Mechanism of activation of coagulation factor XI by factor XIIa studied with monoclonal antibodies.

Abstract

The interaction of Factor XIIa with Factor XI was investigated using two monoclonal antibodies, one (3C1) directed against the heavy chain of Factor Ma and the other (5F4) against its light chain. 3C1 either as intact IgG or as Fab' fragment, enhanced the rate of Factor Ma generation in the fluid phase but inhibited it in the presence of kaolin and high molecular weight (HMW) kininogen. In contrast, the Fab' fragments of 5F4 inhibited only the fluid phase activation and had no effect on the surface-mediated activation. 3C1 was found to block the binding of Factor XI to HMW kininogen, whereas 5F4 did not. We conclude: (a) a domain on the heavy chain region of Factor XI is essential for binding to HMW kininogen and for optimal surface-mediated activation by Factor MIa; and (b) binding of 3C1 to Factor XI changes its conformation rendering it a more favorable substrate for Factor XIIa in the fluid phase.

Factor XI: A Review of Its Biochemistry and Deficiency

“…Factor XI circulates as a zymogen and is nearly totally bound to the general contact procofactor, HMWK 27 (see Table 2). Each of the two heavy chains of Factor XI is bound to a molecule of HMWK 28 at peptide 185-242 of the light chain of HMWK.…”

“…The binding of Factor XI to HMWK greatly enhances the ability of Factor XI to be activated by Factor XIIa. 27 The activated products, Factor XIIa, kallikrein (Ka), and cleaved HMWK in turn activate yet more contact factors, greatly amplifying the signal. 30 From out of this series of reactions, which can best be described as a biochemical scrum, Factor XIa emerges.…”

Short Communication

“…The H-chain bears the high molecular mass kininogen (HK) binding site (Akiyama et al, 1986;van der Graaf et al, 1983;Sinha et al, 1985). Therefore, F.XI circulates in plasma as a complex with HK Thompson etal., 1977), cofactor of intrinsic blood coagulation, like prekallikrein (PK) (Mandleefa/., 1976).…”