Factor XIII Prevents Pulmonary Emboli in Mice by Stabilizing Deep Vein ThrombiFunding This study was partly funded by Canadian Venous Thromboembolism Clinical Trials and Outcomes research (CanVector). J.I. Weitz holds the Canada Research Chair (Tier I) in Thrombosis and the Heart and Stroke Foundation J. Fraser Mustard Chair in Cardiovascular Research. P.Y. Kim holds the Department of Medicine Career Award (McMaster University).
26 September 2018
22 February 2019
20 April 2019 (eFirst)
Background Deep vein thrombosis (DVT) can lead to pulmonary embolism (PE), but the mechanisms responsible for this progression are unknown. Previously, we showed that inhibition of thrombin-mediated activation of factor (F) XIII promotes venous thrombus stability in a murine model.
Aim In this study, we investigate the consequence of attenuating fibrinolysis, using FXIII, α2-antiplasmin (α2-AP) or ε-aminocaproic acid (EACA) supplementation, on clot lysis and venous thrombus stability using the same mouse model.
Methods In vitro plasma clot lysis assay shows that EACA and α2-AP but not FXIII, inhibit fibrinolysis. Ferric chloride induced thrombi in the femoral vein of mice. After thrombus formation, mice received saline, EACA, α2-AP or FXIII, with or without dalteparin or dabigatran. Thrombus sizes and embolization over 2 hours were visualized using intravital videomicroscopy. Lungs were sectioned to quantify emboli presence via histology.
Results The change in thrombus size over time was significantly greater after EACA treatment, but not FXIII or α2-AP supplementation, compared with saline. α2-AP-supplementation did not alter thrombus stability. Thrombi were more stable following EACA treatment and FXIII supplementation as evidenced by less embolic events and PE burden, even when they were anticoagulated with either dalteparin or dabigatran.
Conclusion FXIII supplementation stabilized venous thrombi, even in the presence of anticoagulants, and did not alter thrombus size. Supplemental FXIII may be useful to stabilize DVT and be an alternative adjunctive treatment to minimize PE, even when anticoagulants are used.
S.A.S. performed all experiments, analysed data and results and wrote the manuscript. D.M.G. performed the clot lysis assay. P.Y.K. designed and analysed the clot lysis data, and edited the manuscript. P.L.G. supervised the research, conceived and designed the study. P.L.G. and J.I.W. contributed to the interpretation of data and critically edited the manuscript. All authors have read and approved the article.
- 1 White RH. The epidemiology of venous thromboembolism. Circulation 2003; 107 (23) (Suppl. 01) I4-I8
- 2 Shaya SA, Saldanha LJ, Vaezzadeh N, Zhou J, Ni R, Gross PL. Comparison of the effect of dabigatran and dalteparin on thrombus stability in a murine model of venous thromboembolism. J Thromb Haemost 2016; 14 (01) 143-152
- 3 Inbal A, Lubetsky A, Krapp T. , et al. Impaired wound healing in factor XIII deficient mice. Thromb Haemost 2005; 94 (02) 432-437
- 4 Kurniawan NA, Grimbergen J, Koopman J, Koenderink GH. Factor XIII stiffens fibrin clots by causing fiber compaction. J Thromb Haemost 2014; 12 (10) 1687-1696
- 5 Wolberg AS, Campbell RA. Thrombin generation, fibrin clot formation and hemostasis. Transfus Apheresis Sci 2008; 38 (01) 15-23
- 6 Hethershaw EL, Cilia La Corte AL, Duval C. , et al. The effect of blood coagulation factor XIII on fibrin clot structure and fibrinolysis. J Thromb Haemost 2014; 12 (02) 197-205
- 7 Kagoma YK, Crowther MA, Douketis J, Bhandari M, Eikelboom J, Lim W. Use of antifibrinolytic therapy to reduce transfusion in patients undergoing orthopedic surgery: a systematic review of randomized trials. Thromb Res 2009; 123 (05) 687-696
- 8 Korte W. F. XIII in perioperative coagulation management. Best Pract Res Clin Anaesthesiol 2010; 24 (01) 85-93
- 9 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 (04) 927-939
- 10 Korte WC, Szadkowski C, Gähler A. , et al. Factor XIII substitution in surgical cancer patients at high risk for intraoperative bleeding. Anesthesiology 2009; 110 (02) 239-245
- 11 Singh S, Houng A, Reed GL. Releasing the brakes on the fibrinolytic system in pulmonary emboli: unique effects of plasminogen activation and α2-antiplasmin inactivation. Circulation 2017; 135 (11) 1011-1020
- 12 Lauer P, Metzner HJ, Zettlmeissl G. , et al. Targeted inactivation of the mouse locus encoding coagulation factor XIII-A: hemostatic abnormalities in mutant mice and characterization of the coagulation deficit. Thromb Haemost 2002; 88 (06) 967-974
- 13 Abdul S, Leebeek FW, Rijken DC, Uitte de Willige S. Natural heterogeneity of α2-antiplasmin: functional and clinical consequences. Blood 2016; 127 (05) 538-545
- 14 Kim PY, Stewart RJ, Lipson SM, Nesheim ME. The relative kinetics of clotting and lysis provide a biochemical rationale for the correlation between elevated fibrinogen and cardiovascular disease. J Thromb Haemost 2007; 5 (06) 1250-1256
