The Role of Platelets in the Formation of Immunological Tolerance in Recurrent Miscarriage

Objective of the Review: Аnalysis of literature and summarizing of data on the participation of platelets in the formation of immunological tolerance during the physiological pregnancy and recurrent miscarriage.
Key points. Platelet-derived soluble factors determine their involvement in the endocrine regulation of the placenta, initiate and maintain trophoblast invasion. Platelets are able to influence the balance of M1 and M2 macrophages, inhibit the cytotoxic potential of NK cells and the antigen-presenting ability of dendritic cells. The interaction of platelets with regulatory T cells initiates the recruitment of lymphocyte cells to the site of inflammation and their activation. It has been shown that the differentiation of immune cells and changes in their functional activity, aimed at creating conditions favorable for prolonging pregnancy, are largely determined by both platelet-derived soluble factors and the formation of platelet-leukocyte complexes.
Conclusion. Platelets and products of their activation play an important role in creating the conditions necessary for the onset of pregnancy and its prolongation to full term. The functional state of platelets determines the success of placentation both directly (through the control of hemodynamic parameters in the placental vessels, increased invasiveness of the extracellular trophoblast, the effect on the endocrine background) and indirectly by modulating the functions of decidual immune cells, which determines their contribution in the implementation of idiopathic pregnancy loss.

1. Malyshkina A.I., Talanova I.E., Sotnikova N.Yu., Kroshkina N.V. Prediction of pregnancy outcomes in recurrent miscarriage. Materials of the XXIII All-Russian scientific and educational forum 'Mother and Child'. 2022: 53–4. (in Russian)

2. Shao X., Wang D., Xu Y., Guo L. et al The high platelet counts as predictor for early foetal demise. Ann. Med. 2021; 53(1): 1502–8. DOI: 10.1080/07853890.2021.1968027

3. Dimakou D.B., Lissauer D., Tamblyn J., Coomarasamy A. et al. Understanding human immunity in idiopathic recurrent pregnancy loss. Eur. J. Obstet. Gynecol. Reprod. Biol. 2022; 270: 17–29. DOI: 10.1016/j.ejogrb.2021.12.024

4. Sotnikova N.Yu., Antsiferova Yu.S., Kroshkina N.V., Voronin D.N. The role of innate immunity cells in pregnancy success during early term of gestation. Journal of Obstetrics and Women's Diseases. 2013; 62(2): 151–9. (in Russian)

5. Forstner D., Maninger S., Nonn O., Guettler J. et al Platelet-derived factors impair placental chorionic gonadotropin beta-subunit synthesis. J. Mol. Med. (Berl). 2020; 98: 193–207. DOI: 10.1007/s00109-019-01866-x

6. Moser G. Maternal platelets — friend or foe of the human placenta? Int. J. Mol. Sci. 2019; 20: 5639. DOI: 10.3390/ijms20225639

7. Serebryanaya N.B., Shanin S.N., Fomicheva E.E., Yakutseni P.P. Blood platelets as activators and regulators of inflammatory and immune reactions. Part 1. Basic characteristics of platelets as inflammatory cells. Medical Immunology. 2018; 20(6): 785–96. (in Russian) DOI: 10.15789/1563-0625-2018-6-785-796

8. Iashchuk A.G., Maslennikov A.V., Dautova L.A., Galimov Sh.N. et al. The role of platelets in female reproductive function. Russian Bulletin of Obstetrician-Gynecologist. 2017; 17(4): 20–4. (in Russian) DOI: 10.17116/rosakush201717420-24

9. Osuga Y., Toyoshima H., Mitsuhashi N., Taketani Y. The presence of platelet-derived endothelial cell growth factor in human endometrium and its characteristic expression during the menstrual cycle and early gestational period. Hum. Reprod. 1995; 10(4): 989–93. DOI 10.1093/oxfordjournals.humrep.a136083

10. Forstner D., Guettler J., Gauster M. Changes in maternal platelet physiology during gestation and their interaction with trophoblasts. Int. J. Mol. Sci. 2021; 22: 10732. DOI: 10.3390/ijms221910732

