Thromb Haemost 1988; 60(02): 293-297
DOI: 10.1055/s-0038-1647047
Original Article
Schattauer GmbH Stuttgart

Fibrinolysis Resistant Fibrin Deposits in Lymph Nodes with Hodgkin's Disease

Róza Ádány
1   The Department of Clinical Chemistry, University School of Medicine, Debrecen, Hungary and
,
Andrea Szegedi
1   The Department of Clinical Chemistry, University School of Medicine, Debrecen, Hungary and
,
Richard J Ablin
2   The Department of Urology, School of Medicine, SUNY, Stony Brook, NY, USA
,
László Muszbek
1   The Department of Clinical Chemistry, University School of Medicine, Debrecen, Hungary and
› Author Affiliations
Further Information

Publication History

Received 30 March 1988

Accepted after revision 24 June 1988

Publication Date:
28 June 2018 (online)

Summary

Extravasal fibrin deposition is frequently observed within and around tumorous tissues and has been implicated in various aspects of tumor growth. However, no adequate information has been available on the mechanism how intratumoral interstitial fibrin deposits escape a prompt elimination by the fibrinolytic system. In this study we provide immunomorphological evidence showing that fibrin deposits in lymph nodes with Hodgkin's disease are stabilized and made resistant to fibrinolysis by factor XIII (FXIII) of blood coagulation. By double immuno- fluorescent labelling systems fibrin deposits were simultaneously stained for α2-antiplasmin (α2-AP), the main physiological inhibitor of fibrinolysis and in a number of nodular areas they were also labelled for plasmin (ogen). The detection of α2-antiplasmin-plasmin complex-neoantigen (α2-AP-P-Neo) revealed that α2-AP reacted with plasmin, i.e., α2-AP covalently linked to fibrin indeed inhibited intratumoral fibrinolysis. In addition to fibrin deposits FXIII was also found in cellular elements characterized earlier as tumor associated macrophages. These cells were attached to fibrin strands suggesting that they are involved in the intratumoral fibrin formation and might be a source of fibrin stabilizing factor in the tumor stroma.

