Higher Levels Of Soluble P-selectin Research Articles

High levels of soluble P-selectin, neutrophil extracellular traps, and myeloperoxidase as risk factor of deep vein thrombosis in malignancy patients receiving platinum-based chemotherapy

Backgrounds Venous Thromboembolism (VTE) is a disease entity comprising Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE). VTE events increase the mortality rate of patients with cancer receiving platinum-based chemotherapy. Soluble P-Selectin, Neutrophil Extracellular Traps (NET), and myeloperoxidase (MPO) are risk factors associated with DVT in malignancy patients receiving platinum-based chemotherapy. The purpose of this study was to determine the role of soluble P-selectin, NET, and MPO as risk factors for DVT in patients with malignancy receiving platinum-based chemotherapy. Patients and Methods This study used a case-control design (matched pair case-control study) based on age and gender. The case group consisted of subjects with DVT, whereas the control group consisted of subjects without DVT. The subjects were 31 in each case and control groups. Soluble P-selectin, NET, and MPO levels were measured in each group. Results The mean age of case group was 50.26±12.15 years meanwhile in control group was 52.81±11.64 years. In the case group, 71% of the subjects were female, whereas 51.6% of the control group were male. Most subjects, either in the case group (71%) or the control group (71%), used carboplatin. In the case group, cervix malignancy was the most common malignancy (32.3%), whereas in the control group, it was nasopharyngeal malignancy (25.8%). High soluble P-selectin level was a risk factor for DVT (OR 3.38, CI 1.180 – 9.780, p=0.02). A high NET level was also a risk factor for DVT (OR 2.88, CI 1.026-8.074, p=0.04). The high MPO levels in this study could not be proven as a risk factor. Conclusions Soluble P-selectin and NET are risk factors that play a role in the pathophysiology of DVT through the pathomechanism of immunothrombosis induced by endothelial injury and activation of monocytes and neutrophils due to the use of platinum-based chemotherapy.

Carotid Intima-Media Thickness and Circulation Markers of Inflammation in Patients With Depression

Objective: Growing evidence indicates that depressive disorders (DDs) are an important risk factor for atherosclerosis. The aim of this study was to evaluate the presence of common carotid artery (CCA) intima-media thickness (IMT) and circulation inflammation markers in patients with DD. Methods: A cross-sectional prospective study was undertaken comparing 40 patients with DD to 40 individuals free of depression, matched for age and gender. The Beck Depression Inventory questionnaire, serum total cholesterol, triglycerides, high-sensitivity C-reactive protein, interleukin-6, tumor necrosis factor α, P-selectin, and E-selectin levels were measured. The CCA-IMT was assessed with duplex sonography. Results: Patients with DD were more likely to smoke (65% vs 40%; P = .03) and have higher levels of serum total cholesterol (211 mg/dL vs 181 mg/dL; P = .010), triglycerides (138 mg/dL vs 97 mg/dL; P = .005), and P-selectin (0.87 ng/mL vs 0.61 ng/mL; P = .05) and lower levels of interleukin 6 (4.4 ± 2.1 pg/mL vs 10.3 ± 1.1 pg/mL; P = .002). The CCA-IMT was similar in both groups (0.07 ± 0.02 cm vs 0.06 ± 0.01 cm; P = .31). Among those with CCA-IMT in the upper quartile, subjects in the DD group had lower levels of interleukin 6 ( P = .05) and triglycerides ( P = .01) and higher levels of soluble P-selectin ( P = .03). Conclusion: Patients with DD do not present with higher CCA-IMT than a control group, although smoking and a higher level of serum lipids are present. Inflammatory biomarkers seem to be higher in patients with DD.

Is Higher Soluble P-Selectin a Risk Factor for Chronic Venous Insufficiency?

