Review

Thrombosis and Hemostatic Abnormalities in Hematological Malignancies Riccardo Colombo,1 Paolo Gallipoli,2 Roberto Castelli1 Abstract There is a paucity of data that pertain to thrombosis in patients with hematological malignancies. Recent studies showed that patients with lymphoma, multiple myeloma, and acute leukemia have an increased thrombotic risk, particularly at the time of diagnosis and during chemotherapy. We searched the PubMed database for articles on thromboembolic complications in patients with hematological malignancies published between 1996 and 2013. The incidence of thrombotic events is variable, and is influenced by the type and the stage of hematological malignancy, the antitumor therapy, and the use of central venous devices. The pathogenesis of thromboembolic disease in hematological malignancies is multifactorial. Tumor cell-derived procoagulant, fibrinolytic, or proteolytic factors, and inflammatory cytokines affect clotting activation, and chemotherapy and immunomodulatory drugs increase the thrombotic risk in patients with lymphoma, acute leukemia, and multiple myeloma. Infections might also contribute to the pathogenesis of the thromboembolic complications: endotoxins from gram-negative bacteria induce the release of tissue factor, tumor necrosis factor and interleukin-1b, and gram-positive organisms can release bacterial mucopolysaccharides that directly activate factor XII. In the setting of plasma cell dyscrasias, hyperviscosity, decreased fibrinolysis, procoagulant autoantibody production, inflammatory cytokines, acquired activated protein C resistance, and the prothrombotic effects of antimyeloma agents might be the cause of thromboembolic complications. Anticoagulant therapy is very complicated because of high risk of hemorrhage. Therefore, an accurate estimate of a patient’s thrombotic risk is essential to allow physicians to target thromboprophylaxis in high-risk patients. Clinical Lymphoma, Myeloma & Leukemia, Vol. -, No. -, --- ª 2014 Elsevier Inc. All rights reserved. Keywords: Blood coagulation, Blood malignancies, Haematology, Proinflammatory cytokines, Thromboembolic disease

Introduction The incidence of thromboembolic complications in solid cancer patients is about 5-fold greater than in the general population. Approximately 10% to 15% of patients with overt cancer will have a thrombotic complication during the course of the disease, but the rate of thrombosis in cancer varies greatly from 0.1% to 60% in relation to the tumor type, stage, and treatment (surgery, chemotherapy, radiotherapy, or hormonal treatments). Furthermore, venous thromboembolism (VTE) represents the second cause of morbidity and mortality in cancer patients.1-4 Recent studies have shown that the incidence of thrombosis might be as high (or even higher) in patients with malignant 1 Department of Pathophysiology and Transplantation, Internal Medicine Section, University of Milan, and Department of Haematology, Fondazione IRCCS Ca’ Granda-Ospedale Maggiore Policlinico, Milan, Italy 2 Department of Haematology, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Trust, Cambridge, UK

Submitted: Oct 30, 2013; Accepted: May 19, 2014 Address for correspondence: Roberto Castelli, MD, Department of Pathophysiology and Transplantation, Section of Internal Medicine, University of Milan, Via F Sforza 35, 20122 Milano, Italy Fax: þ39-02-55034722; e-mail contact: [email protected]

2152-2650/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2014.05.003

hematological disorders, but there is a paucity of data that pertain to patients with hematological malignancies.5-10 Moreover, the patients included in the published case series often differ for the type and the stage of hematological malignancy, the antitumor therapy received, and the use of central venous devices (CVDs), thus making it difficult to draw any meaningful conclusions from the published data.11-17 Clinically silent hemostatic abnormalities are found in most patients affected by hematological malignancies but only a limited number of patients show clinical manifestations including VTE, pulmonary embolism (PE), disseminated intravascular coagulopathy (DIC), and life-threatening thrombohemorrhagic syndrome, in which thrombosis and bleeding can occur concomitantly.9 However, in hematological patients, the risk of thrombosis might be obscured by the significant morbidity and mortality due to other complications, such as bleeding and infection. The incidence of these complications depends on the type of hematological malignancy and the phase of treatment.18 In addition, the widespread use of CVDs and the introduction of new immunomodulatory drugs (IMIDs), together with the use of erythropoietin and high doses of steroids have further increased the incidence of thrombotic complications. The pathogenesis of thromboembolic disease in hematological malignancies is complex

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Thrombosis and Hematological Malignancies and multifactorial, and can be due to the underlying disorder or related to therapy. Prothrombotic factors include hyperleukocytosis, increased tissue factor (TF) expression and activation in leukemic cells, and the prothrombotic effects of therapeutic agents and vascular access devices. In addition, comorbidities, including hereditary thrombophilia, infections, cytokine-induced endothelial cell activation, antiphospholipid syndrome, and acquired activated protein C resistance, are major contributory factors.9,10 However, anticoagulant therapy is often complicated in hematological cancer patients, who are at very high hemorrhagic risk because of concomitant thrombocytopenia. Therefore, an accurate estimate of an individual patient’s VTE risk, based on individual clinical risk factors and biomarkers, is essential to allow physicians to target thromboprophylaxis in high-risk patients. In this review article we will discuss the incidence, pathogenesis, risk factors, and the prophylaxis of thromboembolic complications and treatment of VTE in malignant hematological disease. Philadelphia-negative myeloproliferative neoplasms have not been included because thrombosis an intrinsic manifestation of these diseases.

