Trombofilia y pérdida recurrente de embarazo
Palabras clave:
TROMBOFILIA, ABORTO
Resumen
La búsqueda de factores pro trombóticos que incidan en la pérdida recurrente de embarazo, ha adquirido en los últimos años un especial interés para hematólogos y obstetras. La identificación progresiva de las diferentes enfermedades trombofílicas constituye un desafío en el diagnóstico de nuevas causas que puedan ser responsables de la pérdida recurrente de la gestación. Se estudió una población de 115 mujeres con pérdida recurrente de embarazo en quienes se descartaron previamente causas hormonales, anatómicas, infecciosas o genéticas. En ellas se buscaron diferentes causas trombofílicas y se comparó con una población control. Dentro de los factores pro trombóticos estudiados se encontró una prevalencia significativamente mayor en los anticuerpos antifosfolípidos/anticoagulante lúpico, (p<0,0001, OR=8,85, IC95% 3,8-20,8), la lipoproteína (a) (p<0,0001, OR=6,05, IC95% 2,5-14,3), el factor V Leiden (p<0,005, OR=5, IC95% 1,5-21), el factor II G20210A (p< 0,005, OR=4, IC95% 1,4-11,5) y la variante homocigota de la MTHFR C677T (p= 0,0002, OR=2,4, IC95% 1,1-5,1). La asociación de dos o más factores de riesgo trombótico se observa en 65% de las pacientes por lo cual el estudio trombofílico de las mismas debe ser completo.
Citas
1) Bick RL, Madden J, Heller KB. Recurrent miscarriage: causes, evaluation, and treatment. Medscape Womens Health 1998; 3(3): 2.
2) Stirrat GM. Recurrent miscarriage. Lancet 1990; 336(8716): 673-5.
3) Blumenfield Z, Brenner B. Trombophilia-associated pregnancy wastage. Fertil Steril 1999; 72(5): 765-74.
4) Mc Coll MD, Walker ID, Greer IA. The role of inherited thrombophilia in venous thromboembolism associated with pregnancy. Br J Obstet Gynaecol 1999; 106(8): 756-66.
5) Beauchamp NJ, Daly ME, Hampton KK, Cooper PC, Preston FE, Peake IR. High prevalence of a mutation in the factor V gene within the U.K. population: relationship to activated protein C resistance and familial thrombosis. Br J Haematol 1994; 88(1): 219-22.
6) Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3’-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996; 88(10): 3698-703.
7) Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Mathews RG, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995; 10(1): 111-3.
8) Arnout J. Antiphospholipid syndrome: diagnostic aspects of lupus anticoagulant. Thromb Haemost 2001; 86(1): 83-91.
9) Greer IA. The challenge of thrombophilia in maternal-fetal medicine. N Engl J Med 2000; 342(6): 424-5.
10) Lockshin MD. Pregnancy loss in the antiphospholipid syndrome. Thromb Haemost 1999; 82(2): 641-8.
11) Infante-Rivard C, David M, Gauthier R, Rivard GE. Lupus anticoagulants, anticardiolipin antibodies and fetal loss. A case -control study. N Eng J Med 1991; 325(15): 1063-6.
12) Lynch A, Marlar R, Murphy J, Davila G, Santos M, Rutledge J, et al. Antiphospholipid antibodies predicting adverse outcome. A prospective study. Ann Intern Med 1994; 120(6): 470-5.
13) Bowie EJ, Thompson JH Jr, Pascuzzi CA, Owen CA Jr. Thrombosis in systemic lupus erithematosus despite circulating anticoagulants. J Lab Clin Med 1963; 42: 416-8.
14) Triplett DA, Brandt JT, Musgrave KA, Orr CA. The relationship between lupus anticoagulant and antibodies to phospholipid. JAMA 1988; 259(4): 550-3.
15) Asherson RA, Khamashta MA, Ordi-Ros J, Derksen RH, Machin SJ, Barquinero J, et al. The "primary" antiphospholipid syndrome: mayor clinical and serological features. Medicine (Baltimore) 1989; 68(6): 366-74.
16) Sheng Y, Kandiah DA, Krilis SA. Beta-2-glycoprotein: target antigen for antiphospholipid antibodies. Immunological and molecular aspects. Lupus 1998; 7 (Suppl 2): S5-9.
17) Hughes GRV. The antiphospholipid syndrome: ten years on. Lancet 1993; 342(8867): 341-4.
