Von Willebrand Disease: Gaining a global perspective.

INTRODUCTION: Recent guidelines for von Willebrand Disease (VWD) highlighted the challenges in diagnosis and management. Identifying the number of persons with VWD (PwVWD) internationally will help target support to aid diagnosis of PwVWD. AIM: To examine international registration rates of PwVWD, the influence of income status, geographical region and the age and sex profile. Cumulatively, these data will be used to inform future strategy from the World Federation of Haemophilia (WFH) to address unmet clinical and research needs. METHODS: Data from the 2018/2019 WFH Annual Global Survey (AGS) were analysed, providing a global perspective on VWD registration. RESULTS: Registration rates are lowest in South Asia (0.6/million population) and highest in Europe/Central Asia (50.9/million population, 0.005%), but below the expected prevalence rate (0.1%). National economic status impacted VWD registration rates, reflecting variation in access to optimal healthcare infrastructure. Females represented the majority of PwVWD globally, however, in low-income countries (LIC) males predominated. Age profile varied, with markedly higher rates of paediatric registrations in North America, Middle East and North Africa and South Asia. Rates of type 3 VWD registrations were significantly influenced by economic status (81% of VWD diagnoses in LIC), suggesting only the most severe VWD types are diagnosed in resource limited settings. CONCLUSION: Significant variation in registration rates of PwVWD exist internationally and is influenced by income status and the presence of HTC networks. Improved understanding of registration rates will enable targeting of advocacy to improve awareness, diagnosis and support for PwVWD internationally. KEY POINTS: Registration rates of People with Von Willebrand Disease (PwVWD) vary internationally and are influenced by national income status Although females represent the majority of PwVWD globally, in low income countries (LIC) males predominated, possibly related to stigma surrounding gynaecological bleeding. Rates of type 3 VWD registration were significantly influenced by economic status (81% of VWD diagnoses in LIC), suggesting only the most severe VWD types are diagnosed in resource limited settings.

Endothelial BMPR2 Loss Drives a Proliferative Response to BMP (Bone Morphogenetic Protein) 9 via Prolonged Canonical Signaling.

OBJECTIVE: Pulmonary arterial hypertension is a disease of proliferative vascular occlusion that is strongly linked to mutations in BMPR2-the gene encoding the BMPR-II (BMP [bone morphogenetic protein] type II receptor). The endothelial-selective BMPR-II ligand, BMP9, reverses disease in animal models of pulmonary arterial hypertension and suppresses the proliferation of healthy endothelial cells. However, the impact of BMPR2 loss on the antiproliferative actions of BMP9 has yet to be assessed. Approach and Results: BMP9 suppressed proliferation in blood outgrowth endothelial cells from healthy control subjects but increased proliferation in blood outgrowth endothelial cells from pulmonary arterial hypertension patients with BMPR2 mutations. This shift from growth suppression to enhanced proliferation was recapitulated in control human pulmonary artery endothelial cells following siRNA-mediated BMPR2 silencing, as well as in mouse pulmonary endothelial cells isolated from endothelial-conditional Bmpr2 knockout mice (Bmpr2EC-/-). BMP9-induced proliferation was not attributable to altered metabolic activity or elevated TGFß (transforming growth factor beta) signaling but was linked to the prolonged induction of the canonical BMP target ID1 in the context of BMPR2 loss. In vivo, daily BMP9 administration to neonatal mice impaired both retinal and lung vascular patterning in control mice (Bmpr2EC+/+) but had no measurable effect on mice bearing a heterozygous endothelial Bmpr2 deletion (Bmpr2EC+/-) and caused excessive angiogenesis in both vascular beds for Bmpr2EC-/- mice. CONCLUSIONS: BMPR2 loss reverses the endothelial response to BMP9, causing enhanced proliferation. This finding has potential implications for the proposed translation of BMP9 as a treatment for pulmonary arterial hypertension and suggests the need for focused patient selection in clinical trials.

A Population-Based Cohort Study of Venous Thromboembolism Rates Following Surgery and During Adjuvant Chemotherapy in Patients With Colon Cancer.

