Identification of diagnostic signature and immune microenvironment subtypes of venous thromboembolism.

The close link between immune and pathogenesis of venous thromboembolism (VTE) has been recognized, but not fully elucidated. The current study was designed to identify immune microenvironment related signature and subtypes using explainable machine learning in VTE. We first observed an alteration of immune microenvironment in VTE patients and identified eight key immune cells involved in VTE. Then PTPN6, ITGB2, CR2, FPR2, MMP9 and ISG15 were determined as key immune microenvironment-related genes, which could divide VTE patients into two subtypes with different immune and metabolic characteristics. Also, we found that prunetin and torin-2 may be most promising to treat VTE patients in Cluster 1 and 2, respectively. By comparing six machine learning models in both training and external validation sets, XGboost was identified as the best one to predict the risk of VTE, followed by the interpretation of each immune microenvironment-related gene contributing to the model. Moreover, CR2 and FPR2 had high accuracy in distinguishing VTE and control, which may act as diagnostic biomarkers of VTE, and their expressions were validated by qPCR. Collectively, immune microenvironment related PTPN6, ITGB2, CR2, FPR2, MMP9 and ISG15 are key genes involved in the pathogenesis of VTE. The VTE risk prediction model and immune microenvironment subtypes based on those genes might benefit prevention, diagnosis, and the individualized treatment strategy in clinical practice of VTE.

Association of Neutrophil Activation, More Than Platelet Activation, With Thrombotic Complications in Coronavirus Disease 2019.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 infection is associated with hypercoagulability, which predisposes to venous thromboembolism (VTE). We analyzed platelet and neutrophil activation in patients with coronavirus disease 2019 (COVID-19) and their association with VTE. METHODS: Hospitalized patients with COVID-19 and age- and sex-matched healthy controls were studied. Platelet and leukocyte activation, neutrophil extracellular traps (NETs), and matrix metalloproteinase 9, a neutrophil-released enzyme, were measured. Four patients were restudied after recovery. The activating effect of plasma from patients with COVID-19 on control platelets and leukocytes and the inhibiting activity of common antithrombotic agents on it were studied. RESULTS: A total of 36 patients with COVID-19 and 31 healthy controls were studied; VTE developed in 8 of 36 patients with COVID-19 (22.2%). Platelets and neutrophils were activated in patients with COVID-19. NET, but not platelet activation, biomarkers correlated with disease severity and were associated with thrombosis. Plasmatic matrix metalloproteinase 9 was significantly increased in patients with COVID-19. Platelet and neutrophil activation markers, but less so NETs, normalized after recovery. In vitro, plasma from patients with COVID-19 triggered platelet and neutrophil activation and NET formation, the latter blocked by therapeutic-dose low-molecular-weight heparin, but not by aspirin or dypiridamole. CONCLUSIONS: Platelet and neutrophil activation are key features of patients with COVID-19. NET biomarkers may help to predict clinical worsening and VTE and may guide low-molecular-weight heparin treatment.

COVID-19, immunothrombosis and venous thromboembolism: biological mechanisms.

Thrombotic events that frequently occur in COVID-19 are predominantly venous thromboemboli (VTE) and are associated with increasing disease severity and worse clinical outcomes. Distinctive microvascular abnormalities in COVID-19 include endothelial inflammation, disruption of intercellular junctions and microthrombi formation. A distinct COVID-19-associated coagulopathy along with increased cytokines and activation of platelets, endothelium and complement occur in COVID-19, which is more frequent with worsening disease severity. This proinflammatory milieu may result in immunothrombosis, a host defence mechanism that can become dysregulated, leading to excess formation of immunologically mediated thrombi which predominantly affect the microvasculature. The haemostatic and immune systems are intricately linked, and multifactorial processes are likely to contribute to VTE and immunothrombosis in COVID-19. This state-of-the-art review will explore the pathobiological mechanisms of immunothrombosis and VTE in COVID-19 focusing on: COVID-19-associated coagulopathy, pathology, endothelial dysfunction and haemostasis, the immune system and thrombosis, genetic associations and additional thrombotic mechanisms. An understanding of the complex interplay between these processes is necessary for developing and assessing how new treatments affect VTE and immunothrombosis in COVID-19.