18) Rai R, Regan L, Hadley E, Dave M, Cohen H. Second-trimester pregnancy loss is associated with activated protein C resistance. Br J Haematol 1996; 92(2): 489-90.
19) Amengual O, Atsumi T, Khamashta MA, Hughes GR. The role of the tissue factor pathway in the hypercoagulable state in patients with the antiphospholipid syndrome. Thromb Haemost 1998; 79(2): 276-81.
20) Oosting JD, Derksen RH, Bobbink IW, Hackeng TM, Bouma BN, de Groot PG. Antiphospholipid antibodies directed against a combination of phospholipid with prothrombin, protein C, or protein S: an explanation for their pathogenic mechanism? Blood 1993; 81(10): 2618-25.
21) Rand JH, Wu XX. Antibody-mediated disruption of annexin-V antithrombotic shield: a new mechanism for thrombosis in the antiphospholipid syndrome. Thromb Haemost 1999; 82(2): 649-55.
22) Rand JH, Wu XX, Andree HA, Ross JB, Rusinova E, Gascon-Lema MG, et al. Antiphospholipid antibodies accelerate plasma coagulation by inhibiting annexin-V binding to phospholipid syndrome: a "lupus procoagulant" phenomenon. Blood 1998; 92(5): 1652-60.
23) Forastiero RR, Martinuzzo ME, Kordich LC, Carreras LO. Reactivity to beta 2 glycoprotein I clearly differentiates anticardiolipin antibodies from phospholipid syndrome and syphilis. Thromb Haemost 1996; 75(5): 717-20.
24) Matsuda J, Saitoh N, Gohchi K, Tsukamoto M. Anti-annexin V antibody in systemic lupus erythematosus patients with lupus anticoagulant and/or anticardiolipin antibody. Am J Hematol 1994; 47(1): 56-8.
25) Kupferminc MJ, Eldor A, Steinman N, Many a, Bar-Arm A, Jaffa A, et al. Increased frecuency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 1999; 340(1): 9-13.
26) Miller GJ. Lipoproteins and haemostatic system in the atherothrombotic disorders. Baillieres Best Pract Res Clin Haematol 1999; 12(3): 555-75.
27) Bostom AG, Gagnon DR, Cupples LA, Wilson PW, Jenner JL, Ordovas JM, et al. A prospective investigation of elevated lipoprotein (a) detected by electrophoresis and cardiovascular disease in women: The Framingham Heart Study. Circulation 1994; 90(4): 1688-95.
28) Nowak-Gottl U, Sonntag B, Junker R, Cirkel U, von Eckardstein A. Evaluation of lipoprotein (a) and genetic prothrombotic risk factors in patients with recurrent fetal loss. Thromb Haemost 2000; 83(2): 350-1.
29) Ogunyemi D, Ku W, Arkel Y. The association between inherited thrombophilia, antiphospholipid antibodies and lipoprotein A levels with obstetrical complications in pregnancy. J Thromb Thrombolysis 2002; 14(2): 157-62.
30) Sattar N, Clark P, Greer IA, Shepherd J, Packard CJ. Lipoprotein (a) levels in normal pregnancy and in pregnancy complicated with preeclampsia. Atherosclerosis 1999; 148(2): 407-11.
31) van Pampus MG, Koopman MM, Wolf H, Buller HR, Prins MH, van den Ende A. Lipoprotein (a) concentrations in women with a history of severe preeclampsia: a case control study. Thromb Haemost 1999; 82(1): 10-3.
32) Brenner B, Sarig G, Weiner Z, Younis J, Blumenfeld Z, Lanir N. Thrombophilic polimorphisms are common in women with fetal loss without apparent cause. Thromb Haemost 1999; 82(1): 6-9.
33) van der Molen EF, Arends GE, Nelen WL, van der Put NJ, Heil SG, Eskes TK, et al. A common mutation in the 5, 10-methylenetrahydrofolate reductase gene as a new risk factor for placental vasculopathy. Am J Obstet Gynecol 2000; 182(5): 1258-63.
34) Bokarewa MI, Bremme K, Blomback M. Arg 506-Gln mutation in factor V and risk of thrombosis during pregnancy. Br J Haematol 1996; 92(2): 473-8.
35) Grandone E, Margaglione M, Colaizzo D, d’Addedda M, Capucci G, Vecchione G, et al. Factor V Leiden mutation is associated with repeated and recurrent unexplained fetal losses. Thromb Haemost 1997; 77(5): 822-4.
