Magnetic resonance imaging evidence for subclinical joint bleeding in a Dutch population of people with severe hemophilia on prophylaxis

Leeuwen, Flora H P van; Bergen, Eline P.D. van; Timmer, Merel A.; Vulpen, Lize F D van; Schutgens, Roger E.G.; Jong, Pim A. de; Fischer, Kathelijn; Foppen, Wouter

doi:10.1016/j.jtha.2023.01.035

Cited by 19 publications

(14 citation statements)

References 30 publications

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“…All of these co-morbidities could affect the PK of FVIII and the consequent regimen and effectiveness. In recent years, the level of physical activity with the possibility of subclinical bleeding, as proved by sonography or MRI of joints, in PwHA who reported no bleeding has also been thought to be a determining factor in the pharmacokinetics of FVIII [ 30 , 31 , 32 ]. Searching for predictors of rFVIII-Fc half life may help us to understand which determinants can impact the half life and help physicians make better decisions on both the initiation of regimens and the adjustment of regimens.…”

Section: Discussionmentioning

confidence: 99%

“…There may be other covariates that have not been put into the linear regression analysis. For example, the level of activity with the possibility of subclinical bleeding that we previously mentioned [ 30 , 31 ] and bone biomarkers [ 32 ] may be important predictors of rFVIII-Fc half life that are worthy of further study. That is, the prediction models developed in our study still have room for improvement.…”

Section: Discussionmentioning

confidence: 99%

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Clinical Predictors and Prediction Models for rFVIII-Fc Half Life in Real-World People with Severe Hemophilia A

Chang

Chiou

Weng

et al. 2023

JCM

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The half life of recombinant factor VIII-Fc (rFVIII-Fc) for people with hemophilia A (PwHA) varies greatly. Understanding the factors influencing the variation and assessment of rFVIII-Fc half life is important for personalized treatment. Eighty-five severe-type PwHA with rFVIII-Fc treatment receiving an evaluation of half life by the Web-Accessible Population Pharmacokinetic (PK) Service—Hemophilia during 2019–2021 were retrospectively enrolled. The 50-patient PK profiles before 2021 were used for analysis and developing prediction models of half life, and the 35-patient PK profiles in 2021 were used for external validation. The patients in the development cohort were aged 8–64, with a median rFVIII-Fc half life of 20.75 h (range, 8.25–41.5 h). By multivariate linear regression analysis, we found two, four, and five predictors of rFVIII-Fc half life for the blood groups non-O, O patients, and overall patients, respectively, including VWF:Ag, BMI, VWF:activity/VWF:Ag ratio, body weight, O blood group, inhibitor history, HCV infection, and hematocrit. The three prediction equations of rFVIII-Fc half life (T) were respectively developed as T for non-O group patients = −0.81 + 0.63 × (BMI, kg/m2) + 6.07 × (baseline VWF:Ag, IU/mL), T for O group patients = −0.68 + 13.30 × (baseline VWF:Ag, IU/mL) + 0.27 × (BW, kg) − 1.17 × (BMI, kg/m2) + 16.02 × (VWF:activity/VWF:Ag ratio), and T for overall patients = −1.76 + 7.24 × (baseline VWF:Ag, IU/mL) − 3.84 × (Inhibitor history) + 2.99 × (HCV infection) − 2.83 × (O blood group) + 0.30 × (Hct, %), which explained 51.97%, 75.17%, and 66.38% of the half life variability, respectively. For external validation, there was a significant correlation between the predicted and observed half lives in the validation cohort. The median half life deviation was +1.53 h, +1.28 h, and +1.79 h for the equations of non-O group, O group, and overall group patients, respectively. In total, eight predictors influencing rFVIII-Fc half life were identified. Prediction equations of rFVIII-Fc half life were developed for the non-O and O blood groups and overall PwHA with a good degree of external validation. The equations could be applied to patients aged 8–64 without the need for PK blood sampling and clinically valuable for personalized therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Clinical Predictors and Prediction Models for rFVIII-Fc Half Life in Real-World People with Severe Hemophilia A

Chang

Chiou

Weng

et al. 2023

JCM

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“…1,39 Nonetheless, hemosiderin deposits, whose presence reveal non-optimal disease control in PwH without clinically evident bleeds (i.e., ABR = 0) and asymptomatic joints, are detectable only at MRI evaluations. 41 The need for more sensitive diagnostic tools is of utmost importance given the high efficacy of prophylaxis with EHL replacement therapies and non-replacement therapies to meet the primary original goal of arthropathy prevention but also to favor the accomplishment of the main goal of treatment of a chronic disease which should aim at optimal health and well-being. In fact, the possibility to provide hemostatic protection in the non-hemophilic range has been already advocated as the most desirable outcome to satisfy the need for a hemophilia-free life.…”

Section: New Therapeutic Goals and Related Outcomesmentioning

confidence: 99%

Benefits and risks of non‐factor therapies: Redefining haemophilia treatment goals in the era of new technologies

