The polymorphism of platelet membrane integrin α2β1 (α2807TT) is associated with premature onset of fetal loss

Summary

Inherited thrombophilia could increase susceptibility to adverse pregnancy outcomes such as fetal loss. We determined the G1691A mutation of the factorV gene (FVL), the G20210A mutation of the prothrombin gene, the C677T polymorphism of the methylenetetrahydrofolate-reductase (MTHFR) gene, the HPA-1 polymorphism of the β₃ subunit of the platelet integrin α_IIbβ₃ and the C807T polymorphism of the α₂ subunit of integrin α₂ β₁ in 104 women with fetal loss and 277 normal women. In a subgroup analysis of women with recurrent early fetal loss (n=34), the prevalence of the genetic markers did not differ significantly between the women with early fetal loss and the normal women. However, in this subgroup of patients the onset of fetal loss was significantly earlier in women with the α₂807TT genotype (7.1 ± 1.9 vs. 8.8 ± 1.5 weeks, p=0.001). No such significant difference was observed in carriers of the other genetic markers. In the subgroup analysis of women with late fetal loss (n=70), only the prevalence of heterozygous FVL was significantly associated with late fetal loss (odds ratio 3.2, p=0.002). There was no significant association of any genetic risk factor with premature fetal loss in the subgroup analysis of women with at least one late miscarriage.This study demonstrates a significant association of the α₂ 807TT genotype of the platelet membrane integrin α₂β₁ with premature onset of early fetal loss. It appears that this risk factor does not induce the pathomechanism, but modulates the course of fetal loss. Furthermore, our study confirms the association of FVL with late fetal loss.

Keywords

Fetal loss - platelet receptor polymorphisms - HPA-1/Pl^A - α_IIbβ₃ - glycoprotein IIb-IIIa - α₂807TT genotype - α₂β₁ - glycoprotein Ia-IIa

 

