Antibodies against Fibrinogen in Pregnant Women, in Post Delivery Women and in the Newborns

Summary

Pregnancy and delivery have measurable effects on haemostatic and immunological changes. Degradation of fibrinogen induces significant structural and conformational modulation and leads to the progressive loss of antigenic sites present on the parent molecule but also exposes some new sites. These neoantigens may be recognized by the immune system and may be elicited by the autologous host manifested by the production of autoantibodies. Therefore in the present study, in pregnant and post delivery women and in the newborns, levels of antibodies against fibrinogen, fibrin(ogen) degradation products (FDP) and fibrin degradation products (D-dimer) were examined.

Enzyme immunoassay (ELISA) was used to detect and quantitate autoantibodies against fibrinogen (class G immunoglobulin) in human sera. In all sera there were found varying concentrations of autoantibodies and their levels were significantly higher in all pregnant women in comparison with non-pregnant ones. Significantly higher levels were found in Rh immunized and clinically complicated pregnancies.

The level of autoantibodies, coagulation and fibrinolytic system components were higher in post delivery women than in normal pregnant women. Also antibodies to fibrinogen were studied in cord serum of newborns in different terms of delivery. The low levels of antibodies in all newborns raise questions of possible foetal-maternal immunologic interactions. Positive correlation between mothers and newborns was demonstrated after delivery at gestational age from 34th to 41st week, and negative in 42nd and more week. There were no significant differences in antibody level among the newborns delivered by the same mothers.

It was found that autoantibodies bind selectively to the fibrinogen and fibrinogen fragments X, Y and D. These autoantibodies may represent a new interface between the coagulation and the immune systems which may be significant in controlling the pathologic activities of the cleavage fragments.

