leptin and Venous-Thrombosis

Epidemiological evidence strongly links excess body weight with an increased risk to develop atherothrombotic complications. Obesity is frequently associated with systemic and local inflammation as well as elevated circulating leptin levels, and clinical studies found hyperleptinemia to correlate not only with measures of adiposity, but also with circulating biomarkers of an increased metabolic and cardiovascular risk or surrogate markers of subclinical atherosclerosis. Moreover, experimental studies in mice with systemic disruption of the leptin-leptin receptor system as well as after administration or neutralization of the adipokine demonstrated that leptin promotes both arterial and venous thrombosis. In addition to directly binding to and activating platelets and thus potentiating their aggregation in response to agonist stimulation, leptin enhances the expression of prothrombotic and anti-fibrinolytic proteins in vascular and inflammatory cells. On the other hand, its ability to mobilize and recruit vascular progenitor cells from the bone marrow to sites of vascular injury was found to be impaired in hyperleptinemic, obese humans and rodents. Thus, leptin promotes thrombus formation and resolution by several different mechanisms involving primary hemostasis, the coagulation cascade as well as the integrity of the vessel wall. Dissection of the molecular mechanisms underlying each of its actions may pave the road for novel therapeutic options in targeting the increased risk of thrombosis associated with obesity, keeping in mind unresolved issues of a cell-specific leptin resistance as well as individual differences in the responsiveness to leptin.

Topics: Animals; Anticoagulants; Arteries; Humans; Leptin; Models, Cardiovascular; Molecular Targeted Therapy; Receptors, Leptin; Secondary Prevention; Signal Transduction; Thrombosis; Veins; Venous Thrombosis

Platelet activation is involved in the pathogenesis of atherosclerosis and venous thromboembolism, and might therefore be a possible link between the two entities. Prolactin and leptin have recently been recognized as potent co-activators of ADP-dependent platelet aggregation or P-selectin expression, and are therefore suspected as additional risk factors for both arterial and venous thrombosis. There are clinical situations that have a known association with higher prolactin or leptin levels (pregnancy, obesity or anti-psychotic therapy) and increased risk of thromboembolic events. We compared the impact of both hormones on platelet activation in vitro and in vivo, indicating that prolactin has a stronger effect on platelet activation as leptin in vitro and in vivo. We have also demonstrated that prolactin levels are increased in so called idiopathic thrombosis, and that conversely, patients with prolactinoma have an increased frequency of thrombosis during the hyperprolactinemic state, in a retrospective analysis. Moreover, we have demonstrated increased prolactin values in stroke and myocardial infarction. Prospective studies have yet to be performed to give this theory its final confirmation. The involvement of hormonal factors in platelet aggregation and venous or arterial thrombosis may have important clinical implications such as for risk stratification of patients with venous and arterial thrombosis or new therapeutic options such as decreasing pro-coagulant hormone levels in certain risk situations.

Topics: Adenosine Diphosphate; Arteriosclerosis; Female; Gene Expression; Humans; Leptin; P-Selectin; Platelet Activation; Pregnancy; Prolactin; Venous Thrombosis

Post-thrombotic syndrome (PTS) is a common complication of deep vein thrombosis (DVT). Little is known about the involvement of adipokines in the pathogenesis of DVT. We evaluated whether adipokines can predict PTS. In a prospective cohort study, 320 DVT patients aged 70 years or less were enrolled. Serum adiponectin, leptin and resistin levels were measured three months since the index first-ever DVT. After 2 years' follow-up PTS was diagnosed in 83 of 309 available patients (26.9%) who had 13.9% lower adiponectin and 16% higher leptin levels compared with the remainder (both p < 0.0001). No PTS-associated differences in C-reactive protein, fibrinogen, D-dimer, plasminogen activator inhibitor-1 and resistin were observed. The multivariable logistic regression adjusted for age, sex, obesity and tissue plasminogen activator (tPa) showed that lower adiponectin (odds ratio [OR], 0.42; 95% confidence interval [CI], 0.31-0.56) and higher leptin levels (OR, 1.49; 95% CI, 1.31-1.69) are independent predictors for PTS. Obesity-stratified logistic regression analysis confirmed that lower adiponectin (OR, 0.49; 95% CI, 0.38-0.64) and higher leptin (OR, 1.41; 95% Cl, 1.25-1.58) levels predicted PTS. Our findings showed that lower adiponectin and higher leptin measured 3 months after DVT, regardless of obesity, can independently predict PTS, which suggests novel links between adipokines and thrombosis.

