Mutations result in structural abnormality of FVII with decreased secretion or reduced function of protein [28,29]. Regional distribution of several gene defects was observed [22,23,28,31]. FVII deficiency is the most common RBD. The 2010 World Federation of Hemophilia (WFH) Annual Global Survey comprising data from 106 countries reported a total of 4938 persons with FVII deficiency, a number that represents 28% of all RBDs, excluding platelet disorders [32]. The survey demonstrated

a wide variation RO4929097 cell line in the prevalence ranging from 1:>2,000,000 (Japan, Sudan,Pakistan), through 1:500,000 (USA, Australia), 1:200,000 (Canada, Italy, Iran, Poland), 1:100,000 (UK, Croatia) to 1:60,000 (Ireland, Hungary). In Slovakia, the prevalence of persons with FVII level <10 IU/dl is 1:50 000; however, after including individuals with a FVII level ≤50 IU/dl, the prevalence becomes 1:10,000. Large variance in the prevalence may be influenced by the different criteria for patients’ registration Silmitasertib solubility dmso (threshold level of FVII, presence/absence of bleeding symptoms) among other regional differences. Early reports of the disease suggested that intracranial bleeding is a common symptom

of severe FVII deficiency [33]. However, variable symptomatology was later described even in individuals with FVII levels <5 IU/dl [22–25] who experience a mild and asymptomatic phenotype in 58.7% and 14.7% of cases respectively [34]. The International registry of FVII deficiency

(IRF7)/Seven Therapy Evaluation Registry (STER) [22,26] and the Greifswald registry [23], comprising a total of 687 and 717 individuals, respectively, represent the largest registries evaluating the phenotype-genotype relationship in FVII deficiency. The IRF7/STER Research Group proposed the classification of bleeding phenotype as haemophilia-like (severe symptoms), platelet-like (mild mucocutaneous bleedings, including menorrhagia) and BCKDHA asymptomatic [34]. Intracranial, gastrointestinal and joint bleeds classified as severe bleedings are invariably associated with a homozygous or compound heterozygous inheritance and FVII levels <5 IU/dl, without a clear relationship to the type of gene defect [22,23,34]. Menorrhagia is common in women; however, data on gynaecological and obstetric manifestations in FVII deficiency are generally limited [35,36]. Gynaecological bleeding in homozygous women with FVII levels <1.9 IU/dl is often severe and may be life-threatening, requiring frequent replacement therapy, red blood cell transfusions, hormonal therapy or surgical intervention. In this group of patients, the frequency of menorrhagia (92%), severe post haemorrhagic anaemia (46%), ovarian cysts (47%), hemoperitoneum (21%), hysterectomy/ovariectomy (61%) and postpartum bleeding (22%) [20, IRF7 unpublished data] is similar to that in type 3 von Willebrand disease (VWD) [35,36].