 
  • References

  • 1 Rickies FR, Edwards RL. Activation of blood coagulation in cancer: Trousseau's syndrome revisited. Blood 1983; 62: 14-31
  • 2 Ambrus JL, Ambrus CM, Pickern J, Soldes S, Bross I. Hematologic changes and thromboembolic complications in neoplastic disease and their relationship to metastasis. J Med 1975; 6: 433-458
  • 3 Thornes RD, Edlow DW, Wood S. Inhibition of locomotion of cancer cells in vivo by anticoagulant therapy. - 1. Effects of sodium warfarin on V2 cancer cells granulocytes, lymphocytes and macrophages in rabbits. Johns Hopkins Med J 1968; 123: 305-310
  • 4 Cliffton EE, Grossi CE. The rationale of anticoagulants in the treatment of cancer. J Med 1974; 5: 107-113
  • 5 Schlager SI, Dray S. Complete local tumor regression with antibody to fibrin fragment E. J Immunol 1975; 115: 976-981
  • 6 Peterson HI. Fibrinolysis and antifibrinolytic drugs in the growth and spread of tumours. Cancer Treat Rev 1977; 4: 213-233
  • 7 Donati MB, Mussoni L, Poggi A, DeGaetano G, Garattini S. Growth and metastasis of the Lewis lung carcinoma in mice defibrinated with batroxobin. Eur J Cancer 1978; 14: 343-347
  • 8 Zacharski LR, Henderson WG, Rickies FR, Forman WB, Cornell CJ, Forcier RJ, Edwards R, Headley E, Kim SH, O'Donnell JR, O'Dell R, Tornyos K, Kwaan HC. Effect of warfarin on survival in small cell carcinoma of the lung. JAMA 1981; 245: 831-835
  • 9 Hiramoto R, Bernecky J, Jurandowski J, Pressman D. Fibrin in human tumors. Cancer Res 1960; 20: 592-593
  • 10 Chew EC, Wallace AC. Demonstration of fibrin in early stages of experimental metastases. Cancer Res 1976; 36: 1904-1909
  • 11 Harris NL, Dvorak AM, Smith J, Dvorak HF. Fibrin deposits in Hodgkin's disease. Am J Pathol 1982; 108: 119-129
  • 12 Dvorak HF, Senger DR, Dvorak AM. Fibrin as a component of the tumor stroma: origins and biological significance. Cancer Metast Rev 1983; 2: 41-73
  • 13 Nicolson GN. Cancer metastasis: Organ colonization and the cell surface properties of malignant cells. Biochim Biophys Acta 1982; 695: 113-176
  • 14 Duffy MJ, O'Grady PO. Plasminogen activator and cancer. Eur J Cancer Clin Oncol 1984; 20: 577-582
  • 15 Dano K, Andreasen PA, Grondahl-Hansen J, Kristensen P, Nielsen LS, Skrirer L. Plasminogen activators, tissue degradation and cancer. Adv Cancer Res 1985; 44: 139-166
  • 16 Sakata Y, Aoki N. Cross-linking of a2-plasmin inhibitor to fibrin by fibrin-stabilizing factor. J Clin Invest 1980; 65: 290-297
  • 17 Aoki N, Harpel PC. Inhibitors of the fibrinolytic enzyme system. Semin Thromb Hemostas 1984; 10: 24-41
  • 18 Jansen JWCM, Haverkate F, Koopman J, Nieuwenhuis HK, Kluft C, Boschman TAC. Influence of Factor XIII a activity on human whole blood clot lysis in vitro. Thromb Haemostas 1987; 57: 171-175
  • 19 Lukes RJ. Criteria for involvement of lymph node, bone marrow, spleen and liver in Hodgkin's disease. Cancer Res 1971; 31: 1755-1767
  • 20 Brown LF, Chester JF, Malt RA, Dvorak HF. Fibrin deposition in autochthonous Syrian hamster pancreatic adenocarcinomas induced by the chemical carcinogen N-nitroso-bis (2-oxopropyl) amine. J Natl Cancer Inst 1987; 78: 979-984
  • 21 Seitz R, Egbring R, Radtke KP, Wolf M, Fuchs G, Fischer J, Lerch L, Karges HE. The clinical significance of α1-antitrypsin-elastase (α1AT- ELP) and α2-antiplasmin-plasmin (α2P-PL) complexes for the differentiation of coagulation protein turnover: indications for plasma protein substitution in patients with septicaemia. Int J Uss Reac 1985; 7: 321-328
  • 22 Muszbek L, Ádány R, Szegedi G, Polgár J, Kávai M. Factor XIII of blood coagulation in human monocytes. Thromb Res 1985; 37: 401-410
  • 23 Ádány R, Nemes Z, Thomázy V, Muszbek L. Identification of factor XIII in macrophages invading lymph nodes with Hodgkin's disease. In: Haemostasis and Cancer Muszbek L. (ed) CRC Press; Boca Raton, CA: 1978: 115-124
  • 24 Ádány R, Nemes Z, Muszbek L. Characterization of factor XIII containing macrophages in lymph nodes with Hodgkin's disease. Br J Cancer 1987; 55: 421-426
  • 25 Gordon SG, Franks JJ, Lewis B. Cancer procoagulant A: A factor X activating procoagulant from malignant tissue. Thromb Res 1975; 6: 127-137
  • 26 Curatolo L, Colucci M, Cambini AL, Poggi A, Morasca L, Donati MB, Semeraro N. Evidence that cells from experimental tumours can activate coagulant factor X. Br J Cancer 1979; 40: 228-233
  • 27 Lorenzet R, Peri G, Locati D, Allavena P, Colucci M, Semeraro N, Mantovani A, Donati MB. Generation of procoagulant activity by mononuclear phagocytes: A possible mechanism contributing to blood clotting activation within malignant tissues. Blood 1983; 62: 271-273
  • 28 Guarini A, Acero R, Alessio G, Donati MB, Semeraro N, Mantovani A. Procoagulant activity of macrophages associated with different murine neoplasms. Int J Cancer 1984; 34: 581-586
  • 29 Layer GT, Burnand KG, Gaffney PJ, Cederholm-Williams SA, Mahmoud M, Houlbrook S, Pattison M. Tissue plasminogen activators in breast cancer. Thromb Res 1987; 45: 601-607
