Fibrinogen: evolution of the structure-function concept. Keynote address at fibrinogen 2000 congress.
Coagulation of blood is such an evident phenomenon that its observation can be traced back to earliest historical times. The great philosophers and physicians of antiquity discussed and provided interesting explanations. However, it was not until the end of the seventeenth century that the structural component of the blood clot was described by Malpighi as a white fibrous substance. In the middle of the nineteenth century this was identified as a constituent of pathological thrombi and given the name fibrin. At about that time its precursor in blood, fibrinogen, was isolated in a highly purified form by Hammarsten who suggested that, preceding fibrin formation, activation of fibrinogen by thrombin occurred by limited proteolysis. The activation mechanism was eventually clarified in the 1950s. It was shown to proceed in two discrete steps, by removal of low molecular weight activation peptides. Ferry postulated, based on physicochemical observations, that the activated molecules aligned in a half-staggered fashion to form polymers. The rapid post-war development of biochemical technology permitted evaluation of the primary structure of fibrinogen. With that followed identification of molecular domains in the activated firbinogen molecules that participate in polymer formation, crosslinking of polymeric structures, and domains for cellular attachment. Crystallization of fragments and, recently, of the entire molecule has confirmed and extended this knowledge. Lately, it has also been possible to obtain detailed information on the architecture of the fiber network in the fibrin gel. The gel structure is primarily determined by the initial rate of fibrinogen activation, but without infringement of this primary rule, several factors in blood may modulate the structure. Fibrinogen and fibrin play important roles in normal hemostasis, wound healing, and pathological processes, such as thrombosis and atherosclerosis.
Blombäck
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Coagulation Laboratory, Karolinska Institutet, Nobels väg 12A, SE-171 77 Stockholm, Sweden. Birger.Blombäck@mbb.ki.se
D005340:Fibrinogen / Q000737:chemistry* / Q000502:physiology*; D006801:Humans; D013329:Structure-Activity Relationship
D005340:Fibrinogen