Plasma Thrombospondin-1 Levels Research Articles

Plasma THBS1 as a predictive biomarker for poor prognosis and brain metastasis in patients with HER2-enriched breast cancer.

Thrombospondin-1 (THBS1) is a secretory adhesive glycoprotein involved in the progression of multiple malignancies, including breast cancer. However, the clinical significance and prognostic role of plasma THBS1 in breast cancer have yet to be clarified. Plasma THBS1 levels in 627 breast cancer patients were analyzed by enzyme-linked immunosorbent assay. Bone marrow blood was drawn from the anterior/posterior superior iliac spine to detect the presence of disseminated tumor cells (DTCs). The effects of plasma THBS1 on the clinicopathological characteristics and survival prediction of breast cancer patients were explored. Plasma THBS1 did not correlate with overall survival, breast cancer-specific survival (BCSS), and distant disease-free survival (DDFS) in the entire breast cancer cohort. Notably, HER2-enriched patients with high-plasma THBS1 levels had significantly shorter BCSS (P = 0.027) and DDFS (P = 0.011) than those with low levels. Multivariate analyses revealed that plasma THBS1 was an independent prognostic marker of BCSS (P = 0.026) and DDFS (P = 0.007) in HER2-enriched patients. THBS1 levels were 24% higher in positive DTC patients than in negative DTC patients (P = 0.031), and high levels were significantly associated with poor BCSS in positive DTC patients (HR 2.08, 95% CI 1.17-3.71; P = 0.019). Moreover, high-plasma THBS1 levels were specifically associated with an increased occurrence of brain metastasis in HER2-enriched patients (P = 0.041). These findings suggest that plasma THBS1 may be serving as an unfavorable prognosis predictor for HER2-enriched breast cancer and justifies the need for further research.

Obesity-Induced Platelet Mitofusin-1 Expression Causes Vascular Dysfunction

Background:The growing epidemic of obesity is strongly linked to cardiovascular disease (CVD). Obesity leads to endothelial dysfunction, an instigating event that drives vascular injury and subsequent CVD, but the mechanisms by which obesity causes endothelial dysfunction remain unclear. Platelets circulate proximal to the endothelium and are traditionally thought to contribute to obesity-associated vasculopathy through thrombotic activation. However, platelets are metabolically active and release vaso-modulatory molecules into their environment and the role of these functions have not been examined in the context of obesity-induced vasculopathy. We previously showed that alterations in platelet mitochondrial function regulate platelet degranulation. Further, it has been reported that thrombospondin 1 (TSP1), a platelet factor that propagates endothelial dysfunction, is elevated in the plasma of obese humans. We hypothesized that obesity/weight gain modulates platelet mitochondrial function, which stimulates the release of TSP1 from platelets to propagate vascular dysfunction. Methods: Platelets were isolated from lean and obese humans and mitochondrial structure and function measured. To induce diet-induced obesity wildtype (WT) mice were fed with a high fat diet (HFD, 60 kcal% fat) for 10 weeks, and low fat diet (LFD, 10 kcal% fat)- fed WT mice were used as controls. Platelets and plasma from the mice were screened for mitochondrial proteins and plasma TSP-1 was measured by ELISA. A murine model with platelet-specific deletion of mitofusin-1 (MFN1; pltMFN1KO mice), a mitochondrial GTP-ase that increases mitochondrial function was generated and fed either HFD or LFD for 4-10 weeks. Further, endothelial-dependent- and independent- vascular relaxation was measured in both groups by stimulating aortic rings with acetylcholine (Ach) or sodium nitroprusside (SNP) using wire myography. Additionally, platelet-specific TSP1 knockout (plt-TSP1KO) mice were generated and fed with HFD for 10 weeks and measured plasma TSP1 levels. Results: Platelets from obese subjects showed increased levels of MFN1 compared to lean subjects. WT mice fed with HFD had increased platelet MFN1 and plasma TSP1 levels compared to LFD-fed WT mice. Platelet-specific deletion of MFN1 in mice resulted in reduced plasma TSP1 levels compared to control PF4-cre mice after HFD challenge. We found that HFD caused impaired Ach-stimulated vasorelaxation (indicative of endothelial dysfunction) in control PF4-cre mice, and this effect was attenuated in pltMFN1KO mice. Further, we found that HFD-induced increases in plasma TSP1 levels were attenuated in plt-TSP1KO mice, indicating platelets are the major source of TSP1 in HFD induced obesity model. Conclusion:These data demonstrate that obesity/weight gain induces platelet MFN1 expression, which drives TSP1 release from platelets to propagate vascular dysfunction. Our findings elucidate a novel platelet-centric mechanism underlying obesity-associated vasculopathy and have implications for the targeting of non-thrombotic platelet function as a therapeutic strategy for obesity-induced vasculopathy.

