Coagulation factor XIII: a multifunctional transglutaminase with clinical potential in a range of conditions

Summary

Coagulation factor XIII (FXIII), a plasma transglutaminase, is best known as the final enzyme in the coagulation cascade, where it is responsible for cross-linking of fibrin. However, a growing body of evidence has demonstrated that FXIII targets a wide range of additional substrates that have important roles in health and disease. These include antifibrinolytic proteins, with cross-linking of α²-antiplasmin to fibrin, and potentially fibrinogen, being the principal mechanism(s) whereby plasmin-mediated clot degradation is minimised. FXIII also acts on endothelial cell VEGFR-2 and α²β³ integrin, which ultimately leads to downregulation of the antiangiogenic protein thrombospondin-1, promoting angiogenesis and neovascularisation. Under infectious disease conditions, FXIII cross-links bacterial surface proteins to fibrinogen, resulting in immobilisation and killing, while during wound healing, FXIII induces cross-linking of the provisional matrix. The latter process has been shown to influence the interaction of leukocytes with the provisional extracellular matrix and promote wound healing. Through these actions, there are good rationales for evaluating the therapeutic potential of FXIII in diseases in which tissue repair is dysregulated or perturbed, including systemic sclerosis (scleroderma), invasive bacterial infections, and tissue repair, for instance healing of venous leg ulcers or myocardial injuries. Adequate levels of FXIII are also required in patients undergoing surgery to prevent or treat perioperative bleeding, and its augmentation in patients with/at risk for perioperative bleeding may also have potential clinical benefit. While there are preclinical and/or clinical data to support the use of FXIII in a range of settings, further clinical evaluation in these underexplored applications is warranted.

Keywords

Coagulation - factor XIII - infection - scleroderma - wound healing

• References

• 1 Hsieh L, Nugent D. Factor XIII deficiency. Haemophilia 2008; 14: 1190-1200.
• 2 Yee VC, Pedersen LC, Le Trong I. et al. Three-dimensional structure of a transglutaminase: human blood coagulation factor XIII. Proc Natl Acad Sci USA 1994; 91: 7296-7300.
• 3 Nugent DJ. Prophylaxis in rare coagulation disorders – factor XIII deficiency. Thromb Res 2006; 118 (Suppl. 01) S23-S28.
• 4 Levy JH, Greenberg C. Biology of Factor XIII and clinical manifestations of Factor XIII deficiency. Transfusion 2013; 53: 1120-1131.
• 5 Ivaskevicius V, Seitz R, Kohler HP. et al. International registry on factor XIII deficiency: a basis formed mostly on European data. Thromb Haemost 2007; 97: 914-921.
• 6 Peyvandi F, Palla R, Menegatti M. et al. Coagulation factor activity and clinical bleeding severity in rare bleeding disorders: results from the European Network of Rare Bleeding Disorders. J Thromb Haemost 2012; 10: 615-621.
• 7 Duckert F, Jung E, Shmerling DH. A hitherto undescribed congenital haemorrhagic diathesis probably due to fibrin stabilizing factor deficiency. Thromb Diath Haemorrh 1960; 05: 179-186.
• 8 National Hemophilia Foundation: MASAC Recommendations Concerning Products Licensed for the Treatment of Hemophilia and Other Bleeding Disorders. Available at http://www.hemophilia.org/NHFWeb/MainPgs/MainNHF. aspx?menuid=57&contentid=693 Accessed 24 September, 2013
• 9 Mosesson MW, Siebenlist KR, Hernandez I. et al. Evidence that alpha2-antiplasmin becomes covalently ligated to plasma fibrinogen in the circulation: a new role for plasma factor XIII in fibrinolysis regulation. J Thromb Haemost 2008; 06: 1565-1570.
• 10 Richardson VR, Cordell P, Standeven KF. et al. Substrates of Factor XIII-A: roles in thrombosis and wound healing. Clin Sci 2013; 124: 123-137.
• 11 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.
• 12 Korte WC, Szadkowski C, Gahler A. et al. Factor XIII substitution in surgical cancer patients at high risk for intraoperative bleeding. Anesthesiology 2009; 110: 239-245.
