Quantifying the optimal factor VIII levels to achieve patient-centric and clinician-relevant outcomes among people with hemophilia A: a SHELF elicitation study

Beta 2 adrenergic receptor polymorphisms: association with factor VIII and von Willebrand factor levels and the risk of venous thrombosis

Prospective Evaluation of plasma Levels of FVIII in Patients with venous Thromboembolism,

A United Kingdom Haemophilia Centre Doctors’ Organization (UKHCDO) guideline approved by the British Committee for Standards in Haematology Peter W Collins, Elizabeth Chalmers, Daniel Hart, Ian Jennings, Ri Liesner, Savita Rangarajan, Kate Talks, Michael Williams and Charles R. M. Hay School of Medicine, Cardiff University, University Hospital of Wales, Cardiff, Royal Hospital for Sick Children, Glasgow, Royal London Hospital, Barts and The London School of Medicine and Dentistry, Queen Mary University London, London, UK NEQAS Blood Coagulation, Sheffield, Great Ormond Street NHS Trust, London, Hampshire Hospital NHS Foundation Trust, Basingstoke & North Hampshire Hospital, Basingstoke, Newcastle upon Tyne Hospital NHS Foundation Trust, Newcastle, Birmingham Children’s Hospital NHS Foundation Trust, Birmingham, and Manchester University Dept of Haematology, Manchester Royal Infirmary, Manchester, UK

Treatment of von Willebrand disease with FVIII/VWF concentrates.

Increased factor VIII (FVIII) levels are a prevalent and independent risk factor for venous thromboembolism (VTE). The low density lipoprotein receptor-related protein 1 (LRP1) has been associated with FVIII catabolism. After a median of 10 years of the first thrombotic episode, we evaluated FVIII activity levels in 75 patients with VTE and high FVIII levels and in 74 healthy controls. Subsequently, we evaluated the regions of F8 and LRP1 genes coding sites of affinity between these proteins, with the objective of determining genetic alterations associated with plasma FVIII levels. After a median time of 10 years after the VTE episode, FVIII levels were significantly higher in patients when compared to controls (158.6 IU/dL vs. 125.8 IU/dL; P ≤ 0.001]. Despite the fact that we found 14 genetic variations in F8 and LRP1 genes, no relationship was found between FVIII levels with these variations. We demonstrated a persistent increase of FVIII levels in patients with VTE, but in a much lower magnitude after 10 years when compared to 3-years after the episode. Moreover, we observed no relationship of genetic variations in the gene regions coding affinity sites between LRP1 and FVIII with FVIII levels.

High levels of factor VIII (FVIII) but not von Willebrand factor (vWF) are known to increase the risk for venous thromboembolism. Whether high FVIII levels originate from hereditary defects or from acquired conditions remains unanswered. The objective of our study was to investigate whether there is evidence for familial clustering of elevated FVIII levels in families in which >/=1 member has been affected by a thromboembolic event and had reproducibly high FVIII levels. We investigated FVIII levels in 361 patients with previous venous thromboembolism. FVIII levels were measured by a chromogenic assay; the cutoff value was defined as the 98th percentile of FVIII plasma levels of 266 blood donors. vWF levels were determined by an enzyme immunoassay. After exclusion of known causes of FVIII elevation, such as the acute thrombotic event itself; inflammation; malignancy; liver, renal, or vascular disease; surgery; or pregnancy, we included 17 patients with unexplained, reproducibly high FVIII levels. The investigation was also extended to these patients' relatives. Multiple regressive analysis of blood donors and asymptomatic family members showed that the affiliation with a family in which 1 member suffered from venous thromboembolism and had reproducibly high FVIII levels is the second most important predictor for FVIII levels. Familial clustering was analyzed by the Houwing-Duistermaat familial aggregation test. After adjustment for the influence of age, sex, blood group, and vWF, FVIII levels were significantly (P:=0.038) clustered within families. In conclusion, FVIII levels seem to be familially determined in families in which a member showed high FVIII levels after previous venous thromboembolism.

Role of Low Density Lipoprotein Receptor in the Clearance of Coagulation Factor VIII In Vivo.

Elevated levels of factor VIII and subsequent risk of all‐cause mortality: results from the MEGA follow‐up study

Retrospective Audit of a Factor VIII Continuous Infusion Protocol to Examine Inhibitor Formation, Complications and Product Use.

