Fibrin monomer and factor XIII

Summary

Unexplained intraoperative coagulopathies continue to be a diagnostic and therapeutic dilemma. The pathophysiology behind unexplained intraoperative coagulopathies is of great variety and complexity (preexisting coagulopathies, dilutional coagulopathy, interactions of medications etc.). We have shown in prospective studies that patients undergoing elective surgery who develop, unexplained“ intraoperative coagulopathies have significantly less FXIII per unit thrombin available at any point in time (i.e. already preoperatively) than patients without such coagulopathies. The consequence is a significant loss of clot firmness associated with an increase in intraoperative blood loss. Thus, these patients have less cross-linking capacity to begin with, which explains their preoperatively increased fibrin monomer concentration. The association of increased preoperative fibrin monomer and increased intraoperative blood loss was prospectively evaluated and cofirmed in a separate clinical study. It is important to note that the acquired or (compared to the amount of thrombin generated) relative F. XIII deficiency in situations with surgical stress shows early clinical relevance (even if only mild to moderate changes are present); this differs from the experiences with patients with inborn FXIII deficiency, where a pronounced deficiency must be present to have clinically significant spontaneous bleeding.

Patients undergoing elective surgery, without clinically obvious coagulopathy but increased preoperative fibrin monomer concentration (as a marker of decreased crosslinking capacity) are at risk for increased intraoperative blood loss. This new concept helps to explain the pathophysiology behind unexplained intraoperative coagulopathies and thus allows for corresponding treatment strategies. Further clinical studies for early detection and interventions in patients with such coagulopathies are necessary.

