ABSTRACT
Post-thrombotic syndrome (PTS) has been associated to DVT recurrence, increased FVIII, inflammatory biomarker plasma levels, and persistence of vein obstruction. These same features have also been widely reported in non-O blood type subjects. Our aim was to investigate the correlation between the incidence of PTS and ABO blood types. Consecutive patients referred to the Department of Medicine of University of Padua between January 2004 and January 2012 following the diagnosis of a first episode of proximal DVT were enrolled. The presence of PTS was assessed via the Villalta scale at predefined time points (3, 6, 12, 18, 24, 36 months). Hazard ratio (HR) for PTS development was calculated in non-O (exposed) vs O blood (unexposed) type patients. Out of 671 eligible patients, 606 were enrolled. Overall, 192 (31.7%) patients developed PTS: 142 (34.5%) non-O and 50 (25.6%) O blood type patients. Individuals with non-O blood group were associated with a significantly higher risk to develop PTS (HR 1.53, 95% CI, 1.05-2.24; p = 0.028) than O group. Non-O blood type might be a risk factor for the development of PTS.
Subject(s)
ABO Blood-Group System/immunology , Postthrombotic Syndrome/prevention & control , Adult , Aged , Aged, 80 and over , Biomarkers/blood , Cohort Studies , Female , Follow-Up Studies , Hospitals, University , Humans , Incidence , Italy/epidemiology , Male , Middle Aged , Postthrombotic Syndrome/blood , Postthrombotic Syndrome/epidemiology , Postthrombotic Syndrome/immunology , Prevalence , Proportional Hazards Models , Retrospective Studies , Risk Factors , Secondary Prevention , Young AdultABSTRACT
BACKGROUND: The postthrombotic syndrome (PTS) is a severe complication of deep vein thrombosis (DVT). Reduced plasma clot permeability and lysability have been linked to DVT and residual vein obstruction. OBJECTIVES We investigated whether altered fibrin clot properties are associated with the occurrence of PTS. PATIENTS AND METHODS: Plasma fibrin clot permeability (Ks ) and lysability were investigated in a cohort of 197 consecutive patients aged 18 to 65 years recruited 3 months following the first-ever DVT. Patients with severe thrombophilia or comorbidities known to adversely affect clot phenotype were ineligible. RESULTS: During a 1-year follow-up PTS developed in 48 (24%) patients, who were characterized by lower Ks , prolonged fibrin clot lysis time (CLT) and slower release of D-dimer from clots (D-Drate ), together with higher plasma D-dimer, C-reactive protein and thrombin-activatable fibrinolysis inhibitor (TAFI). No PTS-associated differences in fibrinogen, thrombin generation, factor VIII, other fibrinolysis proteins and the quality of anticoagulation were observed. Ks (r = -0.71), CLT (r = 0.45), D-Drate (r = -0.30) and TAFI activity (r = 0.38) were associated with the Villalta scale (all P < 0.05). Recurrent VTE occurred also more commonly in PTS patients during follow-up and the 26 (13.2%) patients had lower Ks , longer CLT and lower D-Drate (all P < 0.05). A multivariate model adjusted for age, body mass index, fibrinogen and glucose showed that independent predictors of PTS were idiopathic DVT, plasma D-dimer, Ks , D-Drate , tissue plasminogen activator and TAFI activity. CONCLUSIONS: This study demonstrates that formation of more compact fibrin clots displaying impaired susceptibility to lysis predisposes to PTS.
