Coagulation Falanga 4

Hypercoagulability and tissue factor gene upregulation in hematologic malignancies Reported by: Falanga A et al. Semin Thromb Hemost. 2008;34:204-210. ABSTRACT Overview: Patients with hematologic malignancies experience thrombotic complications as frequently as do patients with solid tumors. The profile of these complications differs from that of patients with solid tumors; for example, patients with acute leukemia may have concomitant thrombosis and bleeding. Patients with Philadelphiachromosome-negative chronic myeloproliferative disorders (Ph- MPDs) may have thrombosis rates as high as 40%. The pathogenesis of hypercoagulability in these patients is complex; however, it may be attributed to fundamental molecular changes in leukemic cells and of the progeny of hematopoietic progenitor cells that have undergone clonal rearrangement. Data suggest that these cells overexpress procoagulant factors and induce procoagulant changes at the vascular wall.

Figure 1. Hemostatic properties of tumor cells. Reproduced with permission from Falanga 2008

Procoagulant Activities (TF and CP) TC TC TC

INTRODUCTION ! Epidemiologic studies indicate that the rate of venous thromboembolism (VTE) in patients with hematologic malignancies is as high as that observed in patients with solid tumors ! The clinical manifestations of hemostatic changes in patients with leukemia are unique, ranging from localized venous or arterial thrombosis to diffuse life-threatening bleeding ! 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% !

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Patients with hematologic malignancies are predisposed to THS as a result of both prothrombotic factors common to all patients with thrombosis (eg, immobility, advanced age, history of previous thrombosis, etc), anti-cancer therapy, and the use of central venous access devices In addition, tumor cells have unique prothrombotic characteristics that express or release (Figure 1): ! Procoagulant properties and fibrinolytic/proteolytic proteins ! Inflammatory and angiogenic cytokines ! Membrane adhesion counterreceptors for endothelial, platelet, and leukocyte adhesion molecules

Mechanisms of malignancy

Tumor cell hemostatic properties

Purpose: This review focuses on the pathogenic mechanisms underlying the hypercoagulable state in patients with acute leukemia and Ph- MPDs.

TC TC

Coagulation-dependent

Fibrinolytic Activities (t-PA, u-PA, u-PAR, PAI) TC-derived Cytokines (IL-1, TNF, VEGF)

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ADHESION PROLIFERATION

Coagulation-independent

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Similar signaling pathways may play a role in eliciting the hypercoagulable state seen in hematologic malignancies ! In APL cells, a translocation that results in the fusion of the nuclear retinoic acid receptor gene with part of the promyelocytic leukemia gene results in hyperexpression of tissue factor (TF) ! A gain-of-function mutation in JAK2, present in 90% of patients with PV and 50% of patients with ET, is associated with increased TF expression Hemostatic abnormalities (hypofibrinogenemia, increased fibrinogen degradation products, prolonged prothrombin and thrombin times) are observed in patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) ! These abnormalities may worsen with traditional chemotherapy ! Among APL patients who receive all-trans-retinoic acid, improvement in clotting and fibrinolytic variables, paralleling improvement in clinical signs and symptoms, has been observed All hemostatic abnormalities seen in patients with AML and ALL 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

CONCLUSIONS ! Thrombotic complications are common and have important clinical consequences in patients with hematologic cancers

NEOANGIOGENESIS

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METASTASIS

The THS typical of acute leukemia (particularly APL) is associated with profound derangements in the hemostatic system and laboratory clotting abnormalities

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Patients with Ph- MPDs also frequently present with laboratory abnormalities consistent with a hypercoagulable state

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Data suggest that hematologic malignancies have tumor-specific clot-promoting properties

Cell Adhesion Molecules

THE HYPERCOAGULABLE STATE IN PATIENTS WITH ACUTE LEUKEMIA AND Ph- MPDs ! Neoplastic transformation itself (eg, activation of Met, loss of PTEN, induction of K-ras, loss of p53) has been demonstrated to activate clotting in experimental models of human hepatoma, brain tumors, and colon cancer

In ET and PV, quantitative changes leading to a high hematocrit and high platelet and leukocyte count contribute to the coagulopathy; qualitative changes in the molecular characteristics of these cells also contribute ! Neutrophils are activated in patients with ET and PV ! Neutrophils express higher concentrations of the β2 integrin CD11b on their membranes ! Biochemical changes are observed at the erythrocyte cell membrane and intracellularly in ET and PV; these changes promote erythrocyte aggregation, which in turn enhances platelet aggregation and facilitates platelet and leukocyte interaction with the vessel wall ! Platelets are chronically activated ! A gain-of-function mutation in JAK2 enhances expression of platelet surface TF and increases levels of platelet/neutrophil mixed aggregates

PATHOPHYSIOLOGY OF THS IN ACUTE LEUKEMIA AND Ph- MPDs ! Virchow’s triad can be used to describe the pathogenic mechanisms underlying the hypercoagulable state in patients with hematologic malignancies: ! Abnormalities in blood flow (stasis) ! Changes in vessel wall function ! Blood elements (both soluble and cellular) !

Increased blood viscosity, as a result of a high count of blood cellular elements, plays a critical role in the pro-coagulant environment found in patients with acute leukemia or Ph- MPDs

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The molecular properties of the leukemic cell or of the erythrocyte/platelet/leukocyte arising from the clonal rearrangement of hematopoietic cells, also play a role in THS

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Leukemic cells induce a hypercoagulable state by: ! Expressing procoagulant activities (PCAs) ! Releasing fibrinolytic/proteolytic factors and inflammatory cytokines such as interleukin (IL)-1β, TNF-α, and vascular endothelial growth factor (VEGF) ! Expressing membrane adhesion molecules

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All subtypes of AML express some PCA; APL is the most potent producer of PCA ! Cellular differentiation of APL induced by all-/trans/-retinoic acid (ATRA) is associated with rapid loss of PCA expression and rapid partial correction of coagulopathy; ATRA is also associated with a progressive reduction in TF content

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