Pharmacodynamic monitoring of factor VIII replacement therapy in hemophilia A: Combining thrombin and plasmin generation

Valke, L. L. F. G.; Bukkems, Laura H.; Barteling, Wideke; Gorkom, Britta A P Laros-van; Blijlevens, Nicole M A; Mathôt, Ron A. A.; Schols, Saskia E. M.

doi:10.1111/jth.15106

Cited by 16 publications

(25 citation statements)

References 45 publications

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“…6 Interestingly, the current study found that duration of ITI was 1year or less in nine patients (45%), indicating early tolerization in those patients. Likewise, the median time to achieve negative inhibitor titre, 12 (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22) months, was shorter than the time reported in comparable high-risk cohort studies 11,28 and similar to those patients receiving a low dose regimen, 9.2 (4.9-17) months. 6 As previously suggested, this rapid time to tolerization may reduce healthcare resource utilization and the costs associated with ITI.…”

Section: Discussionmentioning

confidence: 69%

“…FVIII inhibitor assay was carried out according to a Nijmegen modification of the Bethesda assay 7 . FVIII recovery was determined by measuring FVIII plasma levels by a standard method 22,23 . Once the inhibitor clearance was reached, patients were monitored for FVIII recovery 3 months after the end of ITI therapy.…”

Section: Methodsmentioning

confidence: 99%

“…Twenty patients with median (range) age of 6.2 (3-12) years and pre-ITI inhibitor titre of 36.5 (12-169) BU were enrolled and followed-up for a median of 12 (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22) months. All patients had severe HA (FVIII levels < 1 IU/dl).…”

Section: Baseline Patient Characteristics and Disease Activitymentioning

confidence: 99%

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Low‐dose immune tolerance induction therapy in children of Arab descent with severe haemophilia A, high inhibitor titres and poor prognostic factors for immune tolerance induction treatment success

et al. 2021

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Introduction Immune Tolerance Induction (ITI) is the first‐choice therapy to eradicate Factor VIII (FVIII) neutralizing antibodies in patients with haemophilia A (HA). There is limited published data on ITI from East Mediterranean countries. Aim To assess the effectiveness of a low‐dose ITI regimen to eradicate FVIII neutralizing antibodies in children with severe HA and high‐titre inhibitors. Methods A prospective, single‐arm study was conducted in children with HA (FVIII < 1 IU/dl), high‐titre inhibitors and poor prognostic factors for successful ITI. Patients were treated with ∼50 IU/kg plasma‐derived FVIII containing von Willebrand factor (pdFVIII/VWF) concentrate (Koate‐DVI, Grifols) three times a week. Time to achieve tolerance, total and partial success were analysed after ITI. Annual bleeding rate (ABR), number of target joints, FVIII recovery and school absence were compared before and after ITI. Results Twenty patients with median (range) age of 6.2 (3–12) years and pre‐ITI inhibitor titre of 36.5 (12–169) BU were enrolled. ITI lasted ≤12 months (early tolerization) in 45% of patients. Median follow‐up was 12 months (3–22) and total response rate was 80% (60% total success; 20% partial success). Patients with two and three poor prognosis factors achieved overall success rate of 60% and 50%, respectively. ABR, target joints and school absence were reduced after ITI by 60%, 50% and 44.1%, respectively. In successful ITI tolerized patients, FVIII recovery was 90 (60–100)%. Conclusion A low‐dose ITI therapy using a pdFVIII/VWF concentrate achieved at least partial tolerance in 80% of patients, and reduced annual bleeds in children with high inhibitor titres and at least one poor prognosis factor for ITI treatment success.

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Section: Discussionmentioning

confidence: 69%

Section: Methodsmentioning

confidence: 99%

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Low‐dose immune tolerance induction therapy in children of Arab descent with severe haemophilia A, high inhibitor titres and poor prognostic factors for immune tolerance induction treatment success

et al. 2021

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“…Van Geffen et al used the NHA assay to study patients with deficiencies of plasminogen and PAI-1, and distinct abnormalities in both PG and TG were found [ 92 ]. The same assay was used to study PG in hemophilia A patients before and after administration of a single dose of 25–50 IU/kg standard half-life factor VIII concentrate [ 93 ]. Patients with severe hemophilia A have higher plasmin production than patients with mild hemophilia or healthy controls, but hyperfibrinolysis observed in these patients is normalized after factor VIII supplementation.…”

Section: Plasmin Generation In Health and Diseasementioning

confidence: 99%

“…Based on the already published studies, PG assays have promising clinical and research potential, in monitoring antifibrinolytic medications, screening for genetic or acquired fibrinolytic disorders, or evaluating changes in fibrinolytic system due to abnormalities in the levels of fibrinolytic factors, both in human and mouse plasmas [ 44 , 81 , 85 , 88 , 92 , 93 , 94 , 95 , 144 ]. Measurement of these changes may better reflect the hemostatic phenotype compared to routine tests (such as D-dimer, PAI-1, PAP complexes and tPA levels, or turbidity, ROTEM and TEG).…”

Section: Summary and Future Directionsmentioning

confidence: 99%

Assessing Plasmin Generation in Health and Disease

Miszta

Huskens

Donkervoort

et al. 2021

IJMS

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Fibrinolysis is an important process in hemostasis responsible for dissolving the clot during wound healing. Plasmin is a central enzyme in this process via its capacity to cleave fibrin. The kinetics of plasmin generation (PG) and inhibition during fibrinolysis have been poorly understood until the recent development of assays to quantify these metrics. The assessment of plasmin kinetics allows for the identification of fibrinolytic dysfunction and better understanding of the relationships between abnormal fibrin dissolution and disease pathogenesis. Additionally, direct measurement of the inhibition of PG by antifibrinolytic medications, such as tranexamic acid, can be a useful tool to assess the risks and effectiveness of antifibrinolytic therapy in hemorrhagic diseases. This review provides an overview of available PG assays to directly measure the kinetics of plasmin formation and inhibition in human and mouse plasmas and focuses on their applications in defining the role of plasmin in diseases, including angioedema, hemophilia, rare bleeding disorders, COVID-19, or diet-induced obesity. Moreover, this review introduces the PG assay as a promising clinical and research method to monitor antifibrinolytic medications and screen for genetic or acquired fibrinolytic disorders.

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Pharmacokinetic–Pharmacodynamic Modelling in Hemophilia A: Relating Thrombin and Plasmin Generation to Factor VIII Activity After Administration of a VWF/FVIII Concentrate

Valke,

Cloesmeijer,

Mansouritorghabeh

et al. 2024

Eur J Drug Metab Pharmacokinet

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Pharmacodynamic monitoring of factor VIII replacement therapy in hemophilia A: Combining thrombin and plasmin generation

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 16 publications

References 45 publications

Low‐dose immune tolerance induction therapy in children of Arab descent with severe haemophilia A, high inhibitor titres and poor prognostic factors for immune tolerance induction treatment success

Low‐dose immune tolerance induction therapy in children of Arab descent with severe haemophilia A, high inhibitor titres and poor prognostic factors for immune tolerance induction treatment success

Assessing Plasmin Generation in Health and Disease

Pharmacokinetic–Pharmacodynamic Modelling in Hemophilia A: Relating Thrombin and Plasmin Generation to Factor VIII Activity After Administration of a VWF/FVIII Concentrate

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