thrombotic episode (25.5%) versus those with no thrombosis (20.8%), with odds ratios of 1.61 (confidence interval (CI) = 0.58-4.52) and 1.24 (CI = 0.42-3.43), respectively. These differences were also nonsignificant. It is concluded that in subjects with inherited thrombophilias, a condition of hyperhomocyst(e)inemia "per se" is not a factor increasing the risk of thrombosis. The risk enhancement conferred by the MTHFR mutation, if any, seems to be slight or limited, and its significance could be ascertained only in a large multicenter trial.
PMID: 9409277 [PubMed - indexed for MEDLINE]
A heparin cofactor II mutation (HCII Rimini) combined with factor V Leiden or type I protein C deficiency in two unrelated thrombophilic subjects.Bernardi F,
Legnani C,
Micheletti F,
Lunghi B,
Ferraresi P,
Palareti G,
Biagi R,
Marchetti G.
Dipartimento di Biochimica e Biologia Molecolare, Università di Ferrara, Italy. BER@DNS.UNIFE.IT
305 patients with juvenile thromboembolic episodes were screened for the presence of heparin cofactor II deficiency. The heterozygous deletion of two bases was found in the exon 5 of the heparin cofactor II gene in two unrelated patients, very likely due to a founder effect. This molecular lesion, causing a frameshift and elongated translation, affects the core of the molecule and should cause the complete unfolding of the protein, which is in accordance with the observed type I deficiency. The corresponding region of antithrombin III gene is affected by a cluster of frameshift mutations suggesting that heparin cofactor II and antithrombin III could share similar mutational patterns. The heparin cofactor II gene alteration was associated with, in one patient, the factor V Leiden mutation and, in the other, type I protein C deficiency. The tracing of the single defects in several family members indicated that the mutations became clinically manifest only when present in the doubly heterozygous condition. This study provides two examples, based on molecular findings, of the interplay of risk factors which is potentially useful to define a role for heparin cofactor II deficiency in inherited thrombophilia.
PMID: 8902986 [PubMed - indexed for MEDLINE]
Risk of venous thromboembolism and stroke associated with oral contraceptives. Role of congenital thrombophilias.Pini M,
Scoditti U,
Caliumi F,
Manotti C,
Quintavalla R,
Pattacini C,
Poli T,
Tagliaferri A,
di Iasio MG,
Bernardi F.
II Divisione Medica, Ospedale, Fidenza, Parma.
To assess the risk of thromboembolism in women using oral contraceptives (OCs), we identified through computer search in the hospitals of the province of Parma, Italy, all women aged 15-44 who were resident in the province and had a documented thromboembolic event in the years 1989-93. The number of users and nonusers of OCs was estimated by the drug sale data for the province and by the demographic statistics. In cases with venous thromboembolism (VT) the prevalence of concomitant deficiency of antithrombin III, protein C, protein S, and of factor V gene mutation Arg506GIn was evaluated. The incidence rate of VT was 37/59,603 woman-years in users (0.62 per 1000) and 13/303,954 woman-years in nonusers (0.042 per 1000), for a relative risk (RR) of 14.5 (95% confidence interval: 7.8-27.1; P < 0.001); the rate of stroke per 1000 woman-years was 0.17 in users and 0.036 in nonusers (RR = 4.6; 2.9-10.7; P < 0.01). A congenital thrombophilia involving the protein C anticoagulant system was documented in about 25% of young women developing venous thromboembolism while on OCs.
PMID: 8831253 [PubMed - indexed for MEDLINE]
]]>
]]>