Plasma-derived human factor X concentrate for the treatment of patients with hereditary factor X deficiency.

INTRODUCTION: Hereditary factor X (FX) deficiency (HFXD) is an autosomal recessive rare bleeding disorder that leads to defects in the FX protein. Depending on the degree of deficiency, patients may be at risk of life-threatening bleeding episodes. Historical treatments for FX deficiency include prothrombin complex concentrates, which can increase the risk of thrombosis, and fresh frozen plasma, which can cause volume overload and transfusion reactions. Plasma-derived FX (pdFX), a single-factor, high-purity, high-potency human FX treatment, was approved in 2015 in the United States and in 2016 in Europe for on-demand treatment and prophylaxis of bleeding episodes and perioperative management of patients with HFXD. METHODS: Five studies that examined the use of pdFX in patients with mild (plasma FX activity [FX:C] ≥5 IU/dL), moderate (FX:C ≥1 and <5 IU/dL), or severe (FX:C < 1 IU/dL) HFXD were reviewed: TEN01, TEN02 and TEN03 were prospective, open-label, multicentre, nonrandomised studies, and TEN05 and TEN06 were multicentre retrospective studies. RESULTS: When used as an on-demand treatment, pdFX was judged by investigators to be successful in treating 41/42 (97.6%), 2/3 (66.6%) and 79/79 (100%) bleeds in TEN01, TEN02 and TEN05, respectively. When used prophylactically, pdFX was judged 'excellent' for the prevention of bleeds in nine (100%) and eight (100%) patients in TEN02 and TEN05, respectively. Perioperative treatment and pharmacokinetics were also assessed. pdFX was safe and well tolerated. CONCLUSIONS: Together, these studies support the use of pdFX for on-demand treatment of bleeding, routine prophylaxis, and perioperative management of bleeding in patients with HFXD.

Retrospective chart review of GI bleeding in people with von Willebrand disease.

INTRODUCTION: Gastrointestinal (GI) bleeding events (BEs) in von Willebrand disease (VWD) are difficult to diagnose and often recurrent. Limited data from clinical trials has led to lack of consensus on treatment options. AIM: Describe current treatments and outcomes for GI BEs in people with VWD. METHODS: This retrospective, observational, multicentre chart review study was conducted from January 2018 through December 2019 and included patients with inherited VWD with ≥1 GI BE in the preceding 5 years. Baseline characteristics, number and aetiology of BEs, associated GI-specific morbidities/lesions, treatment and outcomes were analysed descriptively. RESULTS: Sixty bleeds were reported in 20 patients with type 1 (20%), type 2 (50%) and type 3 (30%) VWD. During the 5-year study period, 31 (52%) BEs had one identified or suspected cause; multiple causes were reported in 11 (18%). Most GI BEs (72%) were treated with a combination of von Willebrand factor (VWF), antifibrinolytics and/or other haemostatic or non-haemostatic treatments. Time to resolution did not differ by VWF treatment use; however, BEs treated with non-VWF treatments tended to resolve later. In patients with GI-specific morbidities/lesions, 84% resolved with first-line treatment; time to resolution tended to be longer than in patients without such morbidities/lesions. Thirteen BEs occurred in patients receiving prophylaxis and 47 in patients receiving on-demand treatment; 18 BEs resulted in a switch to prophylaxis after bleed resolution. CONCLUSIONS: This study confirms the unmet need for the management of recurrent GI BEs in people with VWD and the need for prospective data, especially on prophylaxis.

BAX 335 hemophilia B gene therapy clinical trial results: potential impact of CpG sequences on gene expression.

