A. Shapiro

Sites of initial bleeding episodes, mode of delivery and age of diagnosis in babies with haemophilia diagnosed before the age of 2 years: a report from The Centers for Disease Control and Prevention’s (CDC) Universal Data Collection (UDC) project

Summary.  Lack of detailed natural history and outcomes data for neonates and toddlers with haemophilia hampers the provision of optimal management of the disorder. We report an analysis of prospective data collected from 580 neonates and toddlers aged 0–2 years with haemophilia enrolled in the Universal Data Collection (UDC) surveillance project of the Centers for Disease Control and Prevention (CDC). This study focuses on a cohort of babies with haemophilia whose diagnosis was established before the age of two. The mode of delivery, type and severity of haemophilia, onset and timing of haemorrhages, site(s) of bleeding, provision of prophylaxis with coagulation factor replacement therapy, and the role played by the federally funded Haemophilia Treatment Centers (HTC) in the management of these infants with haemophilia were evaluated. Seventy‐five per cent of haemophilic infants were diagnosed early, in the first month of life, especially those with a family history or whose mothers were known carriers; infants of maternal carriers were more likely to be delivered by C‐section. Involvement of an HTC prior to delivery resulted in avoidance of the use of assisted deliveries with vacuum and forceps. Bleeding from the circumcision site was the most common haemorrhagic complication, followed by intra‐ and extra‐cranial haemorrhages and bleeding from heel stick blood sampling. Eight per cent of the infants were administered factor concentrate within 24 h of birth; more than half were treated to prevent bleeding. This study highlights the significant rate and the sites of initial bleeding unique to very young children with haemophilia and underscores the need for research to identify optimal evidence‐based recommendations for their management.

Prevalence and risk factors of cardiovascular disease (CVD) events among patients with haemophilia: experience of a single haemophilia treatment centre in the United States (US).

Summary.  The primary objective of the study was to examine the prevalence of cardiovascular disease (CVD) events and their known risk factors among persons with haemophilia (PWH). This cross‐sectional study, covering a 5‐year period, included PWH aged ≥35 years who were cared for at a single haemophilia treatment centre in the United States. Medical records were extensively reviewed to collect the information about CVD events and their risk factors such as obesity, hypertension, diabetes, hypercholesterolemia and smoking. Prevalence rates were compared with national population estimates and associations between risk factors and CVD events were examined using logistic regression. The study cohort comprised 185 PWH (102 haemophilia A and 83 haemophilia B). Lifetime prevalence of a CVD event was 19.5% (36/185, 95% confidence interval [CI] 13.8–25.2%). CVD mortality was 5.4% (10/185, 95% CI 2.7–8.1). Compared with US non‐Hispanic White males (NHWH), PWH had about twice the prevalence of coronary artery disease, stroke and myocardial infarction. The prevalence of CVD risk factors for PWH was similar to that for US NHWM with 39.5% of PWH exposed to two or more of these risk factors. Both hypertension and smoking were associated significantly with CVD events, with odds ratios of 4.9 and 6.3, respectively. In conclusion, this study revealed that both CVD events and its risk factors were at least equally prevalent among PWH and might have been even higher than among the US NHWM in the United States. Therefore, it is imperative to implement strategies for CVD prevention among PWH.

Crucial role for the VWF A1 domain in binding to type IV collagen

Von Willebrand factor (VWF) contains binding sites for platelets and for vascular collagens to facilitate clot formation at sites of injury. Although previous work has shown that VWF can bind type IV collagen (collagen 4), little characterization of this interaction has been performed. We examined the binding of VWF to collagen 4 in vitro and extended this characterization to a murine model of defective VWF-collagen 4 interactions. The interactions of VWF and collagen 4 were further studied using plasma samples from a large study of both healthy controls and subjects with different types of von Willebrand disease (VWD). Our results show that collagen 4 appears to bind VWF exclusively via the VWF A1 domain, and that specific sequence variations identified through VWF patient samples and through site-directed mutagenesis in the VWF A1 domain can decrease or abrogate this interaction. In addition, VWF-dependent platelet binding to collagen 4 under flow conditions requires an intact VWF A1 domain. We observed that decreased binding to collagen 4 was associated with select VWF A1 domain sequence variations in type 1 and type 2M VWD. This suggests an additional mechanism through which VWF variants may alter hemostasis.