BACKGROUND: There is an elevated risk of venous thromboembolism in patients treated for colon cancer. Postoperative venous thromboembolism has been studied previously, but no large study has compared the risks during different stages of treatment. OBJECTIVE: This study aimed to quantify and compare the risks of venous thromboembolism before surgery, after surgery, during adjuvant chemotherapy, and up to 365 days after surgery among patients with resected colon cancer. DESIGN: This is a population-based retrospective cohort study. SETTING: This study was conducted in a single-payer, universal health care setting (Ontario) between 2002 and 2008. PATIENTS: A total of 6806 patients with stage I to III colon cancer treated with surgical resection were included. INTERVENTIONS: Phases of treatment were evaluated, including preoperative, in-hospital, postoperative, during adjuvant chemotherapy, and 365 days postoperatively. MAIN OUTCOME MEASURES: Venous thromboembolism, as defined using diagnostic codes from administrative data sources, was the primary outcome measured. RESULTS: Of the 6806 patients included, 327 (5%) developed venous thromboembolism. Patients receiving adjuvant chemotherapy had a higher risk versus surgery-alone patients (6% vs 4%, p < 0.001). Of the 327 who developed venous thromboembolism, 32% (1.6% overall) were diagnosed during hospital admission and 13.5% (0.6% overall) were diagnosed between discharge and 30 days after surgery. The majority of venous thromboembolisms diagnosed in patients receiving adjuvant chemotherapy (53%, 3.1% of all patients receiving adjuvant chemotherapy) were diagnosed within 180 days of starting adjuvant chemotherapy. Venous thromboembolism was an independent risk factor for worse 5-year overall survival (HR, 1.65; 95% CI, 1.43-1.91; p < 0.001). LIMITATIONS: This study was limited by the potential for misclassification of venous thromboembolism and unknown compliance with prophylaxis recommendations. CONCLUSION: Patients who undergo treatment for stage I to III colon cancer are at considerable risk of developing venous thromboembolism. The risk is elevated in those who require adjuvant chemotherapy, and venous thromboembolism is associated with worse long-term outcomes. There may be a role of venous thromboembolism prophylaxis during all phases of treatment, including both after surgery and during adjuvant chemotherapy. See Video Abstract at http://links.lww.com/DCR/B123. UN ESTUDIO DE COHORTE POBLACIONAL DE LAS TASAS DE TROMBOEMBOLISMO VENOSO DESPUÉS DE CIRUGÍA Y DURANTE QUIMIOTERAPIA ADYUVANTE EN PACIENTES CON CÁNCER DE COLON: Existe un riesgo elevado de tromboembolismo venoso en pacientes tratados por cáncer de colon. El tromboembolismo venoso postoperatorio se ha estudiado previamente, pero ningún estudio grande ha comparado los riesgos durante las diferentes etapas del tratamiento.Cuantificar y comparar los riesgos de tromboembolismo venoso antes de la cirugía, después de la cirugía, durante quimioterapia adyuvante y hasta 365 días después de cirugía en pacientes con cáncer de colon resecado.Estudio retrospectivo de cohorte poblacional.Escenario de atención médica universal con pagador único (Ontario) entre 2002-2008.6,806 pacientes con cáncer de colon en estadio I-III tratados con resección quirúrgica.Fase de tratamiento, incluyendo preoperatorio, hospitalización, postoperatorio, durante quimioterapia adyuvante y 365 días después de la operación.Tromboembolismo venoso, tal como se define utilizando códigos de diagnóstico de fuentes de datos administrativos.Se incluyeron 6,806 pacientes, con 327 (5%) que desarrollaron tromboembolismo venoso. Los pacientes que recibieron quimioterapia adyuvante tuvieron un mayor riesgo en comparación con los pacientes con cirugía solamente (6% vs 4%, p <0.001). De los 327 que desarrollaron tromboembolismo venoso, 32% (1.6% en general) fueron diagnosticados durante el ingreso hospitalario y 13.5% (0.6% en general) fueron diagnosticados entre el alta y 30 días después de la cirugía. La mayoría de los tromboembolismos venosos diagnosticados en pacientes que recibieron quimioterapia adyuvante (53%, 3.1% de todos los pacientes con quimioterapia adyuvante) fueron diagnosticados dentro de los 180 días de comenzar la quimioterapia adyuvante. El tromboembolismo venoso fue un factor de riesgo independiente para una peor supervivencia general a 5 años (Hazard Ratio (cociente de riesgo) 1.65, IC 95% 1.43-1.91, p <0.001).Potencial de clasificación errónea del tromboembolismo venoso, cumplimiento desconocido de las recomendaciones de profilaxis.Los pacientes que se someten a tratamiento para el cáncer de colon en estadio I-III tienen un riesgo considerable de desarrollar tromboembolismo venoso. El riesgo es elevado en aquellos que requieren quimioterapia adyuvante y el tromboembolismo venoso se asocia con peores resultados a largo plazo. La profilaxis del tromboembolismo venoso puede desempeñar un papel durante todas las fases del tratamiento, incluyendo tanto el periodo posquirúrgico como durante la quimioterapia adyuvante. Consulte Video Resumen en http://links.lww.com/DCR/B123.