• References

• 1 Preston FE, Rosendaal FR, Walker ID. et al Increased fetal loss in women with heritable thrombophilia. Lancet 1996; 348: 913-6.
• 2 Roberts JM, Taylor RN, Musici TJ. et al Preeclampsia: an endothelial cell disorder. Am J Obstet Gynecol 1989; 161: 1200-4.
• 3 Salafia CM, Pezzulo JC, Lopez-Zeno JA. et al Placental pathologic features of preterm pre-eclampsia. Am J Obstet Gynecol 1995; 173: 1079-105.
• 4 Shanklin DR, Sibai BM. Ultrastructural aspects of preeclampsia. I. Placental bed and uterine boundary vessels. Am J Obstet Gynecol 1989; 161: 735-41.
• 5 Khong TY, Pearce JM, Robertson WB. Acute atherosis in pre-eclampsia: maternal determination and fetal outcome in the presence of the lesion. Am J Obstet Gynecol 1987; 157: 360-3.
• 6 Salafia CM, Minior VK, Pezzulo JC. et al Intrauterine growth restriction in infants of less than thirtytwo weeks`s gestation: associated placental pathologic features. Am J Obstet Gynecol 1995; 173: 1049-57.
• 7 Green JR. Placental previa and abruptio placentae. In: Creasy RK, Resnik R, ed. Maternal Fetal Medicine: Principles and Practice. Philadelphia. WB Saunders 1994; 609-19.
• 8 Infante-Rievard C, David M, Gauthier R. et al Lupus anticoagulants, anticardiolpin antibodies and fetal loss. N Engl J Med 1991; 325: 1063-6.
• 9 Rai R. Is miscarriage a coagulopathy?. Curr Opin Obstet Gynecol 2003; 15: 265-8.
• 10 Rushton DI. Placental pathology in spontaneous miscarriage. In Beard RW, Sharp F. eds Early pregnancy loss: mechanisms and tratment. RCOG; London: 1988. pp 149-58.
• 11 Gris JC, Quere I, Monpeyroux F. et al Case-control study of the frequency of thrombophilic disorders in couples with late fetal loss and no thrombotic antecedent- the Nimes Obstetricians and Haematologists Study 5 (NOHA 5). Thromb Haemost 1999; 81: 891-9.
• 12 Rai RS, Regan L, Hitolie A et al. Placental thrombosis and second trimester miscarriage in association with activated protein C resistance. Brit J Obstet Gynecol 1996; 103: 842-4.
• 13 Younis JS, Ohel G, Brenner B. et al Familial thrombophilia – the scientific rationale for thromboprophylaxis in recurrent pregnancy loss?. Hum Reprod 1997; 12: 1389-90.
• 14 Kupferminc MJ, Eldor A, Steinmann N. et al Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 1999; 340: 9-13.
• 15 Rey E, Kahn SR, David M. et al Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 2003; 361: 901-8.
• 16 Bray PF. Platelet glycoprotein polymorphisms as risk factors for thrombosis. Curr Opin Hematol 2000; 7 (05) 284-9.
• 17 Zotz RB, Scharf RE. Platelet receptor polymorphism and their role in cardiovascular disease. J Lab Med 2002; 26: 584-93.
• 18 Zotz RB, Winkelmann BR, Nauck M. et al Polymorphism of platelet membrane glycoprotein IIIa: human platelet antigen 1b (HPA-1b/PlA2) is an inherited risk factor for premature myocardial infarction in coronary artery disease. Thromb Haemost 1998; 79 4: 731-5.
• 19 Vijayan KV, Goldschmidt-Clermont PJ, Roos C. et al The Pl(A2) polymorphism of integrin beta(3) enhances outside-in signaling and adhesive functions. J Clin Invest 2000; 105 (06) 793-802.
• 20 He L, Pappan K, Grenache DG. et al The contribution of the α 2 β 1 integrin to vascular thrombosis in vivo. Blood 2003; 102: 3652-7.
• 21 Goodall AH, Curzen N, Panesar M. et al Increased binding of fibrinogen to glycoprotein IIIa-proline33 (HPA-1b, PlA2, Zwb) positive platelets in patients with cardiovascular disease. Eur Heart J 1999; 20 (10) 742-7.
• 22 Ridker PM, Hennekens CH, Lindpaintner K. et al Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men. N Engl J Med 1995; 332: 912-7.
• 23 Poort SR, Rosendaal FR, Reitsma PH. et al A common genetic variation in the 3´untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and increase in venous thrombosis. Blood 1996; 88: 3698-703.
• 24 Frosst P, Blom HJ, Milos R. et al A candidate genetic risk factor for vascular disease in methylenetetrahydrofolate- reductase. Nat Genet 1995; 10: 111-3.
• 25 Unkelbach K, Kalb R, Santoso S. et al Genomic RFLP typing of human platelet alloantigens Zw(PlA), Ko, Bak and Br (HPA-1, 2, 3, 5). Br J Haematol 1995; 89 (01) 169-76.
• 26 Corral J, Rivera J, Gonzalez-Conejero R. et al The number of platelet glycoprotein Ia molecules is associated with the genetically linked 807 C/T and HPA-5 polymorphisms. Transfusion 1999; 39 (04) 372-8.
• 27 Littell R, Milliken GA, Stroup WW. et al SAS system for mixed models. SAS Institute Inc; Cary (USA): 1999
• 28 Kritzik M, Savage B, Nugent DJ. et al Nucleotide polymorphisms in the alpha2 gene define multiple alleles that are associated with differences in platelet alpha2 beta1 density. Blood 1998; 92: 2382-8.
• 29 Kunicki TJ, Orchekowski R, Annis D. et al Variability of integrin alpha 2 beta 1 activity on human platelets. Blood 1993; 82: 2693-703.
• 30 Kunicki TJ, Kritzik M, Annis DS. et al Hereditary variation in platelet integrin alpha 2 beta 1 density is associated with two silent polymorphisms in the alpha 2 gene coding sequence. Blood 1997; 89: 1939-43.
• 31 Di Paola J, Federici AB, Mannucci PM. et al Low platelet α 2 β 1 levels in type I von Willebrand disease correlate with impaired platelet function in a high shear stress system. Blood 1999; 93: 3578-82.
• 32 Zygmunt M. Placental circulation: Clinical significance. Early Pregnancy 2001; 5 (01) 72-3.
• 33 Kwak JY, Beer AE, Kim SH. et al Immunopathology of the implantation site utilizing monoclonal antibodies to natural killer cells in women with recurrent pregnancy losses. Am J Reprod Immunol 1999; 41: 91-8.
• 34 Emmrich P, Seifert U. Pathologic-anatomic findings in spontaneous abortion and induced abortion during the 2nd pregnancy trimester. Zentralbl Allg Pathol 1990; 136 (05) 411-8.
• 35 Elices MJ, Hemler ME. The human integrin VLA-2 is a collagen receptor on some cells and a collagen/ laminin receptor on others. Proc Natl Acad Sci USA 1989; 86: 9906-10.
• 36 Kirchhofer D, Languino LR, Ruoslahti E. et al Alpha 2 beta 1 integrins from different cell types show different binding specificities. J Biol Chem 1990; 265: 615-8.