Fibrinogen Bβ Chain Proteolysis by Thrombin and Plasmin - A Regulatory Mechanism in Hemostasis and Thrombosis

Abstract

Thrombin cleaves fibrinogen in two steps producing fibrin I and fibrinopeptide A(FPA) and then fibrin II and fibrinopeptide B(FPB). Plasmin cleaves the Aα chain and the N-terminal Bβ chain to form fragment X. Radioiimminoassay of plasma FPA reflects fibrin I formation. A modified FPB assay detects plasm in-produced Bβ1-42, reflecting fragment X formation. Sequential changes have been studied in saline abortion and in venous thrombosis. Following intra-uterine infusion of hypertonic saline to interrupt pregnancy, FPA levels rose immediately from 1 to 18 pmol/ml in 60 minutes, and after 2 hours began to slowly decline to the baseline level. Bβ1-42 levels rose rapidly after the first hour to reach 67 pmol/ml at 4 hours. Thus fibrin I was formed and then fragment X. In post-surgical patients FPA levels rose and exceeded Bβ1-42 levels for several days preceding thrombosis indicated by 125I-fibrinogen scanning and confirmed by venography. These results suggest that following injury thrombin forms fibrin I. Each fibrin I molecule is then either cleaved by thrombin to form fibrin II or by plasmin to form fragment X. The balance between thrombin and plasmin proteolysis of the N-terminal Bβ chain may be critical. Normally sufficient fibrin II formation occurs for effective hemostasis. Thrombosis occurs with excessive thrombin action and fibrin II formation. Slow thrombin formation as in hemophilia results in preferential formation of fragment X and ineffective hemostasis.