Introduction
Among haemophilic (H) men, hepatitis C virus (HCV) is the leading cause of liver disease and mortality, but demographics and risks of hepatocellular carcinoma (HCC) in H are not well ...known.
Methods
Adult discharges in H and non‐haemophilic (NH) men, with and without HCC were identified in the National Inpatient Sample (NIS) between 1998 and 2014, using ICD‐9 codes. Analyses included NIS‐provided discharge‐level weights to reflect national estimates. Categorical variables were assessed by Rao‐Scott chi‐square and continuous variables by weighted simple linear regression. HCC predictors were determined by weighted multivariable logistic regression.
Results
Of 18 098 H, 144 (0.79%) had HCC between 1998 and 2014. Adjusted rates of HCC increased 3.0‐fold in H vs 1.7‐fold in NH (P = 0.484). Among HCV+, HCC rates adjusted for HIV, increased 2.2‐fold in H vs 1.7‐fold in NH (P = 0.740), while among HIV+, HCC increased 1.4‐fold in H vs 0.2‐fold in NH (P = 0.448). Among those with HCC, H were older than NH (P < 0.001), Caucasian (P = 0.006), platelet transfusion recipients (P < 0.001), with greater comorbidity (P < 0.001) and mortality (P < 0.006). H with HCC also had greater rates of HCV and HIV (each P < 0.001), lower rates of alcoholism and hyperlipidemia (each P < 0.001), and similar rates of HBV (P = 0.866), smoking (P = 0.507) and obesity (P = 0.502). In multivariable logistic regression, HCV was a strong predictor for HCC in haemophilia, (OR: 15.42, 95% CI: 8.75‐27.16).
Discussion
Haemophilic men have increasing rates of HCC, similar to men without haemophilia. HCV is the major predictor of HCC in haemophilia. Future trends in HCC will depend on the impact of newer HCV antiviral therapy.
Safety and pharmacokinetics (PK) of recombinant von Willebrand factor (rVWF) combined at a fixed ratio with recombinant factor VIII (rFVIII) were investigated in 32 subjects with type 3 or severe ...type 1 von Willebrand disease (VWD) in a prospective phase 1, multicenter, randomized clinical trial. rVWF was well tolerated and no thrombotic events, inhibitors, or serious adverse events were observed. The PK of rVWF ristocetin cofactor activity, VWF antigen, and collagen-binding activity were similar to those of the comparator plasma-derived (pd) VWF-pdFVIII. In vivo cleavage of ultra-large molecular-weight rVWF multimers by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; the endogenous VWF protease) and generation of characteristic satellite bands were demonstrated. In 2 subjects with specific nonneutralizing anti-VWF–binding antibodies already detectable before rVWF infusion, a reduction in VWF multimers and VWF activity was observed. Stabilization of endogenous FVIII was enhanced following post–rVWF-rFVIII infusion as shown by the difference in area under the plasma concentration curve compared with pdVWF-pdFVIII (AUC0-∞) (P < .01). These data support the concept of administering rVWF alone once a therapeutic level of endogenous FVIII is achieved. This trial was registered at www.clinicaltrials.gov as #NCT00816660.
•rVWF is safe, well tolerated, and has a PK profile generally comparable to pdVWF, but promotes enhanced stabilization of endogenous FVIII.
Introduction
The B‐Natural study is a multicentre, multinational, observational study of haemophilia B (HB) designed to increase understanding of clinical manifestations, treatment and quality of ...life (QoL).
Aim
To characterise and compare QoL in HB across disease severity groups and individuals with inhibitors to identify gaps in treatment.
