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F. Peyvandi et al.
prophylaxis accessible to all patients with hemophilia A, including those with FVIII inhibitors, and this may help to reduce bleeding events and improve quality of life.12,13
For optimal care of hemophilia, the multidisciplinary team of specialists should include physiotherapists who should be involved from diagnosis and deal with the func- tional recovery after each musculoskeletal bleeding. They should also provide a rehabilitation program tailored to tackle all the problems related to this chronic condition.14
Recommendation 2
With increased treatment options, appropriate instruments should be developed to personalize treatment regimens for all patients with hemophilia A and B.
The aim of prophylaxis is to minimize or abolish bleed- ing events, and thus improve quality of life in patients. Prophylaxis regimens with standard and extended half-life products have been shown to be effective at preserving joint function and preventing bleeding episodes, although significant variability was seen among individuals exposed to the same treatment regimen.15 Inter- and intra- individual variability in coagulation factor pharmacokinet- ics is thought to be the main determinant of uncertainty in the standardization of prophylaxis regimens. Appropriate tools must be developed to personalize treatment regi- mens, taking into account each patient's individual lifestyle and pharmacokinetic profile.16 The individualiza- tion of prophylaxis is the best strategy to improve patients’ quality of life with the ambitious goal of zero bleeding in the near future.
Recommendation 3
With extended half-life therapies, a minimum trough level of 3-5% should be achieved to preserve joint status.
Patients with severe hemophilia suffer from repeated and prolonged spontaneous bleeding episodes, mainly in muscles and joints, that result in disabling musculoskeletal damage and chronic arthropathy. The aim of prophylaxis in hemophilia is to reduce the risk of bleeding in order to preserve normal musculoskeletal function. Prophylaxis dosing regimens using standard half-life FVIII and FIX products can achieve trough plasma levels of 1-2%,17 but the introduction of extended half-life products significant- ly improves efficacy by achieving higher trough levels. A further improvement due to the forthcoming second-gen- eration extended half-life products and gene therapies might lead to a further increase in the achievement of almost normal trough factor levels. For the time being, with the opportunities provided by the availability of extended half-life products, the aim should be to achieve a minimum trough level of 3-5% in order to preserve joint function.
Recommendation 4
For the post infusion measurement of extended half-life products chromogenic assays should be used.
Hemophilia patients must be monitored by laboratory testing in order to assess the optimal plasma factor levels after concentrate infusion. One-stage clotting or chro- mogenic substrate assays have been used for monitoring post-infusion levels. However, with the introduction of extended half-life products, discrepancies between one- stage and chromogenic assays have been observed. The choice of APTT reagents in the one-stage assays, and par- ticularly the source of the contact activator, can influence
assay sensitivity to the extended half-life products. This may lead to factor levels in patients being under- or over- estimated according to the assay used for monitoring, with a potential negative effect on management. Therefore, experts recommended the adoption of a practi- cal approach of switching from one-stage clotting assays to chromogenic assays.18,19
Recommendation 5
When using non-replacement therapies, for example for patients on emicizumab, some laboratory issues should be considered to correctly measure the procoagulant activity, FVIII levels after infu- sion of FVIII concentrate and in the estimation of FVIII inhibitors.
Novel non-replacement therapies that reduce the effect of natural anticoagulants rather than replace the deficient factor have been developed. One approach is based upon the use of a monoclonal antibody (concizumab) against tissue factor pathway inhibitor (TFPI); another emerging class is based on small interference RNA (siRNA) that reduces antithrombin expression. A different approach is represented by a bispecific antibody (emicizumab) that mimics the co-factor function of FVIII by bridging FIXa and FX. Special consideration should be given to labora- tory monitoring in patients on the aforementioned novel approaches, especially for emicizumab, since this is the first non-replacement drug approved by both European and US medicine regulatory agencies (the EMA and the US Food and Drug Administration) for prophylaxis in adult and pediatric patients with hemophilia A, with and without inhibitors, and is currently used in clinical prac- tice.
Emicizumab does not affect the prothrombin and thrombin time, but tests based on intrinsic coagulation are affected by this drug.19,20 Conventional one-stage clotting assay over-estimates the procoagulant activity of emi- cizumab, so that a modified FVIII one-stage clotting assay should be used to monitor this activity. The chromogenic FVIII assay is sensitive to emicizumab and provides an indirect measure of the procoagulant activity and drug concentration when reagents of human origin are used. However, there is no evidence that the procoagulant activ- ity or emicizumab concentrations are correlated with its hemostatic efficacy when assessed by the chromogenic assay employing human reagents. The measurement of plasma FVIII levels after in vitro addition of FVIII concen- trate and the measurement of anti-FVIII inhibitor titer by the conventional Bethesda method employing human reagents are affected by the drug in treated patients. Therefore, in order to measure post-infusion FVIII levels, and accurately detect the inhibitor titer, a chromogenic assay can be used, but only with reagents of bovine origin that are insensitive to the presence of the drug.19-23
Recommendation 6
The management of patients with hemophilia, particularly those using non-replacement therapies and gene therapies, should be supervised by Comprehensive Care Centres, such as the certified European Haemophilia Comprehensive Care Centres (EHCCC).
Hemophilia patients with and without inhibitors in Europe will be using more and more novel subcutaneous and innovative non-replacement therapies such as emi- cizumab. Hemophilia specialists must manage these patients in comprehensive care centers, particularly in the event of major intercurrent bleeds or surgery, because the physicians involved must have sufficient knowledge of
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haematologica | 2020; 105(8)