To cite this article: Falanga A, Marchetti M, Vignoli A. Coagulation and cancer: biological and clinical aspects. J Thromb Haemost 2013; 11: 223-33Summary. Malignancy affects the hemostatic system and the hemostatic system affects malignancy. In cancer patients there are a number of coagulation abnormalities which provide the background for an increased tendency of these patients to both thrombosis and hemorrhage. The causes of this coagulation impairment rely on general risk factors which are common to other categories of patients, and other factors which are specific to cancer, such as tumor type and disease stage. In addition, data from basic research indicate that the hemostatic components and the cancer biology are interconnected in multiple ways. Notably, while cancer cells are able to activate the coagulation system, the hemostatic factors play a role in tumor progression. This opens the way to the development of bifunctional therapeutic approaches that are both capable of attacking the malignant process and resolving the coagulation impairment. On the other hand, the management of thrombosis and hemorrhages in cancer patients can be different. To approach these problems, some guidelines have been released by prominent international scientific societies. Also actively investigated is the issue of identifying new biomarkers to classify the subjects at a higher risk, thus improving the prevention of thrombohemorrhagic events in these patients. Finally, novel prophylactic and therapeutic approaches are currently under development. This review provides an overview of the hemostatic complications in cancer, together with new insights into the interaction between hemostasis and cancer biology. We also review the assessment of the risk of thrombohemorrhagic events in cancer patients, and the prophylaxis and treatment of such manifestations.

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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.

Thrombohemorrhagic complications are a major cause of morbidity and mortality in patients with essential thrombocythemia (ET) and polycythemia vera (PV). The pathogenesis of these complications is not completely clarified. Several studies have described abnormalities of red blood cells and platelets in these patients. However, no studies are available on changes in the polymorphonuclear leukocytes (PMNs), which can play an important role in the activation of the hemostatic system. In patients with ET (n = 37) and PV (n = 34), a series of PMN activation parameters (PMN membrane CD11b and leukocyte alkaline phosphatase [LAP] antigen expression, cellular elastase content, plasma elastase, and myeloperoxidase levels) was evaluated simultaneously with the levels of plasma markers of endothelial damage (thrombomodulin and von Willebrand factor antigen) and hypercoagulation (thrombin-antithrombin complex, prothrombin fragment 1 + 2, and D-dimer). The results show the occurrence of PMN activation in both groups of patients compared with a control group of healthy subjects. An increase in CD11b and LAP expression by PMN membrane was observed, together with a significant increase in cellular elastase content, plasma elastase, and myeloperoxidase levels. In addition, patients had high plasma levels of endothelial and hypercoagulation markers compared with controls. For the first time, these data show that in ET and PV, 2 hematologic conditions that place patients at increased risk for thrombosis, an in vivo leukocyte activation occurs and is associated with laboratory signs of endothelium and coagulation system activation.

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Defibrotide (DF), a polydeoxyribonucleotide with antithrombotic properties, has recently proven effective in patients with severe hepatic veno-occlusive disease (VOD), a life-threatening complication of high-dose chemo/radiotherapy regimens for stem cell transplantation. To understand the mechanism of its beneficial effect, we studied the impact of DF on the expression of tissue factor (TF) and fibrinolytic proteins (PAI-1 and t-PA) on endothelial cells. The in vitro response to DF of two types of human endothelial cells (ECs) of different origins, that is from macrovascular (HUVEC) and microvascular (HMEC-1 cell line) beds, was evaluated in the presence or absence of a proinflammatory stimulus (ie bacterial endotoxin, LPS). The results show that DF was able to significantly reduce the LPSinduced TF expression by HMEC-1, and less prominently by HUVEC. In addition, DF importantly influenced the fibrinolytic properties of both HMEC-1 and HUVEC. Specifically, it dosedependently counteracted the LPS-induced increase in PAI-1 levels and decrease in t-PA activity expression. It also significantly incremented t-PA antigen in resting EC. Decreasing the procoagulant activity and increasing the fibrinolytic potential of EC favors an anticoagulant phenotype of the endothelium, which may protect from fibrin deposition and vascular occlusion.

We used the thrombin generation assay to evaluate the hypercoagulable state according to JAK2 V617F mutational status in essential thrombocythemia (ET) and polycythemia vera (PV) patients. Thrombin generation was determined in the presence and absence of activated protein C (APC), and APC resistance was expressed as normalized APC sensitivity ratio (nAPCsr). Tissue factor pathway inhibitor (TFPI), total and free protein S (PS), prothrombin (