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Semin Thromb Hemost 2021; 47(02): 183-191
DOI: 10.1055/s-0041-1723769
Review Article

Heterogeneity in Bleeding Tendency and Arthropathy Development in Individuals with Hemophilia

Aisling M. Rehill
1   Irish Centre for Vascular Biology, Royal College of Surgeons in Ireland, Dublin, Ireland
,
Seán McCluskey
1   Irish Centre for Vascular Biology, Royal College of Surgeons in Ireland, Dublin, Ireland
2   National Children's Research Centre, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland
,
James S. O'Donnell
1   Irish Centre for Vascular Biology, Royal College of Surgeons in Ireland, Dublin, Ireland
2   National Children's Research Centre, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland
3   St James' Hospital, Dublin, Ireland
,
Michael Dockal
4   Baxalta Innovations GmbH, A Member of the Takeda Group of Companies, Vienna, Austria
,
Roger J.S. Preston
1   Irish Centre for Vascular Biology, Royal College of Surgeons in Ireland, Dublin, Ireland
2   National Children's Research Centre, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland
,
on behalf of the iPATH Study Group› Author Affiliations
Funding This publication has emanated from research supported in part by a research grant from Science Foundation (SFI) under the SFI Strategic Partnership Programme Grant number 16/SPP3303 and research support for the Irish Personalized Approach to the Treatment of Hemophilia project from Shire US Inc., a member of the Takeda group of companies, Lexington, MA, USA.
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Abstract

People with hemophilia (PWH) have an increased tendency to bleed, often into their joints, causing debilitating joint disease if left untreated. To reduce the incidence of bleeding events, PWH receive prophylactic replacement therapy with recombinant factor VIII (FVIII) or FIX. Bleeding events in PWH are typically proportional to their plasma FVIII or IX levels; however, in many PWH, bleeding tendency and the likelihood of developing arthropathy often varies independently of endogenous factor levels. Consequently, many PWH suffer repeated bleeding events before correct dosing of replacement factor can be established. Diagnostic approaches to define an individual's bleeding tendency remain limited. Multiple modulators of bleeding phenotype in PWH have been proposed, including the type of disease-causing variant, age of onset of bleeding episodes, plasma modifiers of blood coagulation or clot fibrinolysis pathway activity, interindividual differences in platelet reactivity, and endothelial anticoagulant activity. In this review, we summarize current knowledge of established factors modulating bleeding tendency and discuss emerging concepts of additional biological elements that may contribute to variable bleeding tendency in PWH. Finally, we consider how variance in responses to new gene therapies may also necessitate consideration of patient-specific tailoring of treatment. Cumulatively, these studies highlight the need to reconsider the current “one size fits all” approach to treatment regimens for PWH and consider therapies guided by the bleeding phenotype of each individual PWH at the onset of therapy. Further characterization of the biological bases of bleeding heterogeneity in PWH, combined with the development of novel diagnostic assays to identify those factors that modulate bleeding risk in PWH, will be required to meet these aspirations.

Keywords

hemophilia - bleeding heterogeneity - coagulation - fibrinolysis - gene therapy

Authors' Contributions

All authors were involved in writing and reviewing the paper.




Publication History

Article published online:
26 February 2021

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