Pathogenetic Approach to Early Preeclampsia and the Feasibility of Pregnancy Prolongation

   Aim. To evaluate the efficacy of cascade plasma filtration (CPF) for the correction of lipid profile and biochemical markers (sFlt-1, PIGF, sFlt-1/PIGF) in pregnant women with early preeclampsia.
   Materials and Methods. A prospective controlled study of 23 CPF procedures was conducted in 11 pregnant women with early preeclampsia at gestational ages 22 to 31 weeks. The evolution of clinical manifestations of preeclampsia (BP, urine output, and proteinuria), laboratory biochemical parameters (protein/creatinine ratio, lipid profile), blood coagulation tests, and thromboelastometry (ROTEM) were assessed. In addition, the effect of CPF on the level of preeclampsia markers (sFlt-1, PIGF, sFlt-1/PIGF-ratio) as predictors of endothelial aggression was analyzed. The efficacy of extracorporeal therapy was evaluated based on the duration of pregnancy prolongation.
   Results. The use of CPF as an adjunct for the treatment of early preeclampsia had a positive effect on the lipid profile by reducing cholesterol and LDL, which helped to decrease atherogenic aggression on the vascular endothelium. In addition, the extracorporeal therapy promoted reduction of the anti-angiogenic effect of sFlt-1, which was confirmed by a significant decrease in the sFlt-1/PIGF ratio from 515 [347; 750] to 378 [285; 557] (P = 0.013). The period of prolongation of pregnancy was longer in the main group (with CPF) and was 19 [5; 26] days, whereas in the comparison group (without CPF) it was 3 [1; 4] days (P < 0.001). All newborns were discharged from the hospital in a stable condition. The paper is supplemented with a clinical observation of the effective use of CPF in early preeclampsia.

   Conclusion. The use of cascade plasma filtration in the treatment of early preeclampsia to prolong pregnancy could be a promising approach.

1. Tkachenko O., Shchekochikhin D., Schrier R. W. Hormones and hemodynamics in pregnancy. Int J Endocrinol Metab. 2014; 12 (2): е14098. DOI: 10.5812/ijem.14098.

2. Turpin C. A., Sakyi S. A., Owiredu W. K. B. A., Ephraim R.K. D., Anto E.O. Association between adverse pregnancy outcome and imbalance in angiogenic regulators and oxidative stress biomarkers in gestational hypertension and preeclampsia. BMC Pregnancy and Childbirth. 2015; 15: 189. DOI: 10.1186/s12884-015-0624-y.

3. Maynard S. E, Min J. Y., Merchan J., Lim K. H., Li J., Mondal S., Libermann T. A., Morgan J. P., Sellke F. W., Stillman I. E., Epstein F. H., Sukhatme V. P., Karumanchi S. A. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest. 2003; 111 (5): 649–658. DOI: 10.1172/JCI17189.

4. Levine R. J., Maynard S. E., Qian C., Lim K. H., England L. J., Yu K. F., Schisterman E. F., Thadhani R., Sachs B. P., Epstein F. H., Sibai B. M., Sukhatme V. P., Karumanchi S. A. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med. 2004; 350: 672–683. DOI: 10.1056/NEJMoa031884.

5. Heydarian M., McCaggrey T., Florea L., Yang Z., Ross M. M., Zhou W., Maynard S. E. Novel splice variants of sFlt-1 are upregulated in preeclampsia. Placenta. 2009; 30 (3): 250-255. DOI: 10.1016/j.placenta.2008.12.010.

6. Sela S., Itin A., Natanson-Yaron S., Greenfield C., Goldman-Wohl D., Yagel S., Keshet E. A novel human-specific soluble vascular endothelial growth factor receptor-1: cell type-specific splicing and implications to vascular endothelial growth factor homeostasis and preeclampsia. Circ Res. 2008; 102 (12): 1566–1574. DOI: 10.1161/CIRCRESAHA.108.171504.

7. Souders C. A., Maynard S. E., Yan J., Wang Y., Boatright N. K., Sedan J., Balyozian D., Cheslock P. S., Molrine D. C., Simas T. A. M. Circulating levers of sFlt-1 splice variants as predictive markers for the development of preeclampsia. Int J Mol Sci. 2015; 16 (6): 12436–12453. DOI: 10.3390/ijms160612436.

