Association Between Soluble CD40L with Thrombosis Occurrence and JAK2 V617F Mutation in Essential Thrombocythemia
American Journal of Internal Medicine
Volume 4, Issue 4, July 2016, Pages: 60-65
Received: May 2, 2016;
Accepted: May 21, 2016;
Published: Jun. 4, 2016
Views 3482 Downloads 104
Wafaa S. Mohammed, Clinical Pathology Department, Faculty of Medicine, Assiut University, Assiut, Egypt
Wael A. Abbas, Internal Medicine Department, Faculty of Medicine, Assiut University, Assiut, Egypt
Ola A. Afifi, Clinical Pathology Department, Faculty of Medicine, Assiut University, Assiut, Egypt
Ahmad F. Thabet, Internal Medicine Department, Faculty of Medicine, Assiut University, Assiut, Egypt
Thrombo-haemorrhagic events are the main cause of mortality in essential thrombocythemia (ET). The aim of this study was to measure soluble CD40 ligand (sCD40L) in the plasma of healthy individuals and in patients with an elevated platelet count and investigate the association of sCD40L with thrombosis in ET patients and their JAK2 V617F mutation. The plasma levels of sCD40L was measured in 75 patients. 35 patients diagnosed as ET, 25 patients diagnosed as reactive thrombocytosis (RT), 15 patients with low platelet count and 15 healthy subjects acted as the control group. 35 ET patients were assessed for JAK2 V617F status by utilizing a JAK2 V617F specific quenching probe. ET patients had the highest levels of sCD40L compared to the patients with RT and controls (225.70±79.34, 160.40±54.54 and 83.54±21.54) respectively and a tight correlation was found between the platelet count and sCD40L. Statistical analysis revealed that the JAK2 V617F mutation was associated with significantly increased levels of WBCs (p˂0.04) and sCD40L (p˂0.001) compared to JAK2 V617F negative patients. There was no significant association between JAK2 V617F mutation and thrombosis, but the level of sCD40L was significantly higher in patients with thrombosis than those without thrombosis (236.43 ± 75.93 vs 184.65 ± 62.31) respectively. Based on these findings, the presence of JAK2 mutation may changes the expression of soluble markers of endothelial and platelet activation besides the quantitative and qualitative changes in platelets. Mechanisms leading to thrombosis are more complex and multifactorial.
Wafaa S. Mohammed,
Wael A. Abbas,
Ola A. Afifi,
Ahmad F. Thabet,
Association Between Soluble CD40L with Thrombosis Occurrence and JAK2 V617F Mutation in Essential Thrombocythemia, American Journal of Internal Medicine.
Vol. 4, No. 4,
2016, pp. 60-65.
Landolfi R, Cipriani MC, Novarese L (2006). Thrombosis and bleeding in polycythemia vera and essential thrombocythemia: pathogenetic mechanisms and prevention. Best Pract Res Clin Haematol; 19: 617–33''.
Tefferi A, Gilliland DJ (2005). The JAK2V617F tyrosine kinase mutation in myeloproliferative disorders: status report and immediate implications for disease classification and diagnosis. Mayo Clin Proc; 80: 947-58''.
Kralovics R, Passamonti F, Buser AS, et al., (2005). A gain of function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 352: 1779 1790''.
Levine RL, Wadleigh M, Cools J, et al., (2005). Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia and myeloid metaplasia with myelofibrosis. Cancer Cell; 7: 387 397''.
James C, Ugo V, Le Couédic JP, et al., (2005). A unique clonal JAK2 mutation leading to constitutive signaling causes polycythaemia vera. Nature; 434: 1144 1148''.
Baxter EJ, Scottl M, Campbell PJ, et al., (2005). Cancer Genome Project: Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet; 365: 1054 1061''.
Scott LM, Tong W, Levine RL, et al., (2007). JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med; 356: 459 468''.
Levine RL, Belisle C, Wadleigh M, et al., (2006). X inactivation based clonality analysis and quantitative JAK2V617F assessment reveal a strong association between clonality and JAK2V617F in PV but not ET/MMM, and identifies a subset of JAK2V617F negative ET and MMM patients with clonal hematopoiesis. Blood; 107: 4139 4141''.