• References

• 1 Halligan A, Bonnar J, Sheppard B, Darling M, Walshe J. Haemostatic, fibrinolytic and endothelial variables in normal pregnancies and pre-eclampsia. Br J Obstet Gynaecol 1994; 101: 488-92.
• 2 Estelles A, Gilabert J, Espana F, Aznar J, Galbis M. Fibrinolytic parameters in normotensive pregnancy with intrauterine fetal growth retardation and in severe preeclampsia. Am J Obstet Gynecol 1991; 165: 138-42.
• 3 Ho CH, Yang ZL. The predictive value of the hemostasis parameters in the development of preeclampsia. Thromb Haemost 1992; 67: 214-8.
• 4 Blombäck B, Hessel B, Hogg P. Disulfide bridges in NH 2-terminal part of human fibrinogen. Thromb Res 1976; 8: 639-58.
• 5 Plow EF, Edgington TS. Immunobiology of fibrinogen. Emergence of neoantigenic expressions during physiologic cleavage in vitro and in vivo. J Clin Invest 1973; 52: 273-82.
• 6 Wilner GD, Hsieh KH, Thomas DW. Immunology of fibrinogen: Comparisons of serologic and cellular immune responses to human fibrinopeptide B (hFPB). Ann NY Acad Sci 1981; 370: 528-35.
• 7 Brönnimann R. Kongenitale Afibrinogenämie. Mitteilung eines Falles mit multiplen Knochenzysten und Bildung eines spezifischen Antikörpers (Antifibrinogen) nach Bluttransfusionen. Acta Haematol 1954; 11: 40-51.
• 8 Plow EF, Edgington TS. Immune responses to the cleavage associated neo-antigens of fibrinogen in man. Identification and characterization of humoral antibodies specific for cleavage fragments. J Clin Invest 1975; 56: 1509-18.
• 9 Whitaker AN, McFarlane JR, Rowe EA, Lee K, Masci PP. Measurement of autoantibodies against fibrinogen and fibrin degradation products by enzyme-linked immunoassay. Thromb Haemost 1985; 53: 80-5.
• 10 Michalski A, Kondera-Anasz Z, Gonciarz Z. Autoantibodies against fibrinogen during interferon therapy in patients with chronic viral hepatitis. Int J Gastroenterol Hepatol 1995; 2 Suppl 226-7.
• 11 Mac Lean MA, Wilson R, Thompson JA, Krishnamurthy S, Walker JJ. Changes in immunologic parameters in normal pregnancy and spontaneous abortion. Am J Obstet Gynecol 1991; 165: 890-5.
• 12 Cierniewski CS, Plow E, Edgington TS. Conformation of the carboxy-terminal region of the A alfa-chain of fibrinogen as elucidated by immuno-chemical analyses. Eur J Biochem 1984; 141: 489-96.
• 13 Cierniewski CS, Janiak A, Nowak P, Augustyniak W. Reactivity of fibrinogen derivatives with antisera to human fibrin D-dimer and its γ-γ chain remnant. Thromb Haemost 1982; 48: 33-7.
• 14 Clauss A. Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acta Haemat 1957; 17: 237-46.
• 15 Itzhaki RF, Gill DMA. A microbiuret method for estimating proteins. Anal Biochem 1969; 9: 401-11.
• 16 Merskey C, Lalezari P, Johnson A. A rapid, simple, sensitive method for measuring fibrinolytic split products in human serum. Proc Soc Exp Biol 1969; 131: 871-80.
• 17 McDonagh J, Messel H, McDonagh RF, Murano G, Blombäck B. Molecu lar weight analysis of fibrinogen and fibrin chains by an improved sodium dodecyl sulfate gel electrophoresis method. Biochim Biophys Acta 1972; 257: 135-42.
• 18 Towbin H, Staehelin T, Gordon J. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci USA 1979; 76: 4350-4.
• 19 MacLean MA, Wilson R, Thomson JA, Krishnamurthy S, Walker JJ. Immunological changes in normal pregnancy. Eur J Obstet Gynecol Reprod Biol 1992; 43: 167-72.
• 20 Proietti AB, Johnson MJ, Proietti FA, Repke JT, Bell WR. Assessment of fibrin(ogen) degradation products in preeclampsia using immunoblot, enzyme-linked immunosorbent assay, and latex-bead agglutination. Obstet Gynecol 1991; 77: 696-700.
• 21 Van Wersch JWJ, Ubachs JMH. Blood coagulation and fibrinolysis during normal pregnancy. Eur J Clin Chem Clin Biochem 1991; 29: 45-50.
• 22 Lindoff C, Lecander J, Åstedt B. Fibrinolytic components in individual consecutive plasma samples during normal pregnancy. Fibrinolysis 1993; 7: 190-4.
• 23 Bremer HA, Brommer EJP, Wallenburg HCS. Effects of labor and delivery on fibrinolysis. Eur J Obstet Gynecol Reprod Biol 1994; 55: 163-8.
• 24 Bremme K, Östlund E, Almqvist I, Heinonen K, Blombäck M. Enhanced thrombin generation and fibrinolytic activity in normal pregnancy and the puerperium. Obstet Gynecol 1992; 80: 132-7.
• 25 Plow EF, Edgington TS. Surface makers of fibrinogen and its physiologic derivatives revealed by antibody probes. Semin Thromb Haemost 1982; 8: 36-56.
• 26 Levesque JP, Hatzfeld A, Hatzfeld D. Mitogenic properties of major extra-cellular proteins. Immunol Today 1991; 12: 258-62.
• 27 Stoll B, Lee FK, Hale E, Schwartz D, Holmes R, Ashby R, Czerkinsky C, Nahmias AJ. Immunoglobulin secretion by the normal and the infected newborn infant. J Pediatr 1993; 122: 780-6.
• 28 Bell SA, Du Clos TW, Khursigara G, Picazo JJ, Rubin RL. Autoantibodies to cryptic epitopes of C-reactive protein and other acute phase proteins in the toxic oil syndrome. J Autoimmun 1995; 8: 293-303.
• 29 De Vries A, Rosenberg T, Kochwa S, Boss J. Precipitating antifibrinogen antibody appearing after fibrinogen infusions in a patient with congenital afibrinogenemia. Am J Med 1961; 30: 486-94.
• 30 Ra’anani P, Levi Y, Varon D, Gitel S, Martinowitz U. Congenital afibrinogenemia with bleeding, bone cysts and antibodies to fibrinogen. Harefuah 1991; 121: 291-3.
• 31 Mammen EF, Schmidt KP, Barnhart MI. Thrombophlebitis migrans associated with circulating antibodies against fibrinogen. A case report. Thrombos Diathes Haemorrh 1967; 18: 605-11.
• 32 Marciniak E, Greenwood MF. Acquired coagulation inhibitor delaying fibrinopeptide release. Blood 1979; 1: 81-92.
• 33 Mertas A, Kondera-Anasz Z. Antifibrinogen antibodies in serum of blood recipients with post-transfusion reactions. Clin Biochem Revs 1993; 14: 199.
• 34 Ghosh S, McEvoy P, McVerry BA. Idiopathic autoantibody that inhibits fibrin monomer polymerization. Br J Haematol 1983; 53: 65-72.
• 35 Hoots WK, Carrell NA, Wagner RH, Cooper HA, McDonagh J. A naturally occurring antibody that inhibits fibrin polymerization. N Engl J Med 1981; 304: 857-61.
• 36 Rosenberg RD, Colman RW, Loand L. A new haemorrhagic disorder with defective fibrin stabilization and cryofibrinogenaemia. Br J Haematol 1974; 26: 269-84.
• 37 Ruiz-Arquelles A. Spontaneous reversal of acquired autoimmune dysfibrinogenemia probably due to an antiidiotypic antibody directed to an interspecies cross-reactive idiotype expressed on antifibrinogen antibodies. J Clin Invest 1988; 82: 958-63.
• 38 Boreham PFL, Facer CA. Autoimmunity in trypanosome infections. II. Anti-fibrin/fibrinogen(Anti-F) autoantibody in Trypanosoma (Trypanozoon) brucei infections of the rabbit. Int J Parasitol 1974; 4: 601-7.
• 39 Thoongsuwan S, Cox HW, Rickman WJ. Antibody to fibrinogen/fibrin products (anti-F) in malaria, babesiosis and trypanosomiasis of rodents. J Parasitol 1979; 65: 426-9.