AbstractAbstract 3166 Background:Chronic venous insufficiency (CVI) represents a spectrum of disease characterized by impaired venous return. Deep venous thrombosis (DVT) when complicated by post thrombotic syndrome (PTS) is a well established etiology for CVI. P-selectin is a cell adhesion molecule involved in thrombus formation; higher levels are related to DVT risk. Thus, P-selectin may play a role in CVI pathophysiology. Objective:We evaluated whether higher levels of soluble P-selectin are a risk factor for CVI. Methods:Data were collected from the San Diego Population Study, an established cohort of 2,404 men and women, in whom CVI was evaluated by symptoms, physical examination, and duplex venous ultrasound. A case-control study was conducted within the cohort to analyze the association of P-selectin with risk and severity of CVI. 352 controls without venous abnormalities were matched by age, race, and sex to 352 cases. Cases consisted of four groups with increasing severity of CVI based on clinical and imaging characteristics. Soluble P-selectin was measured in cases and controls using a commercial immunoassay. Multivariable models were used to determine associations of P-selectin with CVI, controlling for potential confounders. Results:P-selectin levels did not differ by CVI risk factors including age, sex, race, body mass index (BMI), smoking status, diabetes, prior DVT, venous surgery, and history of cancer (not shown). Overall, P-selectin was not associated with risk of CVI. However, comparing the two most severe case groups to controls, the age, sex, and race adjusted odds ratios (ORs) of CVI for P-selectin in the top two versus bottom tertiles were increased at 1.4 and 2.3, respectively (see table), with the top tertile OR being statistically significant. The association of P-selectin in the top tertile with CVI were slightly weakened with adjustment for BMI, as the case groups with higher P-selectin levels had on average a higher BMI. Successive addition of other risk factors to the model, shown in the table, had no impact on the ORs.Odds ratios of chronic venous insufficiency with P-selectin2 highest case groups (80 cases) vs all 352 controlsTertile 2Tertile 3Age, Sex, Race1.4 (0.7–2.7)2.3 (1.2–4.2)+ BMI1.4 (0.7–2.7)1.9 (1.0–3.6)+ History of Venous Thrombosis1.4 (0.7–3.0)1.8 (0.9–3.7)+ Smoking History1.5 (0.7–3.0)1.9 (0.9–3.8)+ FHx of Venous Ulcer1.5 (0.7–3.1)1.9 (0.9–3.8)+ History of Cancer1.5 (0.7–3.2)1.9 (0.9–3.7)BMI=Body Mass Index FHx=Family HistoryOR (95% CI) with Tertile 1 as reference level Conclusions:Higher levels of soluble P-selectin are associated with risk of more severe, but not mild, CVI. This suggests that thrombosis potential or platelet function is important in the pathogenesis of this disease. Disclosures:No relevant conflicts of interest to declare.

Effects of toll-like receptor-4 gene polymorphisms on soluble P-selectin and von Willebrand factor levels in hypercholesterolemic patients

Toll-like receptor-4 (TLR-4) gene polymorphisms have been associated with a lower risk of atherosclerosis. High levels of soluble P-selectin (sP-selectin) and von Willebrand factor predict an increased risk for cardiovascular events and correlate to atherosclerotic risk factors. The relationship between these markers and TLR-4 gene polymorphisms was evaluated in a cohort of consecutive hypercholesterolemic outpatients. TLR-4 gene polymorphisms were detected in 48 out of 330 (14%) patients with hypercholesterolemia. Lipid and inflammatory markers, sP-selectin and von Willebrand were evaluated in carriers and in 96 (ratio 2:1 to cases) age- and sex-matched TLR-4 wild-type patients randomly selected from the same population. A cohort of normocholesterolemic outpatients (n = 262) served as the control group. sP-selectin was sensibly lower in carriers of TLR-4 variants as compared to wild-types and controls (89 ng/ml vs. 162 ng/ml and 163 ng/dl, respectively, p = 0.0001). Similarly, carriers showed lower von Willebrand factor values (683 mU/ml) than wild-types (910 mU/ml; p = 0.001). In multivariate analysis, TLR-4 gene polymorphisms were positively associated with sP-selectin, whereas the relationship with von Willebrand factor was no longer significant. HMG-CoA reductase inhibitors reduced sP-selectin and von Willebrand factor levels independently of TLR-4 gene variants. Plasma concentrations of these markers, however, remained lower in carriers of TLR-4 gene polymorphisms even after cholesterol lowering. In conclusion, carriership of Asp299 and Thr399Ile TLR-4 gene polymorphisms is associated with lower levels of sP-selectin and von Willebrand factor among hypercholesterolemic patients. While the underlying mechanisms remain to be investigated, such an association may indicate a protective effect of TLR-4 variants for atherosclerosis.