Thrombospondin 1 and Nuclear Factor Kappa B Signaling Pathways in Non-alcoholic Fatty Liver Disease.

We aimed to evaluate the circulating thrombospondin-1 (TSP-1) and nuclear factor kappa B (NF-κB) in nonalcoholic fatty liver disease (NAFLD) in order to integrate these signaling pathways in the inflammatory and fibrogenic processes of this liver disorder. Ninety-five NAFLD patients were recruited in the study. The study also included 83 age-sex matched healthy controls. The number of patients with metabolic syndrome (MetS) criteria was 57 (60%). TSP-1 level was found to be statistically significantly lower in the NAFLD group compared to the control group (p=0.037). However, NF-κB level was found to be significantly higher in the NAFLD group compared to the control group (p=0.004). There was a significant negative correlation between plasma TSP-1 levels with glucose (r=-0.235, p=0.022), alanine aminotransferase (r=-0.261, p=0.011) and aspartate transaminase (r=-0.328, p=0.001) levels. In addition, a significant negative correlation was found between plasma TSP-1 and NF-κB levels (r=-0.729, p<0.001). Our results suggest a close relationship between increased NF-κB and reduced TSP-1 in NAFLD. TSP-1 and NF-κB signaling pathways might have a role in the inflammatory and fibrogenic processes. Furthermore, they may be used as a noninvasive marker and could assist as a therapeutic target for NAFLD.

Baseline thrombospondin-1 concentrations are not associated with mortality in septic patients: a single-center cohort study on the intensive care unit

BackgroundThe initial phase of sepsis is characterized by hyperinflammation. Levels of thrombospondin-1 (TSP-1) rise rapidly during acute inflammation. The purpose of this clinical study was to study the association between plasma TSP-1 levels and mortality in patients with sepsis on the intensive care unit.MethodsCritically ill adult patients with sepsis, severe sepsis, or septic shock were included. They were further divided into tertiles based on their baseline plasma TSP-1 concentrations. Primary outcome measure was 28-day mortality. Furthermore, associations with severity of sepsis and platelet counts were studied.ResultsTwo hundred thirty-five patients were included. Median plasma TSP-1 concentrations of the tertiles were 194, 463 and 874 ng/mL, respectively. There were no baseline differences. Mortality rates (26.6, 16.7, and 16.7%, p = 0.20) and cumulative survival curves (p = 0.22) were not statistically different between the tertiles. There was no association of baseline TSP-1 with severity of sepsis (p = 0.08). TSP-1 and platelet counts were positively correlated (159, 198, and 295 × 109/L, p = 0.04).ConclusionsBaseline plasma levels of TSP-1 were not associated with mortality and severity of sepsis in mixed population of septic ICU patients. Further research is needed to clarify the expression of TSP-1 and to unravel the potential prognostic value of this biomarker in human sepsis.

