Fibrinogen and Fibrin in Hemostasis and Thrombosis

Abstract

Despite its recognition as a key component of blood clots, the roles of fibrinogen and fibrin (collectively fibrin[ogen]) in hemostasis and thrombosis are insufficiently understood. Consequently, fibrin(ogen) remains an active focus of investigation at all levels of the research spectrum, including fundamental basic/discovery science, epidemiology, and clinical practice and applications. This article briefly reviews basic biology and biochemistry of fibrinogen and fibrin formation, structure, and stability and highlights recent studies published in Arteriosclerosis, Thrombosis, and Vascular Biology and elsewhere. These have enhanced our understanding of fibrin(ogen) and revealed new potential applications for fibrin detection in thrombosis. The fibrinogen molecule is a 340-kDa homodimeric glycoprotein consisting of 2Aα, 2Bβ, and 2γ polypeptide chains linked by 29 disulfide bridges. Fibrinogen synthesis occurs primarily in hepatocytes (Figure 1). Assembly of the 6 chains takes place in a stepwise manner in which single chains assemble first into Aα-γ and Bβ-γ complexes, then into Aα/Bβ/γ half-molecules, and finally into hexameric complexes (Aα/Bβ/γ)2.1 All 6 fibrinogen chains are assembled with their N termini located in a central E nodule and extend outward in a coiled-coil arrangement. The Bβ and γ chains terminate in globular regions known as βC and γC modules, respectively. These regions collectively comprise the so-called D nodule. The Aα chains are the longest; at the end of the coiled-coil region, each chain extends into a highly flexible series of repeats followed by a globular αC region. Using high-resolution atomic force microscopy, Protopopova et al2 obtained striking images of fibrinogen that visualize each of these structural components. Figure 1. Fibrinogen synthesis and expression. Fibrinogen synthesis is regulated by both transcriptional and translational mechanisms. After individual fibrinogen chains are translated, fibrinogen assembly occurs stepwise. Single chains assemble first into Aα-γ and Bβ-γ precursors, then into Aα/Bβ/γ half-molecules, and finally into hexameric complexes (Aα/Bβ/γ) …