Schutgens, Roger E G

Utrecht University Repository

Downloadedfromhttps://journals.lww.com/hemaspherebyBhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE=on02/12/2021Downloadedfromhttps://journals.lww.com/hemaspherebyBhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE=on02/12/2021High Five for Low FiveBy Roger E.G. SchutgensCorrespondence: Roger Schutgens (e-mail: r.schutgens@umcutrecht.nl).There is a considerable variability in bleeding phenotype within hemophilia A patientswith similar factor VIII (FVIII) levels, which to date has not really been understood. Insearch of an explanation, many studies have been performed to find mechanisms forregulationor compensationof bleeding inhemophilia.Not longago, hemophilia patientswere found to have a 1.5-fold higher platelet factorV (FV) concentration compared to healthy blooddonors.1 The authors suggested this to be the consequence of a compensatory procoagulant responseto hemophilia bleeding. Although the assumption of higher clotting factor levels having moreprocoagulant potential is appealing, recent insights have shed a different light on this topic.The coagulation system is a highly complex network, where multiple proteins interact upon aplatelet surface under flow conditions (Fig. 1). Nonlinear positive and negative feedback loops,individual thresholds and a dynamic continuum make it extremely difficult to study thecontribution of individual proteins in the final coagulation properties in a single patient. Oneapproach to systemically evaluate such complex network is through local or global sensitivityanalysis, where the uncertainty in the output of a model can be appointed to different sources ofuncertainty in themodel input. Recently, Link et al performed a global sensitivity analysis in searchfor a modifier of thrombin generation in hemophilia A.2 Potential candidates from this analysiswere evaluated in a flow model of coagulation and by measuring thrombin generation bycalibrated automated thrombography (CAT). After 110.000 simulations, they found that FV wasresponsible for 50% of the variance in their model. More strikingly, it appeared that low-normallevels of FV enhanced thrombin generation in FVIII-deficient plasma in this model of flow-mediated coagulation. In a next step, they confirmed their findings in flow assays and using CAT.In both experiments, inducing lower FV levels within the normal range (to 60%) resulted in clearlyenhanced thrombin generation. These effects were amplified by high-normal prothrombin levels inboth experimental models. Their hypothesis is that lowering FV reduces competition between FVand FVIII for factor Xa on activated platelet surfaces (Fig. 1), which enhances FVIII activation andrescues thrombin generation in FVIII-deficient blood.2There is a rare bleeding disease with a combined congenital FV and FVIII deficiency (F5F8D). Inthe model of Link et al, very low FV levels (<5% of normal) combined with very low FVIII levels(1%of normal) produced little to no thrombin in the simulations.2 Recently, Shao et al reported onRoger E.G. SchutgensVan Creveldkliniek, Benign HematologyCenter, University Medical CenterUtrecht and University, Utrecht, TheNetherlands.The authors have no conflicts ofinterest to disclose.Copyright © 2020 the Author(s).Published by Wolters Kluwer Health,Inc. on behalf of the EuropeanHematology Association. This is anopen access article distributed underthe terms of the Creative CommonsAttribution-Non Commercial-NoDerivatives License 4.0 (CCBY-NC-ND), where it is permissible todownload and share the workprovided it is properly cited. The workcannot be changed in any way orused commercially without permissionfrom the journal.HemaSphere (2020) 4:2(e355)Citation: HemaSphere, 2020;4:2.http://dx.doi.org/10.1097/HS9.0000000000000355Figure 1. Schematic representation of the coagulation cascade. Factor V, factor VIII and factor X are indicated in colorto highlight the possible competition between factor V and factor VIII for factor Xa. TF = tissue factor.Powered by EHAHemaTopics16 patients with F5F8D.3 They found that the low FV in thosepatients (ranging from 7% to 18% of normal), accompanied bylow tissue factor pathway inhibitor levels, had optimalprocoagulant activity. Moreover, correcting FV levels to 100%of the normal range did not result in increased thrombingeneration, but in an opposite effect. This indicates indeed thatlower FV levels contribute to enhanced thrombin generation.In light of the many therapeutic advances beingmade in the lastyears for hemophilia, mild inhibition of FV to low-normal levelscould be an interesting strategy.References1. Ellery PER, Hilden I, Thyregod P, et al. Measurement of plasma andplatelet tissue factor pathway inhibitor, factor V and Protein S in peoplewith haemophilia. Haemophilia. 2019;25:1083–1091.2. Link KG, Stobb MT, Sorrells MG, et al. A mathematical model ofcoagulation under flow identifies factor V as a modifier of thrombingeneration in hemophilia A. J Thromb Haemost. 2020;18:306–317.3. Shao Y, Wu W, Xu G, et al. Low factor V level ameliorates bleedingdiathesis in patients with combined deficiency of factor V and factor VIII.Blood. 2019;134:1745–1754.HemaTopics HemaTopics2

High Five for Low Five

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High Five for Low Five

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