Search

Introduction: Gene therapy is now a reality for individuals with haemophilia, yet little is known regarding the quality‐of‐life impact of factor correction. As few data exist, and recognizing the analogy to liver transplantation (OLTX), we identified OLTX+ and OLTX‐ men in the ATHNdataset to compare post‐OLTX factor VIII and IX on quality of life (QoL) by Haem‐A‐QoL and PROMIS‐29. Methods: OLTX‐ were matched to OLTX+ by age, race, and haemophilia type and severity. Deidentified demographic data, including post‐transplant factor levels, genotype and target joint disease were analysed by descriptive statistics. Haem‐A‐Qol and PROMIS‐29 were compared in OLTX+ and OLTX‐ by student's t‐test and univariate regression models. Results: Of 86 people with haemophilia A (HA) or haemophilia B (HB) cared for at 10 haemophilia treatment centers (HTCs), 21 (24.4%) OLTX+ and 65 (75.6%) OLTX‐ were identified. OLTX+ and OLTX‐ had a similar frequency of target joint disease (p =.806), HA genotypes, null versus non‐null (p =.696), and HIV infection (p =.316). At a median 9.2 years post‐OLTX, median FVIII,.63 IU/mL [IQR 0.52–0.97] and FIX,.91 IU/mL [IQR.63–1.32], Haem‐A‐QoL, PROMIS‐29, and HOT scores were comparable. Severe HA/HB had lower post‐OLTX 'dealing with haemophilia' scores (p =.022) and higher 'sports and leisure' (p =.010) and 'view of yourself' scores (p =.024) than OLTX+ non‐severe participants. Non‐caucasian OLTX+ had significantly lower scores in sports and leisure (p =.042), future expectations (p =.021) and total score (p =.010). Conclusion: Nine years after OLTX, QoL is comparable to OLTX–, but significantly better in OLTX+ with severe than non‐severe disease and in caucasians than non‐caucasians. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is a major complication of chronic hepatitis C virus (HCV) infection. Among haemophilic (H) men, HCV is the leading cause of liver disease. Direct‐acting antiviral agents (DAA) reduce HCV viral load, but impact on HCC is unknown. Methods: This was a retrospective study of adult H and nonhaemophilic (NH) male discharges, with and without HCC, identified by ICD‐10 codes in the National Inpatient Sample (NIS) database, 2016–2018, with DAA availability. Analyses included 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 correlates were determined by weighted multivariable logistic regression. Results: Among 7,674,969 adult male discharges, 3730 H (.04%) were identified in 2016–2018, of whom 10.06% had HCV and 1.07% had HCC, significantly higher than NH (1.22% and.27%, respectively) all P <.001. Annual HCC rates were similar during the 3‐year period (2016–2018) in H and NH. Among H, HCC is associated with older age and higher rates of HCV, HBV, NASH, end‐stage liver disease, and Charlson comorbidity (CCI), each P <.001. Among HCC, H were younger and more likely HIV+, each P <.001, but less likely alcoholic (P =.018) or hyperlipidaemic (P =.008) compared to NH. In multivariable regression, risk factors for HCC among H included NASH (OR 21.6), HCV (OR 3.96), CCI (OR1.54), all P <.001, while HIV and hyperlipidaemia were protective. Conclusion: From 2016 to 2018, HCC rates did not change significantly in haemophilia discharges. NASH, HCV, and CCI are significant risks for HCC in haemophilia during the DAA‐era. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: While it has been shown that haemophilia patients receiving care at Haemophilia Treatment Centres (HTCs) experience decreased morbidity and mortality, little research has been done on the outcomes of patients with von Willebrand disease (VWD). Aim: To compare the quality of periprocedural care received by patients with VWD at HTCs and non‐HTCs. Methods: We performed a retrospective chart review on all adult VWD patients undergoing an invasive procedure from 2015 to 2017. Quality of periprocedural care was measured using the following surrogate outcomes: periprocedural VWD‐specific therapy use per 2007 National Heart, Lung, and Blood Institute (NHLBI) guidelines, procedural estimated blood loss (EBL), and post‐procedure bleeding. Comparisons were performed according to the setting of care at the time of the invasive procedure, HTC versus non‐HTC. Results: There were 668 invasive procedures performed on 305 patients, of which 8.2% were HTC cases. Non‐type 1 VWD was more likely in HTC cases. VWD‐specific therapy was used per NHLBI guidelines in 100% of HTC cases compared with 10.6% of non‐HTC cases. Procedural EBL > = 100 ml was more likely to occur in HTC differences cases (OR = 2.34; 95% CI, 1.05 to 5.25). There was no difference in post‐procedure bleeding between the two groups (OR = 1.26, 95% CI,.20‐ 7.86). Conclusion: Despite widespread periprocedural use of VWD‐specific therapy outside established guidelines at non‐HTCs, there was no difference in periprocedural bleeding. Possible explanations include diagnostic error, in disease severity and procedure types, and dataset limitations. Additional studies are needed to investigate this further and compare other patient care outcomes between HTCs and non‐HTCs. [ABSTRACT FROM AUTHOR]