Risk of venous thromboembolism in rheumatoid arthritis, and its association with disease activity: a nationwide cohort study from Sweden.

OBJECTIVE: To assess the incidence of venous thromboembolism (VTE) in rheumatoid arthritis (RA) relative to individuals without RA, and to investigate the relationship between aspects of clinical disease activity in RA and the risk of VTE. METHODS: We conducted a nationwide register-based cohort study 2006 through 2018 using the Swedish Rheumatology Quality Register linked to other national patient registers to identify all patients with RA with at least one registered rheumatologist visit during the study period (n=46 316 patients, 322 601 visits). The Disease Activity Score 28 erythrocyte sedimentation rate (ESR) (DAS28 ESR) and its components served as the exposure, and a VTE event within the year following the visit was the main outcome. We also included general population referents (1:5) matched on age, sex and residential area. RESULTS: Based on 2241 incident VTE events within 1 year of each included visit, and 5301 VTE events in the general population cohort, the risk ratio for VTE in RA was 1.88 (95% CI 1.65 to 2.15). Among patients with RA, the risk (and risk ratio) increased with increasing RA disease activity, from 0.52% following visits in remission to 1.08% following visits with DAS28 ESR high disease activity, RR compared with remission=2.03, 95% CI 1.73 to 2.38. Compared with the general population, also patients with RA in DAS28 ESR remission were at elevated VTE risk. CONCLUSIONS: This study demonstrates a strong association between clinical RA disease activity measured by DAS28 ESR and the risk of VTE. RA disease activity can be used as an additional tool for VTE risk stratification in patients with RA.

Association of venous thromboembolic events with skin, pulmonary and kidney involvement in ANCA-associated vasculitis: a multinational study.

OBJECTIVE: To investigate the occurrence of venous thromboembolic events (VTE) in a large cohort of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) across the European Union, Turkey, Russia, UK and North America. METHODS: Patients with a definite diagnosis of AAV who were followed for at least 3 months and had sufficient documentation were included. Data on VTE, including either deep vein thrombosis or pulmonary embolism, were collected retrospectively from tertiary vasculitis centres. Univariate and multivariate regression models were used to estimate odds ratios (ORs) and 95% CIs. RESULTS: Over a median follow-up of 63 (interquartile range: 29, 101) months, VTE occurred in 278 (9.7%) of 2869 AAV patients with a similar frequency across different countries (from 6.3% to 13.7%), and AAV subtype [granulomatosis with polyangiitis: 9.8% (95% CI: 8.3, 11.6%); microscopic polyangiitis: 9.6% (95% CI: 7.9, 11.4%); and eosinophilic granulomatosis with polyangiitis: 9.8% (95% CI: 7.0, 13.3%)]. Most VTE (65.6%) were reported in the first-year post-diagnosis. Multiple factor logistic regression analysis adjusted for sex and age showed that skin (OR 1.71, 95% CI: 1.01, 2.92), pulmonary (OR 1.78, 95% CI: 1.04, 3.14) and kidney [eGFR 15-60 ml/min/1.73 m2, OR 2.86 (95% CI: 1.27, 6.47); eGFR <15 ml/min/1.73 m2, OR 6.71 (95% CI: 2.94, 15.33)] involvement were independent variables associated with a higher occurrence of VTE. CONCLUSION: Two-thirds of VTE occurred during the initial phase of active disease. We confirmed previous findings from smaller studies that a decrease in kidney function, skin involvement and pulmonary disease are independently associated with VTE.

COVID-19 and Its Implications for Thrombosis and Anticoagulation.

