Disclosed is a recombinant FVIII protein comprising: a first polypeptide comprising Formula I: (Al) &mdash； al &mdash； (A2) &mdash； a2 &mdash； [B]； and a second polypeptide comprising Formula II: a3 &mdash； (A3) &mdash； (C1), wherein the first polypeptide and the second polypeptide are fused or exist as a heterodimer, wherein: (a) A1 is an A1 domain of FVIII； (b) A2 is an A2 domain of FVIII； (c) [B] is a B domain of FVIII, a fragment thereof or is deleted； (d) A3 is an A3 domain of FVIII； (e) C1 is a C1 domain of FVIII； and (f) al, a2 and a3 are acidic spacer regions, wherein the Al domain comprises a permissive loop-1 (A1-1) region and a permissive loop-2 (A1-2) region, wherein the A2 domain comprises a permissive loop-1 (A2-1) region and a permissive loop-2 (A2-2) region, wherein the A3 domain comprises a permissive loop-1 (A3-1) region and a permissive loop-2 (A3-2) region, wherein at least one of regions A1-1, A1-2, A2-1, A2-2, A3-1 or A3-2 comprises a heterologous moiety, and wherein the recombinant FVIII protein exhibits procoagulant activity.
