The Relation between Plasma Levels of Thrombomodulin and Endothelial Dysfunction in Syrian Children with Acute Lymphoblastic Leukemia
Keywords:Acute lymphoblastic leukemia (ALL), thrombomodulin, endothelial dysfunction, children, chemotherapy.
Background: Acute lymphoblastic leukemia (ALL) is the most common childhood malignancies, representing nearly one-third of all pediatric cancers. Thrombomodulin is a membrane glycoprotein expressed on endothelial cells, Its plasma level depends on the integrity of the endothelium. Soluble thrombomodulin is derived from injured endothelial cells or proteolytically cleaved from thrombomodulin by proteases. In the past, the endothelium was considered to be inert, described as a 'layer of nucleated cellophane', with only non-reactive barrier properties. However, it is now becoming clear that endothelial cells actively and reactively participate in hemostasis and immune and inflammatory reactions. They regulate vascular tone via production of nitric oxide, endothelin and prostaglandins. Severe endothelial dysfunction is present during the acute phase of acute lymphoblastic leukemia and it result from the disease itself, from treatment, or from other conditions (e.g. sepsis).
Objective:The aim of this study was to determine the level of serum soluble thrombomodulin as a marker of endothelial activation in children with ALL at time of diagnosis and after the chemotherapy.
Methods and Materials: A case - control study included Thirty patients with ALL and twenty healthy children. We analyzed serum soluble thrombomodulin levels by enzyme-linked immunosorbent assay.
Results: In children with acute lymphoblastic leukemia, there was a significant increase in soluble thrombomodulin levels during the acute phase of the disease and during treatment.
Conclusion: severe endothelial dysfunction is present during the acute phase of ALL and during treatment and appears to result from the disease itself and from the treatment.
Ribera JM, Oriol A. Acute lymphoblastic leukemia in adolescents and young adults. Hematol Oncol Clin North Am 2009; 23: 1033-1042. https://doi.org/10.1016/j.hoc.2009.07.002
Gaynon PS, Angiolillo AL, Carroll WL, Nachman JB, Trigg ME. Long-term results of the children’s cancer group studies for childhood acute lymphoblastic leukemia 1983-2002: a Children’s Oncology Group Report. Leukemia 2010; 24: 285-297. https://doi.org/10.1038/leu.2009.262
Li YH, Kuo CH, Shi GY, Wu Hl. The role of thrombomodulin lectin-like domain in inflammation. J Biomed Sci 2012; 19: 34. https://doi.org/10.1186/1423-0127-19-34
Ikezoe T. Thrombomodulin/activated protein C system in septic disseminated intravascular coagulation. Ikezoe Journal of Intensive Care 2015; 3: 1. https://doi.org/10.1186/s40560-014-0050-7
Martin F, Murphy R and Cummins P. Thrombomodulin and the vascular endothelium: insights into functional, regulatory, and therapeutic aspects. Am J Physiol Heart Circ Physiol 2013; 304: 1585-1597. https://doi.org/10.1152/ajpheart.00096.2013
Conway EM. Thrombomodulin and its role in inflammation. Semin Immunopatho 2012; 34: 107-125. https://doi.org/10.1007/s00281-011-0282-8
Adams TE, Huntington JA. Thrombin-cofactor interactions: structural insights into regulatory mechanisms. Arterioscler Thromb Vasc Biol 2006; 26: 1738 -1745. https://doi.org/10.1161/01.ATV.0000228844.65168.d1
Califano F, Giovanniello T, Pantone P. Clinical importance of thrombomodulin serum levels. Eur Rev Med Pharmacol Sci 2000; 4: 59-66.
Lin FY, Tsai YT, Lee CY, et al. TNF-α-decreased thrombomodulin expression in monocytes is inhibited by propofol through regulation of tristetraprolin and human antigen R activities. Shock 2011; 36: 279-288. https://doi.org/10.1097/SHK.0b013e3182236e7e
Hasing Chao T, Chuan Tsai W. Soluble thrombomodulin is a paracrine anti-apoptotic factor for vascular endothelial protection. Int J Cardiol 2014; 172: 340-349. https://doi.org/10.1016/j.ijcard.2014.01.009
Doroszko A, Jakubowski M, Niedzielska E. Elevated plasma ADMA contributes to development of endothelial dysfunction in children with acute lymphoblastic leukemia. Postepy Hig Med Dosw 2016; 70: 562-571. https://doi.org/10.5604/17322693.1203720
Hatzipantelis ES, Athanassiou MM, Gombakis N. Thrombomodulin and von Willebrand factor: relation to endothelial dysfunction and disease outcome in children with acute lymphoblastic leukemia 2011; 125: 130-135.
Hagag A. Prognostic value of plasma levels of thrombomodulin and von Willebrand factor in Egyptian children with acute lymphoblastic leukemia. J Oncol Pharm Practice 2013; 1-6.
Hatzipantelis ES, Athanasiou-Metaxa M, Tzimouli V. Dysfunction of the vascular endothelium in children with ALL. Arch Hellen Med 2008; 25: 771-780.
Schneider P, Van Dreden P, Rousseau A. Increased levels of tissue factor activity and procoagulant phospholipids during treatment of children with acute lymphoblastic leukemia. Br J Hematol 2009; 148: 582-592. https://doi.org/10.1111/j.1365-2141.2009.07958.x
Giordano P, Molinari AC, Del Vecchio GC, Saracco P, Russo G, Altomare M. Prospective study of hemostatic alterations in children with acute lymphoblastic leukemia. Am J Hematol 2010; 85: 325-330. https://doi.org/10.1002/ajh.21665