The thrombin generation assay distinguishes inhibitor from non‐inhibitor patients with severe haemophilia A

Mancuso, Maria Elisa; Chantarangkul, Veena; Clerici, Marigrazia; Fasulo, Maria Rosaria; Padovan, Lidia; Scalambrino, Erica; Peyvandi, Flora; Tripodi, Armando; Santagostino, Elena

doi:10.1111/hae.12927

Cited by 7 publications

(3 citation statements)

References 12 publications

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“…Interestingly, this effect was only seen when emicizumab was present; little difference was seen in TG between HA and HAI plasma when eptacog beta alone was present. It has been reported that TG parameters are reduced in haemophilia plasma containing inhibitors and that this effect is enhanced at low TF concentrations 19,20 …”

Section: Discussionmentioning

confidence: 99%

Exploratory in vitro evaluation of thrombin generation of eptacog beta (recombinant human fviia) and emicizumab in congenital haemophilia A plasma

et al. 2021

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Introduction/Aim Eptacog beta is a recombinant activated human factor VII approved to treat and control bleeding in haemophilia A and B patients with inhibitors. Emicizumab is a factor VIIIa mimetic antibody approved for prophylactic treatment of haemophilia A with and without inhibitors (HAI and HA, respectively). Inhibitor patients treated with emicizumab should expect breakthrough bleeding that requires bypassing agent treatment to restore haemostasis. The aim of this study is to quantify the in vitro thrombin generation induced by the addition of eptacog beta to HAI and HA plasma containing emicizumab. Methods Thrombin generation assays were performed using HAI and HA plasma. Thrombin generation parameters were examined using a fixed effects model with inhibitor titre, eptacog beta concentration and emicizumab concentration as main effects, and eptacog beta concentration with inhibitor and emicizumab concentration with inhibitor as interaction effects. Results A significant increase in peak thrombin, ETP and velocity was observed when combinations of eptacog beta (0, 1, 2 or 5 µg/ml) and emicizumab (0, 50 or 100 µg/ml) were evaluated in HA and HAI plasma; the effect remained below that observed in Normal Plasma (NP). A small shortening of lag time below that of NP was observed. Conclusions Eptacog beta and emicizumab induced thrombin generation in haemophilia A plasma (with and without inhibitors) with the thrombin generation parameters remaining below those of normal plasma. These data provide in vitro proof of concept supporting the concept of use of eptacog beta for the treatment and control of breakthrough bleeding in patients on emicizumab prophylaxis.

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Section: Discussionmentioning

confidence: 99%

Exploratory in vitro evaluation of thrombin generation of eptacog beta (recombinant human fviia) and emicizumab in congenital haemophilia A plasma

et al. 2021

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“…Another study investigated the relationship between FVIII activity level, genetic variations and inhibitor status. Patients with an inhibitor, a neutralizing antibody against FVIII making replacement therapy ineffective, showed decreased thrombin generation capacity compared to patients without inhibitors, despite equal FVIII activity levels ( 47 ). Thereby it can be concluded that TGAs can play a role in unraveling the clinical bleeding phenotype of hemophilia patients and even may play a role in how to treat these patients.…”

Section: Bleeding Disordersmentioning

confidence: 99%

Thrombin generation assays to personalize treatment in bleeding and thrombotic diseases

Valke

Rijpma

Meijer

et al. 2022

Front. Cardiovasc. Med.

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Treatment of bleeding and thrombotic disorders is highly standardized and based on evidence-based medicine guidelines. These evidence-based treatment schemes are well accepted but may lead to either insufficient treatment or over-dosing, because the individuals’ hemostatic properties are not taken into account. This can potentially introduce bleeding or thrombotic complications in individual patients. With the incorporation of pharmacokinetic (PK) and pharmacodynamic (PK-PD) parameters, based on global assays such as thrombin generation assays (TGAs), a more personalized approach can be applied to treat either bleeding or thrombotic disorders. In this review, we will discuss the recent literature about the technical aspects of TGAs and the relation to diagnosis and management of bleeding and thrombotic disorders. In patients with bleeding disorders, such as hemophilia A or factor VII deficiency, TGAs can be used to identify patients with a more severe bleeding phenotype and also in the management with non-replacement therapy and/or bypassing therapy. These assays have also a role in patients with venous thrombo-embolism, but the usage of TGAs in patients with arterial thrombosis is less clear. However, there is a potential role for TGAs in the monitoring of (long-term) antithrombotic therapy, for example with the use of direct oral anticoagulants. Finally this review will discuss controversies, limitations and knowledge gaps in relation to the introduction of TGAs to personalize medicine in daily medical practice.

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“…67 The ETP, a key parameter of TG, is derived from the end amount of free thrombin produced and incorporates all phases from activation to final endpoint. 68 In recent years, TG testing has increasingly been transformed from a research-only tool to a useful and sensitive assay for clinical use for hemophilias, 69,70 and with the ETP identified to have predictive value for the development of recurrent VTE. [71][72][73][74] TG might be an assay of particular importance in APS, as it has been shown to be informative in regard to APS status and identification of LA.…”

Section: Anecdotal Clinical Reports and Case Series On Direct Oral Anmentioning

confidence: 99%

Direct Oral Anticoagulants for Thromboprophylaxis in Patients with Antiphospholipid Syndrome

Cohen

Efthymiou

Gates

et al. 2017

Semin Thromb Hemost

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The current mainstay of the treatment and secondary thromboprophylaxis of thrombotic antiphospholipid syndrome (APS) is anticoagulation with warfarin or other vitamin K antagonists (VKAs). In addition to their well-known limitations, VKAs are often problematic in APS patients because of the variable sensitivity of thromboplastins to lupus anticoagulant. As a result, the international normalized ratio may not accurately reflect the intensity of anticoagulation. Direct oral anticoagulants (DOACs) are established as therapeutic alternatives to VKAs for a wide range of indications, including the treatment and secondary prevention of venous thromboembolism. Definition of the role of DOACs in the treatment of thrombotic APS is emerging with the results of recent and ongoing clinical studies. This review focuses on the current situation with regard to DOACs for secondary thromboprophylaxis in APS and issues pertinent to DOAC use in APS patients, as well as potential future directions.

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The thrombin generation assay distinguishes inhibitor from non‐inhibitor patients with severe haemophilia A

Abstract: This study shows a greater TG impairment in inhibitor patients irrespective of FVIII levels, inhibitor titre and F8 mutation type, suggesting a role for the TGA in unravelling functional interferences of anti-FVIII inhibitors on coagulation system activation.

Cited by 7 publications

References 12 publications

Exploratory in vitro evaluation of thrombin generation of eptacog beta (recombinant human fviia) and emicizumab in congenital haemophilia A plasma

Exploratory in vitro evaluation of thrombin generation of eptacog beta (recombinant human fviia) and emicizumab in congenital haemophilia A plasma

Thrombin generation assays to personalize treatment in bleeding and thrombotic diseases

Direct Oral Anticoagulants for Thromboprophylaxis in Patients with Antiphospholipid Syndrome

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