Introduction: Obesity alters the pharmacokinetic (PK) properties of drugs making it difficult to determine the appropriate dose when administering weight‐based medications. Alternative descriptors of body weight, such as lean body mass (LBM) and ideal body weight (IBW), are sometimes used in these situations. Methods: We performed a single‐centre, randomized, controlled, open‐label, 3 × 3 crossover trial to determine whether recombinant factor VIII (rFVIII) dosing based on LBM and IBW achieves a targeted FVIII recovery with better precision than based on total body weight (TBW) in overweight and obese, adult males with haemophilia A. Participants were randomized to 1 of 6 possible FVIII concentrate dosing sequence scenarios (TBW, LBM and IBW). Recombinant FVIII was administered on 3 separate weeks following a washout period of at least 72 hours. Results: A total of 19 participants were randomized and completed the study. FVIII recovery was lower at 30 minutes post‐rFVIII infusion in LBM vs TBW and IBW vs TBW‐based dosing, mean difference −0.38 (95% CI: −0.56, −0.20) and −0.28 (95% CI: −0.47, −0.10) IU/dL per IU/kg, respectively. In LBM vs TBW and IBW vs TBW‐based dosing, there was a non‐significant increase in the proportion of participants with a targeted FVIII recovery of 2.00 ± 0.20 IU/dl per IU/kg, OR = 1.93 (95% CI: 0.44, 8.55) and OR = 3.65 (0.80, 16.72), respectively. Discussion: Based on our study's findings, overweight and obese patients with haemophilia A may benefit from an individualized PK analysis using LBM and IBW to determine the most accurate, and potentially cost‐effective, method of achieving targeted FVIII recovery. [ABSTRACT FROM AUTHOR]

Introduction: Haemophilia B (HB) is less well studied than haemophilia A (HA); despite similarities between the two inherited bleeding disorders, important differences remain that require further research. Aim: B‐Natural is a multi‐centre, prospective, observational study of HB, designed to increase understanding of clinical manifestations, treatment, quality‐of‐life (QoL), inhibitor development, immune tolerance induction (ITI) outcome, renal function and create a biorepository for future investigations. Methods: Participants include sibling pairs/groups without a current/history of inhibitors and singletons or siblings with a current/history of inhibitors followed for six months. Demographics, medical, social history and treatment were recorded. A physical examination including joint range of motion (ROM) was performed; QoL was assessed. Samples were collected for F9 gene mutation, HLA typing, non‐inhibitory antibodies and renal function testing. Results: Twenty‐four centres enrolled 224 individuals from 107 families including 29 with current/history of inhibitors. Of these, 68, 30.4%, had severe (<1% FIX level of normal); 114, 50.9%, moderate (1%‐5%); and 42, 18.8%, mild (>5‐<40%) disease. At enrolment, 53.1% had 50 + exposure days to exogenous FIX. Comparison of joint scores showed significant (P <.05) differences between those with severe (with/without inhibitors), and those with moderate/mild disease. The majority with severe disease, 80.0% with current/history of inhibitors and 64.3% of those without, were treated with prophylaxis. Conclusion: B‐Natural provides data supporting an increased understanding of HB and its impact throughout life. The need for optimal disease control to normalize physical and psychosocial outcomes is underscored, and further analyses will contribute to an increased understanding of critical issues in HB. [ABSTRACT FROM AUTHOR]

