Fibrin precursors, intermediaries for hemostasis in the clot war

Abstract

Man arises from a clot (The Quaran, Chap. 96 “The Clot”). Clots are essential for birth and for prevention of bleeding throughout life, but are the usual terminal events in life. It has for long been the working paradigm in thrombosis research that hemostasis depends critically on the balance between clot formation and clot dissolution. A balance of these two forces requires a great deal of juggling. Homeostasis in the coagulation mechanism involves complex interplay of numerous processes to modulate the conversion of fibrinogen to a fibrin clot [1,2], and the interplay in fibrinolysis is just as intriguingly numerous [3]. The purpose of this communication is to present a new perspective on the “clot war,” namely that the fibrin monomers, which are the building blocks of clots, are normally disposed-of before they assemble into a clot [4–6], a process that precedes the need for clot lysis. Although this hypothesis had been suggested long ago based on considerations of the fate of soluble fibrin monomer complexes in the generalized Shwartzman reaction (GSR) [5,7], it has been given a lot more credence by the recent studies on knockout mice with defective fibrinolysis [3,8–11]. From those studies, Carmeliet [11] noted that plasminogen-independent mechanisms are involved in normal clot surveillance and the role of the fibrinolytic system becomes evident principally following inflammatory or traumatic challenges. Apart from fibrinolysis, fibrin deposits can be cleared by macrophages and neutrophils [12–14], but again, these clearance mechanisms presuppose fibrin deposition.