Venous thromboembolism, occlusion of dialysis catheters, circuit thrombosis in extracorporeal membrane oxygenation (ECMO) devices, acute limb ischemia, and isolated strokes, all in the face of prophylactic and even therapeutic anticoagulation, are features of novel coronavirus disease 2019 (COVID-19) coagulopathy. It seems well established at this time that a COVID-19 patient deemed sick enough to be hospitalized, should receive at least prophylactic dose anticoagulation. However, should some hospitalized patients have dosage escalation to intermediate dose? Should some be considered for full-dose anticoagulation without a measurable thromboembolic event and how should that anticoagulation be monitored? Should patients receive postdischarge anticoagulation and with what medication and for how long? What thrombotic issues are related to the various medications being used to treat this coagulopathy? Is antiphospholipid antibody part of this syndrome? What is the significance of isolated ischemic stroke and limb ischemia in this disorder and how does this interface with the rest of the clinical and laboratory features of this disorder? The aims of this article are to explore these questions and interpret the available data based on the current evidence.

Antiphospholipid antibodies in critically ill COVID-19 patients with thromboembolism: cause of disease or epiphenomenon?

Coronavirus 2019 disease (COVID-19) is associated with coagulation dysfunction that predisposes patients to an increased risk for both arterial (ATE) and venous thromboembolism (VTE) and consequent poor prognosis; in particular, the incidence of ATE and VTE in critically ill COVID-19 patients can reach 5% and 31%, respectively. The mechanism of thrombosis in COVID-19 patients is complex and still not completely clear. Recent literature suggests a link between the presence of antiphospholipid antibodies (aPLs) and thromboembolism in COVID-19 patients. However, it remains uncertain whether aPLs are an epiphenomenon or are involved in the pathogenesis of the disease.

Immunothrombosis and thromboinflammation in host defense and disease.

Platelets are increasingly being recognized for playing roles beyond thrombosis and hemostasis. Today we know that they mediate inflammation by direct interactions with innate immune cells or secretion of cytokines/chemokines. Here we review their interactions with neutrophils and monocytes/macrophages in infection and sepsis, stroke, myocardial infarction and venous thromboembolism. We discuss new roles for platelet surface receptors like GPVI or GPIb and also look at platelet contributions to the formation of neutrophil extracellular traps (NETs) as well as to deep vein thrombosis during infection, e.g. in COVID-19 patients.

Immunological analysis and differential genes screening of venous thromboembolism.

PURPOSE: To explore the pathogenesis of venous thromboembolism (VTE) and provide bioinformatics basis for the prevention and treatment of VTE. METHODS: The R software was used to obtain the gene expression profile data of GSE19151, combining with the CIBERSORT database, obtain immune cells and differentially expressed genes (DEGs) of blood samples of VTE patients and normal control, and analyze DEGs for GO analysis and KEGG pathway enrichment analysis. Then, the protein-protein interaction (PPI) network was constructed by using the STRING database, the key genes (hub genes) and immune differential genes were screened by Cytoscape software, and the transcription factors (TFs) regulating hub genes and immune differential genes were analyzed by the NetworkAnalyst database. RESULTS: Compared with the normal group, monocytes and resting mast cells were significantly expressed in the VTE group, while regulatory T cells were significantly lower. Ribosomes were closely related to the occurrence of VTE. 10 hub genes and immune differential genes were highly expressed in VTE. MYC, SOX2, XRN2, E2F1, SPI1, CREM and CREB1 can regulate the expressions of hub genes and immune differential genes. CONCLUSIONS: Ribosomal protein family genes are most relevant to the occurrence and development of VTE, and the immune differential genes may be the key molecules of VTE, which provides new ideas for further explore the pathogenesis of VTE.

Prevalence of autoantibodies directed against prothrombin in unprovoked venous thromboembolism.

