Y.V. Sanders

Determinants of bleeding phenotype in adult patients with moderate or severe von Willebrand disease.

We performed a nation-wide cross-sectional study to evaluate determinants of bleeding symptoms in a large unselected cohort of adults with von Willebrand disease (VWD). VWD patients were included (n=664), based on lowest historically measured VWF:Ag and VWF:Act levels ≤30 U/dl. Menorrhagia (85%), cutaneous bleeding (77%), bleeding from minor wounds (77%) and oral-cavity bleeding (62%) occurred most frequently. Higher age was associated with a higher bleeding score (BS), determined according to Tosetto, in females. A 10 year increase in age was associated with 0.8 point (95% confidence interval [CI] 0.4-1.1) higher BS. Females had higher BS than males (median 12 vs. 10, p=0.012). BS differed significantly between VWD type 1, 2 and 3: median 9 (-2-31), 13 (-1-33) and 19.5 (1-35), respectively (p<0.001). BS was strongly associated with VWF and FVIII levels: individuals with VWF:Ag levels ≤10 IU/dl, VWF:Act ≤10 IU/dl and FVIII:C ≤10 IU/dl had, respectively, 5.3 point (95%CI 3.2-7.3), 4.3 point (95%CI 2.9-5.8) and 9.6 point (95%CI 6.5-12.7) higher BS, than those with levels >30 IU/dl. In type 3 patients 1 IU/dl FVIII:C decrease was associated with 0.6 point (95% CI 0.1-1.1) BS increase (p=0.021). In conclusion, in VWD patients the bleeding phenotype is strongly associated with type of VWD and VWF and FVIII levels.

Primary postpartum haemorrhage in women with von Willebrand disease or carriership of haemophilia despite specialised care: a retrospective survey.

Pregnant women with bleeding disorders require specialised peripartum care to prevent postpartum haemorrhage (PPH). If third trimester coagulation factor levels are <0.50 IU mL−1, prophylactic treatment is indicated and administered according to international guidelines. However, optimal dose and duration are unknown and bleeding may still occur. The aim of this study was to investigate the outcome in women with von Willebrand disease (VWD) or haemophilia carriership treated according to current practice guidelines. From the period 2002–2011, 185 deliveries in 154 VWD women or haemophilia carriers were retrospectively included. Data on blood loss, bleeding disorder characteristics and obstetric risk factors were obtained. The outcome was primary PPH, defined as blood loss ≥500 mL within 24 h postpartum and severe PPH as blood loss ≥1000 mL. Primary PPH was observed in 62 deliveries (34%), 14 (8%) of which resulted in severe PPH. In 26 deliveries prophylactic treatment was administered due to factor levels below the 0.50 IU mL−1 cut‐off in the third trimester, 14 of which (54%) were complicated by PPH. We found an increased PPH risk in deliveries given prophylactic treatment compared with deliveries without (OR 2.7, 95% CI 1.2–6.3). In conclusion, PPH incidence was highest in deliveries with the lowest factor levels in the third trimester. Currently, delivery outcome in women with bleeding disorders is unsatisfactory, given the high PPH incidence despite specialised care. Future studies are required to optimise management of deliveries in this patient population.

Effect of Genetic Variation in STXBP5 and STX2 on von Willebrand Factor and Bleeding Phenotype in Type 1 von Willebrand Disease Patients

Background In type 1 von Willebrand Disease (VWD) patients, von Willebrand Factor (VWF) levels and bleeding symptoms are highly variable. Recently, the association between genetic variations in STXBP5 and STX2 with VWF levels has been discovered in the general population. We assessed the relationship between genetic variations in STXBP5 and STX2, VWF levels, and bleeding phenotype in type 1 VWD patients. Methods In 158 patients diagnosed with type 1 VWD according to the current ISTH guidelines, we genotyped three tagging-SNPs in STXBP5 and STX2 and analyzed their relationship with VWF:Ag levels and the severity of the bleeding phenotype, as assessed by the Tosetto bleeding score. Results In STX2, rs7978987 was significantly associated with VWF:Ag levels (bèta-coefficient (β) = −0.04 IU/mL per allele, [95%CI −0.07;−0.001], p = 0.04) and VWF:CB activity (β = −0.12 IU/mL per allele, [95%CI −0.17;−0.06], p<0.0001). For rs1039084 in STXBP5 a similar trend with VWF:Ag levels was observed: (β = −0.03 IU/mL per allele [95% CI −0.06;0.003], p = 0.07). In women, homozygous carriers of the minor alleles of both SNPs in STXBP5 had a significantly higher bleeding score than homozygous carriers of the major alleles. (Rs1039084 p = 0.01 and rs9399599 p = 0.02). Conclusions Genetic variation in STX2 is associated with VWF:Ag levels in patients diagnosed with type 1 VWD. In addition, genetic variation in STXBP5 is associated with bleeding phenotype in female VWD patients. Our findings may partly explain the variable VWF levels and bleeding phenotype in type 1 VWD patients.

Response to desmopressin is strongly dependent on F8 gene mutation type in mild and moderate haemophilia A

Desmopressin causes two- to six-fold increase of factor VIII (FVIII) in mild or moderate haemophilia A patients. However, responses are variable and little is known whether this is associated with F8 gene mutation. The study objective was to assess the relationship between F8 gene mutation and desmopressin response in haemophilia A patients. Desmopressin response (absolute and relative) was determined in 97 hemophilia A patients. Four amino acid changes (Arg2169His, Pro149Arg, Asn637Ser, and Arg612Cys) and a number of other mutations leading to an aberrant FVIII protein or FVIII deficiency were analysed. Patients with Arg2169His showed significantly lower FVIII levels before and after desmopressin compared to all other mutations (p<0.001). Pro149Arg amino acid change showed significantly lower FVIII levels 1 hour after desmopressin compared to all other mutations (p<0.005). An absolute response with FVIII≥0.50 IU/ml after 1 hour was observed in 41% (9 of 22) of patients with Arg2169His; however, this was not sustainable after 6 hours in any of these subjects. No patients with Pro149Arg mutation (n=6) showed an absolute response with FVIII≥0.50 I U/ml. Patients with other mutations showed significantly more complete and partial responses. Relative responses did not differ between mutations. Our study shows that haemophilia A patients with amino acid change Arg2169His or Pro149Arg have a decreased desmopressin response with regard to FVIII levels as compared to other mutations. Our results indicate that response to desmopressin is dependent on the F8 gene mutation type, despite the fact that multiple factors influence the desmopressin response, even within families.

Women prefer proactive support from providers for treatment of heavy menstrual bleeding: A qualitative study in adult women with moderate or severe Von Willebrand disease

To explore key factors for successful support in women with moderate or severe Von Willebrand disease (VWD) who are faced with heavy menstrual bleeding (HMB) and surgery.