8. Thomas C. P., Andrews J. I., Raikwar N. S., Kelley E. A., Herse F., Dechend R., Golos T. G., Liu K. Z. A recently evolved novel trophoblast-enriched secreted form of fms-like tyrosine kinase-1 variant is up-regulated in hypoxia and preeclampsia. J Clin Endocrinol Metab. 2009; 94 (7): 2524–2530. DOI: 10.1210/jc.2009-0017.

9. Whitehead C. L., Palmer K. R., Nilsson U., Gao Y., Saglam B., Lappas M., Tong S. Placental expression of a novel primatepecific splice variant of sFlt-1 is upregulated in pregnancies complicated by severe early onset preeclampsia. BJOG. 2011; 118 (10): 1268–1271. DOI: 10.1111/j.1471-0528.2011.02962.x.

10. Jebbink J., Keijser R., Veenboer G., van der Post J., Ristalpers C., Afink G. Expression of placental FLT-1 transcript variants relates to both gestational hypertensive disease and fetal growth. Hypertension. 2011; 58 (1): 70–76. DOI: 10.1161/HYPERTENSIONAHA.110.164079.

11. Palmer K.R., Kaitu’u-Lino T., Cannon P., Tuohey L., De Silva M. S., Varas-Godoy M., Acuna S., Galaz J., Tong S., Illanes S. E. Maternal plasma concentrations of the placental specific sFlt-1 variant, sFlt-1 e15a, in fetal growth restriction and preeclampsia. J Matern Fetal Neonatal Med. 2017; 30 (6): 635–639. DOI: 10.1080/14767058.2016.1182975.

12. Palmer K. R., Kaitu’u-Lino T., Hastie R., Hannan N. J., Ye L., Binder N., Cannon P., Tuohey L., Johns T. G., Shub A., Tong S. Placental-specific sFlt-1 e15a protein is increased in preeclampsia, antagonizes vascular endothelial growth factor signaling, and has antiangiogenic activity. Hypertension. 2015; 66 (6): 1251–1259. DOI: 10.1161/HYPERTENSIONAHA.115.05883.

13. H., Calda P., Holzgreve W., Galindo A., Engels T., Denk B., Stepan H. The sFlt-1/PlGF ratio in different types of hypertensive pregnancy disorders and its prognostic potential in preeclamptic patients. Am J Obstet Gynecol. 2012; 206 (1): 58.e1-8. DOI: 10.1016/j.ajog.2011.07.037.

14. Stepan H., Herraiz I., Schlembach D., Verlohren S., Brennecke S.,Chantraine F., Klein E., Lapaire O., Llurba E., Ramoni A., Vatish M., Wertaschnigg D., Galindo A. Implementation of the sFlt-1/PlGF ratio for prediction and diagnosis of pre-eclampsia in singleton pregnancy: implications for clinical practice. Ultrasound Obstet Gynecol. 2015; 45 (3): 241–246. DOI: 10.1002/uog.14799.

15. Серов В. Н. Прогностическое значение отношения растворимой fms-подобной тирозинкиназы-1 к плацентарному фактору роста у беременных с преэклампсией / В. Н. Серов, Н. Е. Кан, В. Л. Тютюнник // Акушерство и гинекология. – 2016. – 6: 5–10. DOI: 10.18565/aig.2016.6.5-10 [Serov V. N., Kan N. E., Tyutyunnik V. L. Prognostic value of the ratio of soluble fms-like tyrosine kinase-1 to placental growth factor in pregnant women with preeclampsia. Obstetrics and Gynecology / Akusherstvo i Ginecologiya. 2016; 6: 5–10. DOI: 10.18565/aig.2016.6.5-10 ].

16. Холин А. М. Прогнозирование преэклампсии в 1-м триместре беременности: валидация алгоритмов скрининга на российской популяции // Акушерство и гинекология. – 2017. – 8: 74–84. DOI: 10.18565/aig.2017.8.74-84.

17. Ходжаева З. С. Российская модель оценки эффективности теста на преэклампсию sFlt-1/PIGF / З. С. Ходжаева [и др.] // Акушерство и гинекология. – 2019. – 2: 52–58. DOI: 10.18565/aig.2019.2.52-58.

18. Thadhani R., Hagmann H., Schaarschmidt W., Roth B., Cingoez T., Ananth Karumanchi S., Wenger J., Lucchesi K. J., Tamez H., Lindner T., Fridman A., Thome U., Kribs A., Danner M., Hamacher S., Mallmann P., Stepan H., Benzing T. Removal of soluble Fms-like tyrosine kinase-1 by dextran sulfate apheresis in preeclampsia. J Am Soc Nephrol. 2016; 27 (3): 903–913. DOI: 10.1681/ASN.2015020157.