The anti-phospholipid syndrome (APS) is defined by the laboratory detection of at least one of three anti-phospholipid autoantibodies (lupus anticoagulant, or anti-cardiolipin or anti-ß2-glycoprotein I antibodies) in the clinical setting of thrombosis or pregnancy morbidity in a patient. Recognising APS and administering appropriate secondary thromboprophylaxis is important to reduce risk of recurrent thrombosis and/or pregnancy morbidity. In some instances, patients having clinical manifestations highly suggestive of APS are persistently negative for these antibodies but instead have other autoantibodies. Autoantibodies directed against prothrombin (PT) have been associated with increased thrombotic risk and comprise anti-prothrombin (aPT) and anti-phosphatidylserine/prothrombin (aPS/PT) antibodies. Detection of aPT and aPS/PT may help stratify patients for more effective treatment, however, their prevalence among patients with unprovoked venous thromboembolism (VTE) is unknown and determination of their frequencies is the objective of this study. Sera from 148 patients with unprovoked VTE were analysed. Autoantibodies directed against PT collectively, aPT and aPS/PT were present in 24.3%, 14.9% and 13.5%, respectively. Prevalence of these autoantibodies in unprovoked VTE is much lower compared to cohorts comprising mainly patients with systemic autoimmune disorders. Detection of these autoantibodies in unprovoked VTE has potential therapeutic implications for patients including the duration of anticoagulation and administration, or otherwise, of direct oral anticoagulants. Data from this study will assist in the design of future clinical studies to estimate risk of recurrent VTE and to determine optimal management.

Concomitant Ro/SSA and La/SSB antibodies are biomarkers for the risk of venous thromboembolism and cerebral infarction in primary Sjögren's syndrome.

BACKGROUND: To assess the risk of incident cardiovascular disease in patients with primary Sjögren's syndrome, overall and stratified by Ro/SSA and La/SSB autoantibody status. METHODS: A cohort of patients with primary Sjögren's syndrome in Sweden (n = 960) and matched controls from the general population (n = 9035) were included, and data extracted from the National Patient Register to identify events of myocardial infarction, cerebral infarction and venous thromboembolism. Hazard ratios were estimated using cox proportional hazard regressions. RESULTS: During a median follow-up of 9.5 years, the overall hazard ratio (HR) was 1.6 (95% CI 1.2-2.1) for myocardial infarction, 1.2 (95% CI 0.9-1.7) for cerebral infarction and 2.1 (95% CI 1.6-2.9) for venous thromboembolism. Patients positive for both Ro/SSA and La/SSB autoantibodies had a substantially higher risk of cerebral infarction (HR 1.7, 95% CI 1.0-2.9) and venous thromboembolism (HR 3.1, 95% CI 1.9-4.8) than the general population. These risks were not significantly increased in Ro/SSA- and La/SSB-negative patients. Among autoantibody-positive patients, the highest HR of cerebral infarction was seen after ≥10 years disease duration (HR 2.8, 95% CI 1.4-5.4), while the HR for venous thromboembolism was highest 0-5 years after disease diagnosis (HR 4.7, 95% CI 2.3-9.3) and remained high throughout disease duration. CONCLUSIONS: Primary Sjögren's syndrome is associated with a markedly increased risk of cardiovascular disease and the presence of Ro/SSA and La/SSB autoantibodies identify the subgroup of patients carrying the highest risk. These findings suggest that monitoring and prevention of cardiovascular disease in this patient group should be considered.

The association between ABO blood types and venous thromboembolism in individuals with a positive antiphospholipid profile is varied by sex.

Objectives Although non-O blood type is an established risk factor for venous thromboembolism in the general population, the impact of ABO blood type (ABO) on venous thromboembolism risk in individuals with persistent antiphospholipid antibodies (aPL) has not been studied. We sought to investigate the relationship between ABO and venous thromboembolism in aPL-positive individuals. We also sought to explore potential interactions between ABO and sex or race to determine whether ABO contributes to race or sex differences with respect to the development of venous thromboembolism. Methods We identified all patients over 18 years old followed at a tertiary medical center between January 2000 and January 2015 with serological aPL criteria and ABO data. Episodes of venous thromboembolism were recorded. Logistic regression models were fitted to estimate odds ratios (ORs) of venous thromboembolism for non-O (A, B, or AB blood types) versus O blood type. Results There were 226 patients included in the final analysis, of whom 75 (33%) had reported venous thromboembolism. In the overall sample, there was a non-significant difference between venous thromboembolism in patients with non-O blood type compared to O blood type (OR 1.64, 95% confidence interval (CI) 0.94, 2.88; P = 0.08). Men with non-O blood type had a significantly higher risk of venous thromboembolism as compared to men with O-type blood (OR 4.94, 95% CI 1.37, 17.85; P = 0.02), but there was no significant association between ABO and venous thromboembolism among women (OR 0.96, 95% CI 0.50, 1.83; P = 0.52). Conclusions Non-O blood type may be an under-recognized risk factor for venous thromboembolism among men with persistent aPL antibodies, whereas the risk associated with non-O blood type seen in the general population may be attenuated in aPL-positive women.

