In vitro data suggest that, in haemophilia patients with inhibitors, the thrombin generation Selleckchem INCB018424 assay offers opportunity to monitor response to treatment regimens with bypassing agents and to assess the coagulation profile during ITI therapy and/or during high-dose FVIII replacement therapy. The Predict TGA Study is exploring this possibility clinically by correlating thrombin generation assay results with clinical data collected prospectively over 12 months in patients with severe haemophilia A receiving ITI or high-dose FVIII replacement therapy. Early in
vitro results suggest that the velocity index parameter of the thrombin generation assay curve has the greatest degree of sensitivity in terms of distinguishing among FVIII concentrates. K. PRATT E-mail: [email protected] The opinions or assertions contained herein are Proteases inhibitor the private ones of the author and are not to be construed as official or reflecting the views of the Department of Defense or the Uniformed Services University of the Health Sciences. Many patients with haemophilia A achieve adequate haemostasis by infusion of FVIII. However, approximately one-quarter of patients, and up to 50% of African American and Hispanic patients, develop anti-FVIII antibodies (‘inhibitors’)
which bind to surfaces on FVIII and neutralize its procoagulant activity. Inhibitors are the most serious and costly complication of FVIII replacement therapy. Inhibitors are treated by ITI therapy in which
intensive FVIII is administered Demeclocycline until alloantibody titres subside. Response to ITI therapy is highly variable and a considerable proportion of patients fail treatment. Conversely, it is surprising that so many patients tolerate intravenous infusion of FVIII as it is, in essence, a ‘foreign’ protein. Explanations for this intriguing clinical observation continue to be sought at the basic science level. The production of inhibitory antibodies is driven by T cells, but several steps are required before a neutralizing antibody response can occur (Fig. 5) [27, 28]. Infused FVIII, if recognized by an antigen presenting cell (APC), is taken up inside the cell where it is processed and cleaved into peptides. One or more of these FVIII-derived peptides must then be recognized by major histocompatibility complex (MHC) class II molecules and transported to the surface of the APC. The next requirement is that the MHC class II-peptide complex be recognized by a T-cell receptor on a helper T cell. An effective complex formation between the APC, peptide and T-cell receptor leads to stimulation and proliferation of helper T cells which secrete cytokines, promoting B cell activation. Peptide sequences that mediate a sustained association between APCs and T cells through the formation of the class II-peptide-T-cell receptor complex are termed ‘T-cell epitopes’ [27].
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