Inhibitor formation is among the most severe complications of hemophilia treatment. With a cumulative incidence of ∼30% in those with severe hemophilia A and ∼3% in those with severe hemophilia B, ...inhibitors are caused by a T-cell response directed against infused coagulation factor; these inhibitors neutralize factor VIII or IX activity and disrupt normal hemostasis. Inhibitor patients become unresponsive to standard factor treatment and, as an alternative, use bypass treatment (eg, recombinant factor VIIa or factor VIII inhibitor bypass activity). However, response to bypass agents is poorer and the burden of disease is higher, with greater morbidity, hospitalization, cost, and mortality, than in noninhibitor patients. Furthermore, inhibitor formation interferes with prophylaxis to prevent bleeding episodes and is a contraindication to gene therapy. Thus, more effective therapies for inhibitor patients are greatly needed. In the last several years, there has been an explosion of novel alternative hemostatic agents for hemophilia patients with and without inhibitors. These agents take advantage of technologic manipulation of coagulation factors and natural anticoagulants to promote hemostasis. The approaches include the following: (1) mutants or mimics of coagulation factors, rendering them resistant to natural anticoagulants; or (2) knock-down or disruption of natural anticoagulants, preventing degradation of coagulation factors. The purpose of this article was to review these novel alternative hemostatic agents and their mechanisms of action, as well as the preliminary pharmacokinetic, safety, and efficacy data available from early-phase clinical trials.
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.
Prophylactic factor replacement in patients with hemophilia B improves outcomes but requires frequent injections. A recombinant factor IX Fc fusion protein (rFIXFc) with a prolonged half-life was ...developed to reduce the frequency of injections required.
We conducted a phase 3, nonrandomized, open-label study of the safety, efficacy, and pharmacokinetics of rFIXFc for prophylaxis, treatment of bleeding, and perioperative hemostasis in 123 previously treated male patients. All participants were 12 years of age or older and had severe hemophilia B (endogenous factor IX level of ≤2 IU per deciliter, or ≤2% of normal levels). The study included four treatment groups: group 1 received weekly dose-adjusted prophylaxis (50 IU of rFIXFc per kilogram of body weight to start), group 2 received interval-adjusted prophylaxis (100 IU per kilogram every 10 days to start), group 3 received treatment as needed for bleeding episodes (20 to 100 IU per kilogram), and group 4 received treatment in the perioperative period. A subgroup of group 1 underwent comparative sequential pharmacokinetic assessments of recombinant factor IX and rFIXFc. The primary efficacy end point was the annualized bleeding rate, and safety end points included the development of inhibitors and adverse events.
As compared with recombinant factor IX, rFIXFc exhibited a prolonged terminal half-life (82.1 hours) (P<0.001). The median annualized bleeding rates in groups 1, 2, and 3 were 3.0, 1.4, and 17.7, respectively. In group 2, 53.8% of participants had dosing intervals of 14 days or more during the last 3 months of the study. In groups 1, 2 and 3, 90.4% of bleeding episodes resolved after one injection. Hemostasis was rated as excellent or good during all major surgeries. No inhibitors were detected in any participants receiving rFIXFc; in groups 1, 2, and 3, 73.9% of participants had at least one adverse event, and serious adverse events occurred in 10.9% of participants. These events were mostly consistent with those expected in the general population of patients with hemophilia.
Prophylactic rFIXFc, administered every 1 to 2 weeks, resulted in low annualized bleeding rates in patients with hemophilia B. (Funded by Biogen Idec; ClinicalTrials.gov number, NCT01027364.).
