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Current Opinion in Hematology:
doi: 10.1097/MOH.0000000000000072
HEMOSTASIS AND THROMBOSIS: Edited by Joseph E. Italiano and Jorge A. Di Paola

The coagulopathy of cancer

Falanga, Anna; Russo, Laura; Milesi, Viola

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Author Information

Department of Immunohematology and Transfusion Medicine, Hospital Papa Giovanni XXIII, Bergamo, Italy

Correspondence to Anna Falanga, MD, Department of Immunohematology and Transfusion Medicine and the Hemostasis and Thrombosis Center, Hospital Papa Giovanni XXIII, Piazza OMS, 1 - 24127 Bergamo, Italy. Tel: +39 035 2673663; fax: +39 035 2674832; e-mail: annafalanga@yahoo.com

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Abstract

Purpose of review

To provide an updated overview of the complex coagulopathy associated with malignancy, together with the advances in our knowledge of the interactions of cancer with the hemostatic system. Also, to offer an update of the recent progresses in the risk assessment, prevention, and treatment of thrombohemorrhagic complications in cancer patients.

Recent findings

Mechanisms underlying the hemostatic derangement caused by cancer include many prothrombotic properties of tumor tissues. Of extreme interest are the most recent findings that the regulation of tumor cell hemostatic protein expression is driven by oncogenes, the tumor-derived tissue factor-positive microparticles are an important player in thrombosis, and the changes in the tumor microenvironment in the presence of tissue factor affect ‘dormant’ cells to shift to a malignant phenotype.

On the clinical side, risk assessment models, based on clinical and biological risk factors, are becoming very attractive to identify categories of cancer patients at different thrombotic risk. Unsuspected pulmonary embolism, incidentally discovered, is also opening an intensive area of research. Finally, new updates of the guidelines to help clinicians in the management of venous thromboembolism in cancer patient have been recently released.

Summary

The coagulopathy of cancer is complex. Thrombotic and bleeding complications significantly contribute to morbidity and mortality in this disease. The accrued knowledge of the underlying mechanisms is helping establish more accurate and appropriate interventions for the management of the thrombotic risk in these patients.

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INTRODUCTION

Cancer induces a prothrombotic switch of the host hemostatic system, and vice versa the activation of the clotting system positively feeds back the cancer growth and dissemination. Abnormalities in plasma thrombotic markers are common in these patients and demonstrate that activation of blood coagulation and fibrinolysis parallels the development and spread of cancer [1]. The overt thrombotic occlusions of veins or arteries and the bleeding syndrome due to consumption of platelets and clotting factors are clinical manifestations of the same coagulation disorder.

The pathogenesis of the cancer-associated coagulopathy is complex and multifactorial. Tumor cells are capable of activating, in multiple ways, the host hemostatic system. Recently, molecular studies demonstrate that oncogenes responsible for neoplastic transformation drive the programs for hemostatic protein expression in cancer tissues, which translates into overt symptomatic coagulopathy in vivo[2▪▪]. The tumor shed microparticles are also regulated by oncogenic events and contribute to the hypercoagulable state. Finally, the changes of stromal cells of the tumor ‘niche’ induced by tissue factor (TF) shed new light on the hemostasis and cancer interaction.

Many clinical factors influence the thrombotic risk of cancer patients, including general risk factors, cancer-specific risk factors, and anticancer therapies. Recent data show that the risk of developing venous thromboembolism (VTE) is increased up to seven-fold in these patients as compared with the general population [3]. To help clinicians in the prevention and management of thrombotic events in cancer patients, a number of guidelines have been released from national and international scientific societies, the last updates being published in 2013 by the International multidisciplinary working group [4], and by the American Society of Clinical Oncology (ASCO) [5▪].

This review wishes to provide the most recent information on the coagulopathy of cancer patients, the mechanisms underlying this phenomenon, and finally the risk assessment, prevention and treatment of thrombohemorrhagic manifestations in this condition.  

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THROMBOHEMORRHAGIC COMPLICATIONS

The coagulopathy of cancer is characterized by the activation of the clotting system to different extents. The clinical manifestations vary from a subclinical asymptomatic hypercoagulable state (i.e., alterations of circulating thrombotic markers) to manifest thrombosis of the large vessels and further to systemic disseminated intravascular coagulation (DIC) with severe bleeding. Preventing these complications is clinically relevant because they significantly contribute to the morbidity and mortality of these patients.

