Tissue factor-dependent and -independent pathways of systemic coagulation activation in acute myeloid leukemia: a single-center cohort study

Abstract

BackgroundIn acute myeloid leukemia (AML), disseminated intravascular coagulation (DIC) contributes to morbidity and mortality, but the underlying pathomechanisms remain incompletely understood.MethodsWe conducted a prospective study on 69 patients with newly diagnosed AML to further define the correlates of systemic coagulation activation in this hematological malignancy. Tissue factor procoagulant activity (TF PCA) of isolated peripheral blood mononuclear cells (PBMCs) and TF expression by circulating microparticles (MPs) were assessed by single-stage clotting and thrombin generation assay, respectively. Soluble plasma TF antigen and secretion of vascular endothelial growth factor (VEGF) by cultured PBMCs were measured by ELISA. Cell-free plasma DNA was quantified by staining with a fluorescent dye.ResultTF PCA of PBMCs was significantly increased in AML patients as compared to healthy controls. Furthermore, TF PCA was significantly associated with decompensated DIC at presentation, as defined by a plasma fibrinogen level of ≤1 g/L (n = 11). In addition to TF PCA and circulating blasts, serum lactate dehydrogenase, a surrogate marker for leukemic cell turnover, correlated with plasma D-Dimer in the total patient cohort and was significantly increased in DIC patients, suggesting a role for myeloblast apoptosis/necrosis in activation of the TF-dependent coagulation pathway. Consistently, TF-bearing plasma MPs were more frequently detected and levels of soluble TF antigen were significantly higher in DIC vs. non-DIC patients. No association was found between TF PCA expression and VEGF secretion by isolated PBMCs, but significantly increased levels of cell-free plasma DNA pointed to a contribution of the intrinsic contact pathway to systemic coagulation activation in the total patient cohort and in patients with lower TF PCA expression. While PBMC-associated TF PCA had no effect on long-term survival, DIC occurrence at presentation increased the risk of early mortality.ConclusionIn newly diagnosed AML, TF expression by PBMCs and shedding of TF-bearing plasma MPs are central to the pathogenesis of DIC, but additional pathways, such as DNA liberation, may contribute to systemic coagulation activation.

Circulating Extracellular DNA: Cause or Consequence of Thrombosis?

“…97 Plasma DNA and nucleosomes were also associated with an increased risk of mortality within 150 days, suggesting the use of ceDNA as prognostic marker in DIC patients. 97 DNA concentration in cancer patients with DIC was increased compared with healthy controls 98 and DNA levels correlated with plasma levels of D-dimer, thus supporting an association of ceDNA and coagulation in DIC. 98 An independent study showed that levels of nucleosomes in plasma positively correlated with factor XII (FXII) and were significant predictor of mortality in DIC patients.…”

“…97 DNA concentration in cancer patients with DIC was increased compared with healthy controls 98 and DNA levels correlated with plasma levels of D-dimer, thus supporting an association of ceDNA and coagulation in DIC. 98 An independent study showed that levels of nucleosomes in plasma positively correlated with factor XII (FXII) and were significant predictor of mortality in DIC patients. 99 In summary, these data suggest an association between ceDNA and coagulation, thus identifying ceDNA as a prognostic marker for mortality in DIC.…”

Effect of Huisheng oral solution on coagulation function in perioperative period in patients with primary lung cancer

“…Secondly, caner and blood hypercoagulability correlates with each other. Inflammatory reaction, vascular endothelial injury, coagulation initiation, platelet activation, tumor cell adhesion and aggregation are involved in this process, with a numerous number of cytokines and proteins (27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37). Take platelet activation for example, though it has been demonstrated to correlate with tumor metastasis (38)(39)(40), it is rare to detect the plate activation relevant cytokines.…”

“…We chose these indices based mainly on the considerations of representativeness, feasibility, and practicality. In the process of malignant tumor progression or treatment, many biochemical indices can be used to assess coagulation status, such as clotting factors, platelet activation related factors, inflammatory mediators, coagulant substances produced by tumors, tissue factor, and anticoagulant related proteins (27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37). Choosing appropriate indices for evaluating VTE is of clinical importance.…”

Microparticle-associated tissue factor activity in dogs with disseminated intravascular coagulation

“…In people, several studies have reported that MP-associated TF (MP-TF) activity is associated with increased risk of thrombosis and DIC [3,4,10,19]. On the contrary, there have been few studies of MP-TF activity in dogs with a spontaneous disease.…”