Materials and Methods The citations from PubMed between January 1996 and March 2013 were searched using the keywords “thrombotic events,” “pulmonary embolism,” and “hematological malignancies,” “acute leukemia,” “lymphoproliferative disease,” and “multiple myeloma.” Our search was limited to randomized controlled trials without language restriction. To ensure completeness of the search strategy, we independently searched the citations using databases from the Web of Science, EMBASE, and the Cochrane Library for all relevant randomized controlled trials. When there was a duplication of publications, we reviewed each article and included only the most recent or the most complete version of the trial for analysis.

Pathogenetic Mechanism of Thrombosis in Acute Leukemia The Pathogenesis of Thromboembolic Disease in Acute Leukemias The pathogenesis of thromboembolic disease in leukemia is complex and multifactorial. The major determinants are: (1) prothrombotic factors produced by leukemic cells, including TF, cancer procoagulant (CP), and inflammatory cytokine; (2) therapeutic agents used; (3) infectious complications; and (4) comorbid thrombophilia.9

Prothrombotic Factors Produced by Leukemic Cells

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Prothrombotic factors produced by blasts cells, including TF, CP, and inflammatory cytokines, might induce the development of DIC and thrombin generation. Cancer procoagulant is a cysteine protease derived from a broad spectrum of malignant and embryonic tissues that have vitamin K-dependent activity and directly activate factor X in the absence of factor VII.19-21 Increased levels of CP have been reported in various advanced cancers and acute promyelocytic leukemia (APL). The leukemic promyelocytes show the highest procoagulant activity and thrombin generation correlates with blast cell count in APL. The procoagulant

Clinical Lymphoma, Myeloma & Leukemia Month 2014

state in APL is partially due to the TF-dependent procoagulant properties of circulating promyelocytic-derived microparticles (MPs).22 Leukocytosis is commonly observed in leukemia. Studies on the pathophysiology of leukostasis and tissue infiltration by leukemic blast cells have revealed that cytokines (tumor necrosis factor-alpha [TNF-alpha] and interleukin 1b [IL1b]) secreted by leukemic cells, together with direct contact between adhesion receptors expressed by blasts and endothelial cells, are responsible for endothelial activation, that leads to the activation of the clotting cascade and thrombotic complications.23 A summary of the pathophysiological mechanisms leading to thrombosis in cancer and specifically in hematological malignancies is represented in Figure 1.

Therapeutic Agents L asparginase and steroids, typically used during induction treatment of acute lymphoblastic leukemia (ALL), have been shown to suppress natural anticoagulants, especially antithrombin and plasminogen, and cause increases in factor VIII and von Willebrand factor (vWF) complex.24 All-trans-retinoic acid (ATRA), used to treat APL, instead has been shown to decreases the expression of TF and CP, thus reducing blast cell procoagulant activity, fibrinolytic and proteolytic activities, and the secretion of inflammatory and angiogenetic cytokines.25,26 However, ATRA also increases the production of cytokines affecting endothelial status, and might be involved in activating the prothrombotic and proadhesive functions of the endothelium and some studies have suggested that ATRA-induced modifications in the balance between procoagulant and fibrinolytic properties of leukemic promyelocytes might favor the development of prothrombotic events, especially during ATRA syndrome and in patients with hyperleukocytosis.27 Moreover, retinoic acid isomers (either ATRA or 13-cis-retinoic acid) might also contribute to an increased thrombotic risk by altering serum triglyceride metabolism, which leads to the hypertriglyceridemia often observed in patients treated with either retinoids or rexinoids. This appears to be secondary to a reduced capacity to clear infused lipids, suggesting reduced tissue lipolytic activity.28 Based on these experimental data we conclude that ATRA-induced hypertriglyceridemia, in addition to ATRA-induced hypercoagulability, might contribute to venous and arterial thromboembolic events in patients with hematological malignancies and in fact thromboembolic events have been reported during ATRA therapy including myocardial infarction, cerebral thrombosis, and VTE.9

Infectious Complications Endotoxins from gram-negative bacteria induce the release of TF, TNF-alpha, and IL1b, and gram-positive organisms can release bacterial mucopolysaccharides that directly activate FXII.29

Comorbid Thrombophilia Age, hospitalization-related immobility, and especially the presence of a CVD are additional important factors that contribute to the development of thrombosis. The pathogenesis of CVD-related thrombosis is multifactorial, and the risk factors include CVD