Elevated Plasma Thrombospondin-1 (TSP1) Levels Are Correlated with Oxidative Stress and Worse Cognitive Function in Sickle Cell Disease

IntroductionCognitive impairment (CI) is a serious complication of sickle cell disease (SCD) with a prevalence of more than 40% (Vichinsky, JAMA 2010). It is responsible for functional limitations in schooling in children and in occupation and compliance with therapy in adults, and is therefore recognized as both a medical and social devastation of SCD. While the pathophysiology of SCD-related cognitive impairment is not fully elucidated, SCD patients are exposed to high levels of chronic inflammation and oxidative stress, which are responsible for cognitive impairment in other vascular diseases, suggesting that these factors may also play a role in SCD. Thrombospondin-1 (TSP1) is a secreted protein that stands at the crossroads of multiple inflammatory and oxidative pathways crucial to the SCD pathology (Isenberg, PNAS 2005, JBC 2006, Blood 2008, Csanyi, ATVB 2012; Yao, JASN 2014). Importantly, TSP1 levels are elevated in patients with SCD and correlate with an increased risk of vaso-occlusive complications in adults (Novelli, AJH 2012) and a higher burden of silent cerebral infarcts in children (Faulcon, BJH 2013). Herein, we explored the association between TSP1, oxidative stress and cognitive function in a cohort of patients with SCD.MethodsThirty-four SCD patients (HbSS, HbSC and HbS/β-thalassemia) >18 years and in steady state were recruited from the UPMC Adult Sickle Cell Program outpatient clinic (Pittsburgh, PA). Upon obtaining informed consent, patients underwent a blood draw and the Hopkins Verbal Learning Test - Revised (HVLT-R), a test of episodic memory whose scores are associated with cerebral small vessel disease in SCD patients (Novelli, PRN 2015). Platelet-poor plasma was collected and stored for analysis by ELISA of TSP1 and the oxidized derivative of deoxyguanosine, 8-hydroxy-2-deoxy guanosine (8-OH2dG), a marker of oxidative stress. Statistical analyses were completed using SAS 9.3.ResultsSCD patients had a mean age of 35 (22-65), were 65% female, 66% had greater than high school education, and 65% had HbSS disease, 30% had HbSC disease, and 5% had S/β-thalassemia. Elevated plasma TSP1 levels correlated inversely with HVLT-R retention score (standardized b=-0.457, p=0.007). Conversely, elevated plasma TSP1 levels positively correlated with increased levels of plasma 8-OH2dG (standardized b=0.361, p<0.001). The association between TSP1 and HVLT-R was potentiated after adjustment for 8-OH2dG (standardized b=-0.762, p<0.001). Moreover, the association between 8-OH2dG and cognitive function was also significant after adjusting for TSP1 (standardized b=-0.633, p=0.015).DiscussionElevated plasma TSP1 levels are associated with poorer episodic memory in SCD patients. This is the first evidence of a link between a plasma protein associated with vascular disease and cognitive function in adults with SCD. TSP1 levels were also positively correlated with 8-OH2dG, and adding 8-OH2dG to the model of TSP1 and HVTL-R retention appeared to increase the detrimental effect of TSP1. These results suggest that the effect of 8-OH2dG on cognitive function becomes evident only in the presence of higher TSP1 levels and implicate oxidative stress as intermediary to the effect of TSP1 on cognitive function in SCD. [Display omitted] DisclosuresIsenberg:RCTI, Inc.: Equity Ownership, Patents & Royalties: US Patent No. 8236313; Vasculox, Inc.: Equity Ownership, Patents & Royalties: US Patent No. 8236313.

Plasma thrombospondin-1 and clinical outcomes in traumatic brain injury.

