Key Points• The inhibitor incidence in nonsevere hemophilia A patients with certain F8 mutations approaches the inhibitor incidence in severe patients.• These findings are highly relevant for clinical practice, as they facilitate identification of high-risk patients based on F8 genotype.Neutralizing antibodies (inhibitors) toward factor VIII form a severe complication in nonsevere hemophilia A, profoundly aggravating the bleeding pattern. Identification of high-risk patients is hampered by lack of data that take exposure days to therapeutic factor VIII concentrates into account. In the INSIGHT study, we analyzed the association between F8 mutation and inhibitor development in patients with nonsevere hemophilia A (factor VIII 2-40 IU/dL). This analysis included 1112 nonsevere hemophilia A patients from 14 centers in Europe and Australia that had genotyped at least 70% of their patients. Inhibitor risk was calculated as KaplanMeier incidence with cumulative number of exposure days as the time variable. During 44 800 exposure days (median, 24 exposure days per patient; interquartile range [IQR], 7-90), 59 of the 1112 patients developed an inhibitor; cumulative incidence of 5.3% (95% confidence interval [CI], 4.0-6.6) after a median of 28 exposure days (IQR,. The inhibitor risk at 50 exposure days was 6.7% (95% CI, 4.5-8.9) and at 100 exposure days the risk further increased to 13.3% (95% CI, 9.6-17.0). Among a total of 214 different F8 missense mutations 19 were associated with inhibitor development. These results emphasize the importance of F8 genotyping in nonsevere hemophilia A. (Blood. 2013; 122(11):1954-1962 IntroductionPatients with hemophilia A who are treated with factor VIII concentrates are at risk of developing factor VIII neutralizing alloantibodies (inhibitors).1,2 Inhibitor development is one of the most challenging complications in the treatment of hemophilia A, as it increases the bleeding tendency while it renders treatment with therapeutic factor VIII concentrates ineffective. Although inhibitor development is less frequently observed in patients with nonsevere hemophilia A (baseline factor VIII activity of 2-40 IU/dL), the clinical impact can be profound. In these patients, inhibitors may also interact with their endogenous factor VIII, resulting in a decrease of the factor VIII plasma level below 1 IU/dL 1 and major bleeding complications. 4 Identification of patients at risk of developing inhibitors may help to prevent this serious complication. However, currently there are no tools available to predict individual inhibitor risk in nonsevere hemophilia patients.The type of mutation in the factor VIII gene (F8) is an important risk factor for inhibitor development. [5][6][7] Nonsevere hemophilia A is generally caused by F8 missense mutations.8 Despite information on large numbers of F8 mutations associated with nonsevere hemophilia A that is collected in international databases, 9,10 it is not possible to calculate the inhibitor risk for specific F8 mutations, as data on exposure days to thera...

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.

The gray platelet syndrome is a hereditary, usually autosomal recessive bleeding disorder caused by a deficiency of alpha granules in platelets. We detected a nonsense mutation in the gene encoding the transcription factor GFI1B (growth factor independent 1B) that causes autosomal dominant gray platelet syndrome. Both gray platelets and megakaryocytes had abnormal marker expression. In addition, the megakaryocytes had dysplastic features, and they were abnormally distributed in the bone marrow. The GFI1B mutant protein inhibited nonmutant GFI1B transcriptional activity in a dominant-negative manner. Our studies show that GFI1B, in addition to being causally related to the gray platelet syndrome, is key to megakaryocyte and platelet development.

Summary. Background: Because the number of elderly von Willebrand disease (VWD) patients is increasing, the pathophysiology of aging in VWD has become increasingly relevant. Objectives: To assess age-related changes in von Willebrand factor (VWF) and factor VIII (FVIII) levels and to compare age-related differences in bleeding phenotype between elderly VWD patients and those < 65 years. We also studied co-morbidity in elderly patients. Patients/ Methods: We included VWD patients with VWF levels ≤ 30 U dL À1 in the nationwide cross-sectional 'Willebrand in the Netherlands' (WiN-) study. Patients reported bleeding episodes and treatment of VWD in the year preceding inclusion and during life. This was compared between VWD patients older (n = 71) and younger (16-64 years, n = 593) than 65 years. In elderly patients, agerelated changes in VWF and FVIII levels were studied longitudinally by including all historically measured levels. All medical records were examined for co-morbidity. Results: In elderly type 1 patients, a decade age increase was associated with a 3.5 U dL À1 (95% CI, À0.6 to 7.6) VWF:Ag increase and 7.1 U dL À1 (95% CI, 0.7 to 13.4) FVIII:C increase. This increase was not observed in elderly type 2 patients. Elderly type 2 patients reported significantly more bleeding symptoms in the year preceding inclusion than younger patients (16/27, 59% vs. 87/ 221, 39%; P = 0.048), which was not observed in type 1 VWD. Conclusions: von Willebrand factor parameters and bleeding phenotype evolve with increasing age in VWD. VWF and FVIII levels increase with age in type 1 patients with no mitigation in bleeding phenotype. In type 2 patients VWF parameters do not increase with age and in these patients aging is accompanied by increased bleeding.

Key Points VWFpp discriminates between type 3 VWD patients and severe type 1 VWD patients with very low VWF levels. The pathophysiological mechanisms of all types of VWD can be defined by the combined ratios of VWFpp/VWF:Ag and FVIII:C/VWF:Ag.