Current factor VIII (FVIII) products display a half-life (t1/2) of ∼ 8-12 hours, requiring frequent intravenous injections for prophylaxis and treatment of patients with hemophilia A. rFVIIIFc is a ...recombinant fusion protein composed of a single molecule of FVIII covalently linked to the Fc domain of human IgG1 to extend circulating rFVIII t1/2. This first-in-human study in previously treated subjects with severe hemophilia A investigated safety and pharmacokinetics of rFVIIIFc. Sixteen subjects received a single dose of rFVIII at 25 or 65 IU/kg followed by an equal dose of rFVIIIFc. Most adverse events were unrelated to study drug. None of the study subjects developed anti-rFVIIIFc antibodies or inhibitors. Across dose levels, compared with rFVIII, rFVIIIFc showed 1.54- to 1.70-fold longer elimination t1/2, 1.49- to 1.56-fold lower clearance, and 1.48- to 1.56-fold higher total systemic exposure. rFVIII and rFVIIIFc had comparable dose-dependent peak plasma concentrations and recoveries. Time to 1% FVIII activity above baseline was ∼ 1.53- to 1.68-fold longer than rFVIII across dose levels. Each subject showed prolonged exposure to rFVIIIFc relative to rFVIII. Thus, rFVIIIFc may offer a viable therapeutic approach to achieve prolonged hemostatic protection and less frequent dosing in patients with hemophilia A. This trial was registered at www.clinicaltrials.gov as NCT01027377.
Gastrointestinal tract bleeding (GIB) is a serious complication of von Willebrand Disease (VWD), but little is known regarding prevalence and risk factors. We, therefore, evaluated correlates of GIB ...among VWD using a large national database.
We conducted a retrospective analysis of adult discharges from the National Inpatient Sample (NIS) between 2009 and 2014. International Disease Classification codes were used to identify those with and without VWD with and without GIB. Prevalence estimates were weighted using NIS-provided discharge-level weights to reflect national estimates. Categorical variables were compared by Rao-Scott chi-square test, continuous variables by weighted simple linear regression, and independent factors associated with GIB in VWD were determined by weighted multivariable logistic regression.
GIB is more prevalent in VWD, 3.70%, than those without VWD, 1.49%, p < .0001, and is more common in those who are younger, male, or Black than in VWD without GIB, each p < .001. Comorbidities of GIB in VWD include surgery, hypertension, hyperlipidemia, and smoking, each more common than in VWD without GIB, p < .0001. VWD with GIB also have higher length of stay and inpatient mortality, p < .0001. In a multivariable model, variables significantly associated with GIB in VWD were angiodysplasia, diverticulitis, hepatitis C, black race, male gender, and smoking, each p < .001.
GIB is more common in VWD who are young, black, or male, and the most significant predictors of GIB include angiodysplasia, diverticulitis, hepatitis C, and smoking. After a first GIB, such individuals should consider factor prophylaxis to prevent GIB recurrence and associated morbidity.
•Gastrointestinal bleeding (GIB) in VWD is common in young, black, or male patients.•Predictors of GIB in VWD include angiodysplasia, diverticulitis, HCV, and smoking.•The most common cause of GIB recurrence in VWD is angiodysplasia.•GIB recurrence accounts for the majority of VWD hospitalizations.•Prophylactic factor should be considered to reduce VWD GIB recurrence.
In this issue of Blood, Chen et al demonstrate that platelets expressing factor VIII (FVIII) shield FVIII from immune detection. In the naive FVIII null hemophilia A (HA) mouse, platelet-derived VIII ...prevents both a primary and memory anti-FVIII immune response, and together with total body irradiation, suppresses anti-FVIII immune response.
rFVIIIFc (Eloctate) is an extended-half-life recombinant factor VIII-Fc fusion protein that may promote factor VIII (FVIII) tolerance through Fc immunoregulatory properties. Yet, little is known ...regarding its immunogenicity in patients with hemophilia A (HA) or in HA with inhibitors (HA-I), including tolerized, immune tolerance induction (ITI)-refractory, or ITI-naïve.
We reviewed medical records of 60 patients, including 2 previously-untreated patients (PUPs) and 58 previously-treated patients (PTPs), cared for between 01/01/06 and 06/01/17, on whom anti-FVIII antibody data were available before and after initiating rFVIIIFc. Continuous data were analyzed by student's t-test, and discrete data by chi square or Fisher's exact test.