11. Sato Y., Fujiwara H., Zeng B.X., Higuchi T. et al. Platelet-derived soluble factors induce human extravillous trophoblast migration and differentiation: platelets are a possible regulator of trophoblast infiltration into maternal spiral arteries. Blood. 2005; 106(2): 428–35. DOI: 10.1182/blood-2005-02-0491

12. Ludwig N., Hilger A., Zarbock A., Rossaint J. Platelets at the crossroads of pro-inflammatory and resolution pathways during inflammation. Cells. 2022; 11: 1957. DOI: 10.3390/cells11121957

13. Hilt Z.T., Pariser D.N., Ture S.K., Mohan A. et al. Platelet-derived β2M regulates monocyte inflammatory responses. JCI Insight. 2019; 4(5): e122943. DOI: 10.1172/jci.insight.122943

14. Hamzeh-Cognasse H., Damien P., Nguyen K.A., Zeni F. et al Contribution of activated platelets to plasma IL-27 levels. Crit. Care. 2013; 17(1): 411. DOI: 10.1186/cc11925

15. Park D.-W., Yang K.-M. Hormonal regulation of uterine chemokines and immune cells. Clin. Exp. Reprod. Med. 2011; 38(4): 179–85. DOI: 10.5653/cerm.2011.38.4.179

16. Bódis J., Papp S., Vermes I., Sulyok E. et al. “Platelet-associated regulatory system (PARS)” with particular reference to female reproduction. J. Ovarian Res. 2014; 16(7): 55. DOI: 10.1186/1757-2215-7-55

17. Qi Q., Liu X., Zhang Q., Guo S.-W. Platelets induce increased estrogen production through NF-kB and TGF-β1 signaling pathways in endometriotic stromal cells. Sci. Rep. 2020; 10(1): 1281. DOI: 10.1038/s41598-020-57997-6

18. Dupuis M., Severin S., Noirrit-Esclassan E., Arnal J.-F. et al. Effects of estrogens on platelets and megakaryocytes Int. J. Mol. Sci. 2019; 20(12): 3111. DOI: 10.3390/ijms20123111

19. Sedgwick A.E., D’Souza-Schorey C. The biology of extracellular microvesicles. Traffic. 2018; 19(5): 319–27. DOI: 10.1111/tra.12558

20. Heemskerk J.W.M., Mattheij N.J.A., Cosemans J.M.E.M. Platelet-based coagulation: different populations, different functions. J. Thromb. Haemost. 2013; 11(1): 2–16. DOI: 10.1111/jth.12045

21. Andreeva T., Komsa-Penkova R., Langari A., Krumova S. et al. Morphometric and nanomechanical features of platelets from women with early pregnancy loss provide new evidence of the impact of inherited thrombophilia. Int. J. Mol. Sci. 2021; 22(15): 7778. DOI: 10.3390/ijms22157778

22. Rajaratnam N., Ditlevsen N.E., Sloth J.K., Bæk R. et al. Extracellular vesicles: an important biomarker in recurrent pregnancy loss? J. Clin. Med. 2021; 10(12): 2549. DOI 10.3390/jcm10122549

23. Loguinova M., Pinegina N., Kogan V., Vagida M. et al. Monocytes of different subsets in complexes with platelets in patients with myocardial infarction. Thromb. Haemost. 2018; 118(11): 1969–81. DOI: 10.1055/s-0038-1673342

24. Pavlov O.V., Chepanov S.V., Selutin A.V., Zainulina M.S. et al. Flow cytofluorimetric detection and immunophenotyping of platelet-monocyte complexes in peripheral blood. Medical Immunology. 2021; 23(2): 401–10. (in Russian) DOI: 10.15789/1563-0625-FCD-2124

25. Serebryanaya N.B., Shanin S.N., Fomicheva E.E., Yakutseni P.P. Blood platelets as activators and regulators of inflammatory and immune reactions. Part 2. Thrombocytes as participants of immune reactions. Medical Immunology. 2019; 21(1): 9–20. (in Russian) DOI: 10.15789/1563-0625-2019-1-9-20

