Inhibition of thrombin-catalyzed activation of fVIII by group D and E mAbs. The activation of full-length fVIII (A1-A2-B/ap-A3-C1-C2) is associated with proteolytic cleavages catalyzed by thrombin. The fastest cleavage occurs at Arg740 in the A1-A2-B heavy chain, producing the A1-A2 fragment and the ap-A2-C1-C2 light chain. Cleavage then occurs at Arg372 or Arg1689. Cleavage at Arg372 is necessary for the development of fIXa cofactor activity of fVIIIa, whereas cleavage at Arg1689 is necessary for the dissociation of fVIII from VWF. Cleavage at Arg740 is not necessary for either fVIIIa formation or the dissociation of fVIII from VWF.