The role of collagen in thrombosis and hemostasis

Collagens represent up to 40% of the total protein of the vessel wall, forming an insoluble scaffold which is essential for tissue integrity and which provides a surface for the attachment of other matrix constituents and for the adhesion of vascular cells. Thus collagens exercise important regulatory functions within the vasculature. At least 25 different types of collagen exist [1], a number of which, including major, widely distributed types I, III, IV, V and VI, occur in the vessel wall [2]. Three polypeptide chains (a-chains) form the fundamental structure of the collagen molecule, which is characterized by the presence of one or more triple-helical domains. Within these domains, the three a-chains, which are different gene products depending on collagen type, wind around one another in a characteristic lefthanded triple helix (Fig. 1). This conformation of collagen is of crucial importance, since the three-dimensional structure is needed for recognition of collagen by its ligands. The primary structure of the triple-helical regions of collagen chains is characterized by its repetitive Gly–X–Y sequence, with Gly– Pro–Hyp (GPO) as the most frequent, forming about 10% of the primary structure of collagen types I and III [3]. The presence of glycine as every third residue is essential for the close packing of the chains. The high content of the imino acids proline and hydroxyproline is responsible for hydrogen bonds which hold the three chains of the helix together, and which stabilize helix–helix interactions within the polymeric structure of collagen. Collagens can be divided into fibrous and non-fibrous types. Triple-helical monomers of the fibrous collagens, types I–III, V and XI, self-associate to form typical highly ordered tissue collagen fibers, cross-striated with a periodicity of 67 nm, as observed by electron microscopy (Fig. 1). In vivo, mixed fibers may be assembled from various types of collagens. In contrast, non-fibrous collagens form other higher order structures. For example, type IV collagen has a modular structure composed of triple-helical segments separated by globular domains. A two-dimensional network forms, stabilized via lateral interaction between the globular domains, and forming an important component of basement membranes. Collagens, located in the matrix underlying vascular endothelial cells, are not exposed to flowing blood. After injury, however, blood will flow directly over subendothelial structures including connective tissue that contains a high percentage of collagen. Thus collagen is ideally situated to initiate hemostasis. There is ample evidence that collagen is one of the major activators of the platelet response after injury. Collagen is the only matrix protein which supports both platelet adhesion and complete activation. When collagen becomes exposed to flowing blood, platelets rapidly adhere, spread, become activated and begin to form an aggregate. Figure 2 shows the intimate contact between aggregating platelets and collagen, and Fig. 3, the extent of platelet activation and aggregate formation on collagen, compared with the adhesion only that occurs on fibrinogen-coated surfaces. The early concept that collagen was also directly responsible for the activation of the intrinsic coagulation cascade [4] turned out to be incorrect [5]. However, collagen indirectly plays a crucial role in regulating thrombin formation because negatively charged phospholipids such as phosphatidylserine become exposed on the surface of platelets after interaction with collagen and form the catalytic surface for the assembly of active coagulation complexes and thrombin generation [6]. There is additional evidence (reviewed below) that collagen participates in other ways in the regulation of the coagulation cascade. Here we will review the role of collagen in the regulation of hemostasis, embracing both coagulation and platelet aggregation.