Antiphosphatidylserine/prothrombin (aPS/PT) antibodies are associated with Raynaud phenomenon and migraine in primary thrombotic antiphospholipid syndrome.

Objectives Antibodies to phosphatidylserine/prothrombin complex (aPS/PT) detectable in sera of some patients with antiphospholipid syndrome (APS) have been shown to correlate with thrombosis. However, associations of aPS/PT antibodies with APS related disorders remain unclear. Aim To evaluate whether there are any associations between aPS/PT antibodies and Raynaud phenomenon, migraine and/or valvular lesions in primary thrombotic APS (PAPS). Methods We enrolled 67 consecutive patients (56 women) with thrombotic PAPS (VTE in 80.6%), aged 46.2 ± 13.5 years. The exclusion criteria were: acute coronary syndromes or stroke within preceding 6 months, cancer, severe comorbidities and pregnancy. The IgG and IgM aPS/PT antibodies were determined by ELISA with the cut-off of 30 units. We recorded Raynaud phenomenon, migraine and valvular lesions. Results Positive IgM or/and IgG aPS/PT antibodies were observed in 29 patients (43.3%), with a higher prevalence of IgM antibodies ( n = 27, 40.3%) compared with IgG isotype ( n = 12, 17.9%, p = 0.014). aPS/PT antibodies were observed most commonly in patients with triple aPL ( n = 12, 85.7%) compared with those with double ( n = 5, 35.7%) or single aPL antibodies (n = 12, 30.8%, p = 0.03), with no association with demographics, the ANA titre, the type of thrombotic events or medications. Raynaud phenomenon, migraine and valvular lesions were observed in 15% ( n = 10), 30% ( n = 20) and 18% ( n = 12) of the patients, respectively. Raynaud phenomenon and migraine, but not valvular lesions, were markedly more frequent in PAPS patients presenting with positive aPS/PT antibodies ( n = 10, 34.5% vs. n = 0, 0%; p = 0.0001). Conclusions In PAPS patients aPS/PT antibodies are related to the occurrence of both Raynaud phenomenon and migraine.

Antiphospholipid antibody syndrome: The difficulties of diagnosis.

Antiphospholipid antibody syndrome (APS) is an autoantibody-mediated thrombophilic disorder that causes a hypercoagulable state and can lead to venous thromboembolism, stroke, multiple miscarriages, and other pregnancy complications with the presence of antiphospholipid antibodies. This article reviews screening, diagnosis, and management of APS with a focus on the prevention of long-term complications.

Thrombosis in Autoimmune Diseases: A Role for Immunosuppressive Treatments?

Autoimmune diseases are not infrequently associated with arterial or venous thrombotic events. Chronic inflammation and immune system impairment are considered the main pathogenetic mechanisms. Some of the drugs used in the treatment of such diseases have been associated with an increased risk of thrombosis. On the contrary, their anti-inflammatory and immune modulator activity could correct some mechanisms leading to thrombosis. In this review, recent evidence available on this topic is examined. There is a lack of adequate studies, but available evidence suggests that glucocorticoids and high-dose immunoglobulins are associated with an increased incidence of venous thromboembolism. Although available data do not allow drawing definite conclusions and more data are needed from future studies and registries, physicians should be aware of these associations.

Association of Mycobacterium infections in patients with Mendelian susceptibility to mycobacterial disease with venous thromboembolism.