- 15 Gross PL, Furie BC, Merrill-Skoloff G, Chou J, Furie B. Leukocyte-versus microparticle-mediated tissue factor transfer during arteriolar thrombus development. J Leukoc Biol 2005; 78 (06) 1318-1326
- 16 Bai X, Weitz JI, Gross PL. Leukocyte urokinase plasminogen activator receptor and PSGL1 play a role in endogenous arterial fibrinolysis. Thromb Haemost 2009; 102 (06) 1212-1218
- 17 Wienen W, Stassen JM, Priepke H, Ries UJ, Hauel N. In-vitro profile and ex-vivo anticoagulant activity of the direct thrombin inhibitor dabigatran and its orally active prodrug, dabigatran etexilate. Thromb Haemost 2007; 98 (01) 155-162
- 18 Francis CW, Marder VJ. Increased resistance to plasmic degradation of fibrin with highly crosslinked alpha-polymer chains formed at high factor XIII concentrations. Blood 1988; 71 (05) 1361-1365
- 19 Sakata Y, Aoki N. Cross-linking of alpha 2-plasmin inhibitor to fibrin by fibrin-stabilizing factor. J Clin Invest 1980; 65 (02) 290-297
- 20 Mimuro J, Kimura S, Aoki N. Release of alpha 2-plasmin inhibitor from plasma fibrin clots by activated coagulation factor XIII. Its effect on fibrinolysis. J Clin Invest 1986; 77 (03) 1006-1013
- 21 Mosesson MW, Siebenlist KR, Hernandez I, Lee KN, Christiansen VJ, McKee PA. 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; 6 (09) 1565-1570
- 22 Ichinose A, Aoki N. Reversible cross-linking of alpha 2-plasmin inhibitor to fibrinogen by fibrin-stabilizing factor. Biochim Biophys Acta 1982; 706 (02) 158-164
- 23 Tamaki T, Aoki N. Cross-linking of alpha 2-plasmin inhibitor and fibronectin to fibrin by fibrin-stabilizing factor. Biochim Biophys Acta 1981; 661 (02) 280-286
- 24 Karkouti K, McCluskey SA, Syed S, Pazaratz C, Poonawala H, Crowther MA. The influence of perioperative coagulation status on postoperative blood loss in complex cardiac surgery: a prospective observational study. Anesth Analg 2010; 110 (06) 1533-1540
- 25 Gödje O, Gallmeier U, Schelian M, Grünewald M, Mair H. Coagulation factor XIII reduces postoperative bleeding after coronary surgery with extracorporeal circulation. Thorac Cardiovasc Surg 2006; 54 (01) 26-33
- 26 Reynolds TC, Butine MD, Visich JE. , et al. Safety, pharmacokinetics, and immunogenicity of single-dose rFXIII administration to healthy volunteers. J Thromb Haemost 2005; 3 (05) 922-928
- 27 Visich JE, Zuckerman LA, Butine MD. , et al. Safety and pharmacokinetics of recombinant factor XIII in healthy volunteers: a randomized, placebo-controlled, double-blind, multi-dose study. Thromb Haemost 2005; 94 (04) 802-807
- 28 Ponce RA, Visich JE, Heffernan JK. , et al. Preclinical safety and pharmacokinetics of recombinant human factor XIII. Toxicol Pathol 2005; 33 (04) 495-506
- 29 Weitz JI, Hudoba M, Massel D, Maraganore J, Hirsh J. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest 1990; 86 (02) 385-391
- 30 Bates SM, Weitz JI. The mechanism of action of thrombin inhibitors. J Invasive Cardiol 2000; 12 (Suppl F): 27F-32
- 31 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 (05) 1564-1569
- 32 Caps MT, Meissner MH, Tullis MJ. , et al. Venous thrombus stability during acute phase of therapy. Vasc Med 1999; 4 (01) 9-14
- 33 Johnson BF, Manzo RA, Bergelin RO, Strandness Jr DE. Relationship between changes in the deep venous system and the development of the postthrombotic syndrome after an acute episode of lower limb deep vein thrombosis: a one- to six-year follow-up. J Vasc Surg 1995; 21 (02) 307-312
- 34 Franzeck UK, Schalch I, Bollinger A. On the relationship between changes in the deep veins evaluated by duplex sonography and the postthrombotic syndrome 12 years after deep vein thrombosis. Thromb Haemost 1997; 77 (06) 1109-1112
- 35 Kahn SR, Shrier I, Julian JA. , et al. Determinants and time course of the postthrombotic syndrome after acute deep venous thrombosis. Ann Intern Med 2008; 149 (10) 698-707
- 36 Malgor RD, Labropoulos N. Re-modelling of venous thrombosis. Phlebology 2013; 28 (Suppl. 01) 25-28
- 37 Modarai B, Burnand KG, Humphries J, Waltham M, Smith A. The role of neovascularisation in the resolution of venous thrombus. Thromb Haemost 2005; 93 (05) 801-809
- 38 Rallidis LS, Politou M, Komporozos C. , et al. Factor XIII Val34Leu polymorphism and the risk of myocardial infarction under the age of 36 years. Thromb Haemost 2008; 99 (06) 1085-1089
- 39 Kreutz RP, Bitar A, Owens J. , et al. Factor XIII Val34Leu polymorphism and recurrent myocardial infarction in patients with coronary artery disease. J Thromb Thrombolysis 2014; 38 (03) 380-387
- 40 Wells PS, Anderson JL, Rodger MA, Carson N, Grimwood RL, Doucette SP. The factor XIII Val34Leu polymorphism: is it protective against idiopathic venous thromboembolism?. Blood Coagul Fibrinolysis 2006; 17 (07) 533-538
- 41 Van Hylckama Vlieg A, Komanasin N, Ariëns RA. , et al. Factor XIII Val34Leu polymorphism, factor XIII antigen levels and activity and the risk of deep venous thrombosis. Br J Haematol 2002; 119 (01) 169-175