Leukemic cells release their nuclear contents into the extracellular space upon activation. The released nuclear contents, called extracellular traps, can activate the contact system of coagulation. This study accessed the extent of contact system activation, the levels of extracellular traps, and coagulation activation in hematologic malignancies including acute leukemia. In 154 patients with hematologic malignancies (acute leukemia, n = 29; myelodysplastic syndrome, n = 20; myeloproliferative neoplasms, n = 69; plasma cell myeloma, n = 36) and 48 normal controls, the levels of coagulation factors (fibrinogen and factor VII, VIII, IX, and XII), D-dimer, thrombin generation, extracellular trap markers (histone–DNA complex, cell-free dsDNA, leukocyte elastase), and contact system markers (activated factor XII [XIIa], high-molecular-weight kininogen, prekallikrein, bradykinin) were measured. Patients with acute leukemia showed the highest levels of peak thrombin, extracellular trap markers, and factor XIIa. Factor XIIa level was significantly associated with the presence of acute leukemia. The histone–DNA complex and cell-free dsDNA were revealed as significant associated factors with the factor XIIa level. Three markers of extracellular traps and two markers of thrombin generation significantly contributed to the hemostatic abnormalities in hematologic malignancies. Contact system was activated in acute leukemia and its activation was significantly associated with the extent of extracellular trap formation. This finding suggests that extracellular traps might be a major source of contact system activation and therapeutic strategies targeting extracellular trap formation or contact system activation may be beneficial in acute leukemia.
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This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health and Welfare, Republic of Korea (Grant No. HI17C1134).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.
Informed consent was obtained from all individual participants included in the study.
Colombo R, Gallipoli P, Castelli R (2014) Thrombosis and hemostatic abnormalities in hematological malignancies. Clin Lymphoma Myeloma Leuk 14(6):441–450CrossRefPubMedGoogle Scholar
van Montfoort ML, Meijers JC (2014) Recent insights into the role of the contact pathway in thrombo-inflammatory disorders. Hematol Am Soc Hematol Educ Progr 2014(1):60–65Google Scholar
Naudin C, Burillo E, Blankenberg S, Butler L, Renne T (2017) Factor XII Contact Activation. In: Seminars in thrombosis and hemostasisGoogle Scholar
Nakayama T, Saitoh H (2015) Tunicamycin-induced neutrophil extracellular trap (NET)-like structures in cultured human myeloid cell lines. Cell Biol Int 39(3):355–359CrossRefPubMedGoogle Scholar
Yoo HJ, Lee JS, Kim JE, Gu J, Koh Y, Kim I et al (2016) Extracellular histone released from leukemic cells increases their adhesion to endothelium and protects them from spontaneous and chemotherapy-induced leukemic cell death. PLoS ONE 11(10):e0163982CrossRefPubMedPubMedCentralGoogle Scholar
Park HS, Gu J, You HJ, Kim JE, Kim HK (2016) Factor XII-mediated contact activation related to poor prognosis in disseminated intravascular coagulation. Thromb Res 138:103–107CrossRefPubMedGoogle Scholar
Long AT, Kenne E, Jung R, Fuchs TA, Renne T (2016) Contact system revisited: an interface between inflammation, coagulation, and innate immunity. J Thromb Haemost 14(3):427–437CrossRefPubMedGoogle Scholar
Kim JA, Kim JE, Song SH, Kim HK (2015) Influence of blood lipids on global coagulation test results. Ann Lab Med 35(1):15–21CrossRefPubMedGoogle Scholar
Tripodi A (2016) Thrombin generation assay and its application in the clinical laboratory. Clin Chem 62(5):699–707CrossRefPubMedGoogle Scholar
Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A et al (2009) The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 114(5):937–951CrossRefPubMedGoogle Scholar
Ueki S, Konno Y, Takeda M, Moritoki Y, Hirokawa M, Matsuwaki Y et al (2016) Eosinophil extracellular trap cell death-derived DNA traps: their presence in secretions and functional attributes. J Allergy Clin Immunol 137(1):258–267CrossRefPubMedGoogle Scholar
Ma R, Li T, Cao M, Si Y, Wu X, Zhao L et al (2016) Extracellular DNA traps released by acute promyelocytic leukemia cells through autophagy. Cell Death Dis 7(6):e2283.15CrossRefGoogle Scholar
Kouyoumdjian M, Nagaoka MR, Borges DR (2005) Kallikrein-kinin system in hepatic experimental models. Peptides 26(8):1301–1307CrossRefPubMedGoogle Scholar
Hamberg U, Karkkainen T, Tallberg T (1986) Kininogen by the SRI method in human serum during an acute phase inflammatory reaction. Adv Exp Med Biol 198(Pt A):161–166CrossRefPubMedGoogle Scholar
de Maat S, Tersteeg C, Herczenik E, Maas C (2014) Tracking down contact activation—from coagulation in vitro to inflammation in vivo. Int J Lab Hematol 36(3):374–381CrossRefPubMedGoogle Scholar
Kim SY, Kim JE, Kim HK, Kim I, Yoon SS, Park S (2013) Influence of coagulation and anticoagulant factors on global coagulation assays in healthy adults. Am J Clin Pathol 139(3):370–379CrossRefPubMedGoogle Scholar
Coppola A, Tufano A, Di Capua M, Franchini M (2011) Bleeding and thrombosis in multiple myeloma and related plasma cell disorders. Semin Thromb Hemost 37(8):929–945CrossRefPubMedGoogle Scholar
Biro L, Domjan G, Falus A, Jakab L, Cseh K, Kalabay L et al (1998) Cytokine regulation of the acute-phase protein levels in multiple myeloma. Eur J Clin Investig 28(8):679–686CrossRefGoogle Scholar
Kenne E, Nickel KF, Long AT, Fuchs TA, Stavrou EX, Stahl FR et al (2015) Factor XII: a novel target for safe prevention of thrombosis and inflammation. J Intern Med 278(6):571–585CrossRefPubMedGoogle Scholar
Zhu S, Travers RJ, Morrissey JH, Diamond SL (2015) FXIa and platelet polyphosphate as therapeutic targets during human blood clotting on collagen/tissue factor surfaces under flow. Blood 126(12):1494–1502CrossRefPubMedPubMedCentralGoogle Scholar