Gene therapy has the potential to maintain therapeutic blood clotting factor IX (FIX) levels in patients with hemophilia B by delivering a functional human F9 gene into liver cells. This phase 1/2, open-label dose-escalation study investigated BAX 335 (AskBio009, AAV8.sc-TTR-FIXR338Lopt), an adeno-associated virus serotype 8 (AAV8)-based FIX Padua gene therapy, in patients with hemophilia B. This report focuses on 12-month interim analyses of safety, pharmacokinetic variables, effects on FIX activity, and immune responses for dosed participants. Eight adult male participants (aged 20-69 years; range FIX activity, 0.5% to 2.0%) received 1 of 3 BAX 335 IV doses: 2.0 × 1011; 1.0 × 1012; or 3.0 × 1012 vector genomes/kg. Three (37.5%) participants had 4 serious adverse events, all considered unrelated to BAX 335. No serious adverse event led to death. No clinical thrombosis, inhibitors, or other FIX Padua-directed immunity was reported. FIX expression was measurable in 7 of 8 participants; peak FIX activity displayed dose dependence (32.0% to 58.5% in cohort 3). One participant achieved sustained therapeutic FIX activity of ∼20%, without bleeding or replacement therapy, for 4 years; in others, FIX activity was not sustained beyond 5 to 11 weeks. In contrast to some previous studies, corticosteroid treatment did not stabilize FIX activity loss. We hypothesize that the loss of transgene expression could have been caused by stimulation of innate immune responses, including CpG oligodeoxynucleotides introduced into the BAX 335 coding sequence by codon optimization. This trial was registered at www.clinicaltrials.gov as #NCT01687608.

Evaluation of the Use of Low-Dose 4-Factor Prothrombin Complex Concentrate in the Reversal of Direct Oral Anticoagulants in Bleeding Patients.

OBJECTIVE: This study investigated the percentage of patients who achieved hemostasis with 4-factor prothrombin complex concentrate (4-factor PCC) 35 U/kg. The primary end point was to determine the effect of 4-factor PCC 35 U/kg on bleeding progression, assessed using computed tomography. METHODS: This was a retrospective, observational, single-center study conducted in patients with a major bleed admitted to a level 1 trauma center from May 1, 2013, to June 15, 2015, who received 4-factor PCC 35 U/kg for reversal of a direct factor Xa inhibitor taken prior to admission. RESULTS: Thirty-three patients were included in the study, with 31 patients in the final analysis. The mean (standard deviation) age was 73 (14.8) years; 54.5% of patients were female. Of the 33 patients, 13 presented with a traumatic brain injury, 9 with an aneurysmal subarachnoid hemorrhage, 8 with an intracerebral hemorrhage, 1 with a gastrointestinal bleed, 1 with a hematoma with active extravasation, and 1 with an intra-abdominal bleed. The most frequently used direct factor Xa inhibitor was rivaroxaban (81.8%). Overall, 83.8% of patients achieved hemostasis with 4-factor PCC 35 U/kg. Progression of hemorrhage was observed in 4 patients on repeat computed tomography scan and 1 patient had continued surgical bleeding. No thromboembolic events were reported. CONCLUSIONS: Low-dose, 4-factor PCC 35 U/kg appeared to produce hemostasis in a majority of the patients. This may be an effective dosing regimen for anticoagulant reversal of factor Xa inhibitors in clinically bleeding patients.

Clinical utility of viscoelastic testing (TEG and ROTEM analyzers) in the management of old and new therapies for hemophilia.

Hemophilia A and B are rare inherited bleeding disorders resulting from deficiency of coagulation factors VIII and IX respectively. In the past few decades, the field of hemophilia has witnessed pivotal management challenges and therapeutic advances. Routine coagulation and factor assays, while useful in the classification of severity and treatment monitoring in hemophilia patients, have been shown to be of limited use in managing clinical presentations and outcomes. This prompted the investigation of viscoelastic studies in hemophilia care, which have established their utility in various bleeding and thrombotic states. In this review, we will discuss and critically assess the current literature highlighting the use of viscoelastic studies in various aspects of hemophilia including the determination of clinical phenotype, management of patients with inhibitors, perioperative management, and monitoring of novel agents.

Efficacy and safety of rVIII-SingleChain: results of a phase 1/3 multicenter clinical trial in severe hemophilia A.