Riccardo Colombo et al Figure 1 Tumor Cells (Solid Tumor and Leukemic Cells) Express and Synthesize Tissue Factor (TF) and Cancer Procoagulant (CP) on Their Surface. CP Directly Activates Factor X (FX) to Activated FX (FXa). TF Activates F VII (FVIIa). The Complex Factor VIIa and TF (FVIIa D TF) Activate FX to FXa Which in Turn Activates Prothrombin to Thrombin (Which Acts on Endothelial Cells as Mitogen). Thrombin in Turn Activate Fibrinogen to Fibrin. Recently, the Role TF Circulating in Blood in Association with SubCellular Membrane Vesicles, So-Called Plasma Microparticles (MPs) in the Pathogenesis of Thrombotic Complications Especially in Cancer Patients Have Been Clarified. Elevated Levels of TF-Positive MPs Have Been Reported in Acute Leukemias. MPs are Cell-Derived Membrane Fragments Measuring 0.1e1.0 mm, Originating From Platelets, Blood Cells and Endothelial Cells (EC), or Malignant Cells. Soluble or Free TF Found in the Plasma is Carried by MPs and Binds Directly to Factor VIIa TF-MPs Also Facilitate the Binding of Cells and Platelets to Neutrophils and Monocytes via P-Selectin. Thus, Hypothetically, MPs are Involved Directly and Indirectly in Activating Coagulation. The Effects of Tumor Cell Procoagulants are Enhanced by the Production of Proangiogenetic Cytokines Such as Interleukin -8 (IL-8) and Vascular Endothelial Growth Factor (VEGF). Interleukin 1b (IL1b) Secreted by Tumor Cells, are Responsible for Endothelial Activation, that Leads to the Activation of the Clotting Cascade and Thrombotic Complications by Three Mechanisms: (1) Down Regulation of Thrombomodulin (TM) (2) Increased Synthesis by Endothelial Cells of TF and Plasminogen Activator Type I (PAI-1) (3) Production of IL-8 by Injured Endothelial Cells. Immobilization, Surgery, Infection, Central Venous Catheters, Hyperleukocytosis use of Erythropoietin, Acquired and Inherited Hypercoagulable State, Accelerated Neoplastic Activity Chemotherapy Agents Acts on Both Coagulation Cascade and/or Endothelial Surface Contributing in the Pathogenesis of Cancer-Related Thrombosis

biocompatibility, the position of the catheter tip, the side of insertion, the puncture site, thrombophilic abnormalities, and CVD-related infections.30,31 Vessel damage plays an important role, and might be caused by mechanical injury of the venous endothelium during catheter insertion or irritation of the vessel wall by chemotherapeutic agents. The use of peripherally inserted central catheters (PICCs) has increased rapidly in modern medical practice for several reasons, including ease of insertion, perceived safety, and cost-effectiveness compared with other central CVDs.32 Despite these benefits, PICCs are associated with deep vein thrombosis (DVT) of the arm and PE.33 A recent meta-analysis by Chopra et al showed that PICCs were associated with greater risk of DVT of the arm than were CVDs. The incidence of PICC-related DVT seemed to be greatest in critically ill patients and those with cancer,

and was more frequent in studies that used prospective designs and screened for DVT in the absence of clinical symptoms.33 These findings suggest that PICC-related DVT is a complication that might be more prevalent than clinically perceived or more evident when robust study designs are used. The greatest incidence of thrombosis seems to be related to several factors that include: insertion into peripheral veins that are more likely to occlude in the presence of a catheter that occupies much of the luminal diameter; site of PICC insertion; and intimal injury from repeated arm movements. Moreover an increased frequency of mechanical complications coupled with longer dwell times of PICCs compared with CVDs might also increase the risk of DVT.33 Recently, the role of TF circulating in blood in association with subcellular membrane vesicles, so-called plasma MPs in the

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Thrombosis and Hematological Malignancies pathogenesis of thrombotic complications, especially in cancer patients, have been clarified. Increased levels of TF-positive MPs have been reported in acute leukemias.22,34 Microparticles are cell-derived membrane fragments measuring 0.1 to 1.0 mm, originating from platelets, blood cells, endothelial cells, or malignant cells. Soluble or free TF found in the plasma is carried by MPs and binds directly to factor VIIa. TF-MPs also facilitate the binding of cells and platelets to neutrophils and monocytes via P-selectin. Thus, hypothetically, MPs are involved directly and indirectly in activating coagulation.35 In APL, the leukemic promyelocytes express a high level of TF, and, as a consequence the MPs derived from the leukemic cells also carry TF. Thus the populations of TF-bearing MPs in APL plasma are correspondingly increased. In APL patients, at onset of disease, circulating MPs are mostly from the APL promyelocytes. During ATRA treatment, the population of promyelocytes decreases and the platelet counts return to normal and therefore the number of MPs decreases.36

Incidence of Thromboembolic Events in Acute Leukemias

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A wide variety of clinical manifestations characterize patients with acute leukemia, including clotting alterations, ranging from localized venous or arterial thrombosis to DIC. Depending on leukemia type (acute myeloid leukemia [AML] or ALL) and the associated disease treatment, the rate of thrombotic complication ranges from 2.1% to 12.1%.37 De Stefano et al38 recruited 379 consecutive adult patients with newly diagnosed acute leukemia. Twenty-four patients had first thrombosis (6.3%), venous in 19 patients (80%) and arterial in 5 patients (20%). At diagnosis, thrombosis was a presenting manifestation in 13 cases: 1.4% in ALL, 9.6% in APL, and 3.2% in other AML patients. The cumulative incidence of thrombosis after 6 months from diagnosis was 10.6% in ALL, 8.4% in APL, and 1.7% in other AML patients. The patients who received L-asparaginase had a 4.9-fold increased risk of thrombosis compared with those who did not (95% confidence interval, 1.516.0). The fatality rate due to thrombosis was 0.8%. The authors concluded that thrombosis can be a presenting symptom at diagnosis in a significant portion of cases with APL (9.6%) and other AML (3.2%); a similar rate of thrombosis can occur during the subsequent course of the disease. The incidence of symptomatic thrombosis at diagnosis is relatively low in ALL patients (1.4%), but is significantly increased by further treatment up to 10.6%. The pathogenesis of thrombosis in ALL is likely to be therapeutically related, with most events occurring during remission induction. Furthermore, thrombosis is quite rare in children and its incidence increases with age. However incidence of thrombotic complications increase in ALL patients, in children and adults treated with L-asparaginase because 5% of pediatric patients and 34% of adult patients treated with protocols including L-asparaginase suffered a thrombotic event.39 Most thrombotic events occurring in association with L-asparaginase are venous, but also arterial thromboses are reported. As expected, prolonged use of L-asparginase increased the VTE risk. Treatment with prednisolone instead of dexamethasone, anthracycline use, induction phase of treatment, and presence of CVD are strongly associated with upper vein thrombosis and the

