Vascular endothelial growth factor is an important