Thrombin Activable Fibrinolysis Inhibitor (TAFI): Molecular Genetics of an Emerging Potential Risk Factor for Thrombotic Disorders

M.   B.   Boffa; M.   E.   Nesheim; M.   L.   Koschinsky

Abstract

The balance between the activities of the coagulation and fibrinolytic cascades is crucial for normal hemostasis. However, imbalances can lead to pathological thrombotic events, as is observed in heart attacks and strokes, as well as excessive bleeding, as in hemophilia. Recent investigations have uncovered a novel molecular connection between the two cascades that has been termed thrombin-activable fibrinolysis inhibitor (TAFI) as well as procarboxypeptidase U, procarboxypeptidase R or plasma procarboxypeptidase B. TAFI is the precursor of an enzyme (TAFIa) with basic carboxypeptidase activity that attenuates the lysis of fibrin clots by removal of the carboxyl-terminal lysine residues from partially-degraded fibrin that mediate positive feedback in the fibrinolytic cascade. The plasma concentration of TAFI varies substantially (up to ˜10-fold) in the human population and may constitute a novel risk factor for thrombotic disorders. Sixteen single nucleotide polymorphisms have been identified i n the 5-flanking, protein coding, and 3-untranslated regions of the TAFI gene. The polymorphisms all have been shown to be associated with variations in plasma TAFI concentrations. One amino acid substitution has been found to directly alter the properties of the TAFIa enzyme. This review provides a general overview of the TAFI pathway, including a discussion of the spectrum of inhibitors of TAFIa that have been described, and summarizes the recent advances in the molecular genetics of the TAFI gene as well as the results of studies that may implicate the TAFI pathway in risk for arterial and venous thrombotic disorders.

Keywords: Thrombin Activable, Fibrinolysis Inhibitor (TAFI), activated protein C (APC), INHIBITORS, HUMAN TAFI GENE, THROMBOTIC DISORDERS, (Pro)carboxypeptidase R, Leech carboxypeptidase inhibitor, Plasminogen activator inhibitor, Reverse transcriptase-polymerase chain, Urokinase-type plasminogen activator