Plasma-derived FVIII/VWF Complex Shows Higher Protection Against Inhibitors Than Isolated FVIII After Infusion in Haemophilic Patients: A Translational Study

Overview

Journal Haemophilia

Specialty Hematology

Date 2022 Jun 2

PMID 35654086

Authors

Maria Isabel Bravo

Alba Perez

Aida Raventos

Salvador Grancha

Juan Ignacio Jorquera

Nora Viviana Butta

Maria Teresa Alvarez-Roman

Montserrat Costa

Todd Willis

Victor Jimenez-Yuste

Affiliations

Soon will be listed here.

Abstract

Introduction: Presence of von Willebrand factor (VWF) in FVIII concentrates offers protection against neutralizing inhibitors in haemophilia A (HA). Whether this protection is more evident in plasma-derived (pd) FVIII/VWF or recombinant (r) FVIII concentrates remains controversial.

Aim: We investigated the protection exerted by VWF against FVIII inhibitors in an in vivo mouse model of HA exposed to pdFVIII/VWF or to various rFVIII concentrates.

Methods: Haemophilia A mice received the different FVIII concentrates after administration of vehicle or an inhibitory IgG purified from a commercial pool of HA plasma with inhibitors and FVIII:C recoveries were measured. Furthermore, using a novel clinically oriented ex vivo approach, Bethesda inhibitory activities (BU) of a commercial pool of HA plasma with inhibitors were assessed using normal plasma, or plasma from severe HA patients, without inhibitors, after treatment with the same concentrates.

Results: in vivo studies showed that pdFVIII/VWF offers markedly higher protection against inhibitors when compared with any of the FVIII products without VWF. More importantly, in the ex vivo studies, plasma from patients treated with pdFVIII/VWF showed higher protection against inhibitors (P values ranging .05-.001) in comparison with that observed in plasma from patients who received FVIII products without VWF, regardless of the type of product evaluated.

Conclusion: Data indicate that FVIII+VWF complexes assembled in the circulation after rFVIII infusion are not equivalent to the naturally formed complex in pdFVIII/VWF. Therefore, rFVIII infused into HA patients with inhibitors would be less protected by VWF than the FVIII in pdFVIII/VWF concentrates.

Citing Articles

Plasma-derived FVIII/VWF complex shows higher protection against inhibitors than isolated FVIII after infusion in haemophilic patients: A translational study.

Bravo M, Perez A, Raventos A, Grancha S, Jorquera J, Butta N Haemophilia. 2022; 28(5):737-744.

PMID: 35654086 PMC: 9545517. DOI: 10.1111/hae.14589.

References

Berntorp E, Ekman M, Gunnarsson M, Nilsson I . Variation in factor VIII inhibitor reactivity with different commercial factor VIII preparations. Haemophilia. 2016; 2(2):95-9. DOI: 10.1111/j.1365-2516.1996.tb00022.x. View

Hartholt R, van Velzen A, Peyron I, Ten Brinke A, Fijnvandraat K, Voorberg J . To serve and protect: The modulatory role of von Willebrand factor on factor VIII immunogenicity. Blood Rev. 2017; 31(5):339-347. DOI: 10.1016/j.blre.2017.07.001. View

Springer T . Biology and physics of von Willebrand factor concatamers. J Thromb Haemost. 2011; 9 Suppl 1:130-43. PMC: 4117350. DOI: 10.1111/j.1538-7836.2011.04320.x. View

Duncan E, Collecutt M, Street A . Nijmegen-Bethesda assay to measure factor VIII inhibitors. Methods Mol Biol. 2013; 992:321-33. DOI: 10.1007/978-1-62703-339-8_24. View

Qian J, Borovok M, Bi L, Kazazian Jr H, HOYER L . Inhibitor antibody development and T cell response to human factor VIII in murine hemophilia A. Thromb Haemost. 1999; 81(2):240-4. View

Repesse Y, Peyron I, Dimitrov J, Dasgupta S, Moshai E, Costa C . Development of inhibitory antibodies to therapeutic factor VIII in severe hemophilia A is associated with microsatellite polymorphisms in the HMOX1 promoter. Haematologica. 2013; 98(10):1650-5. PMC: 3789472. DOI: 10.3324/haematol.2013.084665. View