Background: Increases in plasma von Willebrand Factor (VWF) levels, accompanied by decreases in the metalloprotease ADAMTS13, have been demonstrated soon after traumatic injury while downstream effects remain unclear.Study Design and Methods: A cohort of 37 injured trauma patients from a randomized control trial investigating the use of prehospital plasma transfusion were analyzed for activity and antigen levels of ADAMTS13 and VWF at 0 and 24 hours after admission. Relevant clinical data were abstracted from the medical records. Trauma patient plasma was analyzed via agarose gel electrophoresis to evaluate the effects of injury on VWF multimer composition compared to healthy controls.Results: von Willebrand factor levels were elevated at presentation (189% [110%-263%] vs. 95% [74%-120%]), persisting through 24 hours (213% [146%-257%] vs. 132% [57%-160%]), compared to healthy controls. Ultralarge VWF (UL-VWF) forms were elevated in trauma patients at both 0 and 24 hours, when compared to pooled normal plasma (10.0% [8.9%-14.3%] and 11.3% [9.1%-21.2%], respectively, vs. 0.6%). Circulating plasma ADAMTS13 activity was decreased at 0 hours (66% [47%-86%] vs. 100% [98%-100%]) and at 24 hours (72.5% [56%-87.3%] vs. 103% [103%-103%]) in trauma patients. ADAMTS13 activity independently predicted the development of coagulopathy and correlated with international normalized ratio, thromboelastography values, injury severity, and blood product transfusion.Conclusion: Traumatic injury is associated with acute coagulopathy that is characterized by increased UL-VWF multimers and reduction in ADAMTS13, which correlates with blood loss, transfusion requirement, and injury severity. These findings suggest the potential for future trials targeting ADAMTS13 repletion to enhance clearance of VWF multimers. [ABSTRACT FROM AUTHOR]

Introduction: Emicizumab is a bispecific monoclonal antibody that mimics factor VIII (FVIII) by binding to factors IXa and X to promote hemostasis in haemophilia A (HA) and HA with inhibitors (HA‐I). As emicizumab differs biochemically from FVIII, there is interest in its real‐world haemostatic efficacy. Aim: To describe real‐world patient experience with emicizumab by retrospective chart review. Methods: We reviewed medical records of patients cared for at the Hemophilia Center of Western PA, who initiated emicizumab following its licensure, and on whom bleeding events and factor use were available. Comparisons between groups were done by Student's t test for continuous data and by chi‐square or Fisher's exact test for discrete data. Results: A total of 42 patients whose charts were reviewed included 18 (42.9%) with HA and 24 (52.1%) with HA‐I. Groups were similar in age, 17 (40.5%) <18 years, race, and haemophilia severity, and initiated weekly subcutaneous emicizumab 1.5 mg/kg, following 4‐week induction. Fourteen (33.3%) experienced at least one breakthrough bleed, of which 11 (44.0%) were joint bleeds, with an annualized bleed rate (ABR), 0.9 ± 0.3, not different between groups, P =.251. Surgical procedures were performed in 10 (23.8%), of whom 4 (40.0%) had postoperative bleeding and one developed postoperative thrombosis in association with FEIBA despite emicizumab discontinuation 1 month preoperatively. Local skin reactions occurred in three and headache in one. Overall, 85.0% of those who rated their health indicated it was improved. Discussion: Despite breakthrough bleeds and postoperative thrombosis associated with emicizumab, most HA and HA‐I experienced improved health. [ABSTRACT FROM AUTHOR]