• 13 Gerlach R, Raabe A, Zimmermann M. et al. Factor XIII deficiency and postoperative hemorrhage after neurosurgical procedures. Surg Neurol 2000; 54: 260-264.
• 14 Jambor C, Reul V, Schnider TW. et al. In vitro inhibition of factor XIII retards clot formation, reduces clot firmness, and increases fibrinolytic effects in whole blood. Anesth Analg 2009; 109: 1023-1028.
• 15 Theusinger OM, Baulig W, Asmis LM. et al. In vitro factor XIII supplementation increases clot firmness in Rotation Thromboelastometry (ROTEM). Thromb Haemost 2010; 104: 385-391.
• 16 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.
• 17 von Heymann C, Schoenfeld H, Sander M. et al. Clopidogrel-related refractory bleeding after coronary artery bypass graft surgery: a rationale for the use of coagulation factor concentrates?. Heart Surg Forum 2005; 08: E39-E41.
• 18 Lechner C. Factor XIII (Fibrogammin P). Clinical experience in perioperative bleeding and wound healing – a case collection. CliniCum. The Magazine for Executives in Hospital. Wien: Medizin Medien Austria GmbH; 2011. 2012. pg. 27-39.
• 19 Karkouti K, von Heymann C, Jespersen CM. et al. Efficacy and safety of recombinant factor XIII on reducing blood transfusions in cardiac surgery: a randomized, placebo-controlled, multicenter clinical trial. J Thorac Cardiovasc Surg 2013; 146: 927-939.
• 20 Hayashi T, Kadohira Y, Morishita E. et al. A case of acquired FXIII deficiency with severe bleeding symptoms. Haemophilia 2012; 18: 618-620.
• 21 Society of Thoracic Surgeons Blood Conservation Guideline, Task Force. Ferraris VA, Brown JR. et al. 2011 update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines. Ann Thorac Surg 2011; 91: 944-982.
• 22 Kozek-Langenecker SA, Afshari A, Albaladejo P. et al. Management of severe perioperative bleeding: guidelines from the European Society of Anaesthesiology. Eur J Anaesthesiol 2013; 30: 270-382.
• 23 Dallabrida SM, Falls LA, Farrell DH. Factor XIIIa supports microvascular endothelial cell adhesion and inhibits capillary tube formation in fibrin. Blood 2000; 95: 2586-2592.
• 24 Dardik R, Shenkman B, Tamarin I. et al. Factor XIII mediates adhesion of platelets to endothelial cells through alpha(v)beta(3) and glycoprotein IIb/IIIa integrins. Thromb Res 2002; 105: 317-323.
• 25 Dardik R, Solomon A, Loscalzo J. et al. Novel proangiogenic effect of factor XIII associated with suppression of thrombospondin 1 expression. Arterioscler Thromb Vasc Biol 2003; 23: 1472-1477.
• 26 Dardik R, Leor J, Skutelsky E. et al. Evaluation of the pro-angiogenic effect of factor XIII in heterotopic mouse heart allografts and FXIII-deficient mice. Thromb Haemost 2006; 95: 546-550.
• 27 Kilian O, Fuhrmann R, Alt V. et al. Plasma transglutaminase factor XIII induces microvessel ingrowth into biodegradable hydroxyapatite implants in rats. Biomaterials 2005; 26: 1819-1827.
• 28 Mirochnik Y, Kwiatek A, Volpert OV. Thrombospondin and apoptosis: molecular mechanisms and use for design of complementation treatments. Curr Drug Targets 2008; 09: 851-862.
• 29 Nor JE, Mitra RS, Sutorik MM. et al. Thrombospondin-1 induces endothelial cell apoptosis and inhibits angiogenesis by activating the caspase death pathway. J Vasc Res 2000; 37: 209-218.
• 30 Streit M, Velasco P, Riccardi L. et al. Thrombospondin-1 suppresses wound healing and granulation tissue formation in the skin of transgenic mice. EMBO J 2000; 19: 3272-3282.
• 31 Dardik R, Loscalzo J, Eskaraev R. et al. Molecular mechanisms underlying the proangiogenic effect of factor XIII. Arterioscler Thromb Vasc Biol. 2005; 25: 526-532.