Thrombospondin-1 (TSP-1) acts as an anti-angiogenic factor, and its expression in rat brain is upregulated after intracerebral hemorrhage. The current study was designed to investigate the change of plasma TSP-1 levels and assess the prognostic predictive effect of plasma TSP-1 level and it is associated with head trauma severity in the patients with severe traumatic brain injury (STBI). The plasma TSP-1 levels of 134 patients and 134 healthy controls were measured using enzyme-linked immunosorbent assay. The relationships between plasma TSP-1 levels and trauma severity reflected by Glasgow Coma Scale (GCS) scores as well as between plasma TSP-1 levels and short-term and long-term clinical outcomes were analyzed using multivariate analysis. Plasma TSP-1 levels were statistically significantly higher in patients than in healthy controls. The multivariate analysis demonstrated close association of TSP-1 with GCS scores and also identified TSP-1 as an independent predictor for 1-week mortality, 6-month mortality, and 6-month unfavorable outcome. Plasma TSP-1 levels had high prognostic predictive value based on receiver operating characteristic curve. The difference between its prognostic predictive value and GCS scores was not statistically significant. Plasma TSP-1 levels are elevated and are highly associated with head trauma severity and short-term and long-term outcomes of STBI. TSP-1 may be a good prognostic biomarker of STBI.

Association of Plasma Thrombospondin-1 Level with Cardiovascular Disease and Mortality in Hemodialysis Patients.

Thrombospondin-1 (TSP-1) is known to be involved in the regulation of angiogenesis, inflammation, and vascular function. Clinical studies have demonstrated its correlation with peripheral artery disease, coronary artery disease, and pulmonary hypertension. In this study, we explored its potential roles in the background of end-stage renal disease (ESRD). A total of 140 ESRD outpatients (ages 61.0 ± 12.4 years) were prospectively followed for 34 ± 7 months. Their TSP-1 levels were analyzed from pre-hemodialysis blood sample. Cardiovascular survey included ankle- brachial index (ABI), echocardiography and Tl-201 dipyridamole single-photon emission computed tomography (SPECT). Plasma TSP-1 levels were higher in those patients with preexisting clinical evidence of cardiovascular disease (CVD) than those without (p = 0.002). TSP-1 concentrations were also correlated with ABI, left ventricular ejection fraction, and scar burden in SPECT. Stepwise logistic regression analysis revealed that TSP-1 level was independently associated with the presence of CVD, with an odds ratio of 1.38 [95% confidence interval (CI), 1.09-1.75, p = 0.008]. In survival analyses, 31 patients (22%) died during the follow-up, 16 (52%) arising from cardiovascular causes. Cox hazards analysis revealed that the patients with TSP-1 levels in the highest tertile had a 5.32- and 6.75-fold higher risk for all-cause and cardiovascular mortality than those in the lowest tertile. This predictive value for all-cause mortality still persisted after multivariate adjustment (hazard ratio, 8.71; 95% CI, 1.36-55.68; p = 0.02). This study hallmarks the association of elevated TSP-1 level with CVD and adverse outcome among hemodialysis patients. Thrombospondin-1; End-stage renal disease; Cardiovascular disease; Mortality.

Effect and Mechanism of Thrombospondin-1 on the Angiogenesis Potential in Human Endothelial Progenitor Cells: An In Vitro Study

ObjectiveCoronary collateral circulation plays a protective role in patients with coronary artery disease (CAD). We investigated whether thrombospondin-1(TSP-1) has an inhibitory effect on angiogenesis potential in endothelial progenitor cells(EPCs) and tested whether TSP-1 are altered in plasma of patients who had chronic total occlusion (CTO) in at least one coronary artery and with different collateral stages(according to Rentrop grading system).Methods and ResultsWe isolated early and late EPCs from human cord blood and investigated a dose-dependent effect of TSP-1 on their angiogenesis potential by Matrigel angiogenesis assay. We found that TSP-1 (5 µg/ml) inhibited early EPCs incorporation into tubules after pretreatment for 1, 6 and 12 hours, respectively (83.3±11.9 versus 50.0±10.1 per field for 1 hour,161.7±12.6 versus 124.0±14.4 for 6 hours, 118.3±12.6 versus 68.0±20.1 for 12 hours, p<0.05). TSP-1 also inhibited late EPCs tubule formation at 1 µg/ml (6653.4±422.0 µm/HPFversus 5552.8±136.0 µm/HPF, p<0.05), and the inhibition was further enhanced at 5 µg/ml (6653.4±422.0 µm/HPF versus 2118.6±915.0 µm/HPF p<0.01). To explore the mechanism involved, a small interfering RNA was used. In vitro, CD47 siRNA significantly attenuated TSP-1's inhibition of angiogenesis on late EPCs and similar results were obtained after functional blocking by anti-CD47 antibody. Then we investigated pathways downstream of CD47 and found TSP-1 regulated VEGF-induced VEGFR2 phosphorylation via CD47. Furthermore, we examined plasma TSP-1 levels in patients with CTO who developed different stages of collaterals and found a paradoxical higher level of TSP-1 in patients with good collaterals compared with bad ones (612.9±554.0 ng/ml versus 224.4±132.4 ng/ml, p<0.05).ConclusionTSP-1 inhibited angiogenesis potential of early and late EPCs in vitro. This inhibition may be regulated by TSP-1's interaction with CD47, resulting in down regulation of VEGFR2 phosphorylation. In patients with CTO, there may be a self-adjustment mechanism in bad collaterals which is shown as low level of angiogenesis inhibitor TSP-1, and thus favoring collateral formation.