19. Winkler K., Contini C., König B., Krumrey B., Pütz G., Zschiedrich S., Pecks U., Stavropoulou D., Prömpeler H., Kunze M., Markfeld-Erol F. Treatment of very preterm preeclampsia via heparin-mediated extracorporeal LDL-precipitation (H. E. L. P.) apheresis: The Freiburg preeclampsia H. E. L. P.-Apheresis study. Pregnancy Hypertens. 2018; 12: 136–143. DOI: 10.1016/j.preghy.2018.04.007.

20. Wang Y., Walli A. K., Schulze A., Blessing F., Fraunberger P., Thaler C., Seidel D., Hasbargen U. Heparin-mediated extracorporeal low density lipoprotein precipitation as a possible therapeutic approach in preeclampsia. Transfus Apher Sci. 2006; 35 (2): 103–110. DOI: 10.1016/j.transci.2006.05.010.

21. Sattar N., Bendomir A., Berry C., Shepherd J., Greer I. A., Packard C. J. Lipoprotein subfraction concentrations in preeclampsia: pathogenic parallels to atherosclerosis. Obstet. Gynecol. 1997; 89 (3): 403–408. DOI: 10.1016/S0029-7844(96)00514-5.

22. Hubel C. A., Lyall F., Weissfeld L., Gandley R. E., Roberts J. M. Small low-density lipoproteins and vascular cell adhesion molecule-1 are increased in association with hyperlipidemia in preeclampsia. Metabolism. 1998; 47 (10): 1281–1288. DOI: 10.1016/s0026-0495(98)90337-7.

23. Winkler K., Wetzka B., Hoffmann M. M., Friedrich I., Kinner W., Baumstark M. W., Zahradnik H.-P., Wieland H., März W. Triglyceride-rich lipoproteins are associated with hypertension in preeclampsia. J. Clin. Endocrinol. Metab. 2003; 88 (3): 1162–1166. DOI: 10.1210/jc.2002-021160.

24. Enquobahrie D. A., Williams M. A., Butler C. L., Frederick I. O., Miller R. S., Luthy D. A. Maternal Plasma Lipid Concentrations in Early Pregnancy and Risk of Preeclampsia. Am J Hypertens. 2004; 17 (7): 574–581. DOI: 10.1016/j.amjhyper.2004.03.666.

25. Sanches S. E., Williams M. A., Muy-Rivera M., Qiu C., Vadachkoria S., Bazul V. A Case-Control Study of Oxidized Low Density Lipoproteins and Preeclampsia Risk. Gynecol Endocrinol. 2005; 21 (4): 193-199. DOI: 10.1080/09513590500154019.

26. Dallinga-Thie G. M., Kroon J., Boren J., Chapman M. J. Triglyceride-rich lipoproteins and remnants: targets for therapy? Curr. Cardiol. Rep. 2016; 18 (7): 67. DOI: 10.1007/s11886-016-0745-6.

27. Ray J. G., Diamond P., Singh G., Bell C. M. Brief overview of maternal triglycerides as a risk factor for pre-eclampsia. BJOG. 2006; 113 (4): 379–386. DOI: 10.1111/j.1471-0528.2006.00889.x.

28. Gallos I. D., Sivakumar K., Kilby M. D., Coomarasamy A., Thangaratinam S., Vatish M. Pre-eclampsia is associated with, and preceded by, hypertriglyceridaemia: a meta-analysis. BJOG. 2013; 120 (11): 1321–1332. DOI: 10.1111/1471-0528.12375.

29. Konrad E., Güralp O., Shaalan W., Elzarkaa A. A., Moftah R., Aleman D., Malik E., Soliman A. A. Correlation of elevated Levels of lipoprotein (a), high-density lipoprotein and low-density lipoprotein with severity of preeclampsia: a prospective longitudinal study. J Obstet Gynaecol. 2020; 40 (1): 53–58. DOI: 10.1080/01443615.2019.1603214.

30. Матковский А. А, Уровень антитромбина III у женщин с гипертензивными расстройствами во время беременности / А. А. Матковсекий [и др.] // Тромбоз, гемостаз и реология. – 2017. – 1 (69): УДК 616-089.1: 618.3:616.16.

31. Пылаева Н. Ю. Антитромбин III — эволюция от антикоагулянта к маркеру тяжелых форм преэклампсии / Н. Ю. Пылаева [и др.] // Анестезиология и реаниматология. – 2020. – (6): 57–62. DOI: 10.17116/anaesthesiology202006157.