Dataset Information

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

ABSTRACT:

Background

Clinical severity of hemophilia A (HA) varies, possibly due to interplay of many factors in the hemostatic pathway. Pharmacokinetic monitoring of factor VIII (FVIII) replacement therapy in HA patients consists of measuring FVIII activity levels and subsequent dose adjustment. The Nijmegen Hemostasis Assay (NHA) measures thrombin generation (TG) and plasmin generation (PG).

Objective

To determine differences in TG and PG between HA patients before and during a pharmacokinetic study and identify best parameters to develop a pharmacodynamic model.

Methods

Twenty-five HA patients (baseline FVIII < 1-9 IU/dL) underwent a pharmacokinetic study with a single dose of 25-50 IU/kg standard half-life FVIII concentrate. At baseline and after administration of FVIII TG and PG parameters were measured with the NHA.

Results

FVIII activity level increased from median 1.0 IU/dL (interquartile range < 1.0-6.0) to 71 IU/dL (62-82) 15 minutes after administration and decreased to 15 IU/dL (10-26) at 24 hours. TG was enhanced simultaneously, with thrombin peak height (TPH) increasing from 22nM (15-35) to 222nM (159-255), and thrombin potential (TP) from 404nM/min (undetectable-876) to 1834nM/min (1546-2353). Twenty-four hours after infusion, TG parameters remained high (TPH 73nM [58.5-126.3]; TP 1394nM/min [1066-1677]) compared to FVIII activity level. PG showed hyperfibrinolysis in severe HA patients compared to mild patients and controls, which normalized after FVIII supplementation.

Conclusion

HA patients showed clear differences in baseline TG and PG despite having comparable FVIII activity levels. These results reveal a discrepancy between FVIII activity level and TG, in which the latter may be a better parameter to monitor individualized treatment in HA patients.

SUBMITTER: Valke LLFG

PROVIDER: S-EPMC7756259 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Publications

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

Valke Lars L F G LLFG Bukkems Laura H LH Barteling Wideke W Laros-van Gorkom Britta A P BAP Blijlevens Nicole M A NMA Mathôt Ron A A RAA van Heerde Waander L WL Schols Saskia E M SEM

Journal of thrombosis and haemostasis : JTH 20201021 12

<h4>Background</h4>Clinical severity of hemophilia A (HA) varies, possibly due to interplay of many factors in the hemostatic pathway. Pharmacokinetic monitoring of factor VIII (FVIII) replacement therapy in HA patients consists of measuring FVIII activity levels and subsequent dose adjustment. The Nijmegen Hemostasis Assay (NHA) measures thrombin generation (TG) and plasmin generation (PG).<h4>Objective</h4>To determine differences in TG and PG between HA patients before and during a pharmacoki ...[more]

PMID: 32979031

Similar Datasets

Project description:Development of inhibitory antibodies to coagulation factor VIII (fVIII) is the primary obstacle to the treatment of hemophilia A in the developed world. This adverse reaction occurs in 20-30% of persons with severe hemophilia A treated with fVIII-replacement products and is characterized by the development of a humoral and neutralizing immune response to fVIII. Patients with inhibitory anti-fVIII antibodies are treated with bypassing agents including recombinant factor VIIa (rfVIIa). However, some patients display poor hemostatic response to bypass therapy and improved treatment options are needed. Recently, we demonstrated that fVIII inhibitors display widely variable kinetics of inhibition that correlate with their respective target epitopes. Thus, it was hypothesized that for antibodies that display slow rates of inhibition, supplementation of rfVIIa with fVIII would result in improved thrombin generation and be predictive of clinical responses to this novel treatment regimen. In order to test this hypothesis, 10 murine monoclonal antibodies (MAbs) with non-overlapping epitopes spanning fVIII, differential inhibition titers, and inhibition kinetics were studied using a thrombin generation assay. Of the 3 MAbs with high inhibitory titers, only the one with fast and complete (classically defined as "type I") kinetics displayed significant inhibition of thrombin generation with no improvement upon supplementation of rfVIIa with fVIII. The other two MAbs that displayed incomplete (classically defined as "type II") inhibition did not suppress the potentiation of thrombin generation by fVIII. All antibodies that did not completely inhibit fVIII activity demonstrated potentiation of thrombin generation by the addition of fVIII as compared to rfVIIa alone. In conclusion, fVIII alone or in combination with rfVIIa corrects the thrombin generation defect produced by the majority of anti-fVIII MAbs better than single agent rfVIIa. Therefore, combined fVIII/rfVIIa therapy may provide better hemostatic control than current therapy in some patients with anti-fVIII inhibitors.

Dataset Information

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

Background

Objective

Methods

Results

Conclusion

Publications

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

Similar Datasets

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