Previously, venous thromboembolism (VTE) was regarded as a separate disease from arterial thromboembolism.1 However, this hypothesis has been challenged. In 2003, Prandoni et al.2 reported that transient venous thrombosis patients had more atherosclerotic plaques in the carotid arteries, suggesting that atherosclerosis can cause venous thrombosis or that the two conditions share risk factors. In the Lancet in 2007, Srensen et al.3 assessed the hospitalization rate due to acute arterial cardiovascular events over 20 years in a cohort of venous thrombosis patients, and found that VTE patients had significantly increased risk for cardiovascular events. In 2008, a meta-analysis on the correlation between cardiovascular risk factors and VTE showed that the major risk factors for atherothrombotic disease were significantly associated with VTE.4 It has been suggested that cardiovascular risk factors are also directly involved in the pathogenesis of VTE. To further investigate the potential mechanisms underlying this correlation, it would be helpful to elucidate the pathogenesis of VTE and to screen high-risk subjects for primary and secondary prevention of VTE. On the basis of previous findings, this study was undertaken to compare T-cell immune function in VTE patients, CAA patients and healthy controls, to elucidate whether inflammatory immunity is involved in the occurrence and development of venous thrombosis as in atherosclerosis. We further investigated T-cell immune function, hs-CRP and cardiovascular risk factors in VTE patients, CAA patients and healthy controls, and also evaluated the correlation between VTE and arterial thrombosis, aiming to explore the pathogenesis and risk factors of VTE.

VTE, including deep vein thrombosis and pulmonary embolism, has high morbidity, mortality and misdiagnosis rate.5 A US study reported the incidence of deep vein thrombosis as 0.5%.6 In the past 20 years, the incidence of pulmonary embolism has increased in Asia, including China, Japan, Thailand, Singapore and Taiwan.7 The pathogenesis and etiology of VTE are still unclear. Virchow's triad (hypercoagulability, hemodynamic changes [stasis, turbulence] and endothelial injury/dysfunction) is still used to explain the pathogenesis of VTE.8 However, this concept does not always explain the occurrence of acquired VTE in clinical practice. In the American College of Chest Physicians guidelines for antithrombotic therapy and prevention of thrombosis, patients receiving surgery are stratified according to risk factors, and anti-coagulation therapy for prevention of VTE is based on these guidelines. However, the incidence of VTE continues to increase.

The pathogenesis of atherosclerosis (AS) has been investigated for more than 150 years. Currently, AS is regarded as a chronic inflammatory disease. Statins may delay the occurrence and development of AS through their anti-inflammatory activity, making them a milestone in the treatment of AS. Until recently, venous thrombosis was regarded as a separate disease from AS, but there is correlation between the two, and they share risk factors that include obesity, diabetes, hypertension, dyslipidemia (hypertriglyceridemia and low HDL-C) and smoking. Our results showed that the traditional risk factors for CAA (such as hypertension, hyperglycemia, TC, HDL-C and LDL-C) were significantly associated with venous thrombosis. The correlation between AS and VTE provides support for investigation of the pathogenesis of VTE, screening of high-risk populations and the development of strategies for primary and secondary prevention of VTE.

Since 2004, we have been engaged in basic and clinical investigation of VTE, employing microarray assay and fluorescence quantitative PCR to detect mRNA expression in peripheral blood of VTE patients. This showed that mRNA expression of T-lymphocyte proteins is significantly reduced, particularly CD3G, CD3D, CD247, ZAP-70 and T-cell granzyme A and B. This suggests that the cytotoxic activity of T cells is impaired.10 In AS, T lymphocytes are recruited and activated and inflammatory cytokines are secreted, which are observed in different stages in the occurrence and development of AS. Whether venous thrombosis is an inflammatory process like arterial thrombosis, and whether impaired T cell function is involved in the occurrence and development of VTE, are still largely unclear.

On the basis of our previous findings, VTE in patients and outpatients were recruited from Tongji Hospital between January 2008 and August 2012. Patients with CAA were also enrolled, as well as healthy subjects as controls. T-cell function and serum hs-CRP levels were determined in these subjects. Impaired T-cell function was observed in VTE patients, characterized by reduced expression of CD3 and CD8, increased CD4/CD8 ratio and unchanged CD4 expression. Reduction in CD3+ T cells suggests compromised antigen recognition and transduction activation, while reduction in CD8 indicates a decrease in CD8+ cytotoxic T lymphocytes, which are the major effector cells of cellular immunity. This suggests that direct killing of pathogens by T cells is compromised. The CD4/CD8 ratio is a sensitive indicator for clinically determining immune function, and when increased suggests that cellular immunity is compromised, with reduced activation and killing activity. However, CD4+ T cells, the cells principally responsible for assisting other leukocytes and regulating the immune response, were not affected. At the same time, our findings also revealed that the impaired T cell function in CAA patients was similar to that in VTE patients, and both presented with impaired T-cell immune function.

Activation, cloning and proliferation of T cells require the presence of specific antigens. Certain autoantibodies and pathogens (such as Chlamydia pneumoniae, herpes simplex and cytomegalovirus) serve as antigens to activate T lymphocytes. Infection is a major cause of AS, as has been reported in numerous studies.9 In 2006, Smeeth et al. reported that the occurrence of VTE was associated with infection, usually occurring within two weeks.11 In 2011, Schmidt et al. retrospectively investigated 15 009 cases of VTE and showed that risk for VTE was increased twofold in patients with infection, especially within two weeks of infection, gradually declining thereafter.12 In the present study, about 50% of VTE patients had concomitant infection, and an additional 16% of them developed VTE within two weeks after bone fracture. In 2010, we reported venous thrombi in multiple organs of a patient who died of SARS,13 and we have also found virus-like structures in the lymph nodes of a young patient with pulmonary hypertension.14 Whether the pathogens in these lesions cause pathological changes directly or by eliciting an immune response is still poorly understood. Other risk factors might also contribute to the pathogenesis of VTE.

Infection, especially viral infection, may attack T cells and induce damage to these cells, which can affect the immune system, leading to secondary immunodeficiency. However, cancer, severe malnutrition, medication with immunosuppressants and other factors (old age, obesity, diabetes, hypertension and smoking) are also accompanied by varying degrees of immune dysfunction. Thus, we speculate that immune mechanisms are involved in the occurrence and development of arterial and venous thrombosis.

Among inflammatory cytokines, hs-CRP is a potent marker for inflammation and can be used to predict risk for cardiovascular diseases; increased hs-CRP is closely linked to the severity of coronary lesions. In the present study, hs-CRP was significantly increased in both VTE and CAA patients, suggesting that inflammatory mechanisms are involved in the pathogenesis of venous thrombosis.

Taking these factors together, we speculate that inflammation and immune mechanisms are the bridge between AS and VTE, their shared risk factors leading to damage to vascular endothelial cells by inducing an inflammatory immune response and interfering with the coagulation balance, resulting in venous or arterial thrombosis. However, the methodology of this study is relatively simple, which is a limitation. In-depth clinical trials and studies in animal models are required to elucidate the symptoms and pathogenesis of VTE and their relation with the immune response. However, the inflammation and immunity theory of VTE inspires us and provides support for further studies on the pathogenesis of VTE.

The authors have no conflicts of interest to declare.