The effect of a single nucleotide polymorphism on human α2-antiplasmin activity

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Abstract
The primary inhibitor of plasmin, α2-antiplasmin (α2AP), is secreted by the liver into plasma with Met as the amino-terminus. During circulation, Met-α2AP is cleaved by antiplasmin-cleaving enzyme (APCE), yielding Asn-α2AP, which is crosslinked into fibrin approximately 13 times faster than Met-α2AP. The Met-α2AP gene codes for either Arg or Trp as the sixth amino acid, with both polymorphic forms found in human plasma samples. We determined the Arg6Trp genotype frequency in a healthy population and its effects on Met-α2AP cleavage and fibrinolysis. Genotype frequencies were RR 62.5%, RW 34.0%, and WW 3.5%. The polymorphism related to the percentage of Met-α2AP in plasma was WW (56.4%), RW (40.6%), and RR (23.6%). WW plasma tended to have shorter lysis times than RR and RW plasmas. APCE cleaved purified Met-α2AP(Arg6) approximately 8-fold faster than Met-α2AP(Trp6), which is reflected in Asn-α2AP/Met-α2AP ratios with time in RR, RW, and WW plasmas. Removal of APCE from plasma abrogated cleavage of Met-α2AP. We conclude that the Arg6Trp polymorphism is functionally significant, as it clearly affects conversion of Met-α2AP to Asn-α2AP, and thereby, the rate of α2AP incorporation into fibrin. Therefore, the Arg6Trp polymorphism may play a significant role in governing the long-term deposition/removal of intravascular fibrin.