Recombinant VIII (rVIII)-SingleChain is a novel B-domain-truncated recombinant factor VIII (rFVIII), comprised of covalently bonded factor VIII (FVIII) heavy and light chains. It was designed to have a higher binding affinity for von Willebrand factor (VWF). This phase 1/3 study investigated the efficacy and safety of rVIII-SingleChain in the treatment of bleeding episodes, routine prophylaxis, and surgical prophylaxis. Participants were ≥12 years of age, with severe hemophilia A (endogenous FVIII <1%). The participants were allocated by the investigator to receive rVIII-SingleChain in either an on-demand or prophylaxis regimen. Of the 175 patients meeting study eligibility criteria, 173 were treated with rVIII-SingleChain, prophylactically (N = 146) or on-demand (N = 27). The total cumulative exposure was 14 306 exposure days (EDs), with 120 participants reaching ≥50 EDs and 52 participants having ≥100 EDs. Hemostatic efficacy was rated by the investigator as excellent or good in 93.8% of the 835 bleeds treated and assessed. Across all prophylaxis regimens, the median annualized spontaneous bleeding rate was 0.00 (Q1, Q3: 0.0, 2.4) and the median overall annualized bleeding rate (ABR) was 1.14 (Q1, Q3: 0.0, 4.2). Surgical hemostasis was rated as excellent/good in 100% of major surgeries by the investigator. No participant developed FVIII inhibitors. In conclusion, rVIII-SingleChain is a novel rFVIII molecule showing excellent hemostatic efficacy in surgery and in the control of bleeding events, low ABR in patients on prophylaxis, and a favorable safety profile in this large clinical study. This trial was registered at www.clinicaltrials.gov as #NCT01486927.

Safety and efficacy of recombinant activated coagulation factor VII in congenital hemophilia with inhibitors in the home treatment setting: A review of clinical studies and registries.

Self-administration of factor and bypassing agents by persons with hemophilia in the home setting is recommended to facilitate earlier intervention after bleeding episodes. The objective of this review was to summarize recombinant activated coagulation factor VII (rFVIIa) safety and efficacy data from clinical trials and patient registries documenting use in the home treatment setting in people with congenital hemophilia with inhibitors (CHwI). A total of 16 studies and registries were identified for inclusion; 14 evaluated on-demand treatment of acute bleeding episodes (865 patients, 9024 bleeding episodes) and 2 evaluated use for secondary prophylaxis (108 patients, 42,861 prophylaxis days). In the on-demand studies, efficacy was consistently high (81%-96%), and thrombotic events were uncommon (n = 3). In the secondary prophylaxis studies, rFVIIa was associated with a 45% to 59% reduction in bleeding episodes and no thrombotic events. These data support the clinical practice of administering rFVIIa in patients in the home treatment setting after initiation under a physician's care.

Optimising musculoskeletal care for patients with haemophilia.

Despite recent improvements in the quality of care and treatment outcomes for haemophilia, joint disease remains a major concern for patients with and without inhibitors. Most bleeding episodes occur in the musculoskeletal system, and recurrent bleeding may result in progressive joint damage, leading to haemophilic arthropathy. Consequently, early identification and management of musculoskeletal bleeding episodes are important to prevent crippling deformities and dysfunction. Management strategies should aim at optimising joint function by reducing the frequency of, and preventing, joint bleeds. Although prophylactic factor replacement is proven to be effective in reducing bleeding frequency into joints and preserving musculoskeletal function in patients without inhibitors, the role for prophylaxis (with bypassing agents) in patients with inhibitors remains unclear. The available bypassing agents, activated prothrombin complex concentrate and recombinant activated factor VII (rFVIIa), are currently the standard of care for acute bleeding episodes in patients with high-titre inhibitors. These agents also prevent bleeding during elective orthopaedic surgery (EOS) in this patient population. This review discusses published data and uses illustrative cases to describe effective strategies for assessing joint health and maintaining optimal musculoskeletal care, focusing on the use of rFVIIa for haemostatic control in haemarthroses and when EOS is required in patients with inhibitors.

Characteristics of hemophilia patients with factor VIII inhibitors detected by prospective screening.

