Mammalian VWF and FVIII evolved under analogous selective pressure. Temporal emergence of unique amino acid substitutions diverging from the common ancestral sequence An63 are shown for primate (A), ungulate (B), and rodent (C) lineages. The number of unique residue differences is shown as the percentage of all amino acids. Total accumulation of mutations within specific subdomains of VWF (D) or FVIII (E) is shown as percent non-human relative to the size of each domain across primate evolution. Human VWF and FVIII define 0% nonidentity. (F) The number of amino acid substitutions within FVIII light chain or VWF D′D3 domains is shown for the primate lineage. mya, million years ago.