Lussana F, Caberlon S, Pagani C, et al., (2009). Association of V617F Jak2 mutation with the risk of thrombosis among patients with essential thrombocythemia or idiopathic myelofibrosis: Asystemic review. Thrombosis Research, 124: 409-417''.
Linnemann B, Kraft C, Roskos M, et al (2012). Inferior vena cava thrombosis and its relationship with the JAK2V617F mutation and chronic myeloproliferative disease. Thrombosis Research, 129: 720-724''.
Austin SK, Lambert JR (2008). The JAK2V617F mutation and thrombosis. Br. J. Haematology, 143: 307-320''.
Barbui T, Finazzi G, Falanga A (2013). Myeloproliferative neoplasms and thrombosis. Blood, 122: 2176-2184''.
Wykes M, Poudrier J, Lindstedt R, et al., (1998). Regulation of cytoplasmic, surface and soluble forms of CD40 ligand in mouse B cells. Eur J Immunol; 28: 548–59''.
Berger G, Hartwell DW, Wagner DD (1998). P-selectin and platelet clearance. Blood; 92: 4446–4452''.
Inwald DP, McDowall A, Peters MJ, et al., (2003). CD40 is constitutively expressed on platelets and provides a novel mechanism for platelet activation. Circ Res; 92: 1041–1048''.
Lindmark E, Tenno T, Seigbahn A (2000). Role of P-selectin and CD40 ligand in the induction of monocyte tissue factor expression. Arterioscler Thromb Vasc Biol; 20: 2322–2328.
Prasad KSS, Andre P, He M, et al., (2003). Soluble CD40 ligand induces b3 integrin tyrosine phosphorylation and triggers platelet activation by outside-in signaling. Proc Natl Acad Sci USA; 100: 12367–12371''.
Cervantes F, Passamonti F, Barosi G (2008). Life expectancy and prognostic factors in the classic BCR/ABL-negative myeloproliferative disorders. Leukemia; 22: 905–914''.
Matsumura I, Horikawa Y, Kanakura Y (1999). Functional roles of thrombopoietin-c-mpl system in essential thrombocythemia. Leuk Lymphoma, 32(3-4): 351-358''.
Craig S, Kitchens BAK, Craig M, et al., (2013). Consultative hemostasis and thrombosis. Elsevier Health Sciences(ed)''.
Wadleigh M, Tefferi A (2010). Classification and diagnosis of myeloproliferative neoplasms according to 2008 World Health Organization criteria. Int J Hematol; 91: 174-179''.
Aukrust P, Muller F, Ueland T, et al (1999). Enhanced levels of soluble and membrane-bound CD40 ligand in patients with unstable angina. Possible reflection of T lymphocyte and platelet involvement in the pathogenesis of acute coronary syndromes. Circulation; 100: 614–20''.
Viallard JF, Solanilla A, Gauthier B et al., (2002). Increased soluble and platelet-associated CD40 ligand in essential thrombocythemia and reactive thrombocytosis. Blood; 99: 2612–4''.
Bilgir F, Bilgir O, Kebapcilar L, et al., (2012). Soluble CD40 ligand, high sensitive C-reactive protein and fetuin-A levels in patients with essential thrombocythemia. Transfusion and Apheresis Science; 46: 67-71''.
Tefferi A, Vardiman JW (2008). Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia; 22(1): 14–22''.
Tefferi A (2012). Polycythemia vera and essential thrombocythemia: 2012 update on diagnosis, risk stratification, and management. Am J Hematol; 87(3): 285–293''.
Patriarca A, Pompetti F, Malizia R et al., (2010). Is the absence of JAK2 V617F mutation a risk factor for bleeding in essential thrombocythemia? An analysis of 106 patients. Blood Transfusion; 8: 21-27''.
Swerdlow SH, Campo E, Harris NL, et al., (2008). WHO classification of tumors of haematopoietic and lymphoid tissues. WHO press; 76-86''.