Keywords

Thrombin - fibrin monomer - FXIII - clot firmness - intraoperative blood loss

• References

• 1 Lorand L. Fibrinoligase: the fibrin-stabilizing factor system of blood plasma. Ann NY Acad Sci 1972; 202: 6-30.
• 2 Duckert F, Jung E, Shmerling DH. A hitherto undescribed congenital haemorrhagic diathesis probably due to fibrin stabilizing factor deficiency. Thromb Diath Haemorrh 1960; 5: 179-186.
• 3 Schroeder V, Meili E, Cung T. et al. Characterisation of six novel A-subunit mutations leading to congenital factor XIII deficiency and molecular analysis of the first diagnosed patient with this rare bleeding disorder. Thromb Haemost 2006; 95: 77-84.
• 4 Loewy AG. Some thoughts on the state in nature, biosynthetic origin, and function of factor XIII. Ann NY Acad Sci 1972; 202: 41-58.
• 5 Inbal A, Lubetsky A, Krapp T. et al. Impaired wound healing in factor XIII deficient mice. Thromb Haemost 2005; 94: 432-437.
• 6 Siebenlist KR, Meh DA, Mosesson MW. Protransglutaminase (factor XIII) mediated crosslinking of fibrinogen and fibrin. Thromb Haemost 2001; 86: 1221-1228.
• 7 Siebenlist KR, Meh DA, Mosesson MW. Plasma factor XIII binds specifically to fibrinogen molecules containing gamma chains. Biochemistry 1996; 35: 10448-10453.
• 8 Mosesson MW, Siebenlist KR, Meh DA. The structure and biological features of fibrinogen and fibrin. Ann NY Acad Sci 2001; 936: 11-30.
• 9 Weisberg LJ, Shiu DT, Greenberg CS. et al. Localization of the gene for coagulation factor XIII a-chain to chromosome 6 and identification of sites of synthesis. J Clin Invest 1987; 79: 649-652.
• 10 Ichinose A, Hendrickson LE, Fujikawa K. et al. Amino acid sequence of the a subunit of human factor XIII. Biochemistry 1986; 25: 6900-6906.
• 11 Ichinose A, McMullen BA, Fujikawa K. et al. Amino acid sequence of the b subunit of human factor XIII, a protein composed of ten repetitive segments. Biochemistry 1986; 25: 4633-4638.
• 12 Kangsadalampai S, Board PG. The Val34Leu polymorphism in the A subunit of coagulation factor XIII contributes to the large normal range in activity and demonstrates that the activation peptide plays a role in catalytic activity. Blood 1998; 92: 2766-2770.
• 13 Adany R, Muszbek L. Immunohistochemical detection of factor XIII subunit a in histiocytes of human uterus. Histochemistry 1989; 91: 169-174.
• 14 Fear JD, Jackson P, Gray C. et al. Localisation of factor XIII in human tissues using an immunoperoxidase technique. J Clin Pathol 1984; 37: 560-563.
• 15 Muszbek L, Adany R, Mikkola H. Novel aspects of blood coagulation factor XIII. I. Structure, distribution, activation, and function. Crit Rev Clin Lab Sci 1996; 33: 357-421.
• 16 Casadio R, Polverini E, Mariani P. et al. The structural basis for the regulation of tissue transglutaminase by calcium ions. Eur J Biochem 1999; 262: 672-679.
• 17 Fox BA, Yee VC, Pedersen LC. et al. Identification of the calcium binding site and a novel ytterbium site in blood coagulation factor XIII by x-ray crystallography. J Biol Chem 1999; 274: 4917-4923.
• 18 Tamaki T, Aoki N. Cross-linking of alpha 2-plasmin inhibitor to fibrin catalyzed by activated fibrin- stabilizing factor. J Biol Chem 1982; 257: 14767-14772.
• 19 Fickenscher K, Aab A, Stuber W. A photometric assay for blood coagulation factor XIII. Thromb Haemost 1991; 65: 535-540.
• 20 Wilmer M, Rudin K, Kolde H. et al. Evaluation of a sensitive colorimetric FXIII incorporation assay. Effects of FXIII Val34Leu, plasma fibrinogen concentration and congenital FXIII deficiency. Thromb Res 2001; 102: 81-91.
• 21 Dempfle CE, Harenberg J, Hochreuter K. et al. Microtiter assay for measurement of factor XIII activity in plasma. J Lab Clin Med 1992; 119: 522-528.
• 22 Nishida Y, Ikematsu S, Fukutake K. et al. A new rapid and simple assay for factor XIII activity using dansylcadaverine incorporation and gel filtration. Thromb Res 1984; 36: 123-131.
• 23 Bhattacharya M, Biswas A, Ahmed RP. et al. Clinico- hematologic profile of factor XIII-deficient patients. Clin Appl Thromb Hemost 2005; 11: 475-480.
• 24 Padmanabhan LD, Mhaskar R, Mhaskar A. et al. Factor XIII deficiency: a rare cause of repeated abortions. Singapore Med J 2004; 45: 186-187.
• 25 Egbring R, Kroniger A, Seitz R. Factor XIII deficiency: pathogenic mechanisms and clinical significance. Semin Thromb Hemost 1996; 22: 419-425.