Ramipril Sensitizes Platelets to Nitric Oxide: Implications for Therapy in High-Risk Patients

Using 2 sequential studies in HOPE (Heart Outcomes Prevention Evaluation) study-type patients, the aims of this study were: 1) to test the hypothesis that ramipril improves platelet nitric oxide (NO) responsiveness: and 2) to explore biochemical and physiological effects of ramipril in a cohort selected on the basis of platelet NO resistance. Ramipril prevents cardiovascular events, but the bases for these effects remain uncertain. NO resistance at both the platelet and vascular levels is present in a substantial proportion of patients with diabetes or ischemic heart disease and is an independent risk factor for cardiovascular events. Study 1 was a double-blind, randomized comparison of ramipril (10 mg) with placebo in a cohort of patients (n = 119) with ischemic heart disease or diabetes plus additional coronary risk factor(s), in which effects on platelet responsiveness to NO were compared. Study 2 was a subsequent short-term evaluation of the effects of ramipril in a cohort of subjects (n = 19) with impaired platelet NO responsiveness in whom additional mechanistic data were sought. In study 1, ramipril therapy increased platelet responsiveness to NO relative to the extent of aggregation (p < 0.001), but this effect occurred primarily in patients with severely impaired baseline NO responsiveness (n = 41). In study 2, ramipril also improved platelet NO responsiveness (p < 0.01), and this improvement was correlated directly with increased NO-stimulated platelet generation of cyclic guanosine monophosphate (p < 0.02) but not with changes in plasma thrombospondin-1 levels. Ramipril ameliorates platelet NO resistance in HOPE study-type patients, with associated increases in soluble guanylate cyclase responsiveness to NO. This effect is likely to contribute to treatment benefit and define patients in whom ramipril therapy is particularly effective.

Higher Plasma Thrombospondin-1 Levels in Patients With Coronary Artery Disease and Diabetes Mellitus

Background and ObjectivesThrombospondin-1 (TSP-1) is associated with atherosclerosis in animals with diabetes mellitus (DM). But, no study has investigated the role of TSP-1 in human atherosclerosis. This study investigated the relationship among plasma TSP-1 concentration, DM, and coronary artery disease (CAD).Subjects and MethodsThe study involved 374 consecutive subjects with suspected CAD, who had undergone coronary angiography to evaluate effort angina. Patients were divided into four groups as follows: DM(-) and CAD(-), DM(-) and CAD(+), DM(+) and CAD(-), and DM (+) and CAD(+).ResultsWe found that plasma TSP-1 levels were higher in patients with DM(+) and CAD(+) (n=103) than those in other patients (n=271) (p<0.01). A multivariate analysis showed that male gender {odds ratio (OR), 2.728; 95% confidence interval (CI), 1.035-7.187}, high density lipoprotein-cholesterol (OR, 0.925; 95% CI, 0.874-0.980), glycated hemoglobin (OR, 1.373; 95% CI, 1.037-1.817), and plasma TSP-1 (OR, 1.004; 95% CI, 1.000-1.008) levels were independently associated with the presence of CAD in patients with DM.ConclusionPlasma TSP-1 levels were higher in patients with DM(+) and CAD(+) than those in other patients, and plasma TSP-1 levels were independently associated with the presence of CAD in patients with DM. These findings show a possible link between human plasma TSP-1 concentration and CAD in patients with DM.

