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Summary: Congenital platelet disorders (CPDs) are rare bleeding disorders that are associated with mucocutaneous bleeds. However, data on vaginal bleeding in women with CPDs are scarce. A set of generic and bleeding‐specific questionnaires were used to evaluate the prevalence of vaginal bleeding, its impact on quality of life (QoL) and sexual functioning and the consequences for pregnancy, miscarriage and delivery in a cohort of women who were referred for diagnostic evaluation for CPDs. A total of 78 women included in the study were either diagnosed with a CPD (n = 35) or were clinically suspected of a CPD (n = 43). Heavy menstrual bleeding (HMB) was reported by a large proportion of women, which mainly started at menarche. In all, 76% of women received any kind of HMB treatment, often leading to surgical prodecures. HMB was shown to have a high impact on QoL, which improved upon treatment. Even though women reported that vaginal bleeding affects sexuality, this topic is not frequently discussed with physicians. Heavy blood loss frequently occurred after miscarriage/delivery, often requiring treatment. Women with (suspected) CPDs frequently encounter HMB, negatively impacting daily life and sexual functioning. Together with peripartum bleeding, these data highlight the burden of vaginal bleeding in CPDs and importance of adequate treatment. [ABSTRACT FROM AUTHOR]

The thrombotic microangiopathy observed in malignant hypertension is similar to that of thrombotic thrombocytopenic purpura, which is associated with a deficiency of ADAMTS13, a von Willebrand factor (VWF)-cleaving protease that cleaves large prothrombogenic multimers. We hypothesized that ADAMTS13 is deficient in malignant hypertension and that the severity of thrombotic microangiopathy is associated with decreased ADAMTS13 activity. We included 20 patients with malignant and 20 patients with severe hypertension, and 20 matched normotensive individuals served as control subjects. VWF, active VWF, and free hemoglobin were assessed to explore predictors of ADAMTS13 activity. Patients with malignant hypertension had lower ADAMTS13 activity (80%; interquartile range: 53% to 130%) compared with control subjects (99% interquartile range: 82% to 129%; P<0.01) but not compared with patients with severe hypertension (P=0.14). ADAMTS13 activity negatively correlated with lactic dehydrogenase levels after logarithmic transformation (r=-0.65; P<0.001) and was associated with platelet count (r=0.34; P=0.04) and the presence of schistocytes (r=-0.37; P=0.02). Apart from the association with thrombotic microangiopathy, ADAMTS13 was inversely associated with creatinine (r=-0.42; P=0.008). Increasing levels of VWF were associated with a decrease in ADAMTS13 activity (r=-0.34; P=0.03). There was no significant association between ADAMTS13 activity and other parameters, including blood pressure. In conclusion, ADAMTS13 is decreased in malignant hypertension and associated with the severity of thrombotic microangiopathy, likely because of the release of VWF after endothelium stimulation. A severe deficiency could not be demonstrated. More studies are needed to identify the role of ADAMTS13 in the thrombotic microangiopathy and ischemic complications of malignant hypertension. [ABSTRACT FROM AUTHOR]

Background: Aberrant activation of the Hedgehog (Hh) signaling pathway in different organisms has shown the importance of this family of morphogens during development. Genetic screens in zebrafish have assigned specific roles for Hh in proliferation, differentiation and patterning, but mainly as a result of a loss of its activity. We attempted to fully activate the Hh pathway by removing both receptors for the Hh proteins, called Patched1 and 2, which are functioning as negative regulators in this pathway. Results: Here we describe a splice-donor mutation in Ptc1, called ptc1hu1602, which in a homozygous state results in a subtle eye and somite phenotype. Since we recently positionally cloned a ptc2 mutant, a ptc1;ptc2 double mutant was generated, showing severely increased levels of ptc1, gli1 and nkx2.2a, confirming an aberrant activation of Hh signaling. As a consequence, a number of phenotypes were observed that have not been reported previously using Shh mRNA overexpression. Somites of ptc1;ptc2 double mutants do not express anteroposterior polarity markers, however initial segmentation of the somites itself is not affected. This is the first evidence that segmentation and anterior/posterior (A/P) patterning of the somites are genetically uncoupled processes. Furthermore, a novel negative function of Hh signaling is observed in the induction of the fin field, acting well before any of the previously reported function of Shh in fin formation and in a way that is different from the proposed early role of Gli3 in limb/fin bud patterning. Conclusion: The generation and characterization of the ptc1;ptc2 double mutant assigned novel and unexpected functions to the Hh signaling pathway. Additionally, these mutants will provide a useful system to further investigate the consequences of constitutively activated Hh signaling during vertebrate development. [ABSTRACT FROM AUTHOR]