Anti-Tissue Factor Pathway Inhibitor polyclonal antibody

Replacement therapy with missing factor (F) VIII or IX in haemophilia patients for bleed management and preventative treatment or prophylaxis is standard of care. Restoration of thrombin generation through novel mechanisms has become the focus of innovation to overcome limitations imposed by protein replacement therapy. Tissue factor pathway inhibitor (TFPI) is a multivalent Kunitz-type serine protease inhibitor that regulates tissue factor (TF)-induced coagulation through a FXa-dependent feedback inhibition of the TF.FVIIa complex in plasma and on endothelial surfaces. Concizumab is a monoclonal, humanised antibody, specific for the second Kunitz domain of TFPI that binds and inhibits FXa, abolishing the inhibitory effect of TFPI. Concizumab restored thrombin generation in FVIII and FIX deficient plasmas and decreased blood loss in a rabbit haemophilia model. Phase 1 single and multiple dose escalation studies in haemophilia patients demonstrated a dose dependent decrease in TFPI levels and a pro-coagulant effect with increasing d-dimers and prothrombin fragment 1 + 2. A dose dependent increase in peak thrombin and endogenous thrombin potential was observed with values in the normal range when plasma TFPI levels were nearly undetectable. A few haemophilia patients in the highest dose cohorts with complete inhibition of plasma TFPI showed a decreased fibrinogen concentration with normal levels of anti-thrombin and platelets and no evidence of thrombosis. Pharmacokinetic parameters were influenced by binding to the target (TFPI), demonstrating target mediated drug disposition. A trend towards decreasing bleeding tendency was observed and this preventative effect is being studied in Phase 2 studies with additional data gathered to improve our understanding of the therapeutic window and potential for thrombosis.

Tissue factor (TF) pathway inhibitor (TFPI) is an endogenous natural anticoagulant that readily inhibits the extrinsic coagulation initiation complex (TF-FVIIa-Xa) and prothrombinase (FXa, FVa and calcium ions). Alternatively, spliced TFPI isoforms (alpha, beta and delta) are expressed by vascular and extravascular cells and regulate thrombosis and haemostasis, as well as cell signalling functions of TF complexes via protease-activated receptors (PARs). Proteolysis of TFPI plays an important role in regulating physiological roles of the TF pathway in host defense and possibly haemostasis. Elimination of TFPI inhibition has therefore been proposed as an approach to improve haemostasis in haemophilia patients. In this review, we focus on posttranscription and translational modification of TFPI and its function in thrombosis and how pharmacological inhibitors and endogenous proteases interfere with TFPI and alter haemostasis. (C) 2018 Wolters Kluwer Health, Inc. All rights reserved.