Factor VIII prophylaxis effects outweigh other hemostasis contributors in predicting severe haemophilia A joint outcomes

• Type of Material: Article
• Authors: Beth Boulden Warren, University of Colorado; Linda Jacobson, University of Colorado; Christine Kempton, Emory University; George R. Buchanan, University of Texas Southwestern Medical Center; Michael Recht, Phoenix Childrens Hospital; Deborah Brown, University of Texas Houston; Cindy Leissinger, Tulane University; Amy D. Shapiro, Indiana Hemophilia & Thrombosis Center; Thomas C. Abshire, Emory University; Marilyn J. Manco-Johnson, University of Colorado
• Language: English
• Date: 2019-09-01
• Publisher: Wiley
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019 John Wiley & Sons, Inc. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1111/hae.13778
• Title of Journal or Parent Work: Haemophilia
• Volume: 25
• Issue: 5
• Start Page: 867
• End Page: 875
• Grant/Funding Information: The Hemophilia and Thrombosis Research Society recruited sites for participation. Clinical research and laboratory personnel, laboratory reagents, and study database management were funded in part by the Health Resources and Services Administration (HRSA) of the U.S. Department of Health and Human Services (HHS) Maternal and Child Health Bureau 340B Program (2H30MC24049, Mountain States Hemophilia Network).; The JOS was supported by grants from the Centers for Disease Control and Prevention (U27/CCU812106) and the National Institutes of Health (R00069).; For this analysis, BBW was funded by the HTRS/Novo Nordisk Clinical Fellowship Award and the Bayer Hemophilia Awards Program Fellowship Project Award.; Bayer HealthCare donated the factor VIII (Kogenate) used in the study but had no role in study design, data accrual, data analysis, or manuscript preparation.
• Keywords: Factor consumption; Science & Technology; Pharmacokinetics; Recombinant factor VIII; Clinical expression; blood coagulation factors; global assays; Prothrombotic mutations; Hematology; Coagulability; Life Sciences & Biomedicine; paediatric; Global assay; prophylaxis; Thrombin generation; Children; joints; Plasma; haemophilia
• Research Categories: Health Sciences, Public Health; Health Sciences, Pathology; Health Sciences, Health Care Management; Health Sciences, Human Development

Abstract

Introduction: The Joint Outcome Study (JOS) demonstrated that previously untreated children with severe hemophilia A treated with prophylactic factor VIII (FVIII) concentrate had superior joint outcomes at age six years compared to those children treated episodically for bleeding. However, variation in joint outcome within each treatment arm was not well-explained. Aim: In this study, we sought to better understand variation in joint outcomes at age 6 years in participants of the JOS. Methods: We evaluated the influence of FVIII half-life, treatment adherence, constitutional coagulant and anticoagulant proteins, and global assays on joint outcomes (number of joint bleeds, total number of bleeds, total MRI score, and joint physical exam score). Logistic regression was used to evaluate the association of variables with joint failure status on MRI, defined as presence of subchondral cyst, surface erosion, or joint-space narrowing. Each parameter was also correlated with each joint outcome using Spearman correlations. Results: Prophylaxis treatment arm and FVIII trough were each found to reduce risk of joint failure on univariate logistic regression analysis. When controlling for treatment arm, FVIII trough was no longer significant, likely because of the high level of covariation between these variables. We found no consistent correlation between any laboratory assay performed and any joint outcome parameter measured. Conclusion: In the JOS, the effect of prescribed prophylactic FVIII infusions on joint outcome overshadowed the contribution of treatment adherence, FVIII half-life, global assays of coagulation, and constitutional coagulation proteins. (ClinicalTrials.gov number, NCT00207597)