The transport of alpha-fibrin monomer as a soluble complex with fibrinogen in the blood, and its rapid endocytic uptake serve as plasminogen-independent processes preventing the deposition of fibrin in the vasculature. Even before fibrin monomer is produced it is preceded by formation of substantial quantities of an intermediate, alpha-profibrin, lacking only one of the two A-fibrinopeptides that are cleaved in fibrin formation. Studies proposed here aim to secure the identification of this intermediate and extend our knowledge of its properties and role in hemostasis. Subsequent aims to clarify the chemical and biologic significance of alpha-profibrin address: 1) the equilibria and structural aspects of its interactions with itself and fibrinogen and fibrin; 2) the kinetics of its formation and transformation to fibrin; and 3) the clearance of alpha-profibrin from the circulation in vivo and uptake by cells in vitro. It is hypothesized that clearance of alpha-profibrin from blood safeguards against production of fibrin monomer, while elevations in plasma levels of alpha-profibrin serve as early harbingers of intravascular coagulation. The new separation methods also allow us to distinguish alpha-profibrin from the fibrinogen dimers in blood, arising from direct crosslinking by tissue transglutaminase in atherosclerotic aortic intima. Thus, virtually all of the principal derivatives of fibrinogen occurring in blood of normal subjects and subjects with vascular disease can be profiled for assessing transitions from prethrombotic to hypercoagulable states, and from early stages of atherosclerosis to its end stages predisposing thrombosis.