Introduction: Inhibitor formation is a major complication of haemophilia for which clinical trials are planned. Despite emerging novel haemostatic agents, challenges of rare disease trials are limited subjects and lack of an organized research organization with strategic resources and partnerships. Aim: The charge to Working Group 1 was to establish scientific priorities and innovative implementation strategies to conduct inhibitor prevention and eradication trials. To determine feasibility of trial design and strategic resources and partnerships to be leveraged, two clinical trial concepts were considered. Results: For the Inhibitor Prevention Trial, we considered adaptive design with early stopping rules, dynamic randomization and Master Protocol models to reduce sample size; and registries to provide concurrent controls and natural history data. For the Inhibitor Eradication Trial using gene therapy, an adaptive design was considered in a small number of subjects, and, if safe and meeting regulatory requirements, enrolment would be expanded. A Haemophilia Clinical Trials Group (HCTG) infrastructure was envisioned, with uniform procedures and standardized outcomes, data collection and assays, within which trial concepts would be developed, vetted and prioritized by a Steering Committee, and submitted to NIH and other research sponsors for review and funding. Mechanistic studies would be embedded within the trials, early stage investigators trained and mentored, and the research infrastructure established within the haemophilia centre (HTC) network and supported by partnerships with foundations, community, federal partners and industry. Conclusion: The success of inhibitor trials will depend on innovative trial design and an organized HCTG research infrastructure, leveraged through community partnerships. [ABSTRACT FROM AUTHOR]

The article focuses on the periprocedural management of the von Willebrand disease (VWD), which is a bleeding disorder caused by defective von Willebrand factor (VWF). It discusses the needed performance of restrospective electronic medical record (EMR) review of patients at the Hemophilia Center of Western Pennsylvania (HCWP).

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. [ABSTRACT FROM AUTHOR]

In all three patients, haemarthrosis resolution occurred after Lyme disease was diagnosed and antibiotics were added to their therapy. It is important to note that the short time to initiation of Lyme disease treatment in Patient No. 3 resulted in a faster resolution of haemarthrosis compared to Patients No. 1 and No. 2. [Extracted from the article]

In the phase 3 B-LONG (Recombinant Factor IX Fc Fusion Protein [ rFIXFc] in Subjects With Haemophilia B) study, rFIXFc demonstrated a prolonged half-life compared with recombinant factor IX ( rFIX), and safety and efficacy for prophylaxis and treatment of bleeding in subjects with moderately-severe to severe haemophilia B. In this B-LONG sub-analysis, rFIXFc was evaluated for efficacy in subjects requiring major surgery. Dosing was investigator-determined. Assessments included dosing, consumption, bleeding, transfusions and haemostatic response. A population pharmacokinetics model of rFIXFc was used to predict FIX activity. Twelve subjects underwent 14 major surgeries (including 11 orthopaedic surgeries); most subjects (11/12) received rFIXFc prophylaxis before surgery (range, ~2 weeks-12 months). Investigators/surgeons rated haemostatic responses as excellent ( n = 13) or good ( n = 1). In most surgeries (85·7%), haemostasis from the pre-surgical dose until the end of surgery was maintained with a single rFIXFc infusion. Blood loss was consistent with similar surgeries in subjects without haemophilia. The strong correlation ( R2 = 0·9586, P < 0·001) between observed and population pharmacokinetic model-predicted FIX activity suggests surgery did not impact rFIXFc pharmacokinetics. No unique safety concerns or inhibitors were observed. In conclusion, rFIXFc was safe and efficacious, with prolonged dosing intervals and low consumption, when used perioperatively in haemophilia B. Surgery did not appear to alter rFIXFc pharmacokinetics. [ABSTRACT FROM AUTHOR]

Use of animal models of inherited and induced von Willebrand factor (VWF) deficiency continues to advance the knowledge of VWF-related diseases: von Willebrand disease (VWD), thrombotic thrombocytopenic purpura (TTP), and coronary artery thrombosis. First, in humans, pigs, and dogs, VWF is essential for normal hemostasis; without VWF bleeding events are severe and can be fatal. Second, the ADAMTS13 cleavage site is preserved in all three species suggesting all use this mechanism for normal VWF multimer processing and that all are susceptible to TTP when ADAMTS13 function is reduced. Third, while the role of VWF in atherogenesis is debated, arterial thrombosis complicating atherosclerosis appears to be VWF-dependent. The differences in the VWF gene and protein between humans, pigs, and dogs are relatively few but important to consider in the design of VWF-focused experiments. These homologies and differences are reviewed in detail and their implications for research projects are discussed. The current status of porcine and canine VWD are also reviewed as well as their potential role in future studies of VWF-related disorders of hemostasis and thrombosis. [ABSTRACT FROM AUTHOR]