Campbell PJ, Scott LM, Buck G, et al., (2005). Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2V617F mutation status: a prospective study. Lancet: 366; 1945-53''.
Antonioli E, Guglielmelli P, Poli G etal., (2008). Influence of JAK2V617F allele burden on phenotype in essential thrombocythemia. Haematologica; 93: 41''.
Zhang SP, Li H and Lai RS (2015). Detection of JAK2 V617F mutation increases the diagnosis of myeloproliferative neoplasms. ONCOLOGY LETTERS; 9: 735-738''.
Kittur J, Knudson RA, Lasho TL, et al., (2007). Clinical correlates of JAK2 V617F allele burden in essential thrombocythemia. Cancer; 109: 2279–2284''.
Carobbio A, Antonioli E, Guglielmelli P et al., (2008). Leukocytosis and risk stratification assessment in essential thrombocythemia. J Clin Oncol; 26: 2732–2736''.
Takata Y, Seki R, Kanajii T, et al., (2013). Association between thromboembolic events and the JAK2 V617F mutation in myeloproliferative neoplasms. kurume Medical Journal; 60: 89-97''.
Hsiao HH, Yang MY, Liu YC, et al., (2007). The association of JAK2V617F mutation and leukocytosis with thrombotic events in essential thrombocythemia. Exp Hematol; 35(11): 1704–1707.
Vannucchi AM, Barbui T (2007). Thrombocytosis and thrombosis. Hematology Am Soc Hematol Educ Program; 363–370''.
Hobbs CM, Manning H, Bennett C, et al., (2013). JAK2V617F leads to intrinsic changes in platelet formation and reactivity in a knock-in mouse model of essential thrombocythemia. Blood''.
Cho YU, Chi HS, Lee EH, et al., (2009). Comparison of clinicopathologic findings according to JAK2 V617F mutation in patients with essential thrombocythemia. Int J Hematol; 89(1): 39–44''.
Ivanyi JL, Marton E, Plander M (2011). Significance of the JAK2V617F mutation in patients with chronic myeloproliferative neoplasia. Orv Hetil; 152(45): 1795–1803''.
Pósfai E, Marton I, Király PA. JAK2 V617F, MPL, and CALR Mutations in Essential Thrombocythaemia and Major Thrombotic Complications: A Single-Institute Retrospective Analysis. Pathol Oncol Res''.
Barbui T, Finazzi G, Carobbio A, et al., (2012). Development and validation of an International Prognostic Score of thrombosis in World Health Organization essential thrombocythemia (IPSET-thrombosis). Blood; 120(26): 5128–5133''.
Tefferi A (2013). Polycythemia vera and essential thrombocythemia: 2013 update on diagnosis, risk-stratification, and management. Am J Hematol; 88(6): 507–516''.
De Stefano V, Za T, Rossi E, et al., (2010). Increased risk of recurrent thrombosis in patients with essential thrombocythemia carrying the homozygous JAK2 V617F mutation. Ann Hematol; 89: 141-146''.
Musolino C, Alonci A, Bellomo G, et al., (2000). Markers of endothelial and platelet status in patients with essential thrombocythemia and polycythemia vera. Hematology; 4: 397–402''.
Chakrabarti S, Varghese S, Vitseva O, et al., (2005). CD40 ligand influences platelet release of reactive oxygen intermediates. Arterioscler Thromb Vasc Biol; 25: 2428–2434''.
Khan SY, Kelher MR, Heal JM, et al., (2006). Soluble CD40 ligand accumulates in stored blood components, primes neutrophils through CD40, and is a potential cofactor in the development of transfusion-related acute lung injury. Blood; 108: 2455–2462''.
Arellano-Rodrigo E, Alvarez-Larran A, Reverter JC, et al., (2009). Platelet turnover, coagulation factors, and soluble markers of platelet and endothelial activation in essential thrombocythemia: Relationship with thrombosis occurrence and JAK2 V617F allele burden. Am J Hematol; 84: 102–108''.