Clinical Lymphoma, Myeloma & Leukemia Month 2014

presence of at least 1 genetic prothrombotic defect was another risk factor for thrombosis in ALL children (8-fold increased risk of VTE). Another population-based study showed that the incidence of VTE in patients with acute leukemia was high, particularly during the first 3 months of treatment and specifically associated with insertion of a CVD, female sex, and the presence of 2 chronic comorbid medical conditions in AML and older age, presence of a catheter, and presence of multiple medical comorbidities in ALL. In AML patients, the diagnosis of VTE was not associated with a significant reduction in survival, however, in patients with ALL, development of VTE was associated with a higher risk of death within 1 year.40 The authors concluded that the incidence of VTE in acute leukemia is appreciable, and comparable with the incidence in many solid tumors. APL is a distinct subtype of AML, which typically presents with a life-threatening hemorrhagic diathesis, the clinical and laboratory features of which are consistent with DIC.41,42 In this condition, however, thrombosis and bleeding manifestations might occur concomitantly as a part of the same thrombohemorrhagic syndrome. The bleeding complications are particularly severe in the microgranular variant, which is characterized by hyperleukocytosis. Before the introduction of ATRA, fatal hemorrhages caused by DIC were a major cause of failure during remission induction.43,44 As discussed previously, however, the imbalance caused by ATRA and arsenic trioxid between procoagulant and fibrinolytic forces has been postulated to induce a prothrombotic effect, even if overall incidence of thrombotic events is still low. Rates of thrombosis reported at the time of (or just before) diagnosis of APL were 9.7% including arterial (3.2%) and venous (6.5%). The hypothesis that ATRA might have a prothrombotic effect is supported by the fact that more than 60% of thrombotic events occurred during ATRA treatment, but only a few studies have addressed this issue in large cohorts of patients. Therefore, it might be difficult to determine whether thrombosis in APL is attributable to hypercoagulability caused by the disease itself versus a drug effect from ATRA. The exacerbation of the procoagulant state of APL that can be seen with the development of ATRA-induced differentiation syndrome might lead to an increased risk of hemorrhage and thrombosis. A study by the Gruppo Italiano Malattie Ematologiche dell’Adulto group of 124 APL patients treated with the All- Transretinoic acid þ Idarubicin regimen compared the clinical and biological features of patients who did and did not develop thrombosis. The incidence of thrombosis in this study was 8.8%, with 7 patients (5.6%) developing thrombosis during induction chemotherapy and 4 patients during the postinduction phase. In this study the authors found that the risk factors for developing thrombosis included a higher leukocyte count, prevalence of the promyelocytic leukemia/ retinoic acid receptor (PML/RARa) bcr3 transcript type, and expression of FMS-like tyrosine kinase 3-ITD, CD2, and CD15.45 Interestingly, contradictory data regarding the risk factors for thrombosis emerged in a larger Programa para el Estudio de la Terapéutica en Hemopatías Malignas cooperative study group. The overall incidence of thrombosis was 5.1% (39 of 759), with 6 of the 26 patients who died before initiation of chemotherapy presenting with thrombotic events (3 cerebral strokes, 2 pulmonary emboli,

Riccardo Colombo et al 1 acute myocardial infarction). The incidence of thrombosis in patients who had begun the All- Trans-retinoic acid þ Idarubicin treatment was 4.5% (33 of 733), with 18 DVT, 7 central nervous system (CNS) thrombosis, 3 PE, 3 acute myocardial infarctions, and 2 others. The risk factors for thrombosis in univariate analysis were fibrinogen < 170 mg/dL; hemoglobin > 10 g/dL, APL-variant subtype, and white blood cell (WBC) count > 103  109/L. In multivariate analysis, the APL-variant subtype and low fibrinogen levels retained their statistical significance for predicting thrombosis correlation between the development of thrombosis and differentiation syndrome.46

