Endothelial dysfunction and platelet function disorder in hemostasis in development of hepatic fibrosis in children with autoimmune hepatitis

Abstract

The purpose is: To assess the clinical relevance of the endothelial condition and platelet aggregation in the development of hepatic fibrosis in children with autoimmune hepatitis.

Materials and Methods. 35 patients aged from 3 to 17 years old were studied, including 19 girls - (54%) and 16 boys - (46%). The 1^st group consisted of 17 children with the degree of fibrosis F 0-2 acc. to the METAVIR score; the 2^nd group consisted of 18 patients with the degree of fibrosis F 3-4 (METAVIR) acc. to the METAVIR score based on the indirect elastometry data in children of the 2^nd group hepatic cirrhosis was diagnosed; the control group consisted of 15 children with health group I or II. The endothelium state and the platelet aggregation activity were assessed in all the patients. To test statistical hypotheses, the Mann-Whitney U test, the Spearman correlation coefficient and the Fisher criterion were used. The critical value of the significance level is assumed to be 0.05. Quantitative data are presented as: median and the first; third quartile of Me (Q1; Q3).

Results. In children with autoimmune hepatitis some signs of the various-degree fibrosis formation were revealed in the ¾ of the examined. Patients of the 2^nd group have a more aggressive course as compared to the 1^st group: in the disease debut there were mainly expressed asthenoneurotic complaints (p = 0.021), manifestations of the jaundice syndrome (p = 0.014), more frequently hepatic-cell insufficiency (p = 0.045) is diagnosed and followed by complications of the disease (hypersplenism (p = 0.014), varicose veins of the esophagus (p = 0.003)). All children with autoimmune hepatitis have the endothelial dysfunction, the enhancing platelet aggregation activity. The degree of fibrosis correlates with the concentration of endothelin-1 (r = 0.4, p = 0.004), the von Willebrand factor (vWF) activity (r = 0.5, p <0.001), the platelet count (r = -0.5, p = 0.003). The determination of the endothelin-1 concentration, the von Willebrand factor activity and the platelet count may be used to assess the hepatopathy severity in children with autoimmune hepatitis.

Conclusion. In children with autoimmune hepatitis the endothelial dysfunction and platelet disorders are revealed in the hemostasis system correlating with the severity of the pathological process.

Keywords

children / fibrosis / cirrhosis / endothelium / platelets / hemostasis

References

[1] Kostyrko EV, Shumilov PV. Contemporary Methods of Treating Children with Autoimmune Nephric Diseases. Pediatric Pharmacology. 2015; 12(6):679-85. (In Russ). doi:10.15690/pf.v12i6.1492

[2] Костырко Е.В., Шумилов П.В. Современные методы лечения детей с аутоиммунными заболеваниями печени // Педиатрическая фармакология. 2015. Т. 12, №6. С. 679-685. doi:10.15690/ pf.v12i6.1492

[3] Kliaritskaia IL, Shelihova EO, Semenihina EV. Diagnosis of autoimmune hepatitis according to EASL Clinical Practice Guidelines 2015. Crimean Journal of Internal Diseases. 2015; 27(4):9-17. (In Russ).

[4] Кляритская И.Л., Шелихова Е.О., Семенихина Е.В. Диагностика аутоиммунного гепатита согласно рекомендациям EASL 2015 // Крымский терапевтический журнал. 2015. Т. 27, №4. С. 9-17.

[5] Shvarts VYa, Nogaller AM. Autoimmune hepatitis. Clinical Medicine. 2013;91(9):57-61. (In Russ).

[6] Шварц В.Я., Ногаллер А.М. Аутоиммунный гепатит // Клиническая медицина. 2013. Т. 91, №9. С. 57-61.

[7] Leonardi F, Maria N, Villa E. Anticoagulation in cirrhosis: a new paradigm? Clinical and Molecular Hepatology. 2017;23(1):13-21. doi:10.3350/cmh. 2016.0110

[8] Leonardi F., Maria N., Villa E. Anticoagulation in cirrhosis: a new paradigm? // Clinical and molecular hepatology. 2017. Vol. 23, №1. Р. 13-21. doi:10.3350/cmh.2016.0110

[9] Kurkina IA, Mayevskaya MV, Silayev BV, et al. Hypercoagulation syndrome at liver cirrhosis. Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2014;6:36-44. (In Russ).