Pregnancy and delivery in women with von Willebrand disease.

Given the wide heterogeneity of phenotypes and of the underlying pathophysiological mechanisms associated with the disorder, pregnancy and delivery in von Willebrand disease (VWD) represent a significant clinical challenge. The variable pattern of changes observed during pregnancy of von Willebrand factor (VWF) and factor VIII (FVIII), the protein carried by VWF, prompts a careful evaluation of pregnant women with VWD to plan the most appropriate treatment at the time of parturition. However, there are also instances during pregnancy (amniocentesis, vaginal bleeding associated with placental detachment, sudden abortion) that may require urgent hemostatic treatment to prevent bleeding. Thus, women with VWD should start pregnancy after being well characterised as to their type, subtype and treatments. Women with VWD who have VWF and FVIII basal levels >30 U/dL typically normalise these levels at the end of pregnancy and specific anti-haemorrhagic prophylaxis is seldom required. On the contrary, those with basal levels <20 U/dL usually show a lesser increase and specific treatment is required. Some women with DNA variants associated with increased clearance can be treated with desmopressin, while those unresponsive or with contra-indications to this agent need replacement therapy. For these latter women, the risk of vaginal bleeding during pregnancy may be increased and prophylaxis with VWF concentrates required. Similarly, women with type 2 VWD who maintain reduced VWF activity throughout pregnancy require replacement therapy with FVIII/VWF concentrates. Delayed postpartum bleeding may occur when replacement therapy is not continued for some days. Tranexamic acid is useful at discharge to avoid excessive lochia.

Validation of the school age self-administered pediatric bleeding questionnaire (Self-PBQ) in children aged 8-12 years.

BACKGROUND: In the pediatric population, pathologic bleeding is often challenging to identify. The pediatric bleeding questionnaire (PBQ) was developed as a screening tool for von Willebrand disease (VWD) but was designed to be self-completed by children above 12 years of age. The study objective was to determine whether a modified Self-PBQ could be completed by 8- to 12-year-old children with adult assistance. PROCEDURE: The initial phase involved seven children who underwent cognitive debriefing to identify problems in the questionnaire, resulting in modifications to wording and response options. In phase 2, children completed the modified Self-PBQ independently or with assistance from their parent at five Canadian treatment centers. Parents filled out the Self-PBQ separately to serve as a comparison. Bleeding scores derived from the child self-report were compared to those of the parent proxy. RESULTS: Twenty-nine out of 31 patient/parent pairs successfully completed the Self-PBQ. Child and parent scores demonstrated a high level of agreement with an intraclass correlation (ICC) of 0.825. In the age subgroup analysis, the ICC was 0.834 and 0.824 for the 8- to 9-year-old and 10- to 12-year-old groups, respectively. The ICC was also determined in children with type 1 VWD (ICC = 0.829) versus those with more severe bleeding disorders (ICC = 0.802). Thus, age and disease severity had no significant effect on degree of agreement. CONCLUSIONS: Our study shows that agreement was maintained even in younger children aged 8-9 years and in children with varying bleeding phenotypes. This supports the administration of the modified Self-PBQ to 8- to 12-year-old children.