26. Tetruashvili N.K., Krechetova L.V., Saribegova V.A., Vtorushina V.V. et al. Dynamics of subpopulation structure of lymphocytes of peripheral blood at patients with a habitual abortion of alloimmunny genesis during pregnancy. Obstetrics and Gynecology: News, Opinions, Training. 2017; 4: 28–36. (in Russian)

27. Zagainova V.A., Kogan I.Yu., Bespalova O.N., Selkov S.A. et al. The role of peripheral and endometrial natural killer cells in recurrent reproductive losses. Obstetrics and Gynecology. 2021; 7: 19–27 (in Russian) DOI: 10.18565/aig.2021.7.19-27

28. Mikhailova V.A., Belyakova K.L., Selkov S.A., Sokolov D.I. Peculiarities of NK cells differentiation: CD56dim and CD56bright NK cells at pregnancy and in non-pregnant state. Medical Immunology. 2017; 19(1): 19–26. (in Russian) DOI: 10.15789/1563-0625-2017-1-19-26

29. Mikhaylova V.A., Selkov S.A., Sokolov D.I. Phenotypic and functional characteristics of NK cells in pregnancy. Obstetrics and Gynecology. 2011; 5: 4–9. (in Russain)

30. Du Y., Liu X., Guo S.-W. Platelets impair natural killer cell reactivity and function in endometriosis through multiple mechanisms. Hum. Reprod. 2017; 32(4): 794–810. DOI: 10.1093/humrep/dex014

31. Cluxton C.D., Spillane C., O’Toole S.A., Sheils O. et al. Suppression of natural killer cell NKG2D and CD226 anti-tumour cascades by platelet cloaked cancer cells: implications for the metastatic cascade. PLoS One. 2019; 14(3): e0211538. DOI: 10.1371/journal.pone.0211538

32. Scheuerer B., Ernst M., Dürrbaum-Landmann I., Fleischer J. et al. The CXC-chemokine platelet factor 4 promotes monocyte survival and induces monocyte differentiation into macrophages. Blood. 2000; 95(4): 1158–66.

33. Pavlov O.V., Selkov S.A. Placental macrophages. Morphofunctional characteristics and the role in gestation. SPb.: Eco-Vector; 2018. 223 p. (in Russian)

34. Vishnyakova P.A., Elchaninov A.V., Kiseleva V.V., Muminova K.T. et al. The role of placental macrophages in physiological pregnancy and preeclampsia. Obstetrics and Gynecology. 2022; 4: 5–12. (in Russian) DOI: 10.18565/aig.2022.4.5-12

35. Tsao F.-Y., Wu M.-Y., Chang Y.-L., Wu C.-T. et al. M1 macrophages decrease in the deciduae from normal pregnancies but not from spontaneous abortions or unexplained recurrent spontaneous abortions. J. Formos. Med. Assoc. 2018; 117(3): 204–11. DOI: 10.1016/j.jfma.2017.03.011

36. Gudbrandsdottir S., Hasselbalch H.C., Nielsen C.H. Activated platelets enhance IL-10 secretion and reduce TNF-α secretion by monocytes. J. Immunol. 2013; 191(8): 4059–67. DOI: 10.4049/jimmunol.1201103

37. Linke B., Schreiber Y., Picard-Willems B., Slattery P. et al. Activated platelets induce an anti-inflammatory response of monocytes/ macrophages through cross-regulation of PGE2 and cytokines. Mediators Inflamm. 2017; 463216. DOI: 10.1155/2017/1463216

38. Carestia A., Mena H.A., Olexen C.M., Wilczyñski J.M.O. et al. Platelets promote macrophage polarization toward pro-inflammatory phenotype and increase survival of septic mice. Cell Rep. 2019; 28(4): 896–908. DOI: 10.1016/j.celrep.2019.06.062

39. Lisman T. Platelet-neutrophil interactions as drivers of inflammatory and thrombotic disease. Cell Tissue Res. 2018; 371(3): 567–76. DOI: 10.1007/s00441-017-2727-4