• 32 Dardik R, Loscalzo J, Inbal A. Factor XIII (FXIII) and angiogenesis. J Thromb Haemost 2006; 04: 19-25.
• 33 Gabrielli A, Avvedimento EV, Krieg T. Scleroderma. N Engl J Med 2009; 360: 1989-2003.
• 34 Chen Y, Leask A, Abraham DJ. et al. Thrombospondin 1 is a key mediator of transforming growth factor beta-mediated cell contractility in systemic sclerosis via a mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK)-dependent mechanism. Fibrogenesis Tissue Repair 2011; 04: 9.
• 35 Mimura Y, Ihn H, Jinnin M. et al. Constitutive thrombospondin-1 overexpression contributes to autocrine transforming growth factor-beta signaling in cultured scleroderma fibroblasts. Am J Pathol 2005; 166: 1451-1463.
• 36 Avouac J, Clemessy M, Distler JH. et al. Enhanced expression of ephrins and thrombospondins in the dermis of patients with early diffuse systemic sclerosis: potential contribution to perturbed angiogenesis and fibrosis. Rheumatology 2011; 50: 1494-1504.
• 37 Farina G, Lafyatis D, Lemaire R. et al. A four-gene biomarker predicts skin disease in patients with diffuse cutaneous systemic sclerosis. Arthritis Rheum 2010; 62: 580-588.
• 38 Paye M, Nusgens BV, Lapiere CM. Factor XIII of blood coagulation modulates collagen biosynthesis by fibroblasts in vitro. Haemostasis 1989; 19: 274-283.
• 39 Denton CP, Zheng B, Evans LA. et al. Fibroblast-specific expression of a kinasedeficient type II transforming growth factor beta (TGFbeta) receptor leads to paradoxical activation of TGFbeta signaling pathways with fibrosis in transgenic mice. J Biol Chem 2003; 278: 25109-25119.
• 40 Crawford SE, Stellmach V, Murphy-Ullrich JE. et al. Thrombospondin-1 is a major activator of TGF-beta1 in vivo. Cell 1998; 93: 1159-1170.
• 41 Delbarre F, Godeau P, Thivolet J. Factor XIII treatment for scleroderma. Lancet 1981; 02: 204.
• 42 Euller-Ziegler L, Corolleur YR, Marcou J. et al. [Long-term treatment of systemic scleroderma with coagulation factor XIII. Developmental monitoring, especially of respiratory function]. Rev Rhum Mal Osteoartic 1984; 51: 503-505.
• 43 Guillevin L, Chouvet B, Mery C. et al. Treatment of progressive systemic sclerosis using factor XIII. Pharmatherapeutica 1985; 04: 76-80.
• 44 Guillevin L, Chouvet B, Mery C. et al. [Treatment of generalized scleroderma with factor XIII. Study of 25 cases]. Rev Med Interne 1982; 03: 273-277.
• 45 Guillevin L, Euller-Ziegler L, Chouvet B. et al. [Treatment of systemic scleroderma with factor XIII in 86 patients, with long-term follow-up]. Presse Med 1985; 14: 2327-2329.
• 46 Maekawa Y, Nogita T, Yamada M. Favorable effects of plasma factor XIII on lower esophageal sphincter pressure of progressive systemic sclerosis. Arch Dermatol 1987; 123: 1440-1441.
• 47 Marzano AV, Gasparini G, Colonna C. et al. Treatment of generalized scleroderma and generalized morphea with coagulation factor XIII. Eur J Dermatol 1995; 05: 459-466.
• 48 Thivolet J, Perrot H, Meunier F. et al. [Therapeutic action of coagulation factor XIII in scleroderma. 20 cases]. Nouv Presse Med 1975; 04: 2779-2782.
• 49 Jullien D, Souillet AL, Faure M. et al. Coagulation factor XIII in scleroderma. Eur J Dermatol 1998; 08: 231-234.
• 50 Ichinose A. Factor XIII is a key molecule at the intersection of coagulation and fibrinolysis as well as inflammation and infection control. Int J Hematol 2012; 95: 362-370.
• 51 Schroeder V, Kohler HP. New developments in the area of factor XIII. J Thromb Haemost 2013; 11: 234-244.
