Influence of anti-C1 domain antibodies on fVIII functional and clearance pathways. (A) The C1 and C2 domains of fVIII mediate interaction with VWF as it circulates in plasma, as well as binding to phosphatidylserine (PS)-rich membranes and activated platelets. Antibodies can interfere with each of these C2 domain interactions. This report describes anti-C1 antibodies that enhance clearance of fVIII through inhibition of binding to VWF. (B) The C1 domain epitopes in the context of fVIII. The surface amino acids that comprise the dominant C1 domain epitope, group A, are colored cyan and lie adjacent to previously identified residues of the C1 domain that participate in phospholipid binding (blue) and just below a poorly defined epitope that was previously identified (yellow). It is at a distance from membrane-interactive residues of the C2 domain (also blue). The second C1 epitope, group AB, is colored green and overlaps with previously identified membrane-interactive residues. Professional illustration by Somersault18:24.