Topics: Adiponectin; Adult; Biomarkers; C-Reactive Protein; Female; Fibrin Fibrinogen Degradation Products; Follow-Up Studies; Humans; Leptin; Male; Middle Aged; Obesity; Odds Ratio; Postthrombotic Syndrome; Reactive Oxygen Species; Reproducibility of Results; Sensitivity and Specificity; Venous Thrombosis

It suggests that a high leptin level may increase the risk of venous thromboembolism (VTE) in animal studies. However, clinical studies in this field are still largely unexplored. Our objective was to evaluate the relationship between the preoperative serum leptin levels and postoperative VTE incidence in osteoarthritis (OA) patients who underwent total knee arthroplasty (TKA) at our institute.We conducted a prospective and cross-sectional study in these OA patients from March 2014 to March 2016. Preoperative leptin levels were analyzed by Luminex assays. VTE was assessed preoperatively and on postoperative day 5 and 7. The potential risk factors for VTE were also documented.We enrolled 203 OA patients. No PE was detected and DVT was diagnosed in 34 patients postoperatively. There were significant differences between the median leptin levels in DVT group and non-DVT group [25.13 ng/mL (interquartile range, 14.51-44.31) vs 18.71 ng/mL (8.26-28.99), P = .007]. The relative risk of DVT significantly increased with natural logarithm (ln) leptin (per SD increase) (OR 2.37, 95% confidence interval (95% CI), 1.29-4.33, P = .005). Multivariate analyses adjusted for potential confounders showed ln leptin (per SD increase) was significantly associated with the relative risk of DVT (OR 2.17, 95% CI, 1.01-4.64, P = .046). When patients were subdivided into tertiles according to their leptin values, the OR for DVT increased with increasing tertiles of serum leptin (OR 1.03, 95% CI, 1.01-1.06, P for trend = .023).In the present study, our results indicate that a high preoperative leptin level may be an independent risk factor for postoperative DVT.

Topics: Aged; Arthroplasty, Replacement, Knee; Cross-Sectional Studies; Female; Humans; Incidence; Leptin; Male; Middle Aged; Osteoarthritis, Knee; Postoperative Complications; Preoperative Period; Prospective Studies; Risk Factors; Ultrasonography, Doppler, Duplex; Venous Thromboembolism; Venous Thrombosis

Retinal vein occlusion is an important cause of visual loss. Several ocular and systemic conditions have been reported for retinal vein occlusion. The pathogenesis of thrombus formation in the retinal vein, which results in retinal vein occlusion, is unclear. The aim of this study was to investigate the correlation between increased serum leptin levels and the occurrence of retinal vein occlusion (RVO). The study group consisted of 40 patients with RVO (58.1 +/- 6 years old; 17 males and 23 females): 15 patients with central RVO, 23 with branch RVO, and 2 with hemispheric RVO. The patients who had any ocular or systemic pathology were not included in the study. The control group consisted of 40 healthy individuals of similar gender, age, date and type of health survey, and geographic region. The blood samples of the RVO patients (n = 40) and controls (n = 40) were obtained antecubitally. Leptin levels were measured by an enzyme-linked immunosorbent assay (ELISA) method, and Student's t-test was used to determine differences between the groups. The mean serum leptin levels were 12.5 +/- 1.64 ng/ml in patients with RVO and 8.4 +/- 1.22 ng/ml in the control subjects; namely, the mean serum leptin levels were significantly higher in the patients with RVO (p < 0.001). These results suggest that leptin may be involved in the pathogenesis of venous thrombosis in the retina probably through its effects on homeostasis of the vessel wall.

Topics: Female; Health Surveys; Humans; Leptin; Male; Middle Aged; Reference Values; Retinal Vein; Retinal Vein Occlusion; Venous Thrombosis

Human obesity is associated with an increased risk for arterial and venous thrombosis and with elevated levels of leptin in the blood. Leptin administration promotes arterial thrombosis in mice, and leptin-deficient ob/ob mice have an attenuated thrombotic response to injury. Thus, endogenous leptin may regulate arterial and venous thrombosis in vivo. Experiments were performed to test this hypothesis.. A leptin-neutralizing antibody was administered intravenously into wild-type mice 15 minutes before carotid artery injury with ferric chloride. The antibody-treated mice demonstrated prolonged times to thrombotic occlusion and formed unstable, embolizing thrombi. Thus, inhibiting leptin converted the thrombotic phenotype of wild-type mice into one that closely resembled that of ob/ob mice. The effect of leptin inhibition on venous thrombosis and pulmonary embolism was also investigated. Injection of a mixture of collagen and epinephrine into the jugular vein induced fatal pulmonary embolism in >90% of the control wild-type mice but in <40% of their antibody-treated counterparts. Histological analysis revealed that the antibody significantly reduced the number of occlusive thrombi in the pulmonary vessels.. Inhibition of circulating leptin protects against arterial and venous thrombosis in mice and possibly in hyperleptinemic obese individuals.

Topics: Animals; Antibodies, Blocking; Arterial Occlusive Diseases; Chlorides; Ferric Compounds; Leptin; Mice; Mice, Inbred C57BL; Receptors, Cell Surface; Receptors, Leptin; Venous Thrombosis