36) Kutteh WH, Park VM, Deitcher SR. Hypercoagulable state mutation analysis in white patient with early first-trimester recurrent pregnancy loss. Fertil Steril 1999; 71(6): 1048-53.
37) McColl MD, Ellison J, Reid F, Tait RC, Walker ID, Greer IA. Prothrombin G/20210A, MTHFR C677T mutations in women with venous thromboembolism associated with pregnancy. Br J Obstet Gynecol 2000; 107(4): 565-9.
38) Brenner B, Sarig G, Weiner Z, Younis J, Blumenfeld Z, Lanir N. Thrombophilic polimorphisms in women with fetal loss. Blood 1998; 92 (Suppl 1): 558a.
39) Deitcher SR, Park VM, Kutteh WH. Prothrombin 20210A mutation analysis in Caucasian women with early first trimester recurrent pregnancy loss. Blood 1998; 92 (Suppl 1): S250.
40) van der Molen EF, Verbruggen B, Novakova I, Eskes TK, Monnens LA, Blom HJ. Hyperhomocysteinemia and other thrombotic risk factors in women with placental vasculopaty. BJOG 2000; 107(6): 785-91.
41) Lens D, Otero AM, Brugnini A, Henry S, Trías N, Díaz A. Prevalence of FV Leiden, prothrombin 20210A and the thermolabile MTHFR in the Uruguayan population. Thromb Haemost 2001; 86 (Suppl): P668.
42) Volsett SE, Bjorke-M AAL, Igrens LM. Plasma total homocysteine and previous pregnancies: the Hordalnd homocysteine study. Proceedings of the 2nd International Symposium on Homocysteine. Neth J Med 1998; 52: 854.
43) Zoller B, Berntsdotter A, Garcia de Frutos P, Dahlback B. Resistance to activated protein C as an additional genetic risk factor in hereditary deficiency of protein S. Blood 1995; 85(12): 3518-23.
44) Mandel H, Brenner B, Berant M, Rosenberg N, Lanir N, Jakobs C, et al. Coexistence of hereditary homocystinuria and factor V Leiden-effect on thrombosis. N Eng J Med 1996; 334(12): 763-8.
45) Otero AM, Pou Ferrari R, Dellepiane M, Muxi P, De Lisa E, Attarian D, et al. Pregnancy outcome in women with recurrent pregnant loss treated with enoxaparin. Thromb Hemost 2001; 86 (Suppl): P3029.
46) Sorensen HT, Johnsen SP, Larsen H, Pedersen L, Nielsen GL, Moller M. Birth outcomes in pregnant women treated with low-molecular-weight heparin. Acta Obstet Gynecol Scand 2000; 79(8): 655-9.
47) Brenner B, Hoffman R, Blumenfeld Z, Weiner Z, Younis JS. Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin. Thromb Haemost 2000; 83(5): 693-7.
2) Stirrat GM. Recurrent miscarriage. Lancet 1990; 336(8716): 673-5.
3) Blumenfield Z, Brenner B. Trombophilia-associated pregnancy wastage. Fertil Steril 1999; 72(5): 765-74.
4) Mc Coll MD, Walker ID, Greer IA. The role of inherited thrombophilia in venous thromboembolism associated with pregnancy. Br J Obstet Gynaecol 1999; 106(8): 756-66.
5) Beauchamp NJ, Daly ME, Hampton KK, Cooper PC, Preston FE, Peake IR. High prevalence of a mutation in the factor V gene within the U.K. population: relationship to activated protein C resistance and familial thrombosis. Br J Haematol 1994; 88(1): 219-22.
6) Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3’-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996; 88(10): 3698-703.
7) Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Mathews RG, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995; 10(1): 111-3.
8) Arnout J. Antiphospholipid syndrome: diagnostic aspects of lupus anticoagulant. Thromb Haemost 2001; 86(1): 83-91.
9) Greer IA. The challenge of thrombophilia in maternal-fetal medicine. N Engl J Med 2000; 342(6): 424-5.
10) Lockshin MD. Pregnancy loss in the antiphospholipid syndrome. Thromb Haemost 1999; 82(2): 641-8.
11) Infante-Rivard C, David M, Gauthier R, Rivard GE. Lupus anticoagulants, anticardiolipin antibodies and fetal loss. A case -control study. N Eng J Med 1991; 325(15): 1063-6.
12) Lynch A, Marlar R, Murphy J, Davila G, Santos M, Rutledge J, et al. Antiphospholipid antibodies predicting adverse outcome. A prospective study. Ann Intern Med 1994; 120(6): 470-5.