Menorrhagia is a common health problem in women, particularly those with bleeding disorders. Little is known about the course of menorrhagia or other bleeding symptoms in women with the most common congenital bleeding disorder, von Willebrand disease (vWD). We determined the prevalence of menorrhagia, bleeding symptoms and coagulation abnormalities associated with vWD, including factor VIII activity, von Willebrand factor (vWF) antigen, ristocetin cofactor and bleeding time (BT), on a cohort of 38 females with type 1 vWD referred for diagnosis and medical care. Menorrhagia was the most common bleeding symptom in females with vWD, occurring in 93.1% of adult women. Menorrhagia was also the most common initial bleeding symptom, occurring in 53.1% of adult women in all of whom it began at menarche, median 14 years of age. There was a delay from initial bleeding symptoms, at median age 12 years, to diagnosis, at median age 16 years, P=0.0049. Although 94% undergoing surgery had previous bleeding, a vWD diagnosis was known preoperatively in only 6.2%, resulting in potentially preventable bleeding. In summary, menorrhagia is the most common bleeding symptom in females with vWD and begins at menarche. Obtaining a personal and family bleeding history promotes early diagnosis, potentially prevents postoperative bleeding, and improves the health of women with vWD. [ABSTRACT FROM AUTHOR]

Coagulation profiles were performed in 30 consecutive alcoholic cirrhotic patients without known infection, malignancy, recent surgery, transfusion, or alcoholic intake. Hemorrhagic phenomena were present in 70% and included gastrointestinal bleeding, oozing from venipuncture sites, bruising, and epistaxis. All 30 patients had multiple liver function and coagulation abnormalities, the most frequent of which were increases in F VIII components and decreases in F XI and F VII. Also decreased in half or more of the 30 patients were Fletcher F, F II, F X, prothrombin time (PT), partial thromboplastin time (APTT), thrombin time (TT), repti-lase time (RT), anti-thrombin III, and plasminogen. When comparing cirrhotic bleeders with nonbleeders, four parameters were significantly different in those with a bleeding tendency: F VII, anti-thrombin III, plasminogen, and albumin. The prolonged APTT was associated in four cases with a blocking inhibitor of unknown etiology. The prolonged TT and RT, in the absence of fibrin split products, fibrin monomers, DIC, or shortened euglobulin lysis time in any patient were suggestive of an abnormal fibrinogen, a dysfibrinogen. In three other patients, there was an inhibitor of the TT. Further investigation of the suspected dysfibrinogen in 21 patients by SDS-polyacrylamide gel electrophoresis revealed that the molecular weights of the Aα, B β, and γ polypeptide chains of fibrinogen were not different from normal. Two-dimensional Immunoelectrophoresis of the suspected dysfibrinogen was similar to normal in 18 of 21 patients, with loss of the initial shoulder in three. [ABSTRACT FROM AUTHOR]

In order to determine risk factors associated with the development of AIDS-associated lymphoma (AIDS-NHL) in individuals with haemophilia, we undertook a case-control study of 25 patients with AIDS-NHL identified prospectively in the multicentre Hemophilia Malignancy Study (HMS) and 100 haemophilia controls with AIDS matched 1:4 by age and date of AIDS diagnosis. Clinical, laboratory and lifestyle characteristics and blood product usage during the 2 years before seroconversion and AIDS or AIDS-NHL diagnosis were compared between cases and controls. AIDS-NHL cases had higher haemoglobin, platelets, %CD4 and white blood count, with the latter approaching significance, 5700 μL-1 vs. 4000 μL-1, P = 0.063. The proportion of cases receiving antiretroviral treatment prior to diagnosis was similar to that of AIDS-controls, 72% vs. 86%, but a significantly lower proportion of cases had been treated with intravenous pentamidine, 4% vs. 26%, P = 0.048. There were no differences between cases and controls in prevalence of antibody to hepatitis B or hepatitis C, HIV-related symptoms, lifestyle characteristics, or in the type or amount of blood product usage. Thus, clinical, lifestyle characteristics, antiviral drug treatment and blood product usage appear to have little, if any, effect on the development of AIDS lymphoma in HIV(+) patients with haemophilia. [ABSTRACT FROM AUTHOR]