Building the foundation for a community-generated national research blueprint for inherited bleeding disorders: research priorities for mucocutaneous bleeding disorders.

BACKGROUND: Excessive or abnormal mucocutaneous bleeding (MCB) may impact all aspects of the physical and psychosocial wellbeing of those who live with it (PWMCB). The evidence base for the optimal diagnosis and management of disorders such as inherited platelet disorders, hereditary hemorrhagic telangiectasia (HHT), hypermobility spectrum disorders (HSD), Ehlers-Danlos syndromes (EDS), and von Willebrand disease (VWD) remains thin with enormous potential for targeted research. RESEARCH DESIGN AND METHODS: National Hemophilia Foundation and American Thrombosis and Hemostasis Network initiated the development of a National Research Blueprint for Inherited Bleeding Disorders with extensive all-stakeholder consultations to identify the priorities of people with inherited bleeding disorders and those who care for them. They recruited multidisciplinary expert working groups (WG) to distill community-identified priorities into concrete research questions and score their feasibility, impact, and risk. RESULTS: WG2 detailed 38 high priority research questions concerning the biology of MCB, VWD, inherited qualitative platelet function defects, HDS/EDS, HHT, bleeding disorder of unknown cause, novel therapeutics, and aging. CONCLUSIONS: Improving our understanding of the basic biology of MCB, large cohort longitudinal natural history studies, collaboration, and creative approaches to novel therapeutics will be important in maximizing the benefit of future research for the entire MCB community.

More people experience mucocutaneous bleeding (MCB), affecting tissues like skin and gums, than have hemophilia A or B. MCB is not understood as well as hemophilia. Common types of MCB include nosebleeds, bleeding gums, heavy menstrual bleeding, and digestive tract bleeding. Mucocutaneous inherited bleeding disorders include inherited platelet disorders, hereditary hemorrhagic telangiectasia (HHT), hypermobility spectrum disorders (HSD) and Ehlers-Danlos syndromes (EDS), von Willebrand Disease (VWD), and others. Diagnosing and treating MCB is complicated and sometimes medical providers dismiss the bleeding that patients report when they cannot find a medical explanation for it. Many people with mucocutaneous bleeding (PWMCB) do not receive the care they need; for example, women with VWD live with symptoms for, on average, 16 years before they are diagnosed in the US. This struggle to obtain care has important negative impacts on patients' physical and psychological health and their quality-of-life. The National Hemophilia Foundation (NHF), a large US bleeding disorders patient advocacy organization, set out to develop a National Research Blueprint for Inherited Bleeding Disorders focused on community priorities. They brought together a group of patients, providers, and researchers with MCB expertise to identify the research that would most improve the lives of PWMCB through targeted and accessible diagnostics and therapies. We report in this paper that research is needed to better understand the biology of MCB and to define the mechanisms of disease in these disorders. We also describe high priority research questions for each of the main disorders, novel therapeutics, and aging.

Expanding access to early phase trials: the CATCH-UP.2020 experience.

BACKGROUND: Disparities in cancer outcomes persist for underserved populations; one important aspect of this is limited access to promising early phase clinical trials. To address this, the National Cancer Institute-funded Create Access to Targeted Cancer Therapy for Underserved Populations (CATCH-UP.2020) was created. We report the tools developed and accrual metrics of the initial year of CATCH-UP.2020 with a focus on racial, ethnic, geographic, and socioeconomically underserved populations. METHODS: CATCH-UP.2020 is a P30 supplement awarded to 8 National Cancer Institute-designated cancer centers with existing resources to rapidly open and accrue to Experimental Therapeutics Clinical Trials Network (ETCTN) trials with emphasis on engaging patients from underserved populations. Sites used patient-based, community-based, investigator-based, and program-based tools to meet specific program goals. RESULTS: From September 2020 to August 2021, CATCH-UP.2020 sites opened 45 ETCTN trials. Weighted average trial activation time for the 7 sites reporting this was 107 days. In the initial year, sites enrolled 145 patients in CATCH-UP.2020 with 68 (46.9%) representing racial, ethnic, rural, and socioeconomically underserved populations using the broader definition of underserved encompassed in the grant charge. During the initial year of CATCH-UP.2020, a time impacted by the COVID-19 pandemic, 15.8% (66 of 417) and 21.4% (31 of 145) of patients enrolled to ETCTN trials at network and at CATCH-UP sites, respectively, were from racial and ethnic minority groups, a more limited definition of underserved for which comparable data are available. CONCLUSION: Targeted funding accelerated activation and accrual of early phase trials and expanded access to this therapeutic option for underserved populations.

Dental habits and oral health in children and adolescents with bleeding disorders: A single-institution cross-sectional study.