Thrombotic Risk in Lymphoproliferative Disease Several studies show that the incidence of thromboembolic complications in lymphoproliferative disease is clearly increased and the incidence of VTE is comparable with that in solid tumors.5-10 The rate of thrombotic complications in lymphoproliferative disease is highly variable, ranging from 1.5% up to 59.5%. This wide variability is mainly because of the different study types (prospective or retrospective, with hospitalized or ambulatory patients), types of disease (indolent vs. aggressive), the disease stage, and different intensities and qualities of the chemotherapeutic protocols. Among different lymphoma types, the highest VTE incidence has been observed in patients with primary CNS lymphoma,5,20 reaching an incidence of 59.5% with 7% fatal. The reason for this high incidence might be because of the combination of CNS involvement by tumor-causing hypomobility and the intensive chemotherapy often associated with dexamethasone given to control brain edema.5-20 Similarly, nearly all patients developed thromboembolic complications during the first 3 months of therapy, further suggesting the role of chemotherapy in the pathogenesis of VTE. Mohren et al46 found an overall thromboembolic event incidence of 7.7% in 1038 treated lymphoma patients with a statistically significantly higher incidence in high-grade than in low-grade lymphoma. Most patients had their thrombotic event during or after chemotherapy. The 2 most important messages from this study are that the histotype is very relevant and strictly linked with the incidence of VTE, because thrombotic events were more likely in patients with aggressive lymphoma, and that chemotherapy alone or in association with dexamethasone might play a pivotal role in the pathogenesis of thrombotic events in patients with lymphoproliferative disease. Similar results were also found by Ottinger et al15 in a prospective clinical trial analyzing thromboembolism in high grade nonHodgkin lymphomas (NHLs). Clinical analysis documented a 6.6% incidence of VTE, and 77% of all cases occurred before or within the first 3 months of chemotherapy. Ann Arbor stage IV and B-mediastinal clear cell histology were risk factors for VTE. The authors concluded that VTE in the setting of NHL, although rarely fatal, is a frequent complication with an unfavorable clinical course. Taken together these studies show that the incidence of thrombotic events in patients with lymphoproliferative diseases is similar to that of patients with solid tumors. High grade NHL, high international prognostic index score, and the presence of mediastinal mass or CNS involvement are all predictive factors of

thromboembolic events in patients with lymphoproliferative disease. Other common risk factors are age, stage, immobility, CVD, and intensive chemotherapy. The occurrence of thrombotic events during the first 3 months of therapy or immediately after chemotherapy suggest that a thromboprophylaxis during or after chemotherapy could be effective in reducing thromboembolic events.

Thrombosis in Plasma Cell Dyscrasias and Multiple Myeloma Monoclonal Gammopathy and VTE There are conflicting data on the risk of thrombosis in patients with monoclonal gammopathy of undetermined significance (MGUS). Sallah et al prospectively monitored 310 patients with MGUS every 3 months for a median of 44 months and objectively diagnosed VTE in 6.1% of cases (6 VTE cases per 100 patientyears). Statistical analysis showed that age > 65 years, monoclonal protein levels of > 16 g/L, progression to multiple myeloma (MM), amyloidosis, or the presence of a lymphoproliferative disease are risk factors for VTE in MGUS patients.47 A retrospective analysis of 174 MGUS individuals and 404 MM patients of the Cleveland Clinic between 1991 and 2001 confirmed VTE in 7.5% to 10%. The risk factors associated with VTE in the MGUS patients included a personal or family history of thrombosis, immobility, low albumin levels, and high WBC counts.48 Recently, the increased risk of VTE in MGUS was questioned by Za et al.49 The authors carried out a retrospective multicenter cohort study on 1491 patients with MGUS. Multivariate analysis showed increased risks of arterial thrombosis in patients with cardiovascular risk factors, and of venous thrombosis in patients with a serum M-protein level > 16 g/L at diagnosis. No thrombosis was recorded in patients who developed MM (n ¼ 50) or other neoplastic diseases (n ¼ 21). The incidence of arterial or venous thrombosis in patients with MGUS did not increase relative to that reported in the general population for similarly aged members. Finally, the risk of venous thrombosis did increase when the M-protein concentration exceeded 16 g/L and a personal or family history of VTE was associated with an increased risk in the patients with MM.

Multiple Myeloma and DVT Multiple myeloma is a neoplastic disorder due to the proliferation of clonal plasma cells in bone marrow and characterized by the production of monoclonal proteins, which are detectable in serum or urine, and clinically by destructive bone lesions, anemia, hypercalcemia, and renal insufficiency. It accounts of 15% of hematological malignancies and 1% of all cancers. MM is currently the leading hematological malignancy in terms of venous thrombosis risk (the occurrence of thromboembolic disease is roughly 10%). Risk factors responsible for this complication can be patient-, myeloma-, and treatment-related. Prothrombotic factors include age, chemotherapy, immobility, enhanced expression of TF from malignant cells, circulating MPs, and increased vascular endothelial growth factor.4,19,20 In patients with paraproteinemias, immunoglobulin-specific mechanisms might also be involved and include hypofibrinolysis, hyperviscosity, procoagulant autoantibody production, effects of inflammatory cytokines, and acquired activated protein C resistance.19,20 Its prognosis is severe, with a median survival after diagnosis of approximately 3 years because of frequent

