FEIBA^®: mode of action

Abstract

FEIBA (factor eight inhibitor bypassing activity) has a history of more than 30 years of successful use in controlling bleeding in haemophilic patients who have developed inhibitory antibodies against factor (F)VIII or FIX. Recently it was shown that FEIBA contains the proenzymes of the prothrombin complex factors, prothrombin, FVII, FIX and FX, but only very small amounts of their activation products, with the exception of FVIIa, which is contained in FEIBA in greater amounts. FEIBA controls bleeding by induction and facilitation of thrombin generation, a process for which FV is crucial. A number of biochemical in vitro and in vivo studies have shown that FXa and prothrombin play a critical role in the activity of FEIBA. Consequently, they are considered to be key components of this product. The prothrombinase complex has been found to be a major target site for FEIBA. Apart from prothrombin and FXa, FEIBA contains other proteins of the prothrombin complex, which could also facilitate haemostasis in haemophilia patients with inhibitors.

Zymogen-like factor Xa variants restore thrombin generation and effectively bypass the intrinsic pathway in vitro

“…14 Protein-based products that bypass the intrinsic pathway, such as FVIII bypassing agents (eg, activated prothrombin complex concentrates) and recombinant FVIIa, are effective in treating these patients. 15,16 These products reconstitute thrombin generation by enhancing cell-surface FXa production and ultimately prothrombinase levels. 43,45 However, their short half-lives, effective dose range, cost, and potential for thrombotic complications indicates that other approaches that enhance thrombin generation should be explored.…”

“…It is the principal physiological substrate for the extrinsic (tissue factor [TF]/FVIIa) and intrinsic (FVIIIa/FIXa) tenase complexes, thus linking these 2 pathways. 1 These enzymes cleave FX at a conserved site (between Arg 15 and Ile 16 ; chymotrypsin numbering 2 ), thereby liberating an activation peptide and a new N-terminus (Ile 16 -Val-Gly-Gly.). The ␣-amino group from Ile 16 in the heavy chain forms a salt bridge with Asp 194 , which drives a conformational change that leads to maturation of the catalytic domain and imparts function.…”

“…1 These enzymes cleave FX at a conserved site (between Arg 15 and Ile 16 ; chymotrypsin numbering 2 ), thereby liberating an activation peptide and a new N-terminus (Ile 16 -Val-Gly-Gly.). The ␣-amino group from Ile 16 in the heavy chain forms a salt bridge with Asp 194 , which drives a conformational change that leads to maturation of the catalytic domain and imparts function. 3,4 For FX/FXa, the zymogen to protease transition not only drives catalytic site activation but also contributes to the formation of the FVa binding site.…”

“…14 This has prompted the development of bypass strategies that use other coagulation factors to restore hemostasis in these patients, including recombinant FVIIa and activated prothrombin complex concentrates, which contains a mixture of prothrombin complex zymogens and their activation products. 15,16 Although effective in most cases, their efficacy can vary, and in some circumstances these products can increase the morbidity of the disease. 17,18 Furthermore, these products are costly, and some are derived from plasma with risk of blood borne disease.…”

Prothrombin Time Tests for the Monitoring of Direct Oral Anticoagulants and Their Evaluation as Indicators of the Reversal Effect

“…29,30 Prothrombin complex concentrate contains inactive factors II, IX, X, and VIIa, and aPCC contains activated factor VII and factors II, IX, and X. 8 The American Heart Association guidelines recommended the use of PCC or aPCC as a potential reversal agent. 7 In the present study, the PT measured with Triniclot decreased dose dependently from a PCC dose of 0.63 to 1.25 U/mL, and then the PT started to prolong when the PCC dose was over 2.5 U/mL.…”