INTRODUCTION: Oral health is an important component of care at haemophilia treatment centres (HTCs). Correlations between oral health and inflammation suggest that proper oral health may improve joint health. AIM: To evaluate the dental habits, needs, and oral health status of paediatric patients with bleeding disorders, and identify predicters of poor oral health. METHODS: From May 2016 to October 2017, consecutive paediatric HTC patients completed a 14-question survey and were examined by dental professionals. Descriptive analyses, chi-square tests and logistic regression models identified characteristics associated with four main dental outcomes. RESULTS: Evaluations from 226 consecutive patients (age 1-20 years) were included. Diagnoses included haemophilia A and B (64%), von Willebrand disease (25%) and other bleeding disorders (13%). Nearly half of patients reported not brushing their teeth twice a day (44%). One-quarter of patients did not currently have a dentist (27%), and 15% reported specific challenges with access to dental care. Oral screening demonstrated significant pathology: 89% of patients had plaque accumulation, 37% had gingivitis and 8% had lesions suggestive of dental caries. Multivariate analysis revealed that having a primary caregiver with active decay was associated with significantly higher rates of suspicious lesions (OR 4.34, CI 1.41-13.35) and gingival erythema (OR 3.44, CI 1.63-7.25) and lower rates of twice daily teeth brushing (OR .17, CI .08-.37). CONCLUSION: Children with bleeding disorders commonly have significant dental pathology and report obstacles to dental care, posing the potential risk for morbidity. Primary caregiver dental health is strongly associated with dental pathology in children.

Mid-Term Dental and Nerve-Related Complications of Infant Distraction for Robin Sequence.

BACKGROUND: Mandibular distraction is effective for relieving airway obstruction in Robin sequence; however, mid-term dental and nerve-related complications have not been adequately studied. METHODS: Records were reviewed for patients with a single distraction in infancy using internal devices. Follow-up was 5 years or longer. Craniofacial dysmorphic syndromes and those affecting facial nerve function were excluded. Part I involved a review of dental records, whereas Part II involved assessment of inferior alveolar and marginal mandibular nerve function in returning patients with the use of 1,1,1,2-tetrafluoroethane cold stimulation and photography, respectively. RESULTS: Eighty-five patients met inclusion criteria. Dental records were complete in 44 patients (median follow-up, 7.3 years; range, 5.4 to 13.2 years). First permanent molar injury was seen in 42 of 88 half-mouths (48 percent); 32 of 42 (76 percent) were restorable. Primary second molar damage and ankylosis were observed in 12 of 88 (14 percent) and one of 88 half-mouths (1 percent), respectively. Mandibular second premolar absence was noted unilaterally in eight of 36 patients (22 percent) and bilaterally in six of 36 patients (17 percent). A mean 1.2 ± 0.95 operative rehabilitations were required. Nerve testing was completed in 20 patients (median follow-up, 8.7 years; range, 5.5 to 13.2 years). Complete absence of cold sensation was noted in one of 40 half-mouths (2.5 percent), whereas lower lip depressor weakness was seen in six of 40 half-mouths (15 percent). CONCLUSIONS: Infant distraction is highly successful in averting tracheostomy; however, dental and nerve-related complications remain underreported. Regular follow-up with a pediatric dentist and early recognition of injury is essential. Although inferior alveolar nerve injury appears infrequent (2.5 percent), permanent lower lip depressor weakness is more common than previously reported (15 percent of sides). CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Differential Effect of Renal Cortical and Medullary Interstitial Fluid Calcium on Blood Pressure Regulation in Salt-Sensitive Hypertension.

BACKGROUND: Hypercalciuria is a frequent characteristic of hypertension. In this report we extend our earlier studies investigating the role of renal interstitial fluid calcium (ISF(Ca))(2+) as a link between urinary calcium excretion and blood pressure in the Dahl salt-sensitive (DS) hypertensive model. METHODS: Dahl salt-sensitive and salt-resistant (DR) rats were placed on control (0.45%) and high (8%) salt diets to determine if changes in renal cortical and medullary ISF(Ca)(2+)correlated with changes in urinary calcium excretion and blood pressure. RESULTS: We observed that renal ISFCa(2+) was predicted by urinary calcium excretion (P < 0.05) in DS rats but not DR rats. Renal cortical ISF(Ca)(2+) was negatively associated with blood pressure (P < 0.03) while renal medullary ISF(Ca)(2+) was positively associated with blood pressure in DS rats (P < 0.04). In contrast, neither urinary calcium excretion nor renal ISF(Ca)(2+) was associated with blood pressure in the DR rats under the conditions of this study. CONCLUSION: We interpret these findings to suggest that decreased renal cortical ISF(Ca)(2+) plays a role in the increase in blood pressure following a high salt diet in salt hypertension perhaps by mediating renal vasoconstriction; the role of medullary calcium remains to be fully understood. Further studies are needed to determine the mechanism of the altered renal ISF(Ca)(2+) and its role in blood pressure regulation.