Idiopathic pulmonary arterial hypertension - a unrecognized cause of high-shear high-flow haemostatic defects (otherwise referred to as acquired von Willebrand syndrome) in children.

Acquired von Willebrand syndrome (AVWS) is reported in high-flow high-shear congenital cardiac disorders. We hypothesized that the narrowed pulmonary vasculature in idiopathic pulmonary arterial hypertension (IPAH) may induce AVWS. We conducted a cross-sectional evaluation of children with IPAH. Patients with bleeding symptoms and/or laboratory abnormalities (thrombocytopenia, anomalies in coagulation screening tests) were tested in-depth for haemostatic defects. Fourteen children were followed with IPAH of which 8 were eligible. Four children exhibited abnormal bleeding scores (International Society on Thrombosis and Haemostasis Bleeding Assessment Tool: 3-5). All 8 patients showed very prolonged platelet function analyser (PFA)-100 closure times. Six children demonstrated either mild thrombocytopenia or low-normal von Willebrand factor (VWF) antigen (VWF:Ag) or VWF activity [mean (range), in iu/dl: VWF:Ag: 70 (61-91); VWF activity: 57 (34-70)]. Average VWF collagen binding capacity (VWF:CB) was 64 iu/dl (range: 53-123 iu/dl), with low-normal VWF activity/VWF:Ag or VWF:CB/VWF:Ag ratios occurring in five patients. All children had normal multimers distribution patterns. One patient underwent a lung transplantation, with normalization of haemostatic abnormalities post-surgery. Overall, 8 out of 14 children with IPAH had mild to moderate bleeding symptoms and/or laboratory abnormalities in keeping with AVWS. Normalization of the haemostatic defects following lung transplantation and lack of family history of bleeding attests to the acquired nature of their defects.

Severity and Features of Epistaxis in Children with a Mucocutaneous Bleeding Disorder.

OBJECTIVE: To use standardized bleeding questionnaires to compare the severity and patterns of epistaxis in children with a mucocutaneous bleeding disorder and control children. STUDY DESIGN: The epistaxis sections of the Pediatric Bleeding Questionnaire (PBQ) administered to pediatric patients with von Willebrand disease or a platelet function disorder and healthy control children were reviewed. Scores and features of epistaxis (frequency, duration, onset, site, seasonal correlation, and need for medical/surgical intervention) were recorded. A PBQ epistaxis score ≥2 was defined as clinically significant. The Katsanis epistaxis scoring system was administered to eligible patients, ie, with ≥5 episodes of epistaxis per year. RESULTS: PBQ epistaxis scores were obtained for 66 patients, median age 12 years (range 0.6-18.3 years), and 56 control children. The median PBQ epistaxis score in patients was 2 vs 0 in control children (P <.0001). All of the features of epistaxis, except spontaneous onset, occurred in a significantly greater proportion of patients than control children with epistaxis. A total of 50% of the patients were graded as having severe epistaxis by the Katsanis epistaxis scoring system, and 30 of these (91%) had a clinically significant PBQ epistaxis score. CONCLUSION: Standardized bleeding questionnaires are useful in the assessment of epistaxis severity and pattern and may help to distinguish children with and without a mucocutaneous bleeding disorder.

Characterization of aberrant splicing of von Willebrand factor in von Willebrand disease: an underrecognized mechanism.