Mancuso,

Croteau,

Klamroth

2024

Haemophilia

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IntroductionOver the last decades progress in haemophilia treatment has been remarkable and prophylaxis with clotting factor concentrates in haemophilia A and B has been established as the standard of care in individuals with haemophilia and a severe bleeding phenotype. Besides clotting factor products with prolonged half‐life non‐factor therapies were developed which enable prophylaxis via subcutaneous administration. Factor VIIIa mimetics like emicizumab facilitate the coagulation pathway and are used in routine clinical practice for indivdiduals with haemophilia A. Rebalancing therapeutic agents like fitusiran, concizumab, marstacimab and serpin PC block the anticoagulant pathway and clinical trials using these products in individuals with haemophilia A and B are ongoing.Aim and MethodsA narrative review to asess the benefits and risks of non‐factor therapies taking in to account re‐defined haemophilia treatment goals.ResultsProphylaxis for prevention of bleeds using non‐factor products by subcutaneous administration is effective and results in reductions of bleeding episodes in individuals with haemophilia A or B with and without inhibitors. The treatment with emicizumab showed tolerable safety both in clinical trials and long‐term real‐world observations with few thrombotic events. In some clinical trials with rebalancing therapies (fitusiran and concizumab) thrombotic events occurred. Monitoring of the haemostatic function of novel therapies especially with concomitant haemostatic treatment is not yet established.ConclusionWith the advent of novel therapeutic agents including factor concentrates with ultra‐long half‐life and improved FVIIIa mimetics aimed at raising the bar of protection into the non‐hemophilic range redefinition of haemophilia treatment goals is eagerly needed.

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“…Several studies have demonstrated blood-related joint changes in clinically bleed-free joints. [5][6][7][8][9] Moreover, subclinical synovial proliferation on Magnetic Resonance Imaging (MRI) appears to predict an increased risk of joint bleeding over the next 5 years. 10 Subclinical synovial proliferation can imply various pathologic processes.…”

Section: Introductionmentioning

confidence: 99%

“…There is cumulating evidence of subclinical (non‐observed) joint bleeding and inflammation. Several studies have demonstrated blood‐related joint changes in clinically bleed‐free joints 5–9 . Moreover, subclinical synovial proliferation on Magnetic Resonance Imaging (MRI) appears to predict an increased risk of joint bleeding over the next 5 years 10 …”

Section: Introductionmentioning

confidence: 99%

Subclinical synovial proliferation in patients with severe haemophilia A: The value of ultrasound screening and biochemical markers

van Bergen,

van Leeuwen,

Foppen

et al. 2023

Haemophilia

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AimSubclinical bleeding and inflammation play a role in progression of haemophilic arthropathy. Synovial proliferation is predictive of joint bleeding and its early detection may guide treatment changes and prevent arthropathy progression. This study evaluated the prevalence of active and inactive subclinical synovial proliferation and investigated potential biochemical blood/urine markers to identify patients with active subclinical synovial proliferation.MethodsThis cross‐sectional study included patients with severe haemophilia A born 1970–2006 who were evaluated during routine clinic visits. Patients with (a history of) inhibitors or recent joint bleeding were excluded. Elbows, knees and ankles were examined for subclinical synovial proliferation by ultrasound and physical examination. Active synovial proliferation was distinguished from inactive synovial proliferation using predefined criteria. Blood/urine biochemical markers (serum osteopontin, sVCAM‐1, Coll2‐1, COMP, CS846, TIMP, and urinary CTX‐II) were compared individually and as combined indexes between patients with and without active synovial proliferation.ResultsThis cohort consisted of 79 patients with a median age of 31 years (range 16.5–50.8 years) with 62/79 (78%) of the patients using continuous prophylaxis. The annualized joint bleeding rate over the last 5 years was .6 (.2–1.1). Active (17/79, 22%) and inactive subclinical synovial proliferation (17/79, 22%) were both prevalent in this cohort. Biochemical markers were not correlated with active subclinical synovial proliferation.ConclusionSubclinical synovial proliferation, both active and inactive, was prevalent in patients with severe haemophilia A with access to prophylaxis and would be overlooked without routinely performed ultrasounds. Biochemical markers were unable to identify patients with active subclinical synovial proliferation.

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Magnetic resonance imaging evidence for subclinical joint bleeding in a Dutch population of people with severe hemophilia on prophylaxis

Cited by 19 publications

References 30 publications

Clinical Predictors and Prediction Models for rFVIII-Fc Half Life in Real-World People with Severe Hemophilia A

Clinical Predictors and Prediction Models for rFVIII-Fc Half Life in Real-World People with Severe Hemophilia A

Benefits and risks of non‐factor therapies: Redefining haemophilia treatment goals in the era of new technologies

Subclinical synovial proliferation in patients with severe haemophilia A: The value of ultrasound screening and biochemical markers

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