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In a previous study it was shown that lower factor XI (FXI) levels in women with heavy menstrual bleeding (HMB). Our aim was to determine the single-nucleotide variants (SNVs) in the F11 gene in women with HMB. In addition, an extensive literature search was performed to determine the clinical significance of each SNV. Patients referred for HMB (PBAC-score100) were included. With direct sequencing analysis of all 15 exons and flanking introns of the F11 gene, 29 different non-structural SNVs were detected in 49 patients with HMB. Interestingly, most of these SNVs have previously been associated with venous thrombosis instead of bleeding. These findings have not helped to elucidate the molecular basis of HMB. They also question the specificity of previously reported F11 variations in patients with thrombosis. More studies are needed to explain the lower FXI levels seen in patients with HMB. IMPACT STATEMENT Women with mild deficiencies of factor XI (FXI) ( 70%) are prone to excessive bleeding during menstruation. Bleeding manifestations are not well correlated with plasma FXI levels and bleeding episodes can vary widely among patients with similar low FXI levels. In a previous study we showed that women with heavy menstrual bleeding (HMB) had normal, but on average, lower levels of FXI than controls. In light of these findings, we performed F11 gene analysis to determine the single-nucleotide variants (SNVs) in women with HMB and performed an extensive literature search to determine the clinical significance of each SNV. By direct sequencing analysis of the F11 gene we found 29 different non-structural SNVs in 49 women with heavy menstrual bleeding. Remarkably, a number of these SNVs have previously been implicated in thrombosis. These findings have not helped to elucidate the molecular basis of lower FXI levels in HMB. They also question the specificity of previously reported F11 variations in patients with thrombosis. More studies are needed to explain the lower FXI levels seen in patients with HMB.

Essentials We performed a meta-analysis on thrombosis risk in thrombophilic oral contraceptive (COC)-users. The results support discouraging COC-use in women with a natural anticoagulant deficiency. Contrary, additive risk of factor V Leiden (FVL) or prothrombin-G20210A (PT) mutation is modest. Women with a FVL/PT-mutation as single risk factor can use COCs if alternatives are not tolerated. SummaryBackground Combined oral contraceptives (COCs) are associated with an increased risk of venous thromboembolism (VTE), which is shown to be more pronounced in women with hereditary thrombophilia. Currently, WHO recommendations state that COC-use in women with hereditary thrombophilias (antithrombin deficiency, protein C deficiency, protein S deficiency, factor V Leiden and prothrombin-G20210A mutation) is associated with an unacceptable health risk. Objective To perform a meta-analysis evaluating the additional risk of VTE in COC-users with thrombophilia. Methods The MEDLINE and EMBASE databases were searched on 10 February 2015 for potential eligible studies. A distinction was made between ‘mild’ (factor V Leiden and prothrombin-G20210A mutation) and ‘severe’ thrombophilia (antithrombin deficiency, protein C deficiency, protein S deficiency, double heterozygosity or homozygosity of factor V Leiden and prothrombin-G20210A mutation). Results We identified 12 case–control and three cohort studies. In COC-users, mild and severe thrombophilia increased the risk of VTE almost 6-fold (rate ratio [RR], 5.89; 95% confidence interval [CI], 4.21–8.23) and 7-fold (RR, 7.15; 95% CI, 2.93–17.45), respectively. The cohort studies showed that absolute VTE risk was far higher in COC-users with severe thrombophilia than in those with mild thrombophilia (4.3 to 4.6 vs. 0.49 to 2.0 per 100 pill-years, respectively), and these differences in absolute risks were also noted in non-affected women (0.48 to 0.7 vs. 0.19 to 0.0), but with the caveat that absolute risks were estimated in relatives of thrombophilic patients with VTE (i.e. with a positive family history). Conclusion These results support discouraging COC-use in women with severe hereditary thrombophilia. By contrast, additive VTE risk of mild thrombophilia is modest. When no other risk factors are present, (e.g. family history) COCs can be offered to these women when reliable alternative contraceptives are not tolerated.