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Thrombosis and Hematological Malignancies relapses. The introduction of new drugs such as thalidomide, lenalidomide, and bortezomib has markedly improved MM outcome leading to a significant improvement in overall survival by achieving deeper levels of responses and prolonged duration of remission. Furthermore, myeloma patients can also present with arterial thrombosis. The thrombogenic effects seem to be due to a transient reduction in soluble thrombomodulin levels during the first month of therapy, and the restoration of protease-activated receptor 1 endothelial cell expression after damage by cytotoxic agents such as doxorubicin. Furthermore, by increasing apoptosis, thalidomide leads to the phosphatylserine-induced activation of procoagulant TF on the cell membrane by making apoptotic cells more thrombogenic.19,50-53 However, the incidence of thrombotic events has been increased since thalidomide, lenalidomide, and pomalidomide (IMIDs) have been used in association with chemotherapy and or with dexamethasone.16,54,55 The risk of thrombosis is low (< 5%) when IMIDs are used as single-agent therapy. In contrast, several studies have shown that the incidence of thrombosis (mainly venous but also arterial) increases to 11.5% to 26% when IMIDs are used in combination with high-dose dexamethasone.56 The association of thalidomide with doxorubicine and dexamethasone further increases the risk of DVT to 58%. Limited data are available on the incidence of thrombosis with lenalidomide. Clinical studies have shown, in relapsed/refractory patients, a rate of thrombosis of 3% in patients treated with lenalidomide as a single-agent, with the incidence markedly increased when lenalidomide is associated with dexamethasone (ranging from 6% to75% in the absence of prophylaxis in newly diagnosed patients and from 4% to 15% in relapsed MM).57,58 Recently, a multicenter prospective observational study of 524 MM patient aiming to evaluate VTE incidence and to identify risk factors in IMID-treated patients was reported. Patients were evaluated at baseline, at 4 and at 12 months during MM therapy. VTE incidence was 7% (n ¼ 31), including 2.5% PE (n ¼ 11), similar at 4 or 12 months. VTE occurred in 7% of patients taking aspirin versus 3% for those taking low molecular-weight heparin (LMWH) prophylaxis, and none for those taking vitamin K antagonists (VKAs). The study concluded that VTE prophylaxis, based on individualized VTE risk assessment, is compulsory in IMID-treated MM. Anticoagulation prophylaxis with LMWH should clearly be prioritized in MM patients with high VTE risk, along with VKA.59 Direct comparisons of regimens of thrombogenic potential with or without bortezomib demonstrated lower VTE risk with bortezomib, suggesting a potential protective effect of bortezomib in combination with IMID-based regimens associated with increased risk of VTE. It has been suggested that bortezomib has antihemostatic effects in patients with relapsed or refractory MM, which might explain its protective effects in combination with regimens with an increased risk of VTE.60 Table 1 present the main studies showing thrombotic complications in haematological malignancies.

Thrombotic Microangiopathies After Bone Marrow Transplantation

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Thrombotic microangiopathies (TMAs) are rare disorders characterized by microvascular platelet thrombi leading to microangiopathic hemolytic anemia, consumptive thrombocytopenia, and ischemic manifestations in various organs.61,62

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Identification of the vWF cleaving protease a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (a plasma metalloprotease that cleaves ultralarge thrombogenic vWF multimers secreted by activated endothelial cells) has contributed to clarification of the pathogenesis of thrombotic thrombocytopenic purpura (TTP), the prototype TMA.63-65 Many patients with TTP have undetectable or very low levels of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 enzymatic activity. TMAs are relatively frequent and serious complications after bone marrow transplantation (BMT), particularly in patients undergoing allogeneic BMT (AT).66 The clinical manifestations are similar to those of TTP, but prognosis is generally poorer despite plasma exchange.67 It can often be difficult to establish a diagnosis of AT-TMA in BMT recipients, who frequently have multiple potential etiologies for renal dysfunction and fever, and might show only subtle neurological abnormalities.68 Persistent anemia or thrombocytopenia might be mistakenly attributed to the delayed engraftment of red blood cells or platelets, or to the effects of myelosuppressive medications, infections, or graft versus host disease (GVHD). Furthermore, the presentation of AT-TMA is highly heterogeneous, ranging from asymptomatic low-level red blood cell fragmentation to fulminant disease. TMA is often associated with GVHD or cyclosporine used for GVHD prophylaxis, and usually occurs within the first 150 days after transplant. Unlike classic TTP, postBMT TMA is generally unresponsive to plasma exchange.69,70 Its reported incidence varies widely from 0.5% to 63.6%, possibly because of the variety of diagnostic criteria and diseases leading to BMT.71 The risk factors include acute GVHD, GVHD prophylaxis with cyclosporin, total body irradiation, intensive conditioning chemotherapy, systemic infections, and female sex. There is still no consensus concerning therapy for patients with AT-TMA. Initial treatment usually consists of replacing cyclosporin or tacrolimus with alternative immunosuppressive medications such as mycophenolate mofetil and anti-T cell antibody therapies, although their use might be associated with dose-limiting myelosuppression in BMT recipients. The role of plasma exchange in managing ATTMA is controversial.66 Defibrotide, which has been shown to improve outcome in patients with severe hepatic veno-occlusive disease also prevents TNFealpha-induced endothelial cell apoptosis in vitro.72 The drug appears to prevent the formation of blood clots and to help dissolve blood clots by increasing levels of prostaglandin I2, E2, and prostacyclin, altering platelet activity, increasing TF activator function, and decreasing activity of tissue plasminogen activator inhibitor.