Characteristics of inhibitors identified by prospective screening may differ from those detected clinically. In a prospective study at 17 hemophilia centers with central inhibitor measurement by Nijmegen-Bethesda assay, 23 (2.8%) of 824 hemophilia A patients had new inhibitors detected: nine high-titer inhibitors (HTI: 7 ≥ 5.0 NBU plus 2 of 2.6 and 3.4 NBU at immune tolerance induction initiation) and 14 low-titer inhibitors (LTI: 0.5-1.9 NBU). HTI occurred at an earlier age (median 2 years, range 1-18, vs. median 11 years, range 2-61, P = 0.016). Both HTI (22%) and LTI (43%) occurred in non-severe patients. All HTI, but only 64% of LTI, were found to be FVIII-specific by chromogenic Bethesda assay or fluorescence immunoassay (FLI), indicating a high rate of false-positive LTI. Repeat specimens confirmed all HTI, 7/9 LTI, and 7/7 FVIII-specific LTI. FLI results were similar between HTI and FVIII-specific LTI; all included IgG1 and IgG4 subclasses. A comparable prospective study conducted from 1975 to 1979 at 13 U.S. centers found 31 (2.4%) new inhibitors among 1,306 patients. In both studies, one-third of inhibitors occurred in non-severe patients and one-quarter after 150 exposure days (ED). Significant differences were seen in the age at which inhibitors occurred (median 16 years in the older study vs. 5 years currently, P = 0.024) and in ED before inhibitor development, 10% in the older study and 43% currently study occurring within 20 ED, suggesting a temporal change in inhibitor development. Prospective screening detects inhibitors in patients of all severities, ages, and ED. Some LTI, however, are false positives.

An evaluation of von Willebrand factor (recombinant) therapy for adult patients living with severe type 3 von Willebrand disease.

INTRODUCTION: Von Willebrand Factor (VWF) containing concentrates have been used for the treatment of von Willebrand Disease (VWD) for many years. Recently, however, a novel recombinant VWF (rVWF or vonicog alpha, VONVENDI [US], VEYVONDI [Europe]) has arrived to the market for the treatment of VWD. Initially, rVWF was approved by the U.S. Food and Drug Administration (FDA) for the on-demand treatment and control of bleeding episodes and for the perioperative management of bleeding for patients with VWD. More recently, however, the FDA has approved rVWF for routine prophylaxis to prevent bleeding episodes for those patients with severe type 3 VWD receiving on-demand therapy. AREAS COVERED: This review will focus on recent phase III trial results from NCT02973087 regarding the use of long-term routine twice weekly prophylaxis with rVWF for the prevention of bleed events in patients with severe type 3 VWD. EXPERT OPINION: A novel rVWF concentrate may have greater hemostatic potential over prior plasma-derived VWF concentrates and is now FDA approved for use in routine prophylaxis for patients with severe type 3 VWD in the United States. This greater hemostatic potential may be due to the presence of ultra-large VWF multimers and a more favorable high-molecular-weight multimer pattern compared to prior pdVWF concentrates.

Building the foundation for a community-generated national research blueprint for inherited bleeding disorders: research priorities to transform the care of people with hemophilia.

BACKGROUND: Decades of research have transformed hemophilia from severely limiting children's lives to a manageable disorder compatible with a full, active life, for many in high-income countries. The direction of future research will determine whether exciting developments truly advance health equity for all people with hemophilia (PWH). National Hemophilia Foundation (NHF) and American Thrombosis and Hemostasis Network conducted extensive inclusive all-stakeholder consultations to identify the priorities of people with inherited bleeding disorders and those who care for them. RESEARCH DESIGN AND METHODS: Working group (WG) 1 of the NHF State of the Science Research Summit distilled the community-identified priorities for hemophilia A and B into concrete research questions and scored their feasibility, impact, and risk. RESULTS: WG1 defined 63 top priority research questions concerning arthropathy/pain/bone health, inhibitors, diagnostics, gene therapy, the pediatric to adult transition of care, disparities faced by the community, and cardiovascular disease. This research has the potential to empower PWH to thrive despite lifelong comorbidities and achieve new standards of wellbeing, including psychosocial. CONCLUSIONS: Collaborative research and care delivery will be key to capitalizing on current and horizon treatments and harnessing technical advances to improve diagnostics and testing, to advance health equity for all PWH.