• 52 Soendergaard C, Kvist PH, Seidelin JB. et al. Tissue-regenerating functions of coagulation factor XIII. J Thromb Haemost 2013; 11: 806-816.
• 53 Loof TG, Morgelin M, Johansson L. et al. Coagulation, an ancestral serine protease cascade, exerts a novel function in early immune defense. Blood 2011; 118: 2589-2598.
• 54 Wang Z, Wilhelmsson C, Hyrsl P. et al. Pathogen entrapment by transglutaminase – a conserved early innate immune mechanism. PLoS Pathog 2010; 06: e1000763.
• 55 Thomer L, Schneewind O, Missiakas D. Multiple ligands of von Willebrand factor-binding protein (vWbp) promote Staphylococcus aureus clot formation in human plasma. J Biol Chem 2013; 288: 28283-28292.
• 56 Zeerleder S, Schroeder V, Lammle B. et al. Factor XIII in severe sepsis and septic shock. Thromb Res 2007; 119: 311-318.
• 57 Birnbaum J, Hein OV, Luhrs C. et al. Effects of coagulation factor XIII on intestinal functional capillary density, leukocyte adherence and mesenteric plasma extravasation in experimental endotoxemia. Crit Care 2006; 10: R29.
• 58 Lee SY, Chang SK, Lee IH. et al. Depletion of plasma factor XIII prevents disseminated intravascular coagulation-induced organ damage. Thromb Haemost 2001; 85: 464-469.
• 59 Howes JM, Richardson VR, Smith KA. et al. Complement C3 is a novel plasma clot component with anti-fibrinolytic properties. Diab Vasc Dis Res 2012; 09: 216-225.
• 60 Richardson VR, Schroeder V, Grant PJ. et al. Complement C3 is a substrate for activated factor XIII that is cross-linked to fibrin during clot formation. Br J Haematol 2013; 160: 116-119.
• 61 Nikolajsen CL, Scavenius C, Enghild JJ. Human complement C3 is a substrate for transglutaminases. A functional link between non-protease-based members of the coagulation and complement cascades. Biochemistry 2012; 51: 4735-4742.
• 62 Hess K, Ajjan R, Phoenix F. et al. Effects of MASP-1 of the complement system on activation of coagulation factors and plasma clot formation. PLoS One 2012; 07: e35690.
• 63 Bagoly Z, Katona E, Muszbek L. Factor XIII and inflammatory cells. Thromb Res 2012; 129 (Suppl. 02) S77-S81.
• 64 Dardik R, Krapp T, Rosenthal E. et al. Effect of FXIII on monocyte and fibroblast function. Cell Physiol Biochem 2007; 19: 113-120.
• 65 Cordell PA, Kile BT, Standeven KF. et al. Association of coagulation factor XIII-A with Golgi proteins within monocyte-macrophages: implications for subcellular trafficking and secretion. Blood 2010; 115: 2674-2681.
• 66 Board PG, Losowsky MS, Miloszewski KJ. Factor XIII: inherited and acquired deficiency. Blood Rev 1993; 07: 229-242.
• 67 Seitz R, Duckert F, Lopaciuk S. et al. ETRO Working Party on Factor XIII questionnaire on congenital factor XIII deficiency in Europe: status and perspectives. Study Group. Semin Thromb Hemost 1996; 22: 415-418.
• 68 Inbal A, Lubetsky A, Krapp T. et al. Impaired wound healing in factor XIII deficient mice. Thromb Haemost 2005; 94: 432-437.
• 69 Ogawa T, Morioka Y, Inoue T. et al. Involvement of blood coagulation factor XIII in burn healing in the carbon tetrachloride-induced hepatic injury model in rats. Inflamm Res 1995; 44: 264-268.
• 70 Claes L, Burri C, Gerngross H. et al. Bone healing stimulated by plasma factor XIII. Osteotomy experiments in sheep Acta Orthop Scand 1985; 56: 57-62.
• 71 Vanscheidt W, Hasler K, Wokalek H. et al. Factor XIII-deficiency in the blood of venous leg ulcer patients. Acta Derm Venereol 1991; 71: 55-57.