Erythropoiesis-Stimulating Agents Erythropoiesis-stimulating agents (ESAs; such as epoetin and darbepoetin alpha) are widely used in cases of solid and hematological tumors because they reduce transfusion dependence and allow a good hematological response in clinical practice. However, recent data suggest that these drugs increase the incidence of VTE.73,74 A Cochrane meta-analysis of recombinant human erythropoietin in cancer patients has shown that the overall relative risk (RR) is 1.67, and it is higher in patients with higher target hemoglobin

Riccardo Colombo et al Table 1 Thromboembolic Complications in Haematological Malignancies: An Overview From Literature Disease Acute Leukemia

No. of Patients 379

719

455 High-Grade Non-Hodgkin Lymphoma

348

79 593

Low-Grade Non-Hodgkin Lymphoma Hodgkin Lymphoma B Cell Leukemia

Monoclonal Gammopathies of Unknown Significance

Multiple Myeloma

Incidence of Thrombosis

Risk Factors

Site

Reference

Overall incidence: 6.3%; at diagnosis, thrombosis was a presenting manifestation in 13 cases: 1.4% in ALL, 9.6% in APL, and 3.2% in non-M3 AML patients After 6 months from diagnosis: 10.6% in ALL, 8.4% in APL, and 1.7% in other AML patients Overall incidence: 2%; similar in LMA and LLA. At diagnosis: 2%; during follow-up: NR Overall incidence: 12%; similar in LMA and LLA Overall incidence: 10.6%

Chemotherapy, hematological malignancy

Venous 80%; arterial 20%

De Stefano et al38

65

Overall incidence: 7.5% Overall incidence: 6.6%; 77% of all cases occurred before or within the first 3 months of chemotherapy Overall incidence: 3%

485 63

Overall incidence: 5.77% Overall incidence: 3.17%

193 268

Overall incidence: 7.25% Overall incidence: 5.22%

310

Overall incidence: 6.1%

174

Overall incidence: 7.5%

1491

5326

18,627

404

Venous and pulmonary embolism Chemotherapy, hematological malignancy, CVC Chemotherapy, hematological malignancy High-grade histopathology, bulky disease, vein compression, Ann Arbor stage IV, and B-mediastinal clear cell histology

Venous

Ziegler et al89

Mohren et al90 Venous

Mohren et al91

Venous

Sgarabotto et al92 Ottinger et al15

Concomitant estrogen therapy in 2 patients

Venous

Sgarabotto et al92

NR

Venous

Mohren et al91 Sgarabotto et al92 Mohren et al91 Whittle et al93

Binet stage C (progression of CLL)

Venous and pulmonary embolism

Age of > 65 years, M protein levels of > 16 g/L, progression to multiple myeloma, amyloidosis, or the presence of a lymphoproliferative disease Personal or family history of thrombosis, immobility, low albumin levels, and high WBC counts

Venous

Sallah et al47

Venous

Srkalovic et al48

Overall incidence: 2.7%

Cardiovascular events for arterial thrombosis, M protein level for venous thrombosis

Za et al49

Overall incidence: 3.4% at diagnosis; 2.1% at 1.5 years; 1.5% at 10 years Overall incidence: 7.5% at diagnosis; 4.6% at 1.5 years; 4.1% at 10 years

Age, IgG, and IgA; no correlation with M component concentration

2.5 Arterial events per 1000 patient-years; 1.9 venous events per 1000 patient-years Venous and arterial

Overall incidence: 10%

Immobilization, surgery, infection, central venous catheters, use of erythropoietin, acquired and inherited hypercoagulable state, accelerated neoplastic activity Personal or family history of venous thromboembolism, known hypercoagulable state, immobility, percentage of plasma cells in bone marrow, creatinine levels, serum M protein, chemotherapy

Kristinson et al94

Kristinson et al94

Srkalovic et al48

Abbreviations: ALL ¼ acute lymphoblastic leukemia; AML ¼ acute myeloid leukemia; APL ¼ acute promyelocytic leukemia; CLL ¼ chronic lymphocytic leukemia; CVC ¼ central venous catheter; M protein ¼ monoclonal protein; NR ¼ not reported; WBC ¼ white blood cell.

Clinical Lymphoma, Myeloma & Leukemia Month 2014

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Thrombosis and Hematological Malignancies levels and in those who are not anemic at baseline. In particular, the RR seems to increase from 0.7 for target hemoglobin levels of 12 to 13 g/dL to 1.71 for target levels of 13 to 14 g/dL, and to 1.92 for levels of 14 to 15 g/dL.75,76 The exact mechanism underlying this effect of ESAs is not clear. It does not seem to be a problem of viscosity alone, because hemoglobin levels of 13 to 14 g/dL in a nononcological patients do not lead to an added risk for VTE. It is believed that recombinant human erythropoietin increases the risk of thrombosis by enhancing the thrombogenic activity of the extracellular matrix of endothelial cells, as a result of increased TF expression or by inducing thrombin activatable fibrinolysis inhibitor expression and a hypofibrinolytic state.76 The published findings show no advantage in terms of reduced thrombotic risk between epoetin alpha and darbepoetin, thus suggesting that the risk of VTE is a class effect of ESAs. Moreover, in a meta-analysis of ESA dose and the risk for VTE no correlation between these variables was found.77 ESAs seem to have a favorable benefit-risk ratio, provided that they are correctly used in cancer patients receiving chemotherapy to correct anemia to a target hemoglobin level of approximately 12 g/dL. The dose should be adjusted if the rate of increase in hemoglobin exceeds 2 g/dL per month, which requires the close monitoring of hemoglobin levels. Particular care should be taken in patients at higher risk of VTE, such as MM patients who receive thalidomide and dexamethasone.