40. Ivanova E., Kyurkchiev D., Altankova I., Dimitrov J. et al. CD83 monocyte-derived dendritic cells are present in human decidua and progesterone induces their differentiation in vitro. Am. J. Reprod. Immunol. 2005; 53(4): 199–205. DOI: 10.1111/j.1600-0897.2005.00266.x

41. Wei R., Lai N., Zhao L., Zhang Z. et al. Dendritic cells in pregnancy and pregnancy-associated diseases. Biomed. Pharmacother. 2021; 133: 110921. DOI: 10.1016/j.biopha.2020.110921

42. Singh M.V., Suwunnakorn S., Simpson S.R., Weber E.A. et al. Monocytes complexed to platelets differentiate into functionally deficient dendritic cells. J. Leukoc. Biol. 2021; 109(4): 807–20. DOI: 10.1002/JLB.3A0620-460RR

43. Nishat S., Wuescher L.M., Worth R.G. Platelets enhance dendritic cell responses against Staphilococcus aureus through CD40-CD40L. Infect. Immun. 2018; 86(9): e00186–18. DOI: 10.1128/IAI.00186-18

44. Wang W., Zhao Y., Zhou X., Sung N. et al. Dynamic changes in regulatory T cells during normal pregnancy, recurrent pregnancy loss, and gestational diabetes. J. Reprod. Immunol. 2022; 150: 103492. DOI: 10.1016/j.jri.2022.103492

45. Krechetova L.V., Vanko L.V., Vtorushina V.V., Nikolaeva M.A. et al. Lymphocyte activation in the development of immune tolerance in women with recurrent pregnancy loss. Biochemistry. 2020; 85(5): 682–94. (in Russian) DOI: 10.1134/S0006297920050077

46. Kushwah R., Hu J. Role of dendritic cells in the induction of regulatory T cells. Cell Biosci. 2011; 1(1): 20. DOI: 10.1186/2045-3701-1-20

47. Krechetova L.V., Khachatryan N.A., Tetruashvili N.K., Vtorushina V.V. et al. Specific features of peripheral blood lymphocyte phenotype in women with recurrent miscarriage. Obstetrics and Gynecology. 2014; 10: 27–32. (in Russian)

48. Rossaint J., Thomas K., Mersmann S., Skupski J. et al. Platelets orchestrate the resolution of pulmonary inflammation in mice by T reg cell repositioning and macrophage education. J. Exp. Med. 2021; 218(7): e20201353. DOI: 10.1084/jem.20201353

49. Selyutin A.V., Chepanov S.V., Pavlov O.V., Kornyushina E.A. et al. The role of peripheral blood platelet-monocyte aggregates in reproductive processes and their study methods. Obstetrics and Gynecology. 2021; 8: 50–8. (in Russian) DOI: 10.18565/aig.2021.8.50-58

50. Jung J., Barron C. Elimination of HLA antibodies by platelet adsorption. Immunohematology. 2020; 36(1): 1–3.

51. Placke T., Örgel M., Schaller M., Jung G. et al. Platelet-derived MHC class I confers a pseudonormal phenotype to cancer cells that subverts the antitumor reactivity of natural killer immune cells. Cancer Res. 2012; 72(2): 440–8. DOI: 10.1158/0008-5472.CAN-11-1872

52. Kumpel B.M., Monoussaka M.S. Placental immunology and maternal alloimmune responses. Vox Sang. 2012; 102(1): 2–12. DOI: 10.1111/j.1423-0410.2011.01533.x

53. Ferreira L.M.R., Meissner T.B., Tilburgs T., Strominger J.L. HLA-G: at the interface of maternal-fetal tolerance. Trends Immunol. 2017; 38(4): 272–86. DOI: 10.1016/j.it.2017.01.009

54. Guettler J., Forstner D., Cvirn G., Maninger S. et al. Maternal platelets pass interstices of trophoblast columns and are not activated by HLA-G in early human pregnancy. J. Reprod. Immunol. 2021; 144: 103280. DOI: 10.1016/j.jri.2021.103280