Hemophilia is the best known of the inherited bleeding disorders (BD). This is a rare condition that causes disproportionate bleeding, often into joints and vital organs. Factor replacement, injecting recombinant or plasma-based clotting factor products directly into the vein, became commonplace to control the disorder in the 1990s and 2000s. Prophylaxis, or injecting replacement factor every few days into people with hemophilia (PWH), has revolutionized patients' lives. In the last few years, other advances in new therapies have entered this space, such as non-factor replacement therapies and gene therapy. With many more research advances on the horizon, the National Hemophilia Foundation (NHF) initiated a State of the Science Research Summit in 2020. This event was attended by over 880 interested parties to help design an agenda of research priorities for inherited BDs for the next decade, based on community consultations. NHF formed multiple Working Groups (WG), each exploring a theme resulting from the community consultations, and presenting their results at the Summit. Led by 2 hematologists who manage and treat PWH daily, the 21-community member WG1 assigned to hemophilia A and B divided into 7 subgroups to identify and organize research priorities for different topic areas. The outcomes focused on prioritizing patients' needs, technological advances, and research in the areas of greatest potential for PWH and those who care for them. The results are a roadmap for the future execution of a research plan that truly serves the community.

Bleeding in the patient with a malignancy: is it an acquired factor VIII inhibitor?

Many different factors can account for hemorrhagic complications in patients with malignancies. Potential etiologies include disease- or treatment-related impairment of bone marrow function, or trauma to highly friable and vascularized malignant tissues. Immune impairment may also occur in solid or hematologic malignancies, leading to spontaneous formation of inhibitory antibodies against coagulation factor VIII (FVIII). Because hemorrhage due to acquired FVIII inhibitors will not respond to conventional treatment algorithms for bleeding, failure to promptly recognize and diagnose this condition may result in undue morbidity and mortality. The persistence of FVIII autoantibodies in the patient with cancer may further complicate necessary invasive diagnostic or therapeutic procedures in the short term and lead to lethal bleeding in the long term. Oncologists must therefore maintain a high index of suspicion for this diagnosis as 1 of many potential causes of bleeding in patients with a malignancy.

Hemophilia A: Strategies for Improving Long-Term Holistic Management, Adherence, and Quality of Life.

Hemophilia A is a rare inherited bleeding disorder characterized by a deficiency in factor VIII. The evolution of currently approved prophylaxis therapy in hemophilia A will be reviewed, including the clinical value of prophylaxis, real-world experience with prophylaxis, and patient quality-of-life factors that must be considered when choosing treatment options for these patients.

F5-Atlanta: A novel mutation in F5 associated with enhanced East Texas splicing and FV-short production.

BACKGROUND: Elucidating the molecular pathogenesis underlying East Texas bleeding disorder (ET) led to the discovery of alternatively spliced F5 transcripts harboring large deletions within exon 13. These alternatively spliced transcripts produce a shortened form of coagulation factor V (FV) in which a large portion of its B-domain is deleted. These FV isoforms bind tissue factor pathway inhibitor alpha (TFPIα) with high affinity, prolonging its circulatory half-life and enhancing its anticoagulant effects. While two missense pathogenic variants highlighted this alternative splicing event, similar internally deleted FV proteins are found in healthy controls. OBJECTIVE: We identified a novel heterozygous 832 base pair deletion within F5 exon 13, termed F5-Atlanta (F5-ATL), in a patient with severe bleeding. Our objective is to investigate the effect of this deletion on F5 and FV expression. METHODS & RESULTS: Assessment of patient plasma revealed markedly elevated levels of total and free TFPI and a FV isoform similar in size to the FV-short described in ET. Sequencing analyses of cDNA revealed the presence of a transcript alternatively spliced using the ET splice sites, thereby removing the F5-ATL deletion. This alternative splicing pattern was recapitulated by heterologous expression in mammalian cells. CONCLUSIONS: These findings support a mechanistic model consisting of cis-acting regulatory sequences encoded within F5 exon 13 that control alternative splicing at the ET splice sites and thereby regulate circulating FV-short and TFPIα levels.

Progressive multifocal leukoencephalopathy in a patient without apparent immunosuppression.

