Use of a Low-Molecular Weight Heparin (Enoxaparin) or of a Phenformin-like Substance (Moroxydine Chloride) in Primary Early Recurrent Aborters with an Impaired Fibrinolytic Capacity

Summary

An impaired fibrinolytic capacity, defined as an insufficient venous occlusion-induced shortening of the plasma euglobulin clot lysis time, is a common feature in women suffering from primary early recurrent unexplained miscarriages (1,2). We investigated the therapeutic effect of a low-molecular-weight heparin and of a phenformin-like substance.

In a prospective, randomized trial, 30 consecutive patients initially received either enoxaparin, 20 mg per day during one month, or moroxydine chloride, 1200 mg per day during one month. In case of fibrinolytic status normalization, they were treated during 6 months by the beneficial treatment which was planned to be continued during eventual pregnancies. Patients with hypofibrinolysis persistence received the alternative treatment during another month and a new evaluation was performed. No treatment was given when a persistent abnormal response to the venous occlusion test was evidenced. In case of positive response, the treatment was continued during 6 months. The primary study end-points consisted of any of the following: effect of the treatments on the fibrinolytic response; number of patients becoming pregnant during the 6 months following the last venous occlusion test; number of full-term pregnancies.

Concerning the effects on the fibrinolytic system, 20 out of 29 women responded to the first or second-line enoxaparin treatment whereas only 1 woman out of 19 responded to moroxydine chloride (p=0.00002). Concerning the effects on fertility, responders to LMWH were more likely to initiate a new pregnancy than non-responders (16/20 vs 2/10, p=0.002). In patients conceiving, LMWH responders were more likely to obtain live births than nonresponders (13/16 vs. 0/2, p=0.02). The 9 women who had not responded to both treatments and the one who had responded to moroxydine chloride are still childless. Thirteen of the 20 previously childless women who had responded to enoxaparin had a successful pregnancy whilst taking the low-molecular weight heparin (p=0.0009).

The low-molecular weight heparin enoxaparin was associated with successful pregnancies in patients with recurrent unexplained miscarriages associated with an impaired fibrinolytic capacity.