[10] Куркина И.А., Маевская М.В., Силаев Б.В., и др. Гиперкоагуляционный синдром у больных циррозом печени // Российский журнал гастроэнтерологии, гепатологии, колопроктологии. 2014. Т. 24, №6. С. 36-44.

[11] Mancuso A. The ischemic liver cirrhosis theory and its clinical implications. Medical Hypotheses. 2016;94:4-6. doi:10.1016/j.mehy.2016.06.008

[12] Mancuso A. The ischemic liver cirrhosis theory and its clinical implications // Medical Hypotheses. 2016. Vol. 94. Р. 4-6. doi:10.1016/j.mehy.2016.06.008

[13] Eelen G, De Zeeuw P, Treps L, et al. Endothelial Cell Metabolism. Physiological Reviews. 2018; 98(1):3-58. doi:10.1152/physrev.00001.2017

[14] Eelen G., De Zeeuw P., Treps L., et al. Endothelial Cell Metabolism // Physiological Reviews. 2018. Vol. 98, №1. Р. 3-58. doi:10.1152/physrev.00001.2017

[15] Shiffman FDzh. Patofiziologiya krovi. Moscow: BINOM; 2017. (In Russ).

[16] Шиффман Ф.Дж. Патофизиология крови. М.: БИНОМ; 2017.

[17] Malerba M, Nardin M, Radaeli A, et al. The potential role of endothelial dysfunction and platelet activation in the development of thrombotic risk in COPD patients. Expert Review of Hematology. 2017;10(9):821-32. doi:10.1080/17474086.2017. 1353416

[18] Malerba M., Nardin M., Radaeli A., et al. The potential role of endothelial dysfunction and platelet activation in the development of thrombotic risk in COPD patients // Expert Review of Hematology. 2017. Vol. 10, №9 P. 821-832. doi:10.1080/ 17474086.2017.1353416

[19] Holinstat M. Normal platelet function. Cancer and Metastasis Reviews. 2017;36(2):195-8. doi:10.1007/ s10555-017-9677-x

[20] Holinstat M. Normal platelet function // Cancer and Metastasis Reviews. 2017. Vol. 36, №2. P. 195-198. doi:10.1007/s10555-017-9677-x

[21] Kozlovsky VI, Kovtun OM, Seroukhova OP, et al. Methods of investigation and clinical significance of thrombocytes aggregation with emphasis on spontaneous aggregation of platelets. Vestnik of Vitebsk State Medical University. 2013;12(4):79-91. (In Russ).

[22] Козловский В.И., Ковтун О.М., Серпухова О.П., и др. Методы исследования и клиническое значение агрегации тромбоцитов. Фокус на спонтанную агрегацию // Вестник ВГМУ. 2013. Т. 12, №4. С. 79-91.

[23] Schiff ER, Sorrell MF, Mjeddrej WC. Shiff’s diseases of the liver. 10th ed. Moscow: GJeOTAR-Media; 2012. (In Russ).

[24] Шифф Ю.Р., Соррел М.Ф., Мэддрей У.С. Болезни печени по Шифу. Цирроз печени и его осложнения. Трансплантация печени. 10-е изд. М.: ГЭОТАР-Медиа; 2012.