BackgroundBleeding disorders have been recognized as important etiologic or contributory factors in women with heavy menstrual bleeding. Fibrinolysis in the endometrium plays a role in heavy menstrual bleeding. It is unknown whether increased systemic fibrinolysis might also increase the risk of heavy menstrual bleeding.ObjectiveTo investigate fibrinolytic parameters, including clot lysis time, in women with heavy menstrual bleeding.MethodsWe included 102 patients referred for heavy menstrual bleeding (Pictorial Bleeding Assessment Chart score of >100) in our cohort. Patients and controls (28 healthy volunteers without heavy menstrual bleeding) underwent hemostatic testing in the first week after menstruation. For 79 patients and all controls, fibrinolytic parameters (thrombin-activatable fibrinolysis inhibitor activity, and plasminogen activator inhibitor-1, tissue-type plasminogen activator and plasmin inhibitor levels) and clot lysis time were available.ResultsFibrinolytic parameters were similar between patients and controls, except for thrombin-activatable fibrinolysis inhibitor (89.4% vs. 82.5%) and plasmin inhibitor (106% vs. 96%), the levels of which which were significantly higher in patients. In women with menorrhagia without gynecologic abnormalities, we found lower thrombin-activatable fibrinolysis inhibitor and plasminogen activator inhibitor-1 levels than in women with gynecologic abnormalities (thrombin-activatable fibrinolysis inhibitor, 85.4% vs. 94.8%; plasminogen activator inhibitor-1, 16.0gL(-1) vs. 24.5gL(-1)).ConclusionSystemic fibrinolytic capacity is not increased in women with heavy menstrual bleeding. Overall, levels of the fibrinolytic inhibitors thrombin-activatable fibrinolysis inhibitor and plasmin inhibitor were even higher in patients than in controls. However, in a subgroup of women without gynecologic abnormalities, relatively lower levels of inhibitors may contribute to the heavy menstrual bleeding.

Identification of a novel factor XI gene mutational event in a Dutch Caucasian family with inherited factor XI deficiency

Introduction: In plasma, factor XI (FXI) circulates as a homodimeric precursor of a serine protease (FXIa), which plays an essential role in the contact activation of coagulation through the conversion of FIX to FIXa in a calcium-dependent manner. Each FXI monomer contains a heavy chain and a light chain that are joined together by disulphide bonds. The heavy chain contains all four apple domains and the light chain contains the serine protease domain. The fourth apple domain is necessary for dimerization. The gene for FXI is located on the long arm of chromosome 4 (4q35) and contains 15 exons and 14 introns. To date, more than 240 mutations have been reported (http://www.factorxi.org). The prevalence of FXI deficiency in Caucasians is reported as low, but might be underestimated. Women with low FXI levels ( In our previous study (Knol et al, AJOG, 2013), we found 4% FXI deficiency (< 70%) in unselected Dutch women with heavy menstrual bleeding (HMB). We also found that patients had significantly longer APTT compared to controls (26.5 vs 25.0 sec; p=0.001), despite higher levels of factor VIII. This turned out to be caused by lower median levels of FXI (100 vs 124 IU/dL; p These lower levels of FXI and increased bleeding tendency could be caused by the presence of specific single-nucleotide variants in the FXI gene in women with HMB. To our knowledge, systemic analysis of FXI gene variants in women with HMB has not been reported. Aim: to determine the single-nucleotide variants of the FXI gene in women with heavy menstrual bleeding. Methods: the study was approved by the Institutional Review Board of the University Medical Center of Groningen. Informed consent was obtained from all patients. We included patients referred for heavy menstrual bleeding (PBAC-score >100). We measured the Tosetto bleeding score by questionnaire. FXI activity levels were determined by an one-stage clotting assay (Siemens, Marburg, Germany). Reference interval was 65-150%. Direct sequencing analysis of all 15 exons and flanking introns of the factor XI gene was performed to detect single-nucleotide variants. Results were compared with the HapMap and 1000 genome database using the Fisher exact probability test on a 2x3 contingency table. In addition, we tested each single-nucleotide variant for Hardy-Weinberg equilibrium. Results: We included 49 patients. Median FXI level was 96% (range 61%-155%). We found 31 different single-nucleotide variants in 49 patients with HMB. Seven out of 31 could not be compared to the control group due to small numbers, unknown frequency, or absence from the database. From the remaining 24 single-nucleotide variants (Figure 1), two (rs925451 and rs2241817) showed a significant difference compared to the control group (P Conclusions: Our study provides a detailed analysis of single-nucleotide variants of the factor XI gene. Among these 31 variants, rs925451 and rs2241817 seem to be associated with heavy menstrual bleeding.Overall, these data may serve as reference group for future studies on the molecular background of factor XI deficiency and heavy menstrual bleeding. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.