An association between a hypercoagulable state and Mendelian susceptibility to mycobacterial disease (MSMD) has been established in a few studies; resultant thrombosis is considered rare. In a case-control study, the prevalence of factor V Leiden, prothrombin G20210A and methylenetetrahydrofolate reductase (MTHFR) C677T, A1298C mutations were investigated in mycobacterium-infected patients. The study comprised 30 patients with mycobacterial infections (invasive, disseminated and/or recurrent infections with Bacille Calmette-Guerin or non-tuberculosis mycobacteria and Mycobacterium Tuberculosis with positive results for acid-fast bacilli and tuberculin skin tests) and 30 normal healthy controls. Forty female (66.7%) and 20 male subjects (33.3%) aged from 3 to 70 years were recruited into this study. Genotyping of targeted genes was performed by RT-PCR and cytokine TNF-α concentrations were quantified using a commercially available ELISA kit. Significant associations between mycobacterial infection and TNF-α production after stimulating peripheral blood mononuclear cells with LPS alone and with IFN-γ plus LPS were identified. Moreover, genotyping analysis in the studied population revealed a significant association between MTHFR c.677C>T (OR, 3.28; 95% CI, 1.35-7.92; P < 0.05), MTHFR c.1298A>C (OR, 2.33; 95% CI, 1.10-4.93; P < 0.05) and mycobacterial infection in affected patients, indicating susceptibility to venous thromboembolism according to previous studies. Additionally, mycobacterium-infected patients had a significantly greater prevalence of MTHFR C677T and A1298C mutations than controls.

Anti-DFS antibodies occur more commonly in patients following unprovoked venous thromboembolism.

Introduction: It has been reported in a small group of patients that a significant percentage of patients with anti-DFS (dense fine speckled) antibodies has a history of idiopathic arterial or venous thrombosis and/or obstetric complications. To our knowledge there have been no larger studies regarding the prevalence of anti-DFS antibodies in provoked and unprovoked venous thromboembolism (VTE). Aim of the study: We investigated how common anti-DFS70 antibodies occur in patients following VTE and which factors affect their occurrence in this disease. Material and Methods: We screened 287 consecutive adult patients, aged below 60 years, with documented VTE treated for at least 3 months, and 129 age-matched healthy controls. Patients with cancer, severe comorbidities, documented autoimmune diseases, including antiphospholipid syndrome were ineligible. The anti- -DFS70 antibodies were determined based on immunofluorescence on Hep-2 cells. The specific immunofluorescence pattern, characterized by dense fine speckles distributed the nucleus, observed at serum dilution equal to or greater than 1:100, was considered as positive and was confirmed using the semiquantitative ELISA-DFS that provided results as a ratio (RU/ml) with a cut-off of 1. Results: There was no difference in the prevalence of anti-DFS70 antibodies in the VTE and control patients (n=12, 4.18% vs. n=6, 4.65%, p=0.68). Anti-DFS antibodies represented 9.16% of all positive ANA patterns (n=131) in VTE patients, which was a much lower proportion compared with 26.1% of all 23 positive ANA patterns in healthy subjects (p=0.031). The presence of anti-DFS antibodies did not correlate with demographic or clinical variables including time since last VTE event, type of anticoagulation and its quality. The prevalence of anti-DFS70 antibodies was higher in patients with ANA titer ≥1:320 compared to those with the titer < 1:320 (75% vs. 37%, p=0.01). Of importance, higher prevalence of anti-DFS antibodies was observed in patients with unprovoked VTE compared to those with provoked VTE (75% vs. 25%, p=0.01). Among the VTE patients with heritable thrombophilia, i.e. factor V Leiden or prothrombin G20210A mutations, 25.8% of subjects (n=8) had anti-DFS antibodies. Moreover, anti-DFS titer was associated with serum alpha and gamma globulin levels (r=0.47, p=0.027; and r=0.39, p=0.045, respectively), but not with inflammatory markers or D-dimer in VTE patients. Conclusions: Anti-DFS antibodies are present in <5% of VTE patients and are associated with unprovoked VTE including that related to heritable thrombophilia. It might suggest that these antibodies are involved in the pathogenesis of idiopathic VTE.