13) Bowie EJ, Thompson JH Jr, Pascuzzi CA, Owen CA Jr. Thrombosis in systemic lupus erithematosus despite circulating anticoagulants. J Lab Clin Med 1963; 42: 416-8.
14) Triplett DA, Brandt JT, Musgrave KA, Orr CA. The relationship between lupus anticoagulant and antibodies to phospholipid. JAMA 1988; 259(4): 550-3.
15) Asherson RA, Khamashta MA, Ordi-Ros J, Derksen RH, Machin SJ, Barquinero J, et al. The "primary" antiphospholipid syndrome: mayor clinical and serological features. Medicine (Baltimore) 1989; 68(6): 366-74.
16) Sheng Y, Kandiah DA, Krilis SA. Beta-2-glycoprotein: target antigen for antiphospholipid antibodies. Immunological and molecular aspects. Lupus 1998; 7 (Suppl 2): S5-9.
17) Hughes GRV. The antiphospholipid syndrome: ten years on. Lancet 1993; 342(8867): 341-4.
18) Rai R, Regan L, Hadley E, Dave M, Cohen H. Second-trimester pregnancy loss is associated with activated protein C resistance. Br J Haematol 1996; 92(2): 489-90.
19) Amengual O, Atsumi T, Khamashta MA, Hughes GR. The role of the tissue factor pathway in the hypercoagulable state in patients with the antiphospholipid syndrome. Thromb Haemost 1998; 79(2): 276-81.
20) Oosting JD, Derksen RH, Bobbink IW, Hackeng TM, Bouma BN, de Groot PG. Antiphospholipid antibodies directed against a combination of phospholipid with prothrombin, protein C, or protein S: an explanation for their pathogenic mechanism? Blood 1993; 81(10): 2618-25.
21) Rand JH, Wu XX. Antibody-mediated disruption of annexin-V antithrombotic shield: a new mechanism for thrombosis in the antiphospholipid syndrome. Thromb Haemost 1999; 82(2): 649-55.
22) Rand JH, Wu XX, Andree HA, Ross JB, Rusinova E, Gascon-Lema MG, et al. Antiphospholipid antibodies accelerate plasma coagulation by inhibiting annexin-V binding to phospholipid syndrome: a "lupus procoagulant" phenomenon. Blood 1998; 92(5): 1652-60.
23) Forastiero RR, Martinuzzo ME, Kordich LC, Carreras LO. Reactivity to beta 2 glycoprotein I clearly differentiates anticardiolipin antibodies from phospholipid syndrome and syphilis. Thromb Haemost 1996; 75(5): 717-20.
24) Matsuda J, Saitoh N, Gohchi K, Tsukamoto M. Anti-annexin V antibody in systemic lupus erythematosus patients with lupus anticoagulant and/or anticardiolipin antibody. Am J Hematol 1994; 47(1): 56-8.
25) Kupferminc MJ, Eldor A, Steinman N, Many a, Bar-Arm A, Jaffa A, et al. Increased frecuency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 1999; 340(1): 9-13.
26) Miller GJ. Lipoproteins and haemostatic system in the atherothrombotic disorders. Baillieres Best Pract Res Clin Haematol 1999; 12(3): 555-75.
27) Bostom AG, Gagnon DR, Cupples LA, Wilson PW, Jenner JL, Ordovas JM, et al. A prospective investigation of elevated lipoprotein (a) detected by electrophoresis and cardiovascular disease in women: The Framingham Heart Study. Circulation 1994; 90(4): 1688-95.
28) Nowak-Gottl U, Sonntag B, Junker R, Cirkel U, von Eckardstein A. Evaluation of lipoprotein (a) and genetic prothrombotic risk factors in patients with recurrent fetal loss. Thromb Haemost 2000; 83(2): 350-1.
29) Ogunyemi D, Ku W, Arkel Y. The association between inherited thrombophilia, antiphospholipid antibodies and lipoprotein A levels with obstetrical complications in pregnancy. J Thromb Thrombolysis 2002; 14(2): 157-62.
30) Sattar N, Clark P, Greer IA, Shepherd J, Packard CJ. Lipoprotein (a) levels in normal pregnancy and in pregnancy complicated with preeclampsia. Atherosclerosis 1999; 148(2): 407-11.
31) van Pampus MG, Koopman MM, Wolf H, Buller HR, Prins MH, van den Ende A. Lipoprotein (a) concentrations in women with a history of severe preeclampsia: a case control study. Thromb Haemost 1999; 82(1): 10-3.