High Levels of Soluble P-Selectin Are Associated with the Risk of Venous Thromboembolism and the P-Selectin Thr715 Variant.

The cell adhesion molecule P-selectin, which is found in the alpha granula of platelets and in Weibel-Palade bodies of endothelial cells, has been shown to play an important role in the pathophysiology of thrombosis. However, the meaning of soluble P-selectin (sP-selectin) in venous thromboembolism (VTE) is still uncertain because clinical data are limited. The purpose of this study was to investigate whether sP-selectin is associated with the risk for VTE and to elucidate the association of sP-selectin and the P-selectin gene variation (SELP) Thr715Pro in high risk patients with recurrent VTE. We recruited cases and control individuals between January 2005 and November 2005 for an analysis of sP-selectin plasma levels and the SELP Thr715Pro. Patients with a history of objectively confirmed recurrent VTE and at least one event of an unprovoked deep venous thrombosis or pulmonary embolism were enrolled. Plasma was obtained at least 3 months after the most recent event of VTE. Age and sex-matched healthy individuals served as controls. sP-selectin levels were measured with a high sensitive ELISA. The variant for the P-selectin gene was determined by a mutagenically separated PCR followed by high resolution gel-electrophoresis. Hundred-sixteen patients (53 female / 63 male; mean age +/−SD: 56 +/−12 yrs) and 129 controls (66 female / 63 male; mean age +/−SD: 53 +/−11 yrs) were enrolled. Mean concentration (+/−SD) of sP-selectin (ng/mL) was significantly higher in patients than in controls (47.28 +/−15.00 vs. 36.77 +/−11.00, p<0.001). The unadjusted odds ratio (OR) of elevated sP-selectin (cut-off level 55.10 ng/mL representing the 95th percentile of the controls) was 8.5 (95% confidence interval (CI): [3.7–23.3], p<0.001) and increased after adjustment for factor V Leiden, prothrombin G20210A variant, elevated factor VIII level, hyperhomocysteinemia and BMI (OR=11.1, 95% CI [4.3–33.0], p<0.001). Carriers of the SELP Pro715 were more prevalent among controls than patients (21.7% versus 14.7%), however, the difference was statistically not significant (p=0.19). The subgroup of carriers of the SELP Pro715 (n=45) had significantly lower sP-selectin levels than non-carriers (31.31+/−7.94 vs. 44.10+/−14.08, p<0.001). In conclusion, our study shows a highly significant association between elevated sP-selectin levels and VTE. Furthermore, sP-selectin levels correlate with genotype status and individuals carrying the SELP Pro715 have lower levels of sP-selectin.

P-selectin and leukocyte microparticles are associated with venous thrombogenesis.