Subject(s)
Fibrin/chemistry , Postthrombotic Syndrome/blood , Venous Thrombosis/blood , Adolescent , Adult , Aged , Blood Coagulation , Cohort Studies , Female , Fibrin Clot Lysis Time , Fibrinolysis , Follow-Up Studies , Humans , Male , Middle Aged , Permeability , Postthrombotic Syndrome/immunology , Risk , Thrombin/chemistry , Veins/physiopathology , Venous Thrombosis/immunology , Young AdultABSTRACT
Previous studies suggest that inflammation may play a role in the pathophysiology of post-thrombotic syndrome (PTS). The aims of the present study were to evaluate markers of inflammation as possible predictors for PTS after pregnancy-related deep vein thrombosis (DVT). We included 182 women with a pregnancy-related DVT during 1990-2003 and 314 controls. All women answered a questionnaire and donated a blood sample in 2006. PTS was diagnosed when a self-reported Villalta score was above 4. The following predictors of PTS were included: high sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, IL-8, IL-10, monocyte chemotactic protein (MCP)-1, transforming growth factor (TGF)-ß1, platelet derived growth factor (PDGF)-BB, and the two adhesion molecules intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1. High values were defined as above median value among controls. We found that 41% of cases were diagnosed with PTS 3-16years after index pregnancy. In univariate analyses, high values of hsCRP, IL-6, and IL-10 were significantly associated with PTS with ORs 2.3 (95% CI; 1.2-4.2, p=0.008), 1.9 (1.0-3.5, p=0.04), and 10.8 (1.3-89.8, p=0.01), respectively. Only hsCRP, which has previously been found to be independently associated with PTS, was independently associated with PTS in a multivariate logistic regression model, when adjusting for proximal DVT occurring postpartum, age above 33years, and smoking (adjusted OR 2.4; 95% CI 1.2-4.8, p=0.01). We conclude that hsCRP was associated with PTS 3-16years after pregnancy-related DVT.
Subject(s)
Inflammation/complications , Postthrombotic Syndrome/complications , Pregnancy Complications, Cardiovascular/immunology , Venous Thrombosis/complications , Adult , Biomarkers/blood , C-Reactive Protein/immunology , Chemokine CCL2/blood , Chemokine CCL2/immunology , Cross-Sectional Studies , Female , Humans , Inflammation/blood , Inflammation/immunology , Intercellular Adhesion Molecule-1/blood , Intercellular Adhesion Molecule-1/immunology , Interleukins/blood , Interleukins/immunology , Postthrombotic Syndrome/blood , Postthrombotic Syndrome/immunology , Pregnancy , Pregnancy Complications, Cardiovascular/blood , Transforming Growth Factor beta/blood , Transforming Growth Factor beta/immunology , Vascular Cell Adhesion Molecule-1/blood , Vascular Cell Adhesion Molecule-1/immunology , Venous Thrombosis/blood , Venous Thrombosis/immunologyABSTRACT
BACKGROUND: Post-thrombotic syndrome (PTS) occurs in 20-50% of patients after a deep venous thrombosis (DVT). It is difficult to accurately predict which patients will develop PTS. Biomarkers could be a valuable tool for PTS risk assessment. OBJECTIVES: To investigate whether increased levels of factor (F)VIII, C-reactive protein (CRP) or D-dimer, over time, are associated with the development of PTS in patients after an acute DVT. METHODS: PTS status was assessed using the Villalta scale. Blood sampling was performed at three points during follow-up. RESULTS: A cohort of 228 consecutive patients was included after an acute DVT. At T1 (12 months after index DVT), both levels of D-dimer (median 725 ng mL(-1) [interquartile range, IQR 400-1400[ vs. 378 ng mL(-1) [251-652] P=0.004) and CRP (median 3.9 mg L(-1) [IQR 1.6-8.5] vs. 2.4 mg L(-1) [1.0-4.3] P=0.018) were increased in patients with PTS, compared with patients without PTS. Factor (F)VIII was not associated with PTS. In the multivariate logistic regression analysis, varicosities (odds ratio [OR] 13.4 95% confidence interval [CI] 3.0-59.1 P=0.001), a previous ipsilateral DVT (OR 6.3 95% CI 1.5-26.9 P=0.012) and CRP>5 mg L(-1) on T1 (OR 8.0 95% CI 2.4-26.4 P=0.001) were significantly associated with PTS. CONCLUSIONS: Besides previous ipsilateral DVT and varicosities, CRP>5 mg L(-1) at T1 was strongly and independently associated with PTS. Persistent inflammation rather than hypercoagulability might be the most important etiological factor in PTS, and may be a target for future therapy. The development of a risk score for PTS, including both clinical risk factors and biomarker levels, such as CRP, might be desirable.