[25] Poisson J, Lemoinne S, Boulanger C, et al. Liver sinusoidal endothelial cells: Physiology and role in liver diseases. Journal of Hepatology. 2017; 66(1):212-27. doi:10.1016/j.jhep.2016.07.009

[26] Poisson J., Lemoinne S., Boulanger C., et al. Liver sinusoidal endothelial cells: Physiology and role in liver diseases // Journal of Hepatology. 2017. Vol. 66, №1. P. 212-227. doi:10.1016/j.jhep.2016.07.009

[27] Wereszczynka-Siemiatkowska U, Swidnicka-Sier-giejko A, Siemiatkowski A, et al. Endothelin 1 and transforming growth factor-β1 correlate with liver function and portal pressure in cirrhotic patients. Cytokine. 2015;76(2):144-51. doi:10.1016/j.cyto. 2015.05.025

[28] Wereszczynka-Siemiatkowska U., Swidnicka-Siergiejko A., Siemiatkowski A., et al. Endothelin 1 and transforming growth factor-β1 correlate with liver function and portal pressure in cirrhotic patients // Cytokine. 2015. Vol. 76, №2. Р. 144-151. doi:10. 1016/j.cyto.2015.05.025

[29] Schekotova AP, Kotelnikova LP, Mugatarov IN et al. Endothelial dysfunction, inflammation and fibrosis in the presence of hepatobiliary pathology. Fundamental Research. 2013;5-2:451-5. (In Russ).

[30] Щёкотова А.П., Котельникова Л.П., Мугатаров И.Н., и др. Эндотелиальная дисфункция, воспаление и фиброз при гепатобилиарной патологии // Фундаментальные исследования. 2013. №5-2. С. 451-455.

[31] Kurkina IA, Maevskaya MV, Ivashkin VT. Hypercoagulation and thrombosis in patients with liver cirrhosis. Polyclinic. 2015;4(2):20-6. (In Russ).

[32] Куркина И.А., Маевская М.В., Ивашкин В.Т. Гиперкоагуляция и тромбоз у больных циррозом печени // Поликлиника. 2015. №4-2. С. 20-26.

[33] Wu H, Yan Sh, Wang G, et al. von Willebrand factor as a novel noninvasive predictor of portal hypertension and esophageal varices in hepatitis B patients with cirrhosis. Scandinavian Journal of Gastroenterology. 2015;50(9):1160-9. doi:10.3109/0036 5521.2015.1037346

[34] Wu H., Yan Sh., Wang G., et al. von Willebrand factor as a novel noninvasive predictor of portal hypertension and esophageal varices in hepatitis B patients with cirrhosis // Scandinavian Journal of Gastroenterology. 2015. Vоl. 50, №9. Р. 1160-1169. doi:10.3109/00365521.2015.1037346

[35] Papayan LP. Von Willebrand disease: Structure and function of von Willebrand factor, classification, clinical manifestations, and diagnosis. Pediatric Hematology/Oncology and Immunopathology. 2012; 11(4):5-10. (In Russ)

[36] Папаян Л.П. Болезнь Виллебранда: структура и функция фактора Виллебранда, классификация, клиническая картина и основные принципы диагностики. Лекция // Вопросы гематологии, онкологии и иммунологии в педиатрии. 2012. Т. 11, №4. С. 5-10.

[37] Gabbasov ZA, Popov EG, Gavrilov IYu, et al. Platelet aggregation: the use of optical density fluctuations to study microaggregate formation in platelet suspension. Thrombosis Research. 1989;54(3): 215-23. doi:10.1016/0049-3848(89)90229-6

[38] Gabbasov Z.A., Popov E.G., Gavrilov I.Yu., et al. Platelet aggregation: the use of optical density fluctuations to study microaggregate formation in platelet suspension // Thrombosis Research. 1989. Vol. 54, №3. P. 215-223. doi:10.1016/0049-3848(89)90229-6

[39] González-Reimers E, Quintero-Platt G, Martín-González C, et al. Thrombin activation and liver inflammation in advanced hepatitis C virus infection. World Journal Gastroenterology. 2016;22(18): 4427-37. doi:10.3748/wjg.v22.i18.4427

[40] González-Reimers E., Quintero-Platt G., Martín-González C., et al. Thrombin activation and liver inflammation in advanced hepatitis C virus infection // World Journal of Gastroenterology. 2016. Vol. 22, №18. Р. 4427-4437. doi:10.3748/wjg.v22. i18.4427

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Konovalova E.Y., Lavrova A.E., Presnyakova M.V.