• 72 Hildenbrand T, Idzko M, Panther E. et al. Treatment of nonhealing leg ulcers with fibrin-stabilizing factor XIII: a case report. Dermatol Surg 2002; 28: 1098-1099.
• 73 Wozniak G, Dapper F, Alemany J. Factor XIII in ulcerative leg disease: background and preliminary clinical results. Semin Thromb Hemost 1996; 22: 445-450.
• 74 Peschen M, Thimm C, Weyl A. et al. Possible role of coagulation factor XIII in the pathogenesis of venous leg ulcers. Vasa 1998; 27: 89-93.
• 75 Herouy Y, Hellstern MO, Vanscheidt W. et al. Factor XIII-mediated inhibition of fibrinolysis and venous leg ulcers. Lancet 2000; 355: 1970-1971.
• 76 Gemmati D, Federici F, Catozzi L. et al. DNA-array of gene variants in venous leg ulcers: detection of prognostic indicators. J Vasc Surg 2009; 50: 1444-1451.
• 77 Ariens RA, Philippou H, Nagaswami C. et al. The factor XIII V34L polymorphism accelerates thrombin activation of factor XIII and affects cross-linked fibrin structure. Blood 2000; 96: 988-995.
• 78 Balogh I, Szoke G, Karpati L. et al. Val34Leu polymorphism of plasma factor XIII: biochemistry and epidemiology in familial thrombophilia. Blood 2000; 96: 2479-2486.
• 79 Anwar R, Gallivan L, Edmonds SD. et al. Genotype/phenotype correlations for coagulation factor XIII: specific normal polymorphisms are associated with high or low factor XIII specific activity. Blood 1999; 93: 897-905.
• 80 Nahrendorf M, Hu K, Frantz S. et al. Factor XIII deficiency causes cardiac rupture, impairs wound healing, and aggravates cardiac remodeling in mice with myocardial infarction. Circulation 2006; 113: 1196-1202.
• 81 Nahrendorf M, Aikawa E, Figueiredo JL. et al. Transglutaminase activity in acute infarcts predicts healing outcome and left ventricular remodelling: implications for FXIII therapy and antithrombin use in myocardial infarction. Eur Heart J 2008; 29: 445-454.
• 82 Nahrendorf M, Weissleder R, Ertl G. Does FXIII deficiency impair wound healing after myocardial infarction?. PLoS One 2006; 01: e48.
• 83 Muszbek L, Bereczky Z, Bagoly Z. et al. Factor XIII: a coagulation factor with multiple plasmatic and cellular functions. Physiol Rev 2011; 91: 931-972.
• 84 Myneni VD, Hitomi K, Kaartinen MT. Factor XIII-A transglutaminase acts as a switch between preadipocyte proliferation and differentiation. Blood 2014; 124: 1344-1353.
• 85 Cui C, Wang S, Myneni VD. et al. Transglutaminase activity arising from Factor XIIIA is required for stabilization and conversion of plasma fibronectin into matrix in osteoblast cultures. Bone 2014; 59: 127-138.
• 86 Barry EL, Mosher DF. Factor XIII cross-linking of fibronectin at cellular matrix assembly sites. J Biol Chem 1988; 263: 10464-10469.
• 87 Al-Jallad HF, Myneni VD, Piercy-Kotb SA. et al. Plasma membrane factor XIIIa transglutaminase activity regulates osteoblast matrix secretion and deposition by affecting microtubule dynamics. PLoS ONE 2011; 6.
• 88 Meningitis Research Foundation: Race against time: meningitis and septicaemia can kill in hours, know the symptoms. Available at http://www.meningitis.org/assets/x/51490 Accessed August 2, 2014.
• 89 Welch SB, Nadal S. Treatment of meningococcal infection. Arch Dis Child 2003; 88: 608-614.
• 90 Tunkel AR, Hartman BJ, Kaufman BA. et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis 2004; 39: 1267-1284.
• 91 Busso N, Hamilton JA. Extravascular coagulation and the plasminogen activator/ plasmin system in rheumatoid arthritis. Arthritis Rheum 2002; 46: 2268-2279.
• 92 Hoppe B. Fibrinogen and factor XIII at the intersection of coagulation, fibrinolysis and inflammation. Thromb Haemost 2014; 112.