Thrombin generation as objective parameter of treatment response in patients with severe haemophilia A and high‐titre inhibitors

Abstract

In Mexico, 15% of haemophilia A (HA) patients develop inhibitory alloantibodies in response to replacement therapy with factor VIII (FVIII), requiring bypass therapy such as activated prothrombin complex concentrate (APCC). Because bypass therapy has not been broadly available in Mexico even in recent years, this study aimed to evaluate the thrombin generation assay (TGA) in assessing the response to FVIII or APCC treatment in patients with severe HA positive to inhibitors. We studied 189 patients with severe HA. Clinical severity was verified by one-stage APTT-based clotting assay. Inhibitors to FVIII were investigated by the Nijmegen-Bethesda (N-B) method, and type of inhibition was assessed through serial plasma dilutions. Thrombin generation was measured with the calibrated automated thrombogram in inhibitor-positive plasmas previously spiked and incubated with FVIII or APCC. Data were analysed using anova, Student or Fisher's exact tests. We detected 47 (24.9%) subjects with high-titre (5-1700 N-B U mL(-1)) and 25 (13.2%) subjects with low-titre inhibitor antibodies (0.6-4.7 N-B U mL(-1)). We found an association between kinetic behaviour and clinical response to FVIII (P = 0.0049) or vs. FVIII response evaluated with TGA (P = 0.0007). Global concordance between clinical and in vitro response was 70%. By evaluating the capacity of thrombin formation in a plasma sample, TGA predicts the response to FVIII or APCC therapy and allows individual optimization of resources in patients with severe HA and high-titre inhibitors. The inhibition pattern of the antibodies to FVIII:C correlated with the TGA parameters and showed an association with the clinical response to FVIII.

Molecular characteristics of polysulfated fractions from the green seaweed <i>Caulerpa cupressoides</i> and actions on thrombin generation <i>in vitro

“…However, the physical-chemical and structural features of its SPs have been still poorly investigated regarding their impacts on the haemostatic system. Activated partial thromboplastin time (APTT) test is one of the most used to detect anticoagulant SPs (Shanmugam et al, 2001;Athukorala et al, 2006;Pomin & Mourão, 2008;Pomin, 2012;Fidelis et al, 2014;Mourão, 2015), but contradictions related to the restrict value on the total amount of thrombin formed have currently encouraged the use of thrombin generation (TG) assays as more sensitive tools to analyze the haemostatic status than the APTT method, on a significant prognostic view (Castoldi & Rosing, 2011;Luna-Záizar et al, 2014;Jun et al, 2014). TG-based coagulation tests would offer relevant information of plasma alternative anticoagulants to HEP in prevention of thrombosis in vitro (Nishino, Fukuda, Nagumo, Fujihara, & Kaji, 1999;Glauser et al, 2009;Rodrigues et al, 2016;Salles et al, 2017) or predicting hypercoagulability (Zhang et al, 2014;Barcellos et al, 2018).…”

Monitoring once‐weekly recombinant factor IX prophylaxis in hemophilia B with thrombin generation assay and factor IX activity

“…Enhanced TG compared with baseline was detected in all patients at trough 7 days after infusion, even when FIX activity had fallen to 1–5 IU/dL. Previous TG data with treatment outcome are limited, although some studies even prefer TG over other methods . TG assay has been suggested as a standard in the future with EHL products; thus, our study provides a comparator from the traditional rFIX at a high weekly dose.…”

Over two decades of orthopaedic surgery in patients with inhibitors—Quantifying the complication of bleeding

“…Mancuso et al present their observations around major orthopaedic surgery with the aim of advancing the monitoring of clinical efficacy of bypassing agents. Following on from some evidence in in vitro with inconsistent ex vivo studies, Mancuso et al conclude that thrombin generation assay (TGA) fails as a reliable laboratory tool to monitor haemostatic efficacy and as a predictor of the risk of bleeding in inhibitor patients undergoing orthopaedic surgery. With regards to surgical haemostasis, they report seven bleeding complications in six patients, defining haemostasis as excellent to good in 4 procedures; and fair to poor in 7.…”