P-selectin inhibition has been found to limit venous thrombosis. We hypothesize that elevated levels of P-selectin will amplify thrombosis, mediated by procoagulant microparticles (MPs). Male mice (Mus musculus, n659), 20 to 25 grams, underwent IVC ligation to induce thrombosis. Groups consisted of wild type (WT) C57BL/6 controls, mice with high circulating levels of soluble P-selectin (CT), P-selectin gene-interrupted knockout mice (PKO), and E- and P-selectin gene-interrupted mice (EPKO). Additional groups were used to evaluate the ability of a P-sel antagonist (rPSGL-Ig) and an antibody directed against PSGL-1 to downregulate the effects of P-sel in CT mice and WT mice administered soluble P-sel at time of thrombosis. Animals were sacrificed on days 2 and 6 after IVC ligation. Thrombus mass (TM), vein wall morphometrics, and serum leukocyte/platelet microparticles (MPs) were evaluated by means of double-stained fluorescence-activated cell scanning analysis, and soluble P- and E-sel protein determination by ELISA. At days 2 and 6 in phase I of the experiment, significant differences (P <.01) in TM were noted between groups, with CT animals having the largest thrombi (50% and 57% increase in TM compared to WT at days 2 and 6) while EPKO mice had the smallest thrombi. Statistically, greater levels of neutrophils and total inflammatory cells were noted in the vein walls of CT animals at day 2 compared with WT and PKO animals. A significant difference was noted between CT and EPKO for neutrophils, monocytes, and total inflammatory cells, also at day 2. At day 6, the only statistically significant difference was found for monocytes, with a higher number in the CT animals than in WT animals. The evaluation of MPs revealed that the CT mice had a mixed leukocyte (MAC-1) and platelet (CD41) MP population that was also present in WT and PKO mice on day 2 and day 6. EPKO mice revealed a primarily platelet-derived MP population. Of interest, the CT mice with the highest TM showed a high amount of mean channel fluorescence for MAC-1 (phycoerythrin) antibody, indicative of leukocyte MPs. CT mice revealed statistically higher levels of soluble P-selectin at days 2 and 6. In phase 2, an antibody directed against PSGL-1 was more effective than rPSGL-Ig in decreasing TM and limiting leukocyte-derived MP fluorescence. This study demonstrates that high circulating levels of P-selectin are associated with increased thrombosis, whereas a lack of P-selectin and E-selectin is associated with a lessening of thrombosis. Additionally, leukocyte MPs are associated with venous thrombus formation. These data suggest the importance of selectins to venous thrombogenesis and show that P-selectin and leukocyte-derived MPs should be good targets to limit venous thrombus formation.

Interaction of P-selectin and PSGL-1 generates microparticles that correct hemostasis in a mouse model of hemophilia A.

High plasma levels of soluble P-selectin are associated with thrombotic disorders and may predict future cardiovascular events. Mice with high levels of soluble P-selectin have more microparticles in their plasma than do normal mice. Here we show that chimeras of P-selectin and immunoglobulin (P-sel-Ig) induced formation of procoagulant microparticles in human blood through P-selectin glycoprotein ligand-1 (PSGL-1; encoded by the Psgl1 gene, officially known as Selpl). In addition, Psgl1-/- mice produced fewer microparticles after P-sel-Ig infusion and did not spontaneously increase their microparticle count in old age as do wild-type mice. Injected microparticles specifically bound to thrombi and thus could be involved in thrombin generation at sites of injury. Infusion of P-sel-Ig into hemophilia A mice produced a 20-fold increase over control immunoglobulin in microparticles containing tissue factor. This significantly improved the kinetics of fibrin formation in the hemophilia A mice and normalized their tail-bleeding time. P-sel-Ig treatment could become a new approach to sustained control of bleeding in hemophilia.

Effects of transdermal hormone replacement therapy on levels of soluble P- and E-selectin in postmenopausal healthy women

Objective: To study the adhesion molecule pattern in postmenopausal women who were not receiving hormone replacement therapy (HRT), HRT users, and fertile women. Design: Case-control study. Setting: Second University of Naples, Naples, Italy. Patient(s): Fifty healthy naturally postmenopausal women and 20 fertile women. Intervention(s): Twenty-six women received no HRT and 24 received continuous transdermal 17β−estradiol, 0.05 mg/d, plus oral acetate nomegestrol, 5 mg/d. Main Outcome Measure(s): Levels of the soluble forms of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin, and P-selectin. Result(s): Women who did not received HRT showed a trend toward higher levels of soluble E-selectin and had significantly higher levels of soluble P-selectin than did fertile women. Levels of soluble E-selectin and soluble P-selectin were significantly lower in HRT users than in nonusers. Levels of VCAM-1 levels were significantly higher in HRT users than in fertile women, but no significant differences in CAM concentrations were found between the other groups. Conclusion(s): Menopause may lead to increased levels of soluble E- and soluble P-selectin, whereas long-term HRT is associated with lower selectin concentrations. This suggests that HRT may have a beneficial effect on endothelial function.

Endothelial-derived selectins in the development of organ dysfunction in acute pancreatitis.

