Deep venous thrombosis and endothelial dysfunction in cancer: prevention and early initiated rehabilitation should be integral to a cardio-oncology programme

This editorial refers to ‘Second consensus document on diagnosis and management of acute deep vein thrombosis. Updated document elaborated by the ESC Working Group on Aorta and Peripheral Vascular Diseases and the ESC Working Group on Pulmonary Circulation and Right Ventricular Function’, by L. Mazzolai et al. doi:10.1093/eurjpc/zwab088. This issue brings the second consensus document on diagnosis and management of acute deep vein thrombosis elaborated by the ESC Working Group on Aorta and Peripheral Vascular Diseases and the ESC Working Group on Pulmonary Circulation and Right Ventricular Function.1 In addition to a general update on the previous edition,2 the document focuses on improved managing of acute deep vein thrombosis in cancer patients and reports on coronavirus disease 2019 (COVID 19) as a risk factor for deep venous thrombosis. The increased incidence of venous thromboembolism3–6 observed in COVID-19 and cancer reminds us about the critical gatekeeper function of the vascular endothelium in health and disease. The increased risk for venous thromboembolism in both conditions is associated with the presence of a pronounced hypercoagulability.7–9 In contrast with generally believed, deep venous thrombosis emanates, however, not from a coagulation system disorder but results from triggering immunothrombosis.10–12 In this process, endothelial activation resulting in the transformation into a dysfunctional, prothrombotic, pro-inflammatory phenotype, and activation of the innate immune system plays a pivotal role. Both processes are intertwined and potentiate each other. Pro-inflammatory cytokines released by cancer cells or during the cytokine storm in COVID-19 set the stage for immunothrombosis. Venous flow stagnancy and its related hypoxia of the venous blood, present in weak, more sedentary, or bed-ridden cancer or COVID-19 patients, is the initial trigger that ignites in these predisposing conditions an exploding immunothrombosis leading to deep venous thrombosis and subsequent thrombo-embolism. Figure 1 shows in detail the mechanisms of immunothrombosis responsible for the pathophysiology of deep venous thrombosis in cancer patients. These novel insights in the pathophysiology may foster newer preventive and therapeutic modalities than the classic anticoagulant regimens focusing on treating hypercoagulability as the (incorrectly thought) leading cause of deep venous thrombosis. Importantly, as venous blood stasis is the igniting trigger of immunothrombosis, immobility should be prevented even more intensively in cancer patients than in patients after major surgery, given the immunothrombosis favouring state in these patients. Any physical rehabilitation plan within a cardio-oncology programme should therefore be initiated early during cancer treatment. Pathophysiology of deep venous thrombosis in cancer patients. Cancer cells induce direct activation of the clotting mechanism by expressing procoagulant factors [tissue factor (TF), cancer procoagulant] and the release of procoagulant microparticles. In addition, they release pro-inflammatory cytokines that activate the resting endothelial cells (ECs) in the veins. Flow stagnation and its resulting hypoxia further activate the EC in the veins into a pro-inflammatory and procoagulant phenotype. Activation of the EC results in the exocytosis of the Weibel-Palade bodies (WPB) with the release of von Willebrand factor (VWF) and selectins on the endothelial surface. The rolling and adhesion of neutrophils is the next step. Activated neutrophils expel neutrophil extracellular traps (NET’s), lattices consisting of DNA and histones (H). NET-bound VWF and histones (H) H3, H4 stimulate the recruitment and activation of platelets. NETosis is in turn promoted by the activated platelets. Neutrophil elastase (NE), excreted by the activated neutrophils and subsequently bound to the NET’s, cleaves tissue factor pathway inhibitor (TFPI), a natural anticoagulant, promoting thrombosis. NETs also provide a surface for factor XII (FXII) activation, thereby triggering the intrinsic coagulation pathway. Activation of the EC by the pro-inflammatory cytokines released by cancer cells and activated monocytes and neutrophils reduces protein C and thrombomodulin expression, promoting thrombosis. Platelet- and EC-derived protein disulphide isomerase (PDI) activates tissue factor (TF), released by the activated EC and monocytes. Activated TF (aTF), also present in microparticles released by cancer cells, triggers the extrinsic coagulation pathway. Activation of the endothelium and triggering an innate immune response leading to activation of all pillars of the coagulation system forms the basis of immunothrombosis. Pathophysiology of deep venous thrombosis in cancer patients. Cancer cells induce direct activation of the clotting mechanism by expressing