Endothelial‐derived thrombospondin‐1 promotes macrophage recruitment and apoptotic cell clearance

Rapid apoptotic cell engulfment is crucial for prevention of inflammation and autoimmune diseases and is conducted by special immunocompetent cells like macrophages or immature dendritic cells. We recently demonstrated that endothelial cells (ECs) also participate in apoptotic cell clearance. However, in contrast to conventional phagocytes they respond with an inflammatory phenotype. To further confirm these pro-inflammatory responses human ECs were exposed to apoptotic murine ECs and changes in thrombospondin-1 (TSP-1) expression and in activation of intracellular signalling cascades were determined by real-time qPCR, immunoblotting and immunocytochemistry. Human primary macrophages or monocytic lymphoma cells (U937) were incubated with conditioned supernatant of human ECs exposed to apoptotic cells and changes in activation, migration and phagocytosis were monitored. Finally, plasma levels of TSP-1 in patients with anti-neutrophil cytoplasmic antibody(ANCA)-associated vasculitis (AAV) were determined by ELISA. We provided evidence that apoptotic cells induce enhanced expression of TSP-1 in human ECs and that this increase in TSP-1 is mediated by the mitogen-activated protein kinases (MAPK) ERK1 and 2 and their upstream regulators MEK and B-Raf. We also showed that plasma TSP-1 levels are increased in patients with AAV. Finally, we showed that conditioned supernatant of ECs exposed to apoptotic cells induces pro-inflammatory responses in monocytes or U937 cells and demonstrated that increased TSP-1 expression enhances migration and facilitates engulfment of apoptotic cells by monocyte-derived macrophages or U937 cells. These findings suggest that under pathological conditions with high numbers of uncleared dying cells in the circulation endothelial-derived elevated TSP-1 level may serve as an attraction signal for phagocytes promoting enhanced recognition and clearance of apoptotic cells.

Severe Plasmodium Falciparum Malaria Is Associated with Circulating Ultra-Large Von Willebrand Multimers and ADAMTS13 Inhibition

