Mechanisms and risk factors of thrombosis in cancer

https://doi.org/10.1016/j.critrevonc.2017.08.003Get rights and content

Abstract

The close relationship between cancer and thrombosis is known since more than a century. Venous thromboembolism (VTE) may be the first manifestation of an occult malignancy in an otherwise healthy individual. Cancer patients commonly present with abnormalities of laboratory coagulation tests, indicating an ongoing subclinical hypercoagulable condition. The results of laboratory tests demonstrate that a process of fibrin formation and removal parallels the development of malignancy, which is of particular interest since fibrin and other clotting products are important for both thrombogenesis and tumor progression. Besides general clinical risk factors (i.e. age, previous VTE, immobility, etc.), other factors typical of cancer can increase the thrombotic risk in these patients, including the type of cancer, advanced disease stage, and cancer therapies. In addition, biological factors, including tumor cell-specific prothrombotic properties and the host cell inflammatory response to the tumor, play a central role in the pathogenesis of cancer-associated thrombosis. Cancer cells produce and release procoagulant and fibrinolytic proteins, as well as inflammatory cytokines. In addition, they are capable of directly adhering to host cells (i.e. endothelial cells, monocytes, platelets, and neutrophils), thereby stimulating additional prothrombotic properties of the host effector cells. Tumor-shed procoagulant microparticles also contribute to the patient hypercoagulable state. Finally, the changes of stromal cells of the tumor ‘niche’ induced by tissue factor (TF) highlight new interactions between hemostasis and cancer. Of interest, most of these mechanisms, besides activating the hemostatic system, also promote tumor growth and metastasis, and are regulated by oncogenic events. Indeed, molecular studies demonstrate that oncogenes responsible for the cellular neoplastic transformation drive the programs of hemostatic protein expression and microparticle liberation by cancer tissues. Human and animal experimental models demonstrate that activation of cancer-associated prothrombotic mechanisms parallels the development of overt thrombotic syndromes in vivo.

Introduction

Cancer patients may present many types of hemostatic disorders that significantly contribute to morbidity and mortality in this disease. A tight relationship exists between malignant disease, the occurrence of coagulation abnormalities and thrombosis. The relationship relies on the evidence that cancer induces a prothrombotic switch of the host hemostatic system, and in turn, blood clotting activation stimulates tumor growth and dissemination.

Cancer is associated with a four- to seven-fold increase in the risk of venous thromboembolism (VTE). However, even without thrombosis, the majority of cancer patients present with hemostatic alterations detectable by laboratory tests, which reveal different degrees of coagulation activation and characterize the hypercoagulable state of these subjects (Falanga and Russo, 2012).

Currently, it is fully recognized that cancer patients are at significant risk of developing thrombotic events, spanning from venous or arterial thrombosis to systemic syndromes, such as disseminated intravascular coagulation (DIC) with severe bleeding. Preventing these complications is clinically relevant because they considerably contribute to the morbidity and mortality of these patients (Falanga et al., 2014).

The pathogenesis of the cancer-associated coagulopathy is complex and multifactorial. Most importantly, tumor cells gain the capacity to activate the host hemostatic system, and this phenomenon is driven by the same oncogenes responsible for the cellular neoplastic transformation. By this process, cancer tissues become capable to express different procoagulant proteins (i.e. Tissue Factor [TF], Cancer Procoagulant [CP], Factor VII), which contribute to the occurrence of the overt symptomatic coagulopathy in vivo (Magnus et al., 2014a). The shedding of procoagulant microparticles [MPs] is also regulated by oncogenic events and further adds to the pathogenesis of the cancer-associated hypercoagulable state. Finally, the changes in the stromal cells of the tumor “niche” induced by tumor TF provide new evidence of the influence of the hemostasis system on cancer development.

To the other hand, many clinical factors influence the thrombotic risk of cancer patients, who definitely represent a high-risk category. Clinical factors include general cardiovascular risk factors, cancer specific risk factors, and anti-cancer therapies. Recent data confirm that the risk of developing VTE is increased up to seven-fold in these patients as compared to the general population (Timp et al., 2013). 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 (Lyman et al., 2015).

This paper wishes to provide the most recent discoveries on the coagulopathy of cancer patients, the mechanisms underlying this phenomenon, and the risk assessment to predict thrombosis in the single patient.

Section snippets

Pathogenesis of cancer-associated thrombosis

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 of cancer-associated thrombosis include the expression of hemostatic proteins by tumor cells, the production of microparticles, inflammatory cytokines (i.e., tumor necrosis factor-alpha, interleukin-1b), and proangiogenic factors (vascular

Risk factors and risk assessment in cancer patients

Multiple clinical risk factors, i.e., patient-related or cancer-specific, concur to the activation of blood coagulation and importantly contribute to the thrombotic risk of cancer patients (Table 1) (Khorana and McCrae, 2014, Falanga et al., 2015b).

The clinical thrombotic risk factors, together with the biological procoagulant mechanisms expressed by cancer tissues, contribute to the occurrence of the procoagulant shift in the hemostatic balance of patients with cancer. Indeed, subclinical

Assessment of the thrombotic risk in cancer patients

Recently, the approach to risk assessment for thrombosis in cancer patients relies on the development of “risk assessment models” (RAM). The first was developed by Khorana specifically for cancer patients undergoing chemotherapy (Khorana et al., 2008). This RAM is based on five predictive variables, including cancer site, platelet count, hemoglobin level or the use of erythropoiesis-stimulating agents, leukocyte count, and body mass index. This model using a simple scoring system, is based on

Conclusions

Cancer is associated with an imbalance in the hemostatic system, which predisposes to thrombotic complications. Several procoagulant molecules, among which TF is the most important, are expressed by cancer cells or are induced by cancer cell in normal vascular tissues by both the release of soluble mediators and the direct cancer cell–host cell contact. TF exposure by endothelial cell, leukocyte, or circulating MPs of different origins plays a very important role. A very important advance in

Conflicts of interest

There are no conflicts of interest.

Acknowledgments

The authors wish to thank the Associazione Italiana per la Ricerca sul Cancro (A.I.R.C.), grants “IG2013” n. 14505 and “5 per mille” n. ED12237, for its support.

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