The development of organ dysfunction is the principal determinant of outcome in acute pancreatitis and is mediated through a systemic inflammatory response characterized by leukocyte and endothelial cell activation. Up-regulation of the endothelial cell adhesion molecules, E-selectin and P-selectin, is important for endothelial/leukocyte interactions. Levels of serum-soluble E-selectin and P-selectin have been suggested as markers of endothelial activation. This study examines the kinetics of serum-soluble selectins in patients with acute pancreatitis complicated by organ dysfunction. Prospective observational study. University teaching hospital with a specialist hepato-pancreatico-biliary service. Eighteen patients with acute pancreatitis were studied, nine of whom had organ dysfunction. Serial venous blood samples were collected on the first 3 days after admission for measurement of soluble E-selectin and P-selectin by enzyme-linked immunosorbent assay. In all patients, soluble P-selectin concentrations decreased significantly during the study period. Nonsurvivors had significantly higher levels of soluble P-selectin than survivors. In contrast, soluble E-selectin increased significantly during the study period in patients with organ dysfunction, whereas it remained constant in patients without evidence of organ dysfunction. These results suggest a role for endothelial-derived selectins in the development of organ dysfunction in patients with acute pancreatitis. The observed temporal differences in serum selectin concentrations is in keeping with in vitro observations of endothelial selectin expression.

Pro-coagulant state resulting from high levels of soluble P-selectin in blood.

The plasma concentration of soluble adhesion receptors is increased under pathological circumstances, but their function remains enigmatic. Soluble P-selectin (sP-sel) is shed from activated platelets and endothelial cells. Mice genetically engineered to express P-selectin without the cytoplasmic tail (DeltaCT) constitutively show a 3- to 4-fold increase of sP-sel in plasma. We observed that the DeltaCT mice formed fibrin very readily. In an ex vivo perfusion chamber, there was more fibrin deposited at the site of platelet thrombus formation than in wild type (WT), whereas no fibrin deposits were detected using P-selectin-deficient blood during the same interval. Similarly, in vivo, the hemorrhage produced by local Shwartzman reaction was smaller in the DeltaCT mice than in WT. In contrast, we previously showed hemorrhage to be more prominent in P-selectin knock-out mice. Infusion of mouse P-sel-Ig chimera produced the same protective effect in WT mice as seen in the DeltaCT mice, indicating that the effect was due to increased levels of sP-sel. Mice infused with P-sel-Ig showed significantly more fibrin deposited on the luminal face of the injured vessels than control mice. Plasma from DeltaCT mice or mice infused with P-sel-Ig contained higher concentration of pro-coagulant microparticles and clotted one minute faster than WT. This pro-coagulant phenotype of DeltaCT mice could be reversed by a 4-day treatment with PSGL-Ig, a P-selectin inhibitor. We propose that sP-sel should no longer be considered only as a marker of inflammation or platelet activation, but also as a direct inducer of pro-coagulant activity associated with vascular and thrombotic diseases.

Elevated plasma levels of soluble P-selectin in patients with acute myocardial infarction and unstable angina: An inverse link to lipoprotein(a)

P-selectin in platelets and endothelial cells mediates adhesive interactions between platelet, leukocyte and endothelium to form thrombi. The purpose of the present study was to investigate the plasma level of soluble P-selectin (sP-selectin) in patients with coronary heart disease and the relationship between sP-selectin and plasma concentration of lipoprotein(a) [Lp(a)]. Levels of sP-selectin and Lp(a) were determined by enzyme-linked immunoabsorbent assay on plasma taken from patients with acute myocardial infarction (AMI), old myocardial infarction (OMI), unstable angina (UA), stable angina (SA) and the controls. In patients with AMI and UA, sP-selectin levels (79.62±3.82 ng/ml, 43.75±2.97 ng/ml, respectively) were significantly higher ( P<0.01) than those in patients with OMI (15.92±1.34 ng/ml), SA (15.31±1.51 ng/ml), and the controls (14.93±1.33 ng/ml), but there was no difference between AMI and UA groups. Among all subjects studied, there was an inverse correlation between Lp(a) and sP-selectin ( r=−0.315 P<0.001). These findings indicate that plasma levels of sP-selectin are increased in patients with AMI and UA, and high levels of soluble P-selectin may play a role in the pathogenesis of acute coronary events.