Thrombosis: Among all thrombosis types, VTE, including deep vein thrombosis and pulmonary embolism, is the most extensively studied in cancer, although arterial thromboembolism (ATE), migratory thrombophlebitis, thrombotic nonbacterial endocarditis, thrombotic microangiopathies, and veno-occlusive disease also add to the spectrum of clotting complications of cancer.

VTE is much more prevalent in contemporary reports than previously estimated, as shown by a recent large retrospective population study demonstrating a VTE rate of 12.6% in the cancer patient cohort compared with a 1.4% rate in the control noncancer cohort [6]. A recent systematic review reports an annual incidence of VTE from 0.5 to 20%, depending on the cancer type and time since diagnosis [7]. Undoubtedly, the clinical setting, anticancer treatments, the types and stages of cancer substantially influence the VTE rates.

Differently from VTE, data on cancer-associated ATE are limited [8,9]. According to the most recent evidence, the incidence of ATE in cancer is around 2–5%, accounting for 10–30% of total thrombotic complications. More research is warranted in this as well as in other complications, such as veno-occlusive disease [10], found in about 50–60% of allogeneic hematopoietic stem cell transplanted patients (mortality rate close to 85%), and the thrombotic microangiopathies, a heterogeneous group of diseases representing a rare but severe complication, often associated with the use of specific chemotherapeutic agents [11].

Much attention in the literature is given to the growing evidence that a high proportion of cancer associated VTE is incidentally discovered. The incidence of unsuspected pulmonary embolism (UPE) ranges from 1 to 5%, which probably represents an underestimation. In a recent retrospective cohort analysis, one-third of VTE events in lung cancer patients are incidentally discovered and negatively impact on the clinical outcome [12]. An intensive research is focused on the UPE actual incidence, assessment of risk factors for first and recurrent UPE, and the need for anticoagulation [13▪▪].

Bleeding: In cancer patients, bleeding represents an important cause of mortality, and is observed in about 10% of patients with solid tumor and in a higher proportion of patients with hematologic malignancies [14].

Severe DIC is particularly associated with acute leukemias, causing life-threatening hemorrhages secondary to excessive consumption of clotting factors and platelets. Intracerebral and pulmonary hemorrhages are relatively common in acute promyelocytic leukaemia (APL), and are the most frequent cause of early death in these patients [15▪▪]. The incidence of leukemia early death by large multicenter studies ranges between 5 and 10% [15▪▪]. In the most recent retrospective analysis, the early death rate was 11% in 204 APL patients, 61% of them being caused by hemorrhage. This rate was 33% if therapy with all-trans retinoic acid (ATRA) was administered on the first day of APL diagnosis, and went up to 70% when ATRA was administered one or more days after the disease was suspected [16]. Recently, a phase III multicenter trial found that ATRA plus arsenic trioxide is at least not inferior to and may be superior to ATRA plus chemotherapy in the treatment of patients with low-to-intermediate-risk APL, with a complete remission rate of 100% [17▪▪]. Because of the very low number of events, a comparison of the effect of these distinct regimens on the disease-associated coagulopathy was not feasible. Studies of hemostatic features to promptly identify APL patients at high risk for hemorrhagic early death are warranted.

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PATHOGENIC MECHANISMS

Multiple clinical risk factors (i.e., patient-related, cancer-related, and treatment-related) concur with the activation of blood coagulation and contribute to the thrombotic manifestations in cancer patients [18,19▪▪]. Regarding cancer-related features, the primary site of cancer is important. Large epidemiological studies have recognized that cancers of the brain, pancreas, stomach, liver, lungs, kidneys, and hematologic malignancies, including lymphomas and myeloma, have the strongest association with VTE. In the same guise, the advanced metastatic stage and active anticancer treatments, including chemotherapy, hormonal therapy, antiangiogenic agents, combination regimens, and surgery, significantly increase the thrombotic risk.

