title: Tissue factor-dependent and -independent pathways of systemic coagulation activation in acute myeloid leukemia: a single-center cohort study.
abstract: BACKGROUND
  In acute myeloid leukemia (AML), disseminated intravascular coagulation (DIC) contributes to morbidity and mortality, but the underlying pathomechanisms remain incompletely understood.
  
  
  METHODS
  We 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.
  
  
  RESULTS
  TF 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.
  
  
  CONCLUSIONS
  In 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.
authors.affiliation: II. Medizinische Klinik und Poliklinik, Hubertus Wald Tumorzentrum, Universitäres Cancer Center Hamburg (UCCH), Universitätsklinikum Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Dicke
authors.affiliation: Florida Hospital Center for Thrombosis Research, 2566 Lee Road, Winter Park, FL 32789 USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Amirkhosravi
authors.affiliation: II. Medizinische Klinik und Poliklinik, Hubertus Wald Tumorzentrum, Universitäres Cancer Center Hamburg (UCCH), Universitätsklinikum Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Spath
authors.affiliation: Institut für Klinische Chemie und Laboratoriumsmedizin, Universitätsklinikum Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.
authors.forename: Miguel
authors.initials: M
authors.lastname: Jiménez-Alcázar
authors.affiliation: Institut für Klinische Chemie und Laboratoriumsmedizin, Universitätsklinikum Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Fuchs
authors.affiliation: Florida Hospital Center for Thrombosis Research, 2566 Lee Road, Winter Park, FL 32789 USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Davila
authors.affiliation: Florida Hospital Center for Thrombosis Research, 2566 Lee Road, Winter Park, FL 32789 USA.
authors.forename: John L
authors.initials: JL
authors.lastname: Francis
authors.affiliation: II. Medizinische Klinik und Poliklinik, Hubertus Wald Tumorzentrum, Universitäres Cancer Center Hamburg (UCCH), Universitätsklinikum Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Bokemeyer
authors.affiliation: II. Medizinische Klinik und Poliklinik, Hubertus Wald Tumorzentrum, Universitäres Cancer Center Hamburg (UCCH), Universitätsklinikum Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Langer
keywords: Acute myeloid leukemia; Cell-derived microparticles; DNA; Disseminated intravascular coagulation; Tissue factor