Approximately 10% of von Willebrand factor (VWF) gene mutations are thought to alter messenger RNA (mRNA) splicing through disruption of consensus splice sites. This mechanism is likely underrecognized and affected by mutations outside consensus splice sites. During VWF synthesis, splicing abnormalities lead to qualitative defects or quantitative deficiencies in VWF. This study investigated the pathologic mechanism acting in 3 von Willebrand disease (VWD) families with putative splicing mutations using patient-derived blood outgrowth endothelial cells (BOECs) and a heterologous human embryonic kidney (HEK 293(T)) cell model. The exonic mutation c.3538G>A causes 3 in-frame splicing variants (23del, 26del, and 23/26del) which cannot bind platelets, blood coagulation factor VIII, or collagen, causing VWD through dominant-negative intracellular retention of coexpressed wild-type (WT) VWF, and increased trafficking to lysosomes. Individuals heterozygous for the c.5842+1G>C mutation produce exon 33 skipping, exons 33-34 skipping, and WT VWF transcripts. Pathogenic intracellular retention of VWF lacking exons 33-34 causes their VWD. The branch site mutation c.6599-20A>T causes type 1 VWD through mRNA degradation of exon 38 skipping transcripts. Splicing ratios of aberrant transcripts and coexpressed WT were altered in the BOECs with exposure to shear stress. This study provides evidence of mutations outside consensus splice sites disrupting splicing and introduces the concept that VWF splicing is affected by shear stress on endothelial cells.

Clinical and laboratory variability in a cohort of patients diagnosed with type 1 VWD in the United States.

von Willebrand disease (VWD) is the most common inherited bleeding disorder, and type 1 VWD is the most common VWD variant. Despite its frequency, diagnosis of type 1 VWD remains the subject of debate. In order to study the spectrum of type 1 VWD in the United States, the Zimmerman Program enrolled 482 subjects with a previous diagnosis of type 1 VWD without stringent laboratory diagnostic criteria. von Willebrand factor (VWF) laboratory testing and full-length VWF gene sequencing was performed for all index cases and healthy control subjects in a central laboratory. Bleeding phenotype was characterized using the International Society on Thrombosis and Haemostasis bleeding assessment tool. At study entry, 64% of subjects had VWF antigen (VWF:Ag) or VWF ristocetin cofactor activity below the lower limit of normal, whereas 36% had normal VWF levels. VWF sequence variations were most frequent in subjects with VWF:Ag <30 IU/dL (82%), whereas subjects with type 1 VWD and VWF:Ag ≥30 IU/dL had an intermediate frequency of variants (44%). Subjects whose VWF testing was normal at study entry had a similar rate of sequence variations as the healthy controls (14%). All subjects with severe type 1 VWD and VWF:Ag ≤5 IU/dL had an abnormal bleeding score (BS), but otherwise BS did not correlate with VWF:Ag. Subjects with a historical diagnosis of type 1 VWD had similar rates of abnormal BS compared with subjects with low VWF levels at study entry. Type 1 VWD in the United States is highly variable, and bleeding symptoms are frequent in this population.

Bleeding Scores for the Diagnosis of von Willebrand Disease.

Obtaining a personal history of bleeding is a critical component to the diagnosis of von Willebrand disease (VWD). The collection of this information can be challenging for physicians, however, as the reporting and interpretation of bleeding symptoms is subjective. The need for more precise quantification of bleeding symptoms was recognized and the Vicenza Bleeding Questionnaire was developed in 2005. This questionnaire collects data regarding the presence and severity of bleeding symptoms and generates a bleeding score by summing the severity of all symptoms reported by a patient. Several subsequent bleeding assessment tools (BATs) have been developed based from this original questionnaire and there has been a surge in the use of BATs in various clinical settings for the diagnosis and evaluation of VWD. This review will discuss the evolution of BATs over the past decade, as well as their use and validation in various settings for the diagnosis and evaluation of VWD. Additionally, we will discuss the clinical utility of BATs, the limitations of these tools, and future directions.

Generation and optimization of the self-administered pediatric bleeding questionnaire and its validation as a screening tool for von Willebrand disease.