Subject(s)
Blood Coagulation , Fibrinolysis , Inflammation Mediators/blood , Inflammation/blood , Postthrombotic Syndrome/etiology , Venous Thrombosis/complications , Adolescent , Adult , Aged , Aged, 80 and over , Biomarkers/blood , C-Reactive Protein/metabolism , Factor VIII/metabolism , Female , Fibrin Fibrinogen Degradation Products/metabolism , Humans , Inflammation/immunology , Logistic Models , Male , Middle Aged , Multivariate Analysis , Netherlands , Odds Ratio , Postthrombotic Syndrome/blood , Postthrombotic Syndrome/diagnosis , Postthrombotic Syndrome/immunology , Prospective Studies , Risk Assessment , Risk Factors , Time Factors , Venous Thrombosis/blood , Venous Thrombosis/diagnosis , Venous Thrombosis/immunology , Young AdultABSTRACT
BACKGROUND: Deep vein thrombosis (DVT) and its associated sequelae, post-thrombotic syndrome (PTS), are significant health care problems in the United States. It is estimated that a maximum of 60% of patients diagnosed with DVT develop PTS, which is characterized by extensive perivenous and mural fibrosis. Interleukin-6 (IL-6) has been linked to fibrosis, and high circulating plasma levels have been found to increase the risk of developing DVT. The aim of this study was to elucidate the role of IL-6 in the progression of vein wall fibrosis by using a mouse model of DVT. METHODS AND RESULTS: C57BL/6 mice (n = 136) were treated with either anti-IL-6 monoclonal antibody or control rat-immunoglobulin G. Thrombus was induced by using an inferior vena cava ligation model. The inferior vena cava and thrombus were harvested at days 2, 6, or 14 for thrombus weight, gene expression of IL-6 and/or C-C motif chemokine ligand 2 (CCL2), inflammatory cell recruitment, and morphometric analysis of vein wall fibrosis. Mice treated with anti-IL-6 had smaller thrombus weights at day 2, decreased vein wall gene expression and protein concentration of CCL2 at day 2, and impaired vein wall influx of monocytes from days 2 to 6, as compared with controls. Intimal thickness was reduced by 44% (p < 0.05) and vein wall collagen deposition was decreased by 30% at day 14 in the anti-IL-6 group (p < 0.05). CONCLUSIONS: Neutralizing IL-6 throughout venous thrombogenesis decreased the production of CCL2, reduced monocyte recruitment, and decreased vein wall intimal thickness and fibrosis. These results suggest that IL-6 may serve as a therapeutic target to prevent the fibrotic complications seen in PTS.
Subject(s)
Antibodies, Monoclonal/pharmacology , Interleukin-6/immunology , Postthrombotic Syndrome/prevention & control , Vena Cava, Inferior/drug effects , Venous Thrombosis/drug therapy , Animals , Chemokine CCL2/genetics , Chemokine CCL2/metabolism , Collagen/metabolism , Disease Models, Animal , Enzyme-Linked Immunosorbent Assay , Fibrosis , Immunohistochemistry , Interleukin-6/blood , Interleukin-6/genetics , Male , Mice , Mice, Inbred C57BL , Monocytes/drug effects , Monocytes/immunology , Postthrombotic Syndrome/immunology , Postthrombotic Syndrome/pathology , RNA, Messenger/metabolism , Time Factors , Tunica Intima/drug effects , Tunica Intima/immunology , Up-Regulation , Vena Cava, Inferior/immunology , Vena Cava, Inferior/pathology , Venous Thrombosis/complications , Venous Thrombosis/immunology , Venous Thrombosis/pathologyABSTRACT
Chronic venous insufficiency resulting in post-thrombotic syndrome occurs commonly after acute deep vein thrombosis, and is a prevalent cause of vascular disease morbidity in the community. Therefore, a better understanding of the pathophysiologic mechanisms that promote the development of chronic venous insufficiency could lead to novel approaches to interrupt the natural history and prevent post-thrombotic syndrome. In this paper, we will review the evidence that venous thrombus resolution is an inflammatory process that is dependent on chemokines and leukocytes.