  • 30 Muszbek L, Laki K. Interaction of thrombin with proteins other than fibrinogen (thrombin susceptible bonds). Activation of FXIII. In: The Thrombin Machovich R. (ed) CRC Press; Boca Raton, CA: 1984: 321-342
  • 31 McDonagh RP, McDonagh J, Duckert F. The influence of fibrin crosslinking on the kinetics of urokinase-induced clot lysis. Br J Haematol 1971; 21: 323-324
  • 32 Sakata Y, Aoki N. Significance of cross-linking of α2-plasmin inhibitor to fibrin in inhibition of fibrinolysis and in hemostasis. J Clin Invest 1982; 69: 536-542
  • 33 Duckert F. Documentation of the plasma factor XIII deficiency in man. Ann NY Acad Sci 1972; 202: 190-199
  • 34 Aoki N, Saito H, Kamiya T, Koie K, Sakata Y, Kabakura M. Congenital deficiency of α 2--plasmin inhibitor associated with severe hemorrhagic tendency. J Clin Invest 1984; 63: 877-884
  • 35 Lorand L, Dickenman RC. Assay method for the “fibrin-stabilizing factor”. Proc Soc Exp Biol 1955; 89: 45-48
  • 36 Israels ED, Paraskevas F, Israels LG. Immunological studies of coagulation factor XIII. J Clin Invest 1973; 52: 2398-2403
  • 37 Greenberg CS, Schuman MA. The zymogen forms of blood coagulation factor XIII bind specifically to fibrinogen. J Biol Chem 1982; 257: 6096-6101
  • 38 Dvorak HF, Harvey S, McDonagh J. Quantitation of fibrinogen influx and fibrin deposition and turnover in line 1 and line 10 guinea pig carcinomas. Cancer Res 1984; 44: 3348-3354
  • 39 Henriksson P, Becker S, Lynch G, McDonagh J. Identification of factor XIII in human monocytes and macrophages. J Clin Invest 1985; 76: 528-534
  • 40 Ádány R, Belkin A, Vasilevskaya T, Muszbek L. Identification of blood coagulation factor XIII in human peritoneal macrophages. Eur J Cell Biol 1985; 38: 171-173
  • 41 Ádány R, Kappelmayer J, Muszbek L. Expression of FXIII subunit ain different types of human macrophages. In: The Biology of Phagocytes in Health and Disease Mauri C, Rizzo SC, Ricevuti G. (eds) Adv Biosci; 1987. (; 66). 323-333
  • 42 Kradin RL, Lynch GW, Kurnick JT, Erikson M, Colvin RB, McDonagh J. Factor XIII is synthetized and expressed on the surface of U937 cells and alveolar macrophages. Blood 1987; 69: 778-785
  • 43 Roth WJ, Fleit HB, Chung SI, Janoff A. Characterization of two distinct transglutaminases of murine bone marrow-derived macrophages. J Leuk Biol 1987; 42: 9-20
  • 44 Ádány R, Kiss A, Muszbek L. Factor XIII: a marker of mono- and megakariocytopoiesis. Br J Haematol 1987; 67: 167-172
  • 45 Osterud B, Lindahl U, Seljelid R. Macrophages produce blood coagulation factors. FEBS Lett 1980; 120: 41-43
  • 46 Lindahl U, Kolset SO, Bogwald J, Osterud B, Seljelid R. Studies with a luminogenic substrate on blood coagulation factor X/Xa produced by mouse peritoneal macrophages. Biochem J 1982; 206: 231-237
  • 47 Van Dam-Mieras MCE, Muller DA, Van Deik WA, Hemker H C. Clotting factors secreted by monocytes and macrophages: analytical considerations. Thromb Res 1985; 37: 9-19
  • 48 Chapman HA, Allen LC, Stone OL. Human alveolar macrophages synthesize factor VII in vitro. J Clin Invest 1985; 75: 2030-2037
  • 49 Shelley WB, Juhlin L. Induction of fibrin thrombi by monocytes. Nature 1977; 270: 343-344
  • 50 Hopper KE, Geczy CL, Davies CL. A mechanism of migration inhibition in delayed type hypersensitivity reactions. I. Fibrin deposition on the surface of elicited peritoneal macrophages in vivo. J Immunol 1981; 126: 1052-1057
  • 51 Ciano PS, Colvin RB, Dvorak AM, McDonagh J, Dvorak HF. Macrophage migration in fibrin gel matrices. Lab Invest 1986; 54: 62-70
  • 52 Brown JM. A study of the mechanism by which anticoagulation with warfarin inhibits blood-borne metastases. Cancer Res 1973; 33: 1217-1224
  • 53 Hilgard P, Schulte H, Wetzig G, Schmitt B, Schmidt CG. Oral anticoagulation in the treatment of a spontaneously metastasing murine tumor (3LL). Br J Cancer 1977; 35: 78-85
  • 54 Colvin RB, Dvorak HF. Role of the clotting system in cell mediated hypersensitivity. II. Kinetics of fibrinogen/fibrin accumulation and vascular permeability changes in tuberculin and cutaneous basophil hypersensitivity reactions. J Immunol 1975; 114: 377-387
  • 55 Clark RAF, Lanigan JM, DellaPelle P, Manseau E, Dvorak HF, Colvin RB. Fibronectin and fibrin provide a provisional matrix for epidermal cell migration during wound re-epithellization. J Invest Dermatol 1982; 79: 264-269
  • 56 Dvorak HF, Form DM, Manseau EJ, Smith BD. Pathogenesis of desmoplasia. I. Immunofluorescence identification and localization of some structural proteins of line 1 and line 10 guinea pig tumors and of healing wounds. J Natl Cancer Inst 1984; 73: 1195-1205
  • 57 Miura M, Tomino Y, Yagame M, Endoh M, Suga T, Nomoto Y, Sakai H. Immunofluorescent studies on alpha 2-plasmin inhibitor (α 2-PI) in glomeruli from patients with IgA nephropathy. Clin Exp Immunol 1985; 62: 380-386