OBJECTIVE: Our objective was to generate, optimize, and validate a self-administered pediatric bleeding questionnaire (Self-PBQ) as a screening tool for von Willebrand disease (VWD) in children referred to the hematology clinic for the first time. STUDY DESIGN: The Self-PBQ was generated by combining the validated expert-administered PBQ and the International Society on Thrombosis and Hemostasis (ISTH) bleeding assessment tool (BAT). Medical terminology was translated into lay language requiring a grade 4 reading level. In Phase 1, the Self-PBQ was optimized and the level of agreement between the Self-PBQ and the expert-administered PBQ was determined. Phase 2 established the normal range of bleeding scores (BSs) of the Self-PBQ. Phase 3 examined the Self-PBQ as a screening tool for first-time referrals to the hematology clinic. RESULTS: The Self-PBQ is a reliable surrogate for the expert-administered PBQ with an excellent intraclass correlation (ICC) of 0.917. The Self-PBQ was scored with the PBQ and the ISTH-BAT scoring systems, for which its normal BS ranges are -1 to 2 or 0 to 2, respectively. A positive Self-PBQ BS (≥3) had a sensitivity of 78%, a specificity of 37%, a positive predictive value of 0.18, and a negative predictive value of 0.91 for identifying VWD in children being investigated by a hematologist for a bleeding disorder. CONCLUSION: The Self-PBQ generates comparable BSs to the expert-administered PBQ and is a reliable, reasonably sensitive screening tool to incorporate into the assessment of children presenting to a hematologist for the investigation of an inherited bleeding disorder.

No BS! Bleeding scores predict future bleeding.

In this issue of Blood, Federici et al present compelling evidence that bleeding score (BS) predicts the risk of future bleeding in von Willebrand disease (VWD) patients.

Alloantibodies in von Willebrand disease.

The development of alloantibodies against von Willebrand factor (VWF) represents a rare but serious complication of treatment of von Willebrand disease (VWD), occurring in ~5% to 10% of type 3 VWD patients. Affected patients can present with a range of symptoms, including lack or loss of hemostatic response to infused VWF concentrates up to anaphylactic reactions in rare cases. It is classically reported in multitransfused patients and occurs most frequently in patients with partial or complete VWF gene deletions. A positive family history of anti-VWF antibodies also appears to be a risk factor. There is a lack of standardization of laboratory methods for antibody identification and characterization. Issues of variability in laboratory approaches as well as the rarity of the complication act as a barrier to future studies. Recombinant factor VIII as well as bypassing agents and immune tolerance have been reported as effective treatments; however, aside from case reports, little exists in the literature to guide management. The imminent clinical availability of recombinant VWF has prompted a resurgence of interest in this area. Additional study is warranted to address the deficiencies in our understanding of this treatment complication.

The C-type lectin receptor CLEC4M binds, internalizes, and clears von Willebrand factor and contributes to the variation in plasma von Willebrand factor levels.

Genetic variation in or near the C-type lectin domain family 4 member M (CLEC4M) has been associated with plasma levels of von Willebrand factor (VWF) in healthy individuals. CLEC4M is a lectin receptor with a polymorphic extracellular neck region possessing a variable number of tandem repeats (VNTR). A total of 491 participants (318 patients with type 1 von Willebrand disease [VWD] and 173 unaffected family members) were genotyped for the CLEC4M VNTR polymorphism. Family-based association analysis on kindreds with type 1 VWD demonstrated an excess transmission of VNTR 6 to unaffected individuals (P = .0096) and an association of this allele with increased VWF:RCo (P = .029). CLEC4M-Fc bound to VWF. Immunofluorescence and enzyme-linked immunosorbent assay demonstrated that HEK 293 cells transfected with CLEC4M bound and internalized VWF. Cells expressing 4 or 9 copies of the CLEC4M neck region VNTR showed reduced interaction with VWF relative to CLEC4M with 7 VNTR (CLEC4M 4%-60% reduction, P < .001; CLEC4M 9%-45% reduction, P = .006). Mice expressing CLEC4M after hydrodynamic liver transfer have a 46% decrease in plasma levels of VWF (P = .0094). CLEC4M binds to and internalizes VWF, and polymorphisms in the CLEC4M gene contribute to variable plasma levels of VWF.

Sequence variation in vitamin K epoxide reductase gene is associated with survival and progressive coronary calcification in chronic kidney disease.