An 80-year-old man with no history of an immune-compromising disorder was diagnosed with progressive multifocal leukoencephalopathy (PML). He presented with dysphagia and left-sided weakness; magnetic resonance imaging demonstrated marked signal abnormality in the subcortical white matter of the left frontal lobe and in the posterior limb of the right internal capsule. Polymerase chain reaction (PCR) analysis of the cerebrospinal fluid (CSF) was negative for John Cunningham (JC) virus. On brain biopsy, foamy macrophages infiltrating the white matter were identified, staining positive for anti-simian virus 40 antibodies. Postoperatively, PCR for JC viral DNA in the CSF was positive, establishing the diagnosis of PML. Extensive investigation for an occult immunocompromising disorder was negative. The patient's neurologic deficits rapidly increased throughout his hospital stay, and he died 3.5 months after his diagnosis.

Quantitative HLA-class-II/factor VIII (FVIII) peptidomic variation in dendritic cells correlates with the immunogenic potential of therapeutic FVIII proteins in hemophilia A.

BACKGROUND: Plasma-derived (pd) or recombinant (r) therapeutic factor VIII proteins (FVIIIs) are infused to arrest/prevent bleeding in patients with hemophilia A (PWHA). However, FVIIIs are neutralized if anti-FVIII-antibodies (inhibitors) develop. Accumulating evidence suggests that pdFVIIIs with von Willebrand factor (VWF) are less immunogenic than rFVIIIs and that distinct rFVIIIs are differentially immunogenic. Since inhibitor development is T-helper-cell-dependent, human leukocyte antigen (HLA)-class-II (HLAcII) molecules constitute an important early determinant. OBJECTIVES: Use dendritic cell (DC)-protein processing/presentation assays with mass-spectrometric and peptide-proteomic analyses to quantify the DP-bound, DQ-bound, and DR-bound FVIII-derived peptides in individual HLAcII repertoires and compare the immunogenic potential of six distinct FVIIIs based on their measured peptide counts. PATIENTS/METHODS: Monocyte-derived DCs from normal donors and/or PWHA were cultured with either: Mix-rFVIII, a VWF-free equimolar mixture of a full-length (FL)-rFVIII [Advate® (Takeda)] and four distinct B-domain-deleted (BDD)-rFVIIIs [Xyntha® (Pfizer), NovoEight® (Novo-Nordisk), Nuwiq® (Octapharma), and Afstyla® (CSL Behring GmBH)]; a pdFVIII + pdVWF [Beriate® (CSL Behring GmBH)]; Advate ± pdVWF; Afstyla ± pdVWF; and Xyntha + pdVWF. RESULTS: We showed that (i) Beriate had a significantly lower immunogenic potential than Advate ± pdVWF, Afstyla - pdVWF, and Mix-rFVIII; (ii) distinct FVIIIs differed significantly in their immunogenic potential in that, in addition to (i), Afstyla + pdVWF had a significantly lower immunogenic potential than Beriate, while the immunogenic potential of Beriate was not significantly different from that of Xyntha + pdVWF; and (iii) rFVIIIs with pdVWF had significantly lower immunogenic potentials than the same rFVIIIs without pdVWF. CONCLUSIONS: Our results provide HLAcII peptidomic level explanations for several important clinical observations/issues including the differential immunogenicity of distinct FVIIIs and the role of HLAcII genetics in inhibitor development.

The effect of activated factor VII for intracerebral hemorrhage beyond 3 hours versus within 3 hours.

BACKGROUND AND PURPOSE: Recombinant-activated factor VII (rFVIIa) is an investigational treatment for intracerebral hemorrhage (ICH). We have evaluated the drug's treatment effect based on time to treatment. METHODS: ICH patients treated up to 4 hours from symptom onset were divided based on time to treatment:

Thrombelastography-guided factor VIIa therapy in a surgical patient with severe hemophilia and factor VIII inhibitor.

A patient with hemophilia and factor VIII inhibitors required urgent evacuation of a spinal cord hematoma. Two large doses of recombinant factor VIIa (200 microg/kg followed by 300 microg/kg) were required for hemostasis. Traditional and rotational thrombelastography were used to guide dose and timing of rFVIIa therapy. With the limitations of prothrombin and partial thromboplastin times as perioperative monitors of rFVIIa efficacy, this description of thrombelastography supports reports of in vitro use, and may be helpful when large perioperative doses of rFVIIa are required.