• 26 Hoffman M, Monroe 3rd DM. A cell-based model of hemostasis. Thromb Haemost 2001; 85: 958-965.
• 27 Hoffman M, Monroe DM, Roberts HR. Cellular interactions in hemostasis. Haemostasis 1996; 26 (Suppl. 01) 12-16.
• 28 Hoffman M, Monroe 3rd DM. The action of highdose factor VIIa (FVIIa) in a cell-based model of hemostasis. Sem Hematol 2001; 38 4 Suppl 12 6-9.
• 29 Lorand L. Factor XIII and the clotting of fibrinogen: from basic research to medicine. J Thromb Haemost 2005; 3: 1337-1348.
• 30 Siebenlist KR, Mosesson MW. Factors affecting gamma-chain multimer formation in cross-linked fibrin. Biochemistry 1992; 31: 936-941.
• 31 Mosesson MW. Fibrinogen gamma chain functions. J Thromb Haemost 2003; 1: 231-238.
• 32 Ichinose A. Physiopathology and regulation of factor XIII. Thromb Haemost 2001; 86: 57-65.
• 33 Hornyak TJ, Shafer JA. Role of calcium ion in the generation of factor XIII activity. Biochemistry 1991; 30: 6175-6182.
• 34 Paye M, Nusgens B, Lapiere CM. Factor XIII of blood coagulation decreases the susceptibility of collagen precursors to proteolysis. Biochim Biophys Acta 1991; 1073: 437-441.
• 35 Barry EL, Mosher DF. Factor XIIIa-mediated cross-linking of fibronectin in fibroblast cell layers. Cross-linking of cellular and plasma fibronectin and of amino-terminal fibronectin fragments. J Biol Chem 1989; 264: 4179-4185.
• 36 Brown LF, Lanir N, McDonagh J. et al. Fibroblast migration in fibrin gel matrices. Am J Pathol 1993; 142: 273-283.
• 37 Blome M, Isgro F, Kiessling AH. et al. Relationship between factor XIII activity, fibrinogen, haemostasis screening tests and postoperative bleeding in cardiopulmonary bypass surgery. Thromb Haemost 2005; 93: 1101-1107.
• 38 Godje O, Haushofer M, Lamm P. et al. The effect of factor XIII on bleeding in coronary surgery. Thorac Cardiovasc Surg 1998; 46: 263-267.
• 39 Godje O, Gallmeier U, Schelian M. et al. Coagulation factor XIII reduces postoperative bleeding after coronary surgery with extracorporeal circulation. Thorac Cardiovasc Surg 2006; 54: 26-33.
• 40 Gerlach R, Raabe A, Zimmermann M. et al. Factor XIII deficiency and postoperative hemorrhage after neurosurgical procedures. Surg Neurol 2000; 54: 260-265.
• 41 Gerlach R, Tolle F, Raabe A. et al. Increased risk for postoperative hemorrhage after intracranial surgery in patients with decreased factor XIII activity: implications of a prospective study. Stroke 2002; 33: 1618-1623.
• 42 Korte W, Truttmann B, Heim C. et al. Preoperative values of molecular coagulation markers identify patients at low risk for intraoperative haemostatic disorders and excessive blood loss. Clin Chem Lab Med 1998; 36: 235-240.
• 43 Wettstein P, Haeberli A, Stutz M. et al. Decreased factor XIII availability for thrombin and early loss of clot firmness in patients with unexplained intraoperative bleeding. Anesth Analg 2004; 99: 1564-1569.
• 44 Korte W, Gabi K, Rohner M. et al. Preoperative fibrin monomer measurement allows risk stratification for high intraoperative blood loss in elective surgery. Thromb Haemost 2005; 94: 211-215.
• 45 Chandler WL, Patel MA, Gravelle L. et al. Factor XIIIA and clot strength after cardiopulmonary bypass. Blood Coagul Fibrinol 2001; 12: 101-108.
• 46 Godje O, Haushofer M, Lamm P. et al. The effect of factor XIII on bleeding in coronary surgery. Thorac Cardiovasc Surg 1998; 46: 263-267.
• 47 Shainoff JR, Estafanous FG, Yared JP. et al. Low factor XIIIA levels are associated with increased blood loss after coronary artery bypass grafting. J Thorac Cardiovasc Surg 1994; 108: 437-445.
• 48 Quiel V. Factor XIII deficiency as the cause of postoperative hemorrhage. Zentralbl Gynäkol 1993; 115: 562-564.
• 49 Gerlach R, Raabe A, Zimmermann M. et al. Factor XIII deficiency and postoperative hemorrhage after neurosurgical procedures. Surg Neurol 2000; 54: 260-265.
• 50 Heinle K, Adam O, Rauh G. Factor XIII insufficiency in a patient with severe psoriasis vulgaris, arthritis, and infirmity. Clin Rheumatol 1998; 17: 346-348.
• 51 Hofbauer F, Roka R, Zekert F. Factor XIII and the risk of postoperative impaired wound healing and bleeding. Wien Klin Wochenschr 1979; 91: 265-266.
• 52 Meili EO. Clinical course and management of severe congenital factor XIII deficiency. Hämostaseologie 2002; 22: 48-52.