Hemophilia A and B are rare, X-linked bleeding disorders resulting from a partial or total deficiency of functionally active coagulation factor VIII or factor IX, respectively. Endogenous factor levels have traditionally been used to characterize the severity of the disorder, with severe hemophilia considered as circulating levels of factor less than 1% of normal. Identifying patients with severe hemophilia is essential to effective treatment, since these patients are at highest risk of spontaneous life or limb-threatening bleeding and disability resulting from repeated joint bleeding and are most likely to benefit from prophylaxis. However, there is variability in bleeding tendency, even among patients with severe hemophilia. This article will review potential modifiers of hemophilia-associated bleeding other than endogenous factor activity, which may influence bleeding tendencies and complications in hemophilic patients considered to have severe hemophilia. These potential modifiers include physiologic factors, such as elements of the hemostatic system; pathophysiologic factors, such as hemophilic arthropathy, associated inflammation, and angiogenesis; and others, such as seasonal variation, body weight, and physical activity.

Blunted RHI was seen in the majority of children with SCD, especially with increased symptomatology (1.53 and 1.71; p value .032). RHI was not normal in children on chronic transfusion or hydroxyurea. RHI correlated with reticulocyte fraction (Spearman r = -.47, p = .037). PAT merits further exploration as a measure of EDF in SCD.

The efficacy and safety of rivipansel, a predominately E-selectin antagonist, was studied in a phase 3, randomized, controlled trial for VOC requiring hospitalization (RESET). Three hundred forty-five subjects (204 adults and 141 children) were randomized and 320 were treated (162 with rivipansel, 158 with placebo) with an intravenous loading dose, followed by up to 14 additional 12-hourly maintenance doses of rivipansel or placebo, in addition to standard care. Rivipansel was similarly administered during subsequent VOCs in an open label extension (OLE) study. In the full analysis population, the median time to readiness for discharge (TTRFD), the primary endpoint, was not different between rivipansel and placebo (−5.7 hours, P=.79; hazard ratio=0.97), nor were differences seen in secondary endpoints of time to discharge (TTD), time to discontinuation of IV opioids (TTDIVO), and cumulative IV opioid use (CIVO). Mean soluble E-selectin decreased 61% from baseline after the loading dose in the rivipansel group, while remaining unchanged in the placebo group. In a posthoc analysis, early rivipansel treatment within 26.4 hr of VOC pain onset (earliest quartile of time from VOC onset until treatment) reduced median TTRFD by 56.3 hrs, reduced median TTD by 41.5 hrs, and reduced median TTDIVO by 50.5 hrs, compared to placebo (all P < 0.05). A similar subgroup analysis comparing OLE early-treatment to early-treatment RESET placebo showed a reduction in TTD of 23.1 hours (P=0.062) and in TTDIVO of 30.1 hours (P=0.087). Timing of rivipansel administration after pain onset may be critical to achieving accelerated resolution of acute VOC. Trial Registration: Clinicaltrials.gov, NCT02187003 (RESET), NCT02433158 (OLE).

A231based on the same clinical studies and corresponded to improvement in respiratory symptoms (as measured by the CFQ-R). In one case, the improvement in respiratory symptoms was considered as primary endpoint (aztreonam lysine -one study). ConClusions: There are few PRO labeling claims in products approved for CF in Europe and the United States. Discrepancies exist in the CF guidance issued by the FDA and the EMA, where EMA is more favorable to PRO endpoints.

Rationale : Vaso-occlusive crisis (VOC) is a recurring complication of sickle cell disease (SCD) and a common reason for emergency department visits and hospitalizations among SCD patients. Few qualitative studies on the symptoms and impacts of SCD have been published. Specifically, while the duration of hospitalization for VOC is well-documented, little is known about the patient experience of recovery from a VOC. The purpose of this research was to understand the experience of recovery from VOC from the patient's perspective and to develop a brief measure to assess recovery to be administered across age groups in future clinical trial programs. Methods : A concept elicitation (CE) study consisted of face-to-face, one-on-one interviews with SCD patients, and caregivers of patients hospitalized for a VOC within 90 days prior to their interview. The semi-structured interview guide focused on the symptoms and impacts of VOC and the activities important to recovery following a VOC. A thematic analysis in MAXQDA qualitative software was conducted to identify key concepts. Results informed the development of a draft measure which was refined in two cognitive debriefing (CD) studies, one using interviewer administration format, and one using an electronic self-administration format. Interviews focused on the meaning and interpretation of the questionnaire instructions, items and responses, and feasibility of administration. Results: The CE sample included 16 participants; 5 adults and adolescents, 6 children ages 8-11, and 5 caregivers of younger children. Patients/caregivers reported that pain is not completely eliminated at time of actual discharge but gradually resolves over the week following hospitalization. In addition to pain, fatigue and the effects of pain medication also affect functional status in the immediate post-hospitalization period. The types of activities impaired during recovery were physical activities, social activities, daily activities such as work or school, and self-care activities. This conceptual framework resulted in a draft "Return to Normal Activity Questionnaire" (RNAQ), with equivalent versions for each age group, including caregiver report. Although the precise item wording and activity examples differed slightly by age group, all three versions shared the same four domains and the same response scale; an 11-point NRS with anchors 0 = "Cannot do at all" to 10 = "Can do completely as usual." The first CD study included 9 patients (3 per age group) with the interviewer administering the RNAQ verbally. Based on these interviews, self-report was determined infeasible for children 8-11. Thus, caregiver report was recommended for all children under 12. The self-administered version of the RNAQ was debriefed in a sample of adult and adolescent patients (N=17). Based on participant feedback, the NRS scale was reversed so that 0 indicates best functioning, to be consistent with a familiar pain rating question frequently used in clinical practice to evaluate VOC severity. Most patients reported that the typical time to complete recovery ranged from 2 days to one week; thus daily administration for 7 days following VOC hospitalization was recommended. Conclusions: The RNAQ was developed according to FDA PRO Guidance and appears to be appropriate for assessing recovery in SCD patients following a VOC hospitalization. Due to the small sample size in the first CD study, additional debriefing on the caregiver-reported version is recommended. In addition, psychometric validation is required to obtain full evidence of validity and to understand how to interpret RNAQ scores. Disclosures Vendetti: Pfizer, Inc.: Employment. Sivamurthy:Pfizer: Employment. Pleil:Pfizer Inc: Employment.