Fibrin Formation: The Role of the Fibrinogen-Fibrin Monomer Complex[*]
04 January 1976
Accepted 01 February 1976
03 July 2018 (online)
The process of fibrin formation using highly purified fibrinogen and thrombin was studied using laser fluctuation spectroscopy, a method that rapidly determines particle size in a solution. Two periods in fibrin clot formation were noted: an induction period during which no fibrin polymerization occurred and a period of rapid increase in particle size. Direct measurement of fibrin monomer polymerization and fibrinopeptide release showed no evidence of an induction period. These observations were best explained by a kinetic model for fibrin clot formation incorporating a reversible fibrinogen-fibrin monomer complex. In this model, the complex serves as a buffer system during the earliest phase of fibrin formation. This prevents the accumulation of free polymerizable fibrin monomer until an appreciable amount of fibrinogen has reacted with thrombin, at which point the fibrin monomer level rises rapidly and polymerization proceeds. Clinically, the complex may be a homeostatic mechanism preventing pathological clotting during periods of elevated fibrinogen.
* Presented in part at the Seventeenth Annual Meeting of the American Society of Hematology Atlanta, Georgia, December 7–10, 1974.
- 1 Belitser V. A, Varetskaja T. V, Malneva G. V. 1968; Fibrinogen-fibrin interaction. Biochimica et Biophysica Acta 154: 415.
- 2 Bennett B, Forman W. B, Ratnoff O. D. 1973; Studies on the nature of antihemophilic factor (Factor VIII): further evidence relating the AHF-like antigens in normal and hemophilic plasmas. Journal of Clinical Investigation 52: 219.
- 3 Birnboim H, Lederer K. 1972; Diffusion coefficient of bovine fibrinogen as measured by quasielastic light scattering. Polymer Preparation, American Chemical Society, Division Polymer Chemistry 13: 203.
- 4 Blättler W, Straub P. W, Peyer A. 1974; Effect of in vivo produced fibrinogen-fibrin intermediates on viscosity of human blood. Thrombosis Research 4: 787.
- 5 Blombäck B. 1969; The N-terminal disulphide knot of human fibrinogen. British Journal of Haematology 51: 145.
- 6 Blombäck B, Blombäck M. 1957; Purification of human and bovine fibrinogen. Arkiv for Kemi 10: 415.
- 7 Chang M. L, Wilson J. E, Frenkel E. P. 1974; Soluble fibrin complexes in experimental thrombotic states. Journal of Laboratory and Clinical Medicine 84: 168.
- 8 Chu Benjamin. 1974. Laser Light Scattering. Academic Press; New York, New York:
- 9 Crum E. D, Shainoff J. R, Graham R. C, Ratnoff O. D. 1974; Fibrinogen Cleveland II. An abnormal fibrinogen with defective release of fibrinopeptide A. Journal of Clinical Investigation 53: 1308.
- 10 Endres G. F, Ehrenpreis S, Scheraga H. A. 1966; Equilibria in the fibrinogen-fibrin conversion. VI. Ionization changes in the reversible polymerization of fibrin monomer. Biochemistry 5: 1561.
- 11 von Felten A, Duckert F, Frick P. G. 1966; Familial disturbance of fibrin monomer aggregation. British Journal of Haematology 12: 667.
- 12 Forman W. B, Ratnoff O. D, Boyer M. H. 1968; An inherited qualitative abnormality in plasma fibrinogen. Fibrinogen Cleveland. Journal of Laboratory and Clinical Medicine 72: 455.
- 13 Gans H, Lowman J. T. 1967; The uptake of fibrin and fibrinogen degradation products by the isolated perfused rat liver. Blood 29: 526.
- 14 Godal H. C, Abildgaard U. 1966; Gelation of soluble fibrin in plasma by ethanol. Scandinavian Journal of Haematology 3: 342.
- 15 Graeff H, von Hugo R, Hafter R. 1973; In vivo formation of soluble fibrin monomer complexes in human plasma. Thrombosis Research 3: 465.
- 16 Ham T. H, Curtis F. C. 1938; Plasma fibrinogen response in man; influence of nutritional state, induced hyperpyrexia, infectious disease and liver damage. Medicine 17: 413.
- 17 Hudry-Cluergeon G, Marguerite G, Pouit L, Suscillon M. 1975; Models proposed for the fibrinogen molecule and for the polymerization process. Thrombosis Research 6: 553.
- 18 Jakobsen E, Ly B, Kierulf P. 1974; Incorporation of fibrinogen into soluble fibrin complexes. Thrombosis Research 4: 499.
- 19 Kanaide H, Shainoff J. R. 1975; Cross-linking of fibrinogen and fibrin by fibrin stabilizing factor (factor XIIIa). Journal of Laboratory and Clinical Medicine 85: 574.
- 20 Laki K. 1951; The polymerization of proteins: The action of thrombin on fibrinogen. Archives at Biochemistry and Biophysics 32: 317.
- 21 Laskowski Jr. M, Ehrenpreis S, Donnelly T. H, Scheraga H. A. 1960; Equilibria in the fibrinogen-fibrin conversion. V. Reversibility and thermodynamics of the proteolytic-action of thrombin on fibrinogen. Journal of the American Chemistry Society 82: 1340.
- 22 Latallo Z. S, Fletcher A. P, Alkjaersig N, Sherry S. 1962; Influence of pH, ionic strength, neutral ions and thrombin on fibrin polymerization. American Journal of Physiology 202: 675.
- 23 Lowry O. H, Rosenbrough N. J, Farr A. L, Randall R. J. 1951; Protein measurement with the Folin phenol reagent. Journal of Biological Chemistry 193: 265.
- 24 Ly B, Kierulf P, Jakobsen E. 1974; Stabilization of soluble fibrin-fibrinogen complexes by fibrin stabilization factor (FSF). Thrombosis Research 4: 509.
- 25 Marguerie G, Hudry G, Holland D. 1970; Effects du sodium et du calcium sur la conversion du fibrinogene en fibrine. Thrombosis et Diathesis Haemorrhagica 24: 373.
- 26 Prentice C. R, Ratnoff O. D, Breckenridge R. T. 1967; Experiments on the nature of the prothrombin-converting principle: alteration of proaccelerin by thrombin. British Journal of Haematology 13: 898.
- 27 Ratnoff O. D, Menzie C. 1951; New method for determination of fibrinogen in small samples of plasma. Journal of Laboratory and Clinical Medicine 37: 316.
- 28 Roberts J. D. 1971. Particle Size Determination by Laser Heterodyne Spectroscopy. Case Western Reserve University; Department of Chemical Engineering. Report Number 12–30–71.
- 29 Shainoff J. R, Page I. H. 1960; Cofibrins and fibrin-intermediates as indicators of thrombin activity in vivo. Circulation Research 8: 1013.
- 30 Shainoff J. R, Page I. H. 1962; Significance of cryoprofibrin in fibrinogen-fibrin conversion. Journal of Experimental Medicine 116: 687.
- 31 Shinowara G. Y. 1966; Human thrombin and fibrinogen. The kinetics of their interaction and the preparation of the enzyme. Biochemica et Biophysica Acta 113: 359.
- 32 Steiner R. F, Laki K. 1951; Light scattering studies on clotting of fibrinogen. Archives of Biochemistry 34: 24.
- 33 Waugh D. F, Livingstone B. J. 1951; Kinetics of interaction of bovine fibrinogen and thrombin. Journal of Physics and Colloid Chemistry 55: 1206.