Methods
A total of 224 individuals from 107 families were enrolled from a total of 24 centres in North America (n = 16), Europe (n = 7) and Asia (n = 1). Of these, 68 (30.4%) subjects had severe (<1 IU/dL), median age 15.6 years, 114 (50.9%) moderate (1–5 IU/dL), age 13.3 years, and 42 (18.8%) mild (>5–< 40 IU/dL), age 12.1 years, disease. Twenty‐nine participants had inhibitors or a history of inhibitors. Three versions of the EQ‐5D instrument were used as a measure of QoL: proxy (ages 4–7), youth (ages 8–15) and self (age 16+). Each instrument included a visual analogue scale ranging from 100 (best health) to 0 (worst health) to assess current day's health (EQ VAS). Range‐of‐motion (ROM) for elbows, knees and ankles was assessed using a four‐point scale, from which a composite score was calculated.
Results
In all severity groups, a proportion of subjects showed less than optimal QoL. The majority of the mild and moderate severe participants reported a normal EQ‐5D health profile (79% and 72%, respectively), whereas about half (47%) of the severe participants and only 13% of the inhibitor participants reported this profile.
Conclusion
The B‐Natural study reveals impacted QoL in all disease severities of HB including those with inhibitors. Unmet needs remain and include nonsevere HB.
•Bleeding from angiodysplasia and AVM is common in inpatient HHT, more so than heavy menstrual bleeding and postpartum hemorrhage in women.•IDA is common in HHT whether or not they bleed, suggesting ...need for universal iron screening.
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Hereditary hemorrhagic telangiectasia (HHT) is a common bleeding disorder, but little is known regarding prevalence and risk factors for bleeding. Adult discharges with HHT and bleeding were identified by International Classification of Disease, 10th edition (ICD-10) codes in the National Inpatient Sample (NIS), 2016-2018. Prevalence estimates were weighted using NIS discharge-level weights to reflect national estimates. Risk factors for bleeding were determined by weighted multivariable logistic regression. Among 18 170 849 discharges, 2528 (0.01%) had HHT, of whom 648 (25.6%) had bleeding. Arteriovenous malformation (AVM) (31.9% vs 1.3%), angiodysplasia (23.5% vs 2.3%), telangiectasia (2.3% vs 0.2%), and epistaxis (17.9% vs 0.6%) were more common in HHT than in non-HHT patients (non-HHT), each P < .001. In contrast, menstrual (HMB) and postpartum bleeding (PPH) were less common in reproductive-age HHT than non-HHT, each P < .001. Anemia associated with iron deficiency (IDA), was equally common in HHT with or without bleeding (15.7% vs 16.0%), but more common than in non-HHT (7.5%), P < .001. Comorbidities, including gastroesophageal reflux (25.9% vs 20.0%) and cirrhosis (10.0% vs 3.6%) were greater in HHT than non-HHT, each P < .001. In multivariable logistic regression, peptic ulcer disease (OR, 8.86; P < .001), portal vein thrombosis (OR, 3.68; P = .006), and hepatitis C, (OR, 2.13; P = .017) were significantly associated with bleeding in HHT. In conclusion, AVM and angiodysplasia are more common and HMB and PPH less common in patients in those with HHT than non-HHT. IDA deficiency is as common in HHT with and without bleeding, suggesting ongoing blood loss and need for universal iron screening.
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.
•Type 1 VWD in the United States is highly variable, including patients with very low VWF levels as well as those with mild or minimal VWF deficiency.•The frequency of sequence variants in the VWF gene increases with decreasing VWF level, but BS does not vary by VWF level.
Hepatic adeno-associated virus (AAV)-serotype 2 mediatedgene transfer results in transgene product expression that is sustained in experimental animals but not in human subjects. We hypothesize that ...this is caused by rejection of transduced hepatocytes by AAV capsid-specific memory CD8+ T cells reactivated by AAV vectors. Here we show that healthy subjects carry AAV capsid-specific CD8+ T cells and that AAV-mediated gene transfer results in their expansion. No such expansion occurs in mice after AAV-mediated gene transfer. In addition, we show that AAV-2 induced human T cells proliferate upon exposure to alternate AAV serotypes, indicating that other serotypes are unlikely to evade capsid-specific immune responses.
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