SummaryInherited bleeding disorders are especially problematic for affected girls and women due to the monthly occurrence of menstrual periods and the effects on reproductive health. Although heavy menstrual bleeding (HMB) is the most common manifestation, females with inherited bleeding disorders (FBD) experience other bleeding symptoms throughout the lifespan that can lead to increased morbidity and impairment of daily activities.

Utilization of the synthetic vasopressin analogue (1-deamino-8-D-arginine-vasopressin, DDAVP) in treatment of mild haemophilia A (MHA, specific clotting factor VIII activity level 0.05-0.4 IU mL(-1) ) is convenient and effective for many but not all patients. Genetic testing for patients with MHA is increasingly recognized as providing valuable information for patient care beyond informing reproductive decisions, and as more patients are genotyped, mutation data can be utilized to individualize treatment decisions. To determine if genetic information informs response to DDAVP, a retrospective chart review was performed under Institutional Review Board approval to extract patient data with MHA, genetic mutation results, and response to DDAVP challenge. 62 patients met inclusion criteria. Complete responses (C) presented in mean value IU mL(-1) (range), were recorded for 32 of 62(52%) subjects: pre 0.19(0.04-0.45) and post 0.78(0.5-1.95); partial responses (P) were recorded for 15 of 62(24%) subjects: pre 0.1(0.06-0.15) and post 0.4(0.3-0.47); responses that were not clinically significant (N) were recorded for 15 of 62(24%) subjects: pre 0.17(0.02-0.34) and post 0.25(0.03-0.44). Subjects (related and unrelated) with the same mutation showed a trend towards a similar response to DDAVP. Eight genotypes were common to two or more subjects (n = 26). Two genotypes were concordant in all subjects [p.Ser2192Ile n = 3(C), p.Ala2220Pro n = 2(P)]. Of mutations in the C1 or C2 domains, 13 of 15(87%) subjects responded to DDAVP [C = 9(60%); P = 4(27%); n = 2(13%)]. Baseline FVIII:C did not predict magnitude of response to DDAVP. Genetic mutation results can assist with predicting DDAVP responsiveness, but baseline FVIII:C may not.

Summary Background Inherited human variants that concurrently cause disorders of primary hemostasis and coagulation are uncommon. Nevertheless, rare cases of co-existent damaging variants are likely to cause more severe bleeding and may go undiagnosed. Objective We prospectively sought to determine pathogenic variants in a three-generational pedigree with excessive bleeding. Patients/methods Platelet number, size and light transmission aggregometry to multiple agonists were evaluated in pedigree members. Transmission electron microscopy determined platelet morphology and granule content. Thromboxane release studies and light transmission aggregometry in the presence or absence of prostaglandin G2 assessed specific functional defects in the arachidonic acid pathway. Whole exome sequencing (WES) and targeted nucleotide sequence analysis identified potentially deleterious variants. Results Pedigree members with excessive bleeding had impaired platelet aggregation with arachidonic acid, epinephrine and low-dose ADP, as well as reduced platelet thromboxane B2 release. Impaired platelet aggregation in response to 2MesADP was rescued with prostaglandin G2, a prostaglandin intermediate downstream of prostaglandin synthase-1 (PTGS-1) that aids in the production of thromboxane. WES identified a non-synonymous variant in the signal peptide of PTGS-1 (rs3842787; c.50C>T; p.Pro17-Leu) that completely co-segregated with disease phenotype. A variant in the F8 gene causing hemophilia A (rs28935203; c.5096A>T; p.Y1699F) was also identified. Individuals with both variants had more severe bleeding manifestations than characteristic of mild hemophilia A alone. Conclusion We provide the first report of co-existing variants in both F8 and PTGS-1 genes in a three-generation pedigree. The PTGS-1 variant was associated with specific functional defects in the arachidonic acid pathway and more severe hemorrhage.

Women with factor X deficiency (FXD) who want to become pregnant face uncertain risks to themselves and to an unborn infant from haemorrhagic complications during pregnancy and at parturition. Women with FXD may also experience difficulty achieving pregnancy secondary to haemorrhagic symptoms of the reproductive organs. Case reports describe differences in bleeding phenotypes and pregnancy outcomes that are not easily correlated with prepregnancy bleeding symptoms or factor X levels. The aim of this article is to identify factors for consideration and information to assist the physician in counselling women with FXD who want to become pregnant, and to offer guidelines for management where appropriate. We identified cases of pregnancy among women with FXD and their outcomes from the literature; 15 women with 24 pregnancies were identified and 18 were successful. The women in this small cohort did not have an increased rate of spontaneous abortion, (8.3% vs. 13.5% in the general US population) but did have a 2.5-fold increased risk of preterm labour (37.5% vs. 12.2% in the general US population). The role of prophylaxis to control reproductive haemorrhagic symptoms, including haemorrhagic complications of pregnancy has not yet been defined, but use of prophylaxis may allow more women to be able to attempt pregnancy. Women who had access to a tertiary care centre with a multidisciplinary team including an obstetrician with high-risk obstetric training, a haematologist, a perinatologist, and access to a reference laboratory and blood bank were able in most cases to successfully deliver healthy, term infants.