32) Brenner B, Sarig G, Weiner Z, Younis J, Blumenfeld Z, Lanir N. Thrombophilic polimorphisms are common in women with fetal loss without apparent cause. Thromb Haemost 1999; 82(1): 6-9.
33) van der Molen EF, Arends GE, Nelen WL, van der Put NJ, Heil SG, Eskes TK, et al. A common mutation in the 5, 10-methylenetrahydrofolate reductase gene as a new risk factor for placental vasculopathy. Am J Obstet Gynecol 2000; 182(5): 1258-63.
34) Bokarewa MI, Bremme K, Blomback M. Arg 506-Gln mutation in factor V and risk of thrombosis during pregnancy. Br J Haematol 1996; 92(2): 473-8.
35) Grandone E, Margaglione M, Colaizzo D, d’Addedda M, Capucci G, Vecchione G, et al. Factor V Leiden mutation is associated with repeated and recurrent unexplained fetal losses. Thromb Haemost 1997; 77(5): 822-4.
36) Kutteh WH, Park VM, Deitcher SR. Hypercoagulable state mutation analysis in white patient with early first-trimester recurrent pregnancy loss. Fertil Steril 1999; 71(6): 1048-53.
37) McColl MD, Ellison J, Reid F, Tait RC, Walker ID, Greer IA. Prothrombin G/20210A, MTHFR C677T mutations in women with venous thromboembolism associated with pregnancy. Br J Obstet Gynecol 2000; 107(4): 565-9.
38) Brenner B, Sarig G, Weiner Z, Younis J, Blumenfeld Z, Lanir N. Thrombophilic polimorphisms in women with fetal loss. Blood 1998; 92 (Suppl 1): 558a.
39) Deitcher SR, Park VM, Kutteh WH. Prothrombin 20210A mutation analysis in Caucasian women with early first trimester recurrent pregnancy loss. Blood 1998; 92 (Suppl 1): S250.
40) van der Molen EF, Verbruggen B, Novakova I, Eskes TK, Monnens LA, Blom HJ. Hyperhomocysteinemia and other thrombotic risk factors in women with placental vasculopaty. BJOG 2000; 107(6): 785-91.
41) Lens D, Otero AM, Brugnini A, Henry S, Trías N, Díaz A. Prevalence of FV Leiden, prothrombin 20210A and the thermolabile MTHFR in the Uruguayan population. Thromb Haemost 2001; 86 (Suppl): P668.
42) Volsett SE, Bjorke-M AAL, Igrens LM. Plasma total homocysteine and previous pregnancies: the Hordalnd homocysteine study. Proceedings of the 2nd International Symposium on Homocysteine. Neth J Med 1998; 52: 854.
43) Zoller B, Berntsdotter A, Garcia de Frutos P, Dahlback B. Resistance to activated protein C as an additional genetic risk factor in hereditary deficiency of protein S. Blood 1995; 85(12): 3518-23.
44) Mandel H, Brenner B, Berant M, Rosenberg N, Lanir N, Jakobs C, et al. Coexistence of hereditary homocystinuria and factor V Leiden-effect on thrombosis. N Eng J Med 1996; 334(12): 763-8.
45) Otero AM, Pou Ferrari R, Dellepiane M, Muxi P, De Lisa E, Attarian D, et al. Pregnancy outcome in women with recurrent pregnant loss treated with enoxaparin. Thromb Hemost 2001; 86 (Suppl): P3029.
46) Sorensen HT, Johnsen SP, Larsen H, Pedersen L, Nielsen GL, Moller M. Birth outcomes in pregnant women treated with low-molecular-weight heparin. Acta Obstet Gynecol Scand 2000; 79(8): 655-9.
47) Brenner B, Hoffman R, Blumenfeld Z, Weiner Z, Younis JS. Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin. Thromb Haemost 2000; 83(5): 693-7.
Publicado
2004-08-31
Cómo citar
1.
Otero AM, Pou Ferrari R, Pons E, Lens D, De Lisa E, Dellepiane M, Storch E, Attarian D, Ferrari A, Pierri S, Motta N. Trombofilia y pérdida recurrente de embarazo. Rev. Méd. Urug. [Internet]. 31 de agosto de 2004 [citado 13 de mayo de 2024];20(2):106-13. Disponible en: http://www2.rmu.org.uy/ojsrmu311/index.php/rmu/article/view/915
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