Turner N, Moake J . Factor VIII Is Synthesized in Human Endothelial Cells, Packaged in Weibel-Palade Bodies and Secreted Bound to ULVWF Strings. PLoS One. 2015; 10(10):e0140740. PMC: 4608722. DOI: 10.1371/journal.pone.0140740. View

Bravo M, Da Rocha-Souto B, Grancha S, Jorquera J . Native plasma-derived FVIII/VWF complex has lower sensitivity to FVIII inhibitors than the combination of isolated FVIII and VWF proteins. Impact on Bethesda assay titration of FVIII inhibitors. Haemophilia. 2014; 20(6):905-11. PMC: 4237173. DOI: 10.1111/hae.12494. View

Grancha S, Ortiz A, Maranon C, Hampel K, Moret A, Zimmermann B . Kinetics of the interaction between anti-FVIII antibodies and FVIII from therapeutic concentrates, with and without von Willebrand factor, assessed by surface plasmon resonance. Haemophilia. 2012; 18(6):982-9. DOI: 10.1111/j.1365-2516.2012.02858.x. View

10.

Calvez T, Chambost H, Claeyssens-Donadel S, dOiron R, Goulet V, Guillet B . Recombinant factor VIII products and inhibitor development in previously untreated boys with severe hemophilia A. Blood. 2014; 124(23):3398-408. DOI: 10.1182/blood-2014-07-586347. View

11.

Lin Y, Yang X, Chevrier M, Craven S, Barrowcliffe T, Lemieux R . Relationships between factor VIII:Ag and factor VIII in recombinant and plasma-derived factor VIII concentrates. Haemophilia. 2004; 10(5):459-69. DOI: 10.1111/j.1365-2516.2004.00957.x. View

12.

Higuchi M, Kazazian Jr H, Kasch L, Warren T, McGinniss M, Phillips 3rd J . Molecular characterization of severe hemophilia A suggests that about half the mutations are not within the coding regions and splice junctions of the factor VIII gene. Proc Natl Acad Sci U S A. 1991; 88(16):7405-9. PMC: 52304. DOI: 10.1073/pnas.88.16.7405. View

13.

Aledort L . Is the incidence and prevalence of inhibitors greater with recombinant products? Yes. J Thromb Haemost. 2004; 2(6):861-2. DOI: 10.1111/j.1538-7836.2004.00731.x. View

14.

Goudemand J, Rothschild C, Demiguel V, Vinciguerrat C, Lambert T, Chambost H . Influence of the type of factor VIII concentrate on the incidence of factor VIII inhibitors in previously untreated patients with severe hemophilia A. Blood. 2005; 107(1):46-51. DOI: 10.1182/blood-2005-04-1371. View

15.

Mannucci P . Hemophilia therapy: the future has begun. Haematologica. 2020; 105(3):545-553. PMC: 7049365. DOI: 10.3324/haematol.2019.232132. View

16.

Bravo M, Ortiz A, Costa M, Grancha S, Jorquera J . Neutralizing capacity of inhibitors on FVIII is lower for natural FVIII/VWF complex than for isolated FVIII: in vitro comparative study in eleven different therapeutic FVIII concentrates. Haemophilia. 2016; 22(4):e341-4. DOI: 10.1111/hae.12975. View

17.

Michnick D, Pittman D, Wise R, Kaufman R . Identification of individual tyrosine sulfation sites within factor VIII required for optimal activity and efficient thrombin cleavage. J Biol Chem. 1994; 269(31):20095-102. View

18.

Kawasaki T, Kaida T, Arnout J, Vermylen J, Hoylaerts M . A new animal model of thrombophilia confirms that high plasma factor VIII levels are thrombogenic. Thromb Haemost. 1999; 81(2):306-11. View

19.

Gensana M, Altisent C, Aznar J, Casana P, Hernandez F, Jorquera J . Influence of von Willebrand factor on the reactivity of human factor VIII inhibitors with factor VIII. Haemophilia. 2001; 7(4):369-74. DOI: 10.1046/j.1365-2516.2001.00526.x. View

20.

Peyvandi F, Mannucci P, Garagiola I, El-Beshlawy A, Elalfy M, Ramanan V . A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A. N Engl J Med. 2016; 374(21):2054-64. DOI: 10.1056/NEJMoa1516437. View