Hypercoagulability and tissue factor gene upregulation in hematologic malignancies

Reported by: Falanga A et al. Semin Thromb Hemost. 2008;34:204-210.

ABSTRACT Figure 1. Hemostatic properties of tumor cells. Reproduced with permission from Falanga 2008 ! In ET and PV, quantitative changes leading to a high hematocrit and
Overview: Patients with hematologic malignancies experience high platelet and leukocyte count contribute to the coagulopathy;
thrombotic complications as frequently as do patients with solid qualitative changes in the molecular characteristics of these cells
tumors. The profile of these complications differs from that of patients also contribute
with solid tumors; for example, patients with acute leukemia may have ! Neutrophils are activated in patients with ET and PV
concomitant thrombosis and bleeding. Patients with Philadelphia- ! Neutrophils express higher concentrations of the β2 integrin
CD11b on their membranes
chromosome-negative chronic myeloproliferative disorders Tumor cell hemostatic Mechanisms ! Biochemical changes are observed at the erythrocyte cell
(Ph- MPDs) may have thrombosis rates as high as 40%. The
pathogenesis of hypercoagulability in these patients is complex;
properties of malignancy membrane and intracellularly in ET and PV; these changes
however, it may be attributed to fundamental molecular changes in promote erythrocyte aggregation, which in turn enhances
leukemic cells and of the progeny of hematopoietic progenitor cells platelet aggregation and facilitates platelet and leukocyte
that have undergone clonal rearrangement. Data suggest that these interaction with the vessel wall
cells overexpress procoagulant factors and induce procoagulant Procoagulant Activities ! Platelets are chronically activated
changes at the vascular wall. (TF and CP) ! A gain-of-function mutation in JAK2 enhances expression of
platelet surface TF and increases levels of platelet/neutrophil
ADHESION
Purpose: This review focuses on the pathogenic mechanisms TC Coagulation-dependent mixed aggregates
underlying the hypercoagulable state in patients with acute leukemia
TC Fibrinolytic Activities
CONCLUSIONS
and Ph- MPDs.
TC (t-PA, u-PA, u-PAR, PAI) PROLIFERATION ! Thrombotic complications are common and have important clinical
TC consequences in patients with hematologic cancers

INTRODUCTION TC TC-derived Cytokines NEOANGIOGENESIS ! The THS typical of acute leukemia (particularly APL) is associated
with profound derangements in the hemostatic system and
! Epidemiologic studies indicate that the rate of venous (IL-1, TNF, VEGF) Coagulation-independent laboratory clotting abnormalities
thromboembolism (VTE) in patients with hematologic malignancies
is as high as that observed in patients with solid tumors
METASTASIS ! Patients with Ph- MPDs also frequently present with laboratory
abnormalities consistent with a hypercoagulable state
! The clinical manifestations of hemostatic changes in patients
with leukemia are unique, ranging from localized venous or Cell Adhesion Molecules ! Data suggest that hematologic malignancies have tumor-specific
arterial thrombosis to diffuse life-threatening bleeding clot-promoting properties
! Thrombosis and bleeding manifestations (thrombo-hemorrhagic
syndrome [THS]) may occur concomitantly in patients with
acute promyelocytic leukemia (APL)
! The rate of thrombosis in patients with Ph- MPDs
(eg, polythemia vera [PV] and essential thrombocytopenia [ET])
may be as high as 40%
! Patients with hematologic malignancies are predisposed to THS as
a result of both prothrombotic factors common to all patients with
THE HYPERCOAGULABLE STATE IN PATIENTS WITH ACUTE PATHOPHYSIOLOGY OF THS IN ACUTE LEUKEMIA AND Ph- MPDs
thrombosis (eg, immobility, advanced age, history of previous
LEUKEMIA AND Ph- MPDs ! Virchow’s triad can be used to describe the pathogenic mechanisms
thrombosis, etc), anti-cancer therapy, and the use of central venous
! Neoplastic transformation itself (eg, activation of Met, loss of PTEN, underlying the hypercoagulable state in patients with hematologic
access devices
induction of K-ras, loss of p53) has been demonstrated to activate malignancies:
! In addition, tumor cells have unique prothrombotic characteristics clotting in experimental models of human hepatoma, brain tumors, ! Abnormalities in blood flow (stasis)
that express or release (Figure 1): and colon cancer ! Changes in vessel wall function
! Procoagulant properties and fibrinolytic/proteolytic proteins ! Blood elements (both soluble and cellular)
! Similar signaling pathways may play a role in eliciting the
! Inflammatory and angiogenic cytokines
hypercoagulable state seen in hematologic malignancies ! Increased blood viscosity, as a result of a high count of blood
! Membrane adhesion counterreceptors for endothelial, platelet,
! In APL cells, a translocation that results in the fusion of the cellular elements, plays a critical role in the pro-coagulant
and leukocyte adhesion molecules
nuclear retinoic acid receptor gene with part of the environment found in patients with acute leukemia or Ph- MPDs
promyelocytic leukemia gene results in hyperexpression of ! The molecular properties of the leukemic cell or of the
tissue factor (TF) erythrocyte/platelet/leukocyte arising from the clonal rearrangement
! A gain-of-function mutation in JAK2, present in 90% of patients of hematopoietic cells, also play a role in THS
with PV and 50% of patients with ET, is associated with
increased TF expression ! Leukemic cells induce a hypercoagulable state by:
! Expressing procoagulant activities (PCAs)
! Hemostatic abnormalities (hypofibrinogenemia, increased fibrinogen ! Releasing fibrinolytic/proteolytic factors and inflammatory
degradation products, prolonged prothrombin and thrombin times) cytokines such as interleukin (IL)-1β, TNF-α, and vascular
are observed in patients with acute myeloid leukemia (AML) and endothelial growth factor (VEGF)
acute lymphoblastic leukemia (ALL) ! Expressing membrane adhesion molecules
! These abnormalities may worsen with traditional chemotherapy
! Among APL patients who receive all-trans-retinoic acid, ! All subtypes of AML express some PCA; APL is the most potent
improvement in clotting and fibrinolytic variables, paralleling producer of PCA
improvement in clinical signs and symptoms, has been ! Cellular differentiation of APL induced by all-/trans/-retinoic acid
observed (ATRA) is associated with rapid loss of PCA expression and
rapid partial correction of coagulopathy; ATRA is also
! All hemostatic abnormalities seen in patients with AML and ALL associated with a progressive reduction in TF content
have been observed in patients with ET and PV; in addition,
significantly increased levels endothelial cell, red blood cell, platelet,
and leukocyte activation markers are seen in these patients

For educational purposes only. These were not prepared or reviewed by the primary author.