Cytoadhesion of Plasmodium falciparum-infected erythrocytes (IE) to activated endothelial cell (EC) surfaces plays a key role in the pathophysiology of cerebral malaria. Moreover, recent evidence suggests that platelet adhesion and aggregation are critical in facilitating this cytoadhesion process. We have recently reported marked increased plasma VWF and VWF propeptide levels in severe P. falciparum infection, indicative of acute EC perturbation. Furthermore, plasma VWF:Ag levels in patients with malaria inversely correlated with platelet count, and plasma VWF propeptide levels correlated with other established biochemical markers of malaria severity, including plasma lactate. Nevertheless, it remains unclear whether VWF plays any direct role in mediating IE cytoadhesion, or whether the increased plasma levels of both VWF and propeptide merely serve as a marker of acute EC activation.To address this question, we collected plasma samples from a cohort of African children presenting with cerebral malaria (CM), or non-cerebral severe malaria (SM). In children with CM and SM, plasma VWF:Ag levels were significantly elevated (medians 3.1 and 3.4 IU/ml) as before. VWF collagen binding (VWF:CB) levels were also markedly increased (medians 7.6 and 7.0 IU/ml). Furthermore, the relative rise in VWF:CB was much greater, so that the ratio of CB:Ag was consistently increased. VWF multimer analysis demonstrated abnormal circulating ULVWF multimers in children with CM and SM, consistent with acute, regulated VWF secretion. To characterize mechanisms responsible for the markedly increased VWF:CB and circulating ULVWF in malarial plasma, we investigated ADAMTS13 antigen and activity levels in CM and SM plasma. Plasma ADAMTS13 activity levels (FRETS-VWF73 assay) and antigen levels were both significantly reduced (medians = 0.63 U/ml and 0.56 U/ml; p< 0.001) in children with CM and SM compared to controls. Classical mixing studies of malaria and normal plasma demonstrated no evidence of immediate ADAMTS13 inhibition. However, ADAMTS13 activity in normal plasma was significantly reduced (~60%) following 30 min incubation with malarial plasma (75%:25% mix). This inhibitory ability of malaria plasma was further confirmed by spiking malarial plasmas with recombinant human ADAMTS13. Significant time-dependent inhibition of FRETS-VWF73 activity was again observed in the plasmas of children with severe P. falciparum, but not in normal control plasmas. Potential inhibitors of ADAMTS13 in vivo include interleukin-6 (IL-6), thrombospondin-1 (TSP-1), thrombin and plasmin, free plasma haemoglobin, and reduced FVIII levels. Although plasma IL-6 levels were significantly elevated in children with either CM (mean 240 pg/ml; p<0.001) or SM (mean 217 pg/ml; p=0.01) compared to normal controls, levels did not approach those previously reported necessary to inhibit ADAMTS13 activity. Disseminated intravascular coagulation (DIC) is associated with enhanced thrombin generation, and consumption of FVIII, both of which can inhibit VWF proteolysis by ADAMTS13. However, in children with CM or SM respectively, we observed significantly increased plasma FVIII:C levels. Although intravascular haemolysis is also a recognised complication of malarial infection, we observed only minor increased plasma haemoglobin concentrations, again well below that previously described to significantly inhibit ADAMTS13 activity. Finally, in contrast to the increased plasma levels of IL-6 and FVIII:C, we found that plasma TSP-1 levels were not significantly elevated in children with either CM or SM compared to pooled normal plasma.In conclusion, we demonstrate that the presence of ULVWF multimers in the plasma of children with severe P. falciparum malaria is the result ofacute EC activation and release of ULVWF from WP bodies;significantly reduced plasma ADAMTS13 antigen levelsa circulating but unidentified inhibitor of human ADAMTS13 activity.In view of the critical role played by VWF in mediating platelet adhesion/aggregation, and the accumulating evidence suggesting that platelet adhesion/aggregation also facilitate cytoadhesion of IE, we propose a novel role for ULVWF multimers in the pathophysiology of severe P. falciparum malaria.

Circulating Angiogenic Cytokines in Patients with Advanced Non-Small Cell Lung Cancer: Correlation with Treatment Response and Survival

Tumor angiogenesis is stimulated by a pro-angiogenic shift in both inducers and inhibitors of endothelial growth. To study this shift, we measured serum and plasma levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), endostatin, and thrombospondin 1 (TSP1) in 21 advanced non-small cell lung cancer (NSCLC) patients and 46 healthy control subjects. In addition, we assessed the relevance of these levels to disease outcome. Cytokine levels were prospectively measured in plasma and serum by enzyme-linked immunosorbent assay at three times: before chemotherapy and at 1 and 12 weeks following initiation of chemotherapy. In NSCLC patients, serum VEGF levels (sVEGF) were elevated (p < 0.001), whereas serum and plasma TSP1 levels were lower (p = 0.012 and p = 0.004, respectively) than in healthy control subjects. Pretreatment plasma endostatin and serum bFGF levels were higher in NSCLC patients than in healthy controls (p = 0.05 and 0.01, respectively). Change in sVEGF at week 12 after initiation of chemotherapy correlated with response to therapy (p = 0.002). Patients with pretreatment sVEGF levels < 500 pg/mL had a median survival of 11 months, but those with sVEGF > 500 pg/mL had only a 6 months' median survival (p < 0.03). In NSCLC patients, VEGF levels are increased, whereas TSP1 levels are decreased, which may trigger and sustain tumor angiogenesis. High levels of serum VEGF at the time of presentation with NSCLC may predict worse survival.