The molecular and laboratory features of cancer-associated thrombosis are difficult to assess clinically; therefore, the weight of each of these factors on the overall thrombotic risk of the single patient is unknown at this time. The principal mechanisms include the expression of hemostatic proteins by tumor cells (i.e., TF), the production of microparticles, inflammatory cytokines (i.e., tumor necrosis factor-alphaα, interleukin-1β), and proangiogenic factors (vascular endothelial growth factor, basic fibroblast growth factor) by tumor and/or host cells, and the expression of adhesion molecules to bind platelets, endothelial cells, and leucocytes (Fig. 1). The same properties also contribute to tumor progression [20▪].

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Tumor cell-derived TF plays a central role in the generation of thrombin in cancer but also contributes to tumor progression by directly influencing the expression of vascular endothelial growth factor by both malignant cells and host vascular cells. This property regulates tumor neo-vascularization and provides an important link between activation of coagulation, inflammation, thrombosis, and tumor growth and metastasis [20▪]. Among other tumor cell procoagulant activities, the role of the enzyme heparanase is gaining much relevance. In particular, heparanase, apart from degrading the extracellular matrix, upregulates the expression of TF by interacting with the TF pathway inhibitor on the surface of endothelial and tumor cells, which causes the dissociation of TF pathway inhibitor and increases cell surface TF procoagulant activity [21▪▪]. Another emerging mechanism of tumor-promoted clotting activation is represented by the tumor cell shed microparticle. These small membrane vesicles carry high concentrations of procoagulant phosphatidylserine and TF [22]. The pathogenetic role of microparticle in cancer-associated thrombosis is demonstrated by the development of a DIC-like syndrome in mice after intravenous injection of highly TF-positive microparticles of tumor origin [22].

The contribution of host endothelial cells, platelets, and leukocytes to the prothrombotic state of cancer remains relevant. Recent data support the role for platelets in the maintenance of vascular integrity within tumors and propose that platelets may represent a target for the specific destabilization of tumor vessels, so that platelets may act as ‘guardian of tumor vasculature’ [23▪▪].

Furthermore, extensive experimental evidences show that neutrophils are present in large quantities in the tumor in which they can release extracellular DNA traps [neutrophil extracellular traps (NETs)] and affect growth and angiogenesis [24▪▪].

Most importantly, experimental models of human cancers (including hepatoma, brain, and colon cancer) provide evidence in vivo that oncogene and repressor gene-mediated neoplastic transformation (i.e., activation of Met, loss of PTEN, induction of K-ras, and loss of p53) activates clotting as an integral feature of neoplastic transformation. Furthermore, a mutation in EGFR gene renders cancer cells hypersensitive to the action of coagulation proteins, such as TF; as a result, a microenvironment promoting tumor growth is generated [2▪▪]. These data confirm that a reciprocal cancer-thrombosis connection exists, by which cancer cells support clot formation, and clotting proteins support cancer growth and dissemination. In the development of human cancers, cycles of microenvironmental and genetic changes are increasingly manifest. Indolent or dormant phenotype of cells lacking tumor initiating capacity may be altered in the presence of procoagulant TF, which induces several changes in the tumor microenvironment, capable of affecting the fate of these cells from a ‘dormant’ to fully malignant phenotype [25▪▪].

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ASSESMENT OF THE THROMBOTIC RISK IN CANCER PATIENTS

The role of demographic and clinical (cancer-associated and treatment-related) factors in increasing the risk of thrombosis in cancer (Fig. 2) is established; however, it also appears relevant to establish the possible role of thrombotic biomarkers, including thrombin–antithrombin complex, prothrombin fragment F1+2 (F1+2), fibrinopeptide A and B, plasminogen activator inhibitor 1, and D-dimer. Currently, an intensive search is ongoing to identify suitable biomarkers to characterize cancer patients at high risk [26]. Data from the Vienna Cancer and Thrombosis (CAT) prospective study show a significant association with increased VTE risk of elevated P-selectin [27], and elevated D-dimer and F1+2 levels [28]. High microparticle concentration can also predict VTE and has been utilized to elect patients to entry into a randomized clinical trial of thromboprophylaxis during chemotherapy. The results of this small, but very original, trial are promising [29▪▪]. In this context, the thrombin generation assay, a global test of coagulation activation, also is under evaluation to predict VTE in cancer patients [30].