Granulocyte Colony-Stimulating Factor, Granulocyte-Macrophage Colony-Stimulating Factor, and Thrombosis Granulocyte colony-stimulating factor (G-CSF) and granulocytemacrophage colony-stimulating factor (GM-CSF) are commonly used to treat neutropenia in patients with solid or hematological cancers to decrease the risk of infectious complications, but they have been recently associated with an increased risk of thrombotic events. The thrombotic complications might be arterial or venous. The molecular mechanisms underlying the thrombogenic properties of G-CSF and GM-CSF have not been clearly identified. It has been observed in healthy allogenic stem cell donors that G-CSF increases factor VIII, thrombin-antithrombin complex, and prothrombin fragment F1 and 2 levels, and TF antigen levels and activity, thus suggesting that it plays a role in coagulation and endothelial cell activation.78-80

Prevention of VTE in Hematological Malignancies

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Prevention of thrombotic complications in hematological malignancies remains a challenging issue because of the very high risk of bleeding in these patients. Hemorrhagic complications associated with anticoagulant or antiplatelet therapy pose particular problems in these patients because they are thrombocytopenic for a prolonged time. Current guidelines are not applicable to all hematological patients and because of the lack of well-designed prospective studies, optimal antithrombotic prophylaxis in patients with hematological malignancies remains controversial. Most data on the prevention of thrombosis in patients with hematological malignant diseases come from studies in MM patients. In fact, the increased rate

Clinical Lymphoma, Myeloma & Leukemia Month 2014

of thrombosis observed after the introduction of IMIDs in MM therapy warranted the introduction of antithrombotic prophylaxis particularly in the first 4 to 6 months of an IMID course. Because of the high risk of VTE when these patients are treated with thalidomide or lenalidomide in combination with dexamethasone or multiagent chemotherapy, thromboprophylaxis is recommended. However, which agent is the most appropriate is a matter of debate. Recently, a prospective randomized trial has studied the efficacy of LMWH, warfarin (fixed low-dose or full dose), and aspirin for prophylactic anticoagulation.81 Results of this study suggest that all patients treated with IMIDs should receive prophylaxis against thrombotic events. Aspirin is generally accepted for thromboprophylaxis in patients without a history of thrombotic events and no thrombotic risk factors; conversely, anticoagulant prophylaxis with LMWH or fixed doses of oral anticoagulants is mandatory for patients with previous thromboembolic events or at high thrombotic risk for at least 4 months of treatment with IMIDs then switching to aspirin after this period. The International Myeloma Working Group guidelines recommend the use of aspirin for patients with no or 1 risk factor, and to treat patients with 2 or more risk factors with LMWH or warfarin. Recently, results of the large multicentric observational study to determine risk factors of venous thromboembolism in patients with multiple myeloma treated with immunomodulatory drugs study confirmed extensive use of aspirin as VTE prophylaxis in low risk MM patients treated with IMIDs and that high-risk MM patients should be treated with LMWH or VKA, for at least 6 months of the IMID course, because thrombotic events are more likely to occur at the beginning of IMID treatment.61

Treatment of VTE in Hematological Malignancies Very limited experience on treatment of thromboembolic events in the setting of hematological malignancies is currently available in the literature and generally derives from guidelines of solid cancer patients.82-84 The standard treatment regimen for patients with hematological malignancies carrying thromboembolic complication consist, as in noncancer patients, of an initial treatment with heparins, followed by long-term therapy with VKA agents for at least 3 to 6 months.83 Low molecular-weight heparins are being considered of interest also for long-term anticoagulation as an alternative to VKA, because of their pharmacokinetic safety profile and no need for laboratory monitoring. Nevertheless, the use of LMWH requires strict monitoring of renal function, to prevent their accumulation with subsequent hemorrhagic complications, and strict monitoring of platelet count, to diagnose heparin-induced thrombocytopenia, a complication also described in association with LMWH, and for their temporary suspension when platelet count is < 50,000/mL.85-88

Conclusions Hematological malignant disorders are associated with a perturbed hemostatic system, and patients are at risk of bleeding and thrombotic complications. Thrombotic complications have a significant effect on morbidity and in some cases also on mortality of patients with oncohematological diseases, therefore thromboprophylaxis to prevent VTE in this setting is mandatory. However,

Riccardo Colombo et al thrombocytopenia and hemorrhagic complications pose many difficulties in the management of an anticoagulant or antiplatelet treatment in these patients. Recommendations from current guidelines are limited to myeloma patients treated with thalidomide or lenalidomide associated with dexamethasone or chemotherapy. However, no controlled clinical trials have yet investigated the best strategies for thromboprophylaxis in hematological patients and so, until prospective randomized trials that compare warfarin, aspirin, and LMWH have been conducted in the setting of hematological malignancies, the only approach is to identify and treat subsets of patients at high risk for thrombosis.

Disclosure The authors have stated that they have no conflicts of interest.

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