Submitted January 3, 2007
Accepted February 19, 2007
The effect of a single nucleotide polymorphism on human 
2-antiplasmin activity
Victoria J Christiansen*, Kenneth W. Jackson, Kyung N. Lee, and Patrick A. McKee
William K. Warren Medical Research Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
* Corresponding author; email: victoria-christiansen{at}ouhsc.edu.
The primary inhibitor of plasmin, 
2-antiplasmin (2AP), is secreted by the liver into plasma with Met as the amino-terminus. During circulation, Met-2AP is cleaved by antiplasmin-cleaving enzyme (APCE) yielding Asn-2AP which is crosslinked into fibrin ~13X faster than Met-2AP. The Met-2AP 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 normal population and its effects on Met-2AP cleavage and fibrinolysis. Genotype frequencies were RR 62.5%, RW 34.0%, and WW 3.5%. The polymorphism related to the percentage of Met-2AP in plasma: WW (56.4%), RW (40.6%) and RR (23.6%). WW plasma tended to have shorter lysis times than RR and RW plasma. APCE cleaved purified Met-2AP(Arg6) ~8-fold faster than Met-2AP(Trp6) which is reflected in Asn-2AP/Met-2AP ratios with time in RR, RW and WW plasmas. Removal of APCE from plasma abrogated cleavage of Met-2AP. We conclude that the Arg6Trp polymorphism is functionally significant as it clearly affects conversion of Met-2AP to Asn-2AP, and thereby, the rate of -2AP incorporation into fibrin. Therefore, the Arg6Trp polymorphism may play a significant role in governing the long-term deposition/removal of intravascular fibrin.