FIGURE 2
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The interaction and relative effects of the several risk factors associated with VTE in cancer patients are highly complex, making the pretreatment risk assessment difficult. The combination of some of the clinical factors with laboratory biomarkers allowed the development by Khorana et al. [31] of a VTE risk assessment model (RAM) specifically for cancer patients undergoing chemotherapy. This RAM is based on five predictive variables [31], which consist of readily accessible baseline clinical and laboratory data [32–34] as reported below. Predictive variables of the risk assessment model for chemotherapy-associated VTE are given as follows.

  1. Site of cancer:
    1. very high-risk cancer (stomach, pancreas);
    2. high risk (lung, lymphoma, gynecologic, bladder, testicular);
  2. platelet count more than 350 000/mm3;
  3. hemoglobin level less than 10 g/dl or use of red cell growth factors;
  4. leukocyte count more than 11 000/mm3;
  5. body mass index above 35 kg/m2.

In the Vienna CAT study, the incorporation in this score of two additional biomarkers (i.e., P-selectin and D-dimer) considerably improved the predictive value of VTE [26]. Recently, another modified Khorana's RAM (the Protecht score) was designed by adding platinum-based or gemcitabine-based chemotherapy to the five predictive variables for identifying high-risk cancer patients in a post-hoc analysis of the Protecht study [34]. In the setting of multiple myeloma, Palumbo et al.[35] published a RAM, on the basis of expert recommendations, for the prevention of thalidomide and lenalidomide-associated thrombosis. Finally, the Ottawa Score is capable of distinguishing between cancer patients at high and low risk of recurrent VTE [36,37▪▪]. The ASCO panel recommends the use of RAMs to periodically assess the thrombotic risk of cancer patients during the disease phases.

The search for thrombotic markers capable of predicting survival in cancer patients is currently active. In a large cohort of individuals, free of clinically evident cardiovascular and cancer disease, enrolled in the MOLI-SANI project (a population-based cohort study), elevated plasma D-dimer levels are independently associated with increased risk of death for any cause [38▪]. Furthermore, in patients with ovarian masses, the preoperative D-dimer levels, alone or in combination with CA-125, significantly predict for malignant versus benign ovarian lesions [39].

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PREVENTION AND TREATMENT OF THROMBOHEMORRAGIC COMPLICATIONS

Thromboprophylaxis: There is no evidence that there is a benefit from giving antithrombotic prophylaxis to all cancer patients; however, there are selected conditions in which prophylaxis has to be considered [5▪]. Current guidelines find a good consensus on VTE prevention with low molecular weight heparins (LMWH) in the surgical setting [4,5▪], particularly in cancer patients undergoing ‘high-risk’ major abdominal or pelvic surgery.

Less consensus exists in the medical setting in which two high-risk situations can be identified as follows: the first involves patients hospitalized or bedridden for prolonged periods, and the second relates to outpatients receiving chemotherapy or radiation for cancer. Although hospitalized cancer patients for acute medical illness are considered for thromboprophylaxis with LMWH or fondaparinux, controversial is the role of thromboprophylaxis in outpatients. In recent years, this issue has been addressed by ad-hoc randomized clinical trials (RCTs) [40–42], which overall suggest that outpatient thromboprophylaxis is feasible, well tolerated, and effective. However, at present, routine prophylaxis in outpatients on chemotherapy is not recommended by guidelines, with the exception of multiple myeloma patients treated with thalidomide (Pharmion Ltd, Windsor, UK) or its analogs and steroids or chemotherapy, in whom thromboprophylaxis is recommended [5▪]. In this context, the recent ASCO guideline update emphasizes the importance of VTE risk assessment in ambulatory cancer patients and the need for RCT in patients with a favorable risk–benefit ratio [5▪].

Unlike solid tumors, no ad-hoc studies or guidelines are available to help clinicians with best practices for VTE prophylaxis in hematologic malignancies [43].

As regards arterial thrombosis, cancer patients share the same general risk factors with noncancer patients (i.e., arterial hypertension, diabetes, dislipidemia, obesity); additional risk factors are comorbidities, infections, blood transfusions, and chemotherapy. Today, no guidelines or recommendations are available for ATE prophylaxis in the cancer setting.