Long-term safety and efficacy of extended-interval prophylaxis with recombinant factor IX Fc fusion protein (rFIXFc) in subjects with haemophilia B

The safety, efficacy, and prolonged half-life of recombinant factor IX Fc fusion protein (rFIXFc) were demonstrated in the Phase 3 B-LONG (adults/adolescents ≥12 years) and Kids B-LONG (children <12 years) studies of subjects with haemophilia B (≤2 IU/dl). Here, we report interim, long-term safety and efficacy data from B-YOND, the rFIXFc extension study. Eligible subjects who completed B-LONG or Kids B-LONG could enrol in B-YOND. There were four treatment groups: weekly prophylaxis (20-100 IU/kg every 7 days), individualised prophylaxis (100 IU/kg every 8-16 days), modified prophylaxis (further dosing personalisation to optimise prophylaxis), and episodic (on-demand) treatment. Subjects could change treatment groups at any point. Primary endpoint was inhibitor development. One hundred sixteen subjects enrolled in B-YOND. From the start of the parent studies to the B-YOND interim data cut, median duration of rFIXFc treatment was 39.5 months and 21.9 months among adults/adolescents and children, respectively; 68/93 (73.1 %) adults/adolescents and 9/23 (39.1 %) children had ≥100 cumulative rFIXFc exposure days. No inhibitors were observed. Median annualised bleeding rates (ABRs) were low in all prophylaxis regimens: weekly (≥12 years: 2.3; <6 years: 0.0; 6 to <12 years: 2.7), individualised (≥12 years: 2.3; 6 to <12 years: 2.4), and modified (≥12 years: 2.4). One or two infusions were sufficient to control 97 % (adults/adolescents) and 95 % (children) of bleeding episodes. Interim data from B-YOND are consistent with data from B-LONG and Kids B-LONG, and confirm the long-term safety of rFIXFc, absence of inhibitors, and maintenance of low ABRs with prophylactic dosing every 1 to 2 weeks.

Complications of haemophilia in babies (first two years of life): a report from the Centers for Disease Control and Prevention Universal Data Collection System

To describe the prevalence and complications in babies ≤2 years with haemophilia.

Biologic response to subcutaneous and intranasal therapy with desmopressin in a large Amish kindred with Type 2M von Willebrand disease

Summary. The aim of this study was to characterize the adequacy and longevity of biological response to desmopressin (DDAVP) in a large Amish kindred of Type 2M von Willebrand disease (VWD) possessing C‐to‐T transition at nucleotide 4120 in exon 28 of A1 domain of von Willebrand factor (VWF) gene. Response to both intranasal (Stimate®) and subcutaneous DDAVP administration was assessed. Rise in ristocetin cofactor activity (VWF:RCo) ≥ 40% at 90‐min post‐Stimate® and 1–2 h after subcutaneous DDAVP was defined as initial response; response longevity was assessed only after subcutaneous dosing by measuring VWF:RCo levels at time‐points 1, 2, 4 and 6 h. Eleven patients (five males, six females; age range: 20–56 years) participated in intranasal and 9/11 (four males, five females) in subcutaneous testing. Baseline haemostatic profiles included: VWF:RCo < 15%, VWF:Ag < 40% and normal VWF multimers. Initial response was comparable by both intranasal (6/11; 54.5%) and subcutaneous (4/9; 44%) routes; sustained response (VWF:RCo > 40% for 2 h) was observed in only one in nine (11%) patients tested. Median VWF:RCo peak levels after intranasal (40%) and subcutaneous (39%) routes were equivalent. Peak VWF:Ag levels were significantly higher after subcutaneous than intranasal DDAVP (94% vs. 54%; P = 0.03). Area under the curve for VWF:RCo was significantly decreased (170 μg h mL−1) compared with VWF:Ag (471 μg h mL−1) and FVIII:C (624.60 μg h mL−1). This study suggests that in this population: (i) intra‐individual DDAVP response is consistent with subcutaneous and intranasal administration; and (ii) extending DDAVP challenge test up to at least 6 h is required to characterize adequacy and longevity of biologic response prior to using DDAVP as a sole haemostatic intervention.

Treatment of bleeding episodes with recombinant factor VIII Fc fusion protein in A-LONG study subjects with severe haemophilia A.

The Phase 3 A‐LONG study demonstrated the safety and efficacy of rFVIIIFc for the control and prevention of bleeding episodes in severe haemophilia A.

Low bleeding rates with increase or maintenance of physical activity in patients treated with recombinant factor VIII Fc fusion protein (rFVIIIFc) in the A‐LONG and Kids A‐LONG Studies

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Efficacy, safety and pharmacokinetics of a new high-purity factor X concentrate in women and girls with hereditary factor X deficiency

Essentials Plasma‐derived factor X concentrate (pdFX) is used to treat hereditary factor X deficiency. pdFX pharmacokinetics, safety and efficacy were assessed in factor X‐deficient women/girls. Treatment success rate was 98%; only 6 adverse events in 2 subjects were possibly pdFX related. On‐demand pdFX 25 IU kg−1 was effective and safe in women/girls with factor X deficiency.