• References

• 1 Gris JC, Schved JF, Neveu S, Aguilar-Martinez P, Dupaigne D, Marès P. Impaired fibrinolytic capacity and early recurrent spontaneous abortion. Br Med J 1990; 300: 1500
• 2 Gris JC, Neveu S, Marès P, Biron C, Schved JF. Plasma fibrinolytic activators and their inhibitors in women suffering from early recurrent abortion of unknown etiology. J Lab Clin Med 1993; 122: 606-615
• 3 Stray-Pederson B, Stray-Pederson S. Etiologie factors and subsequent reproductive performances in 195 couples with a prior history of habitual abortion. Am J Obstet Gynecol 1984; 148: 142-146
• 4 Mills JL, Simpson JL, Driscoll SG. Incidence of spontaneous abortion among normal women and insulin-dependent diabetic women whose pregnancy where identified within 21 days of conception. N Engl J Med 1988; 319: 1617-1623
• 5 Lejeune B, Grun JP, DeNayer P, Servais G, Glinoer D. Antithyroid antibodies underlying thyroid abnormalities and miscarriage or pregnancy-induced hypertension. Br J Obstet Gynaecol 1993; 100: 669-672
• 6 Hjort TT. Autoimmunity to sperm. In: Male infertility. Hargreave J. ed. Berlin: Springer Verlag; 1988. pp 160-187
• 7 Triplett DA, Harris AN. Antiphospholipid antibodies and reproduction. AM J Reprod Immunol 1989; 21: 123-131
• 8 Asherson RA, Khamashtama MA, Ordi-Ros J. The “primary” antiphospholipid syndrome: major clinical and serological features. Medicine 1989; 68: 366-377
• 9 Schved JF, Gris JC, Neveu S, Dupaigne D, Marès P. Factor XII congenital deficiency and early spontaneous abortion. Fertil Steril 1989; 52: 335-336
• 10 Rodeghiero F, Castaman GC, DiBona E, Ruggeri M, Dini E. Successful pregnancy in a woman with congenital factor XIII deficiency treated with substitutive therapy. Blut 1987; 55: 45-48
• 11 Evron S, Auteby SO, Brezinsky A, Samneloff A, Eldor A. Congenital afibrinogenemia and recurrent early abortion. Eur J Obstet Gynecol Reprod Biol 1985; 19: 307-311
• 12 Tho TP, Byrd JR, McDunough PG. Etiologies and subsequent reproductive performances in 100 couples with recurrent abortion. Fertil Steril 1979; 32: 389-395
• 13 Nilsson IM, Ljungner H, Tengborn L. Two different mechanisms in patients with venous thrombosis and defective fibrinolysis: low concentrations of plasminogen activator or increased concentrations of plasminogen activator inhibitor. Br Med J 1985; 290: 1453-1455
• 14 Tengborn L, Hedner U, Nilsson IM. Prospective study of a phenformin-like substance (moroxydine chloride) in patients with deficient vessel wall fibri-nolysis. J Med 1982; 13: 353-364
• 15 Eriksson E, Ranby M, Gyzander E, Risberg B. Determination of plasminogen activator inhibitor in plasma using t-PA and a chromogenic single-point poly-D-lysine stimulated assay. Thromb Res 1988; 50: 91-101
• 16 Melissari E, Parker CJ, Wilson NV, Monte G, Kanthou C, Pemberton KD, Nicolaides KH, Barret JJ, Kakkar VV. Use of low molecular weight heparin in pregnancy. Thromb Haemost 1992; 68: 652-656
• 17 Juhan-Vague I, Valadier J, Alessi MC. Deficient t-PA release and elevated PA inhibitor levels in patients with spontaneous or recurrent deep vein thrombosis. Thromb Haemost 1987; 57: 67-72
• 18 Malm J, Laurell M, Nilsson IM, Dahlbäck B. Thromboembolism disease - Critical evaluation of laboratory investigations. Thromb Haemost 1992; 68: 7-13
• 19 Gris JC, Schved JF, Raffanel C, Dubois A, Balmès JL. Impaired fibrinolytic capacity in patients with imtlammatory bowell disease. Thromb Haemost 1990; 63: 472-475
• 20 Archipoff G, Beretz A, Freyssinet JM, Klein-Soyer C, Brisson C, Cazenave JP. Heterogeneous regulation of constitutive thrombomodulin or inducible tissue-factor activities on the surface of human saphenous-vein endothelial cells in culture following stimulationby interleukin-1, tumor necrosis factor, thrombin or phorbol ester. Biochem J 1991; 273: 679-684
• 21 Rushton DI. Placental pathology in spontaneous miscarriage. In: Early pregnancy loss. Beard RW, Sharp F. (eds) London: Springer; 1988. pp 149-157
• 22 Brox JH, Osterud B, Bjorklind E, Fenton JW. Production and availability of thromboplastin in endothelial cells: the effects of thrombin, endotoxin and platelets. Br J Haematol 1984; 57: 239-245
• 23 Slivka SR, Loskutoff D. Platelets stimulate endothelial cells to synthesize type 1 plasminogen activator inhibitor. Evaluation of the role of transforming growth factor beta Blood 1991; 77: 1013-1019
• 24 Glass RH. Degradation of extracellular matrix by mouse trophoblast outgrowth: a model for implantation. J Cell Biol 1983; 96: 1108-1117
• 25 Sappino AP, Huarte J, Belin D, Vassali JD. Plasminogen activators in tissue remodelling and invasion: mRNA localization in mouse ovaries and implanting embryos. J Cell Biol 1989; 109: 2471-2479
• 26 Yagle S, Parhar RS, Jeffrey JJ, Lala PK. Normal nonmetastatic human trophoblast cells share in vitro invasive properties of malignat cells. J Cell Physiol 1988; 136: 455-463
• 27 Feinberg RF, Lee-Chuan K, Haimowitz JE, Queenan Jr JT, Wun TC, Strauss III JF, Kliman HJ. Plasminogen activator inhibitor types 1 and 2 in human trophoblasts: PAI-1 is an immunocytochemical marker of invading throphoblasts. Lab Invest 1989; 61: 20-26
• 28 Konkle BA, Ginsburg D. The addition of endothelial cell growth factor and heparin to human umbilical vein endothelial cell cultures decreases plasminogen activator inhibitor-1 expression. J Clin Invest 1988; 82: 579-586
• 29 Almus FA, Rao LV M, Pendurthi UR, Quattrochi L, Rapaport SI. Mechanism for diminished tissue factor expression by endothelial cells cultured with heparin binding growth factor-1 and heparin. Blood 1981; 77: 1256-1262