procoagulant factors [tissue factor (TF), cancer procoagulant] and the release of procoagulant microparticles. In addition, they release pro-inflammatory cytokines that activate the resting endothelial cells (ECs) in the veins. Flow stagnation and its resulting hypoxia further activate the EC in the veins into a pro-inflammatory and procoagulant phenotype. Activation of the EC results in the exocytosis of the Weibel-Palade bodies (WPB) with the release of von Willebrand factor (VWF) and selectins on the endothelial surface. The rolling and adhesion of neutrophils is the next step. Activated neutrophils expel neutrophil extracellular traps (NET’s), lattices consisting of DNA and histones (H). NET-bound VWF and histones (H) H3, H4 stimulate the recruitment and activation of platelets. NETosis is in turn promoted by the activated platelets. Neutrophil elastase (NE), excreted by the activated neutrophils and subsequently bound to the NET’s, cleaves tissue factor pathway inhibitor (TFPI), a natural anticoagulant, promoting thrombosis. NETs also provide a surface for factor XII (FXII) activation, thereby triggering the intrinsic coagulation pathway. Activation of the EC by the pro-inflammatory cytokines released by cancer cells and activated monocytes and neutrophils reduces protein C and thrombomodulin expression, promoting thrombosis. Platelet- and EC-derived protein disulphide isomerase (PDI) activates tissue factor (TF), released by the activated EC and monocytes. Activated TF (aTF), also present in microparticles released by cancer cells, triggers the extrinsic coagulation pathway. Activation of the endothelium and triggering an innate immune response leading to activation of all pillars of the coagulation system forms the basis of immunothrombosis. Recently, it was shown that microvascular endothelial dysfunction is associated with a two-fold increased risk of developing incident solid-tumour cancer.13 It appears, therefore, that endothelial dysfunction is not only a marker of future risk of cardiovascular disease but may also be a marker of future cancer risk.14 All measures aiming to prevent atherothrombosis complications by reducing cardiovascular risk factors may therefore also improve cancer prevention. Several metabolic disorders (obesity and the metabolic syndrome, diabetes, hyperlipidaemia, hypertension) and unhealthy lifestyles (smoking, unhealthy diet, alcohol, sedentary lifestyle) are indeed common risk factors for cardiovascular diseases and cancer, most probably because of shared biology, genetic, and cellular molecular pathways.15 Indeed, endothelial dysfunction and inflammation are common threads between cardiovascular disease and cancer, leading to an increased risk of venous thromboembolism due to immunothrombosis and favouring atherothrombosis in the arterial circulation.16 In addition, cured cancer patients are at increased risk for cardiovascular disease due to the cardiac and vascular toxicity of anticancer treatments. Therefore, it becomes clear that the time has come for cardiovascular prevention and rehabilitation measures as an integral part of a cardio-oncology programme.17–21 Preventing or reversing vascular endothelial dysfunction by coronary risk factor reduction and cardiac rehabilitation activities may have beneficial effects not only in cardiovascular but also in cancer patients (Figure 2). The dynamic relationship between cardiovascular risk factors and endothelial dysfunction in cancer, COVID-19, and cardiovascular diseases. In all three conditions, endothelial dysfunction is the primordial step that promotes venous immunothrombosis in COVID-19 and cancer and fosters atherothrombosis, venous thrombosis, and heart failure in cardiovascular diseases. Furthermore, there is a reciprocal interaction between cancer and cardiovascular diseases. Therefore, cardiovascular prevention by risk factor reduction and rehabilitation may prevent or reverse vascular endothelial dysfunction with a potential beneficial effect in cardiovascular and cancer patients. Redrawn and adapted after reference 15. The dynamic relationship between cardiovascular risk factors and endothelial dysfunction in cancer, COVID-19, and cardiovascular diseases. In all three conditions, endothelial dysfunction is the primordial step that promotes venous immunothrombosis in COVID-19 and cancer and fosters atherothrombosis, venous thrombosis, and heart failure in cardiovascular diseases. Furthermore, there is a reciprocal interaction between cancer and cardiovascular diseases. Therefore, cardiovascular prevention by risk factor reduction and rehabilitation may prevent or reverse vascular endothelial dysfunction with a potential beneficial effect in cardiovascular and cancer patients. Redrawn and adapted after reference 15. Conflict of interest: The author declares no conflict of interest. The opinions expressed in this article are not necessarily those of the Editors of the European Journal of Preventive Cardiology or of the European Society of Cardiology.