OBJECTIVE: Sequence variations in the gene(s) encoding vitamin K epoxide reductase complex subunit 1 (VKORC1), the enzyme target of warfarin, have been associated with increased cardiovascular disease in the general population. Coronary artery calcification (CAC) is a prevalent form of cardiovascular disease in chronic kidney disease. We tested the hypothesis that the VKORC1 rs8050894 CC genotype would be associated with mortality and progression of CAC ≤ 4 years. APPROACH AND RESULTS: This study is an observational, prospective study of 167 individuals with stages 3 to 5 chronic kidney disease. Survival ≤ 4 years was assessed in all participants, and CAC progression was measured in a subset of 86 patients. Participants with the CG/GG genotype of VKORC1 had higher baseline CAC scores (median score, 112 versus 299; P=0.036). Of those 86 patients who had a 4-year CAC score, those with the CG/GG genotype had an increased risk of progressive CAC (adjusted for age, diabetes mellitus, estimated glomerular filtration rate, and hypertension) compared with those with the CC genotype. Four-year mortality risk was 4 times higher for individuals with the CG/GG genotypes compared with individuals with the CC genotype (odds ratio, 3.8; 95% confidence interval, 1.2-12.5; P=0.02), adjusted for age, sex, diabetes mellitus, estimated glomerular filtration rate, baseline CAC, and hypertension. CONCLUSIONS: Patients with the CG/GG genotype of VKORC1 had a higher risk of CAC progression and a poorer survival. These data provide new perspectives on the potential extrahepatic role of VKORC1 in individuals with chronic kidney disease.

What do we know about why women bleed and what do we not know?

Women or people with a uterus are vulnerable to both normal and abnormal bleeding. During the reproductive years, the uterus is prepared physiologically to accept an embryo and support its growth and development during pregnancy, or in the absence of implantation of an embryo, recycle through the process of menstruation and accept an embryo a month or so later. If fertilization takes place and an embryo or embryos implant in the uterus, the fetal trophoblast, or outer cell layer of the embryo, invades and dilates the maternal spiral arteries and forms the placenta. No matter when in gestation a pregnancy ends, at the conclusion of pregnancy, the placenta should separate from the wall of the uterus and be expelled. Abnormal bleeding occurs during pregnancy or after delivery when the normal uteroplacental interface has not been established or is interrupted; during miscarriage; during ectopic pregnancy; during premature separation of the placenta; or during postpartum hemorrhage. Heavy menstrual bleeding, a subset of abnormal menstrual bleeding, can be quantitatively defined as >80 mL of blood loss per cycle. Unlike postpartum hemorrhage, heavy menstrual bleeding is significantly associated with an underlying bleeding disorder. While there is other reproductive tract bleeding in women, notably bleeding at the time of ovulation or with a life-threatening ruptured ectopic pregnancy, the unique bleeding that women experience is predominantly uterine in origin. Many of the unique aspects of uterine hemostasis, however, remain unknown.

The common VWF variant p.Y1584C: detailed pathogenic examination of an enigmatic sequence change.

BACKGROUND: As knowledge of the human genome has advanced, so too has the recognition that interpretation of the pathogenic nature of sequence variants can be challenging. The von Willebrand factor (VWF) gene exhibits a significant degree of sequence variability, and the first VWF variant associated with type 1 von Willebrand disease (VWD), c.4751 A>G, p.Y1584C, was described in 2003. However, since that time, the pathogenic nature of this variant has remained unclear, being assigned properties ranging from a risk factor to a pathogenic variant. OBJECTIVES: To provide additional evaluation on the interpretation of pathogenicity for this common VWF variant. METHODS: Fifty-eight subjects with only the p.Y1584C variant were recruited from 2 cohort studies (the Zimmerman Program and the Canadian type 1 VWD study). Clinical and laboratory phenotypes were assessed. RESULTS: The prevalence of the p.Y1584C variant in our cohorts was 23- to 27-fold higher than that in large normal population databases. Significantly more p.Y1584C subjects had an abnormal bleeding score when compared to Y1584 individuals. In comparison with a group of 35 subjects without the p.Y1584C variant, subjects with the variant had lower mean VWF:antigen and VWF:ristocetin cofactor values and significantly higher VWF propeptide/VWF:antigen ratios suggestive of enhanced clearance. CONCLUSION: Collectively, the results of this analysis suggest that p.Y1584C is likely pathogenic, however, due to influences such as incomplete penetrance, variable expressivity, and other genetic modifiers like ABO blood group, the straightforward assignment of pathogenicity to this variant is inevitably challenging.