Thrombosis, both venous and arterial, is a leading cause of morbidity and mortality in patients with cancer. Studies on the molecular basis of cancer-associated thrombophilia have a long story ...starting from the first observation of the presence of tumor cells in circulating microthrombi 2 centuries ago. The profound link between pathways of blood coagulation and tumor biology has been more and more unraveled, and new actors in this complex interaction have been identified. The unfavorable impact of thrombosis in a patient with cancer, on which also hangs a high bleeding risk as compared to the noncancer population, has led during years to the production of large clinical studies to adopt the best prophylaxis and treatment strategies of venous thromboembolism in different medical and surgical settings, now incorporated in dedicated international guidelines. This field, however, still represents an open challenge due to the intrinsic variability of the patient with cancer with his/her personal medical history and cardiovascular risk factors, as well as the type, site and stage of the tumor, and the use of a wide array of new sophisticated anticancer drugs. This review aims to highlight some of the many key observations in the field of cancer and thrombosis, spanning the scope from fundamental tumor biology to advanced clinical trials of new anticoagulants. We hope that some of the examples we have included will inspire readers to explore and discuss these topics, thereby increasing awareness of cancer-related thrombosis in both physicians and patients.
Major causes of morbidity and mortality in myeloproliferative neoplasms are represented by arterial and venous complications, progression to myelofibrosis, and transformation to acute leukemia. The ...pathogenesis of thrombosis results from a complex interplay of clinical and disease-related factors. Abnormalities of blood cells arising from the clonal proliferation of hematopoietic stem cells involve not only quantitative changes but also qualitative modifications that characterize the switch of these cells from a resting to a procoagulant phenotype. According to age and previous thrombosis, patients are classified in a “high risk” or “low risk”. Novel disease-related determinants such as leukocytosis and JAK2V617F mutational status and/or mutational burden are now under active investigation. In low-risk polycythemia vera patients, only phlebotomy and primary antithrombotic prophylaxis with aspirin is recommended, while in high-risk patients cytotoxic therapy is considered. Whether novel drugs targeting the constitutively active JAK2/STAT pathway will improve the management of thrombosis is a challenge for future studies.
Mechanisms and risk factors of thrombosis in cancer Falanga, Anna; Russo, Laura; Milesi, Viola ...
Critical reviews in oncology/hematology,
October 2017, 2017-Oct, 2017-10-00, 20171001, Letnik:
118
Journal Article
Recenzirano
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.
Patients with hematologic malignancies are at high risk of thrombotic or hemorrhagic complications. The incidence of these events is greatly variable and is influenced by many factors, including the ...type of disease, the type of chemotherapy, and the use of a central venous device. As in solid tumors, a number of clinical risk factors have been identified and contribute to the increasing thrombotic rate in hematologic malignancies. Biologic properties of the tumor cells can influence the hypercoagulable state of patients with these malignancies by several mechanisms. Of interest, oncogenes responsible for neoplastic transformation in leukemia also may be involved in clotting activation. Epidemiologic data allow an estimate of the incidence of venous thromboembolism (VTE) in acute leukemia, lymphomas, and multiple myeloma (MM). In this review, we focus on the epidemiology, pathogenesis, and VTE management in these three hematologic malignancies. No recommendation for routine thromboprophylaxis in these conditions, with the exception of MM, is available. Large, prospective, randomized clinical trials are needed to establish the best practice for thromboprophylaxis and treatment of VTE in these types of cancers.
ABSTRACT Patients with cancer may display many types of hemostatic disorders that significantly contribute to morbidity and mortality in this disease. A complex coagulopathy develops in parallel with ...malignancy and is characterized by activation of clotting mechanisms to different extent in different patients and in different types of tumor. The pathogenesis of hemostatic alterations in cancer is multifactorial; however, the tumor tissue capacity to interact with and activate the host hemostatic system plays an important role. New molecular pathways of regulation of these properties have been recently demonstrated. Intervention strategies to prevent and treat venous thromboembolism (VTE) in cancer patients have been addressed by large RCTs and guidelines for VTE management have been updated. In this review, we will present an updated overview of the complex coagulopathy associated to malignancy and of recent advances in the thrombotic risk assessment of cancer patients.
Thrombosis is a major cause of morbidity and mortality in cancer patients. The pathogenesis of blood coagulation activation in oncological patients is complex and involves both clinical and ...biological factors. Abnormalities in one or more coagulation test are common in cancer patients, even without thrombotic manifestations, indicating an ongoing hypercoagulable condition. Moreover, venous thromboembolism (VTE) can be the first symptom of an occult malignancy in an otherwise healthy individual. The levels of laboratory markers of activation of blood coagulation parallel the development of malignancy, being the coagulant mechanisms important for both thrombogenesis and tumor progression. Besides general clinical risk factors for VTE, also disease-specific clinical factors, i.e., type and stage of the tumor, and anticancer therapies increase the thrombotic risk in these patients. Furthermore, biological factors, including the cancer cell-specific prothrombotic properties together with the host cell inflammatory response to the tumor, are relevant as well as unique players in the pathogenesis of the cancer-associated hypercoagulability. Cancer cells produce and release procoagulant and fibrinolytic proteins, inflammatory cytokines, and procoagulant microparticles. They also express adhesion molecules binding to the receptors of host vascular cells (i.e., endothelial cells, platelets, and leukocytes), thereby stimulating the prothrombotic properties of these normal cells, including the shed of cell-specific microparticles and neutrophil extracellular traps. Of interest, several genes responsible for the cellular neoplastic transformation drive the programs of hemostatic properties expressed by cancer tissues. A better understanding of such mechanisms will help the development of novel strategies to prevent and treat the Trousseau's syndrome (i.e., cancer-associated thrombosis).
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