Haemophilia A (HA), defined by factor VIII (FVIII) levels ≤40 IU/dL, is a chronic condition with consequences beyond bleeding complications. Jan Astermark (Professor of Clinical Coagulation Medicine, Senior Consultant, and Head of Department of Translational Medicine, Lund University; and Department of Haematology, Oncology and Radiation Physics, Skåne University Hospital, Malmö, Sweden) outlined the burden of HA on the quality of life (QoL) of patients, including bleeding, joint damage, pain, psychosocial wellbeing, and physical activity. He shared real-world evidence showing that current prophylactic regimens with FVIII or non-factor therapy (NFT) are not sufficient to eliminate all types of bleeds and that many challenges remain. Astermark presented several analyses highlighting that FVIII levels in the non-haemophilia range may be necessary to prevent residual bleeding. These analyses have informed recent treatment goals that transcend historical targets of converting severe HA (SHA) into moderate or mild forms and aim towards normalised haemostasis to eliminate bleeds. Maria Elisa Mancuso (Senior Consultant in Haematology, Centre for Thrombosis and Haemorrhagic Diseases, IRCCS Humanitas Research Hospital and Humanitas University, Milan, Italy) presented a patient case to illustrate the challenges that people with HA (PwHA) face over their lives and the evolution of treatment strategies to address unmet needs. Christoph Königs (Head of Clinical and Molecular Haemostasis at the Department of Paediatrics and Adolescent Medicine, Clinical and Molecular Haemostasis, Goethe University, University Hospital, Frankfurt, Germany) emphasised the unique challenges faced by children with HA and their caregivers, including restrictions in daily activities, regular evaluations for subclinical and evident bleeds, long-term joint protection, delayed inhibitor development, self-injection skills, and suboptimal adherence. He discussed how standard and extended half-life (SHL, EHL) therapies have improved care in children with HA but highlighted how prophylaxis with existing therapies is not sufficient to eliminate evident and subclinical bleeds. He concluded by sharing data on novel therapies that offer the potential to maintain FVIII levels in the non-haemophilia range (≥40 IU/dL) to help address these unmet needs. Robert Klamroth (Head of the Department of Internal Medicine, Vascular Medicine and Haematology, and Director of Haemophilia Treatment Centre, at Vivantes Klinikum Friedrichshain, Berlin, Germany) focused on the evolving challenges of HA in adulthood, including surgery and the need for anticoagulant or antiplatelet therapy for the management of comorbidities. Recent clinical data were shown to demonstrate how high sustained FVIII levels could minimise bleeding risk and improve joint health, surgical management, and overall QoL in adults with HA. In the panel discussion, two patient cases were reviewed to consider unmet needs in people with mild HA and in elderly people with HA, and the panel summarised how sustaining FVIII levels in the non-haemophilia range could help address these needs. The panel concluded by reviewing the evolution of treatment strategies and the importance of targeting normalised haemostasis in a new era of protection in HA.

Albuminuria is directly associated with increased plasma PAI-1 and factor VII levels in NIDDM patients

The aim of this study was to evaluate the relationship between factor VIII (FVIII) levels, measured by chromogenic and clotting assays, and risk of venous thromboembolism (VTE) recurrence. A total of 564 patients underwent clinical follow-up after oral anticoagulant withdrawal (total follow-up = 924.4 years). Recurrent VTE developed in 39 of 309 (12.6%) patients with a first idiopathic VTE and in 14 of 255 (5.5%) patients whose first event was secondary. In patients with a first idiopathic VTE, the risk of recurrence was more than fivefold higher in patients with FVIII levels exceeding the 90th percentile [chromogenic FVIII: relative risk (RR) 5.43 (95% CI 1.76-16.8); clotting FVIII: RR 6.21 (95% CI 1.57-24.5)] after adjustment for all possible confounding variables. In patients with a first secondary VTE, the risk of recurrence was slightly higher in patients with high FVIII levels [chromogenic FVIII: RR 2.62 (95% CI 0.34-19.9); clotting FVIII: RR 1.74 (95% CI 0.25-12.1)], but, given the low number of recurrences, the 95% CI were very large. In conclusion, this study shows that high FVIII levels are associated with increased risk of VTE recurrence in patients with a first idiopathic VTE. Although the measurement of FVIII levels by a specific chromogenic assay might, in principle, be preferred to avoid the risk of aspecific clotting effects, no significant differences in results obtained by chromogenic or clotting methods were found.

The aim of the authors is to examine the relationship between the cytokine levels that are thought to be involved in stroke etiopathogenesis (tumor necrosis factor [TNF]-alpha, interleukin [IL]-2, IL-6, IL-8, IL-11), soluble protein C receptor (sEPCR), and factor VIII (FVIII) levels. The study included 27 patients with stroke and 30 healthy controls, aged 0 to 18. In the comparison of the sEPCR, cytokine, and FVIII levels between patient and control groups, median levels of TNF-alpha, IL-2, IL-6, and IL-8 are found to be high in the patient group when compared with controls, whereas there is no difference in sEPCR, IL-11, and FVIII levels. In the patient group, a positive correlation is seen between TNF-alpha levels and IL-2 and IL-6 levels, between IL-2 and IL-6 levels, and between IL-6 and IL-8 levels, whereas a negative relationship is seen between sEPCR and FVIII. In the control group apart from the patient group, a negative relationship is seen between TNF-alpha and FVIII, whereas there is a positive relationship between IL-11 and sEPCR levels. Median sEPCR levels in patients who have normal or low FVIII levels are significantly high when compared with those with high FVIII levels. In conclusion, in the pediatric population, an increase in TNF-alpha, IL-2, IL-6, and IL-8 levels is seen. Also, an inverse relationship of sEPCR and FVIII levels is shown for the first time. This study provides a basis for ongoing studies that aim to clarify stroke etiopathogenesis. Studies with larger series of patients are warranted to confirm this hypothesis.

Do Elevated Plasma Tissue Factor Pathway Inhibitor (TFPI) Levels Affect Measurement of Factor VIIa?.

Gene Therapy with BMN 270 Results in Therapeutic Levels of FVIII in Mice and Primates and Normalization of Bleeding in Hemophilic Mice.