After initiating rFVIIIFc, one of two HA PUPs developed a low-responding (LR) inhibitor after 10 exposures, which resolved (anti-VIII<0.6 B.U.) within 8 additional exposures, while none of 41 HA PTPS developed an inhibitor. Among 19 HA-I PTPs with detectable inhibitors prior to rFVIIIFc, 5 developed an anamnestic response to rFVIIIFc, including 1 of 8 (12.5%) low-responding (LR), and 4 of 9 (44.9%) high-responding (HR), of whom 3 were ITI-naïve and 1 ITI-refractory. Inhibitors resolved in 4 HR within 2 months of continuing rFVIIIFc (median) but persisted in 1 LR at low titer. The remaining 11 HA-I PTPs, including 4 HR and seven LR, had no detectable inhibitor at the time of or after initiating rFVIIIFc.
rFVIIIFc was immunogenic in HA PUPs and in HA-I PTPs persistently ITI-naïve or ITI-refractory, with inhibitor resolution in the majority. rFVIIIFc immunogenicity appears to be similar to other FVIII products.
Background
Surgical procedures impose hemostatic risk to people with hemophilia, which may be minimized by optimal factor (F) replacement therapy.
Methods
This analysis evaluates the efficacy and ...safety of extended half‐life factor replacement recombinant FVIII and FIX Fc fusion proteins (rFVIIIFc and rFIXFc) during surgery in phase 3 pivotal (A‐LONG/Kids A‐LONG and B‐LONG/Kids B‐LONG) and extension (ASPIRE and B‐YOND) studies. Dosing regimens were determined by investigators. Injection frequency, dosing, blood loss, transfusions, and hemostatic response were assessed.
Results
Forty‐five major (n = 31 subjects) and 90 minor (n = 70 subjects) procedures were performed in hemophilia A; 35 major (n = 22) and 62 minor (n = 37) procedures were performed in hemophilia B. Unilateral knee arthroplasty was the most common major orthopedic procedure (hemophilia A: n = 15/34; hemophilia B: n = 8/24). On the day of surgery, median total dose in adults/adolescents was 81 IU/kg for rFVIIIFc and 144 IU/kg for rFIXFc; most major procedures required ≤2 injections (including loading dose). Through days 1–14, most major procedures had ≤1 injection/day. Hemostasis was rated excellent (rFVIIIFc: n = 39/42; rFIXFc: n = 29/33) or good (n = 3/42; n = 4/33) in evaluable major surgeries, with blood loss comparable with subjects without hemophilia. Most minor procedures in adults/adolescents required one injection on the day of surgery, including median loading dose of 51 IU/kg (rFVIIIFc) and 80 IU/kg (rFIXFc). No major treatment‐related safety concerns were identified. No subjects developed inhibitors or serious vascular thromboembolic events.
Conclusions
rFVIIIFc and rFIXFc were efficacious and well tolerated for the management of perioperative hemostasis across a wide spectrum of major and minor surgeries in hemophilia.
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.
With licensure of extended half‐life (EHL) factor products and the changing landscape of available hemophilia products, patients and providers have options for less treatment‐intense prophylaxis. The ...impact of these products in clinical practice to date remains understudied.
We aimed to quantify the use of EHL products in prophylaxis in the US using the ATHN‐dataset, a database of 145 ATHN‐affiliated hemophilia treatment centers (HTCs). Further, we aimed to quantify the impact of EHL on key hemophilia indicators including annualized bleed rates (ABRs), hemophilia joint health scores (HJHS) and quality of life (QOL) metrics. The use of EHL vs standard half‐life (SHL) products in severe hemophilia was compared between June 2018 and March 2019 using the ATHN‐dataset. A cohort of patients was also recruited from seven participating HTCs in order to compare ABR, HJHS and QOL between product classes.
By March 2019 the number of individuals with severe Hemophilia A (SHA) receiving EHLs remained relatively stable (28.4%), whereas the number of prescribed non‐factor products increased to 7.1%, with a diminishing majority of patients (64.0%) continuing to receive SHLs. The majority of patients with severe hemophilia B (SHB) received treatment with EHLs including 57.5% by March 2019. There was a trend toward lower ABR with use of EHLs in SHA and SHB, although this did not result in improved HJHS nor QOL.
EHL use in the United States in severe hemophilia continues to increase, although at a slower rate in SHA with the availability of non‐factor therapy. The impact of the EHL therapies in clinical practice should continue to be examined prospectively.
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