Postsurgical Inflammation as a Causative Mechanism of Venous Thromboembolism.

Surgery is associated with an increased risk of venous thromboembolic events (VTE) including deep vein thrombosis and pulmonary embolism. Although the current treatment regiments such as mechanical manipulation and administration of pharmacological prophylaxis significantly reduced the incidence of postsurgical VTE, they remain a major cause of postoperative morbidity and mortality worldwide. The pathophysiology of venous thrombosis traditionally emphasizes the series of factors that constitute Virchow triad of factors. However, inflammation can also be a part of this by giving rise to a hypercoagulable state and endothelial damage. The inflammatory response after surgery, which is initiated by a cytokine "storm" and occurs within hours of surgery, creates a prothrombotic environment that is further accentuated by several cellular processes including neutrophil extracellular traps formation, platelet activation, and the generation of tissue factor-bearing microparticles. Although such inflammatory markers are elevated in undergoing surgery, the precise mechanism by which they give rise to venous thrombosis is poorly understood. Here, we discuss the potential mechanisms linking inflammation to thrombosis, and highlight strategies that may minimize surgical inflammation and reduce the incidence of postoperative VTE.

Venous thromboembolism in systemic autoimmune diseases: A narrative review with emphasis on primary systemic vasculitides.

Venous thromboembolism (VTE) is a prevalent multifactorial health condition associated with significant morbidity and mortality. Population-based epidemiological studies have revealed an association between systemic autoimmune diseases and deep venous thrombosis (DVT)/VTE. The etiopathogenesis of increased risk of VTE in systemic autoimmune diseases is not entirely clear but multiple contributors have been explored, especially in the context of systemic inflammation and disordered thrombogenesis. Epidemiologic data on increased risk of VTE in patients with primary systemic vasculitides (PSV) have accumulated in recent years and some of these studies suggest the increased risk while patients have active diseases. This could lead us to hypothesize that venous vascular inflammation has a role to play in this phenomenon, but this is unproven. The role of immunosuppressive agents in modulating the risk of VTE in patients with PSV is not yet clear except for Behçet's disease, where most of the studies are retrospective. Sensitizing physicians to this complication has implications for prevention and optimal management of patients with these complex diseases. This review will focus on the epidemiology and available evidence regarding pathogenesis, and will attempt to summarize the best available data regarding evaluation and treatment of these patients.

Interleukin levels and their potential association with venous thromboembolism and survival in cancer patients.

Cytokines have been found to be elevated in cancer patients and have been associated with worse prognosis in single tumour entities. We investigated the association of eight different cytokines with venous thromboembolism (VTE) and prognosis in cancer patients. The Vienna Cancer and Thrombosis Study (CATS), a prospective study, includes patients with newly diagnosed tumour or disease progression. Patients with an overt infection are excluded. Study end-points are VTE, death, loss to follow-up or study completion. Interleukin (IL) serum levels were measured using the xMAP technology developed by Luminex. Among 726 included patients, no associations between IL levels and VTE were found, with the exception of a trend for IL-1ß and IL-6 in pancreatic cancer. Elevated levels of IL-6 [as continuous variable per double increase hazard ratio (HR) = 1·07, 95% confidence interval (CI) = 1·027-1·114, P = 0·001, IL-8 (HR = 1·12, 95% CI = 1·062-1·170, P < 0·001) and IL-11 (HR = 1·37, 95% CI = 1·103-1·709, P = 0·005] were associated with worse survival. In subgroup analyses based on tumour type, colon carcinoma patients, who had higher IL-6 levels, showed a shorter survival (HR = 2·405, 95% CI = 1·252-4·618, P = 0·008). A significant association of elevated IL-10 levels with a decrease in survival (HR = 1·824, 95% CI = 1·098-3·031, P = 0·020) was seen among patients with lung cancer. No correlation between VTE and IL levels was found, but higher IL-6, IL-8 and IL-11 levels were associated with worse survival in cancer patients. Further, elevated IL-6 levels might be a prognostic marker in colorectal cancer and elevated IL-10 levels in lung cancer patients.