Treatment of thrombosis: Concerning treatment, all guidelines agree that LMWH are more effective and well tolerated than vitamin K antagonists for long-term treatment of VTE (3–6 months after the first acute episode). An indefinite duration of anticoagulation is recommended for patients with active malignancy, that is, those with metastatic disease or receiving continued chemotherapy [5▪]. The role of the new direct oral anticoagulant drugs [i.e. Dabigatran (Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany), Rivaroxaban (Bayer Pharma AG, Berlin, Germany), Apixaban (Bristol-Myers Squibb/Pfizer Eeig, Uxbridge, UK)] is unknown at this time and is the subject of recent and ongoing trials [44,45].

The treatment of ATE in cancer patients relies on antiplatelet and anticoagulant or fibrinolytic agents according to the same protocols recommended for secondary prophylaxis of stroke and myocardial infarction in the noncancer population.

Thrombocytopenia, secondary to cancer treatment, complicates the use of anticoagulant and antiplatelet drugs. Consensus statements are being developed to assist the management of antithrombotic therapies in thrombocytopenic cancer patients [46].

Prophylaxis and treatment of bleeding: On the bleeding side, the most important issue is represented by the prophylaxis and treatment of the fatal hemorrhagic syndrome in APL. Recent recommendations indicate that three simultaneous actions must be immediately undertaken when a diagnosis of APL is suspected: the start of ATRA therapy, the administration of supportive care with transfusions of plasma and platelet, and the confirmation of molecular diagnosis [47]. Aggressive attention to the early initiation of supportive measures is particularly important in the management of acute leukemia because effective chemotherapy often exacerbates the DIC and accentuates the bleeding syndrome by worsening the thrombocytopenia. The most important supportive tool, therefore, is the judicious use of platelet transfusion with the aim of maintaining platelet count above 20 × 109/l in nonbleeding patients and above 50 × 109/l in those with active bleeding [48]. The use of heparin and antifibrinolytic agents, on the other hand, remains a hotly debated issue [49]. A lack of efficacy of tranexamic acid on the hemorrhage-associated mortality in APL was shown in the large Programa de Estudio y Tratamiento de las Hemopatias Malignas (PETHEMA) trial [50].

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CONCLUSION

A complex coagulopathy develops in parallel with malignancies and is characterized by activation of clotting mechanisms to different extents in different patients and in different types of cancers. The pathogenesis of thrombophilia in cancer is multifactorial; however, the tumor tissues’ capacity to interact with and activate the host hemostatic system plays an important role. New pathways of regulation of these properties have been recently displayed. Intervention strategies to prevent and treat VTE in cancer patients have been addressed by large RCTs and guidelines for VTE management have been updated. One of the areas of great uncertainty remains the role of thromboprophylaxis in outpatients undergoing anticancer therapies; in this setting, the identification of high-risk patients by RAMs is recommended. The place for the new direct oral anticoagulant agents needs to be defined.

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Acknowledgements

The authors wish to thank Associazione Italiana per la Ricerca sul Cancro (A.I.R.C., grants IG10558 and ‘5 per mille’ 12237) for its support.

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Conflicts of interest

There are no conflicts of interest.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest

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REFERENCES

1. Falanga A, Russo L. Epidemiology, risk and outcomes of venous thromboembolism in cancer. Hamostaseologie. 2012; 32:115–125.

2▪▪. Magnus N, Meehan B, Garnier D, Rak J. Oncogenes and the coagulation system – forces that modulate dormant and aggressive states in cancer. Thromb Res. 2014; 133:S1–S9.

This article summarizes the most recent research, demonstrating that oncogenes and repressor gene-mediated neoplastic transformation activate blood coagulation as an integral feature of neoplastic transformation. These findings confirm that a close cancer–thrombosis connection exists, by which cancer cells support clot formation, and clotting proteins support cancer growth and dissemination.


3. Timp JF, Braekkan SK, Versteeg HH, Cannegieter SC. Epidemiology of cancer-associated venous thrombosis. Blood. 2013; 122:1712–1723.

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This guideline provides recommendations about prophylaxis and treatment of VTE in patients with cancer. Prophylaxis in the outpatient, inpatient, and perioperative settings was considered, as were treatment and use of anticoagulation as a cancer-directed therapy.


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This is a very up-to-date review of the current knowledge on the incidentally diagnosed pulmonary embolisms in cancer patients, one of the hottest clinical issues currently debated by clinicians.


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In this review the principal aspects regarding the incidence severity, possible pathogenesis and clinical manifestations of thrombohemorragic death in APL are summarized.


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17▪▪. Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013; 369:111–121.

This study shows, for the first time, that the combination of ATRA and arsenic trioxide given for induction and consolidation therapy is at least not inferior and is possibly superior to standard ATRA and anthracycline-based chemotherapy for adults with low-to-intermediate-risk APL. This article opens new perspectives for the APL eradication and the control of APL-associated hemorrhagic deaths.


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19▪▪. Khorana AA, McCrae KR. Risk stratification strategies for cancer-associated thrombosis: an update. Thromb Res. 2014; 133:S35–S38.

A very useful and comprehensive update of risk stratifications approaches, including a validated risk score, is provided by this review.


20▪. Falanga A, Marchetti M, Vignoli A. Coagulation and cancer: biological and clinical aspects. J Thromb Haemost. 2013; 11:223–233.

In this review, the principal aspects of epidemiology, risk factors, and outcome of cancer-associated VTE are summarized.


21▪▪. Nadir Y, Brenner B. Heparanase multiple effects in cancer. Thromb Res. 2014; 133:S90–S94.

This review summarizes the prometastatic, proangiogenic, and procoagulant functions of heparanase and implies that heparanase is potentially a good target for cancer therapies.


22. Falanga A, Tartari CJ, Marchetti M. Microparticles in tumor progression. Thromb Res. 2012; 129:(Suppl 1):S132–S136.

23▪▪. Stegner D, Dutting S, Nieswandt B. Mechanistic explanation for platelet contribution to cancer metastasis. Thromb Res. 2014; 133:S149–S157.

An important overview of the role of platelets in preventing immunological attack, helping tumor cell extravasation, and facilitating tumor metastasis is provided by this article.


24▪▪. Demers M, Wagner DD. Neutrophil extracellular traps: a new link to cancer-associated thrombosis and potential implications for tumor progression. Oncoimmunology. 2013; 2:e22946

A new pathogenic mechanism of thrombosis in cancer is described. Tumor-induced neutrophils are more sensitive to NET formation and NETs can be implicated in many steps of tumor progression.


25▪▪. Magnus N, Garnier D, Meehan B, et al. Tissue factor expression provokes escape from tumor dormancy and leads to genomic alterations. Proc Natl Acad Sci U S A. 2014; 111:3544–3549.

This study highlights the importance of the procoagulant microenvironment in the control of tumor dormancy and suggests that the clotting system may exert an unsuspected impact on genetic and epigenetic alterations, tumor dormancy, and progression.


26. Pabinger I, Thaler J, Ay C. Biomarkers for prediction of venous thromboembolism in cancer. Blood. 2013; 122:2011–2018.

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29▪▪. Zwicker JI, Liebman HA, Bauer KA, et al. Prediction and prevention of thromboembolic events with enoxaparin in cancer patients with elevated tissue factor-bearing microparticles: a randomized-controlled phase II trial (the Microtec study). Br J Haematol. 2013; 160:530–537.

This is an original randomized clinical trial of thromboprophylaxis in outpatients receiving chemotherapy. The novelty consists in that cancer patients were enrolled on the basis of high levels of circulating TF-bearing microparticles. The results, although preliminary, show an 80% risk reduction with enoxaparin prophylaxis.


30. Ay C, Dunkler D, Simanek R, et al. Prediction of venous thromboembolism in patients with cancer by measuring thrombin generation: results from the Vienna Cancer and Thrombosis Study. J Clin Oncol. 2011; 29:2099–2103.

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This study assesses the reproducibility of the modified Ottawa score in an independent cohort of patients with cancer-associated VTE. The results show that the Ottawa score accurately identifies patients either low risk or high risk for recurrent thromboembolic complications.


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Elevated D-dimer levels are associated with high risk of total mortality in study participants enrolled in a population-based study. The results show that elevated D-dimer levels were independently associated with increased risk of death from any cause in an apparently healthy adult population.


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Keywords

cancer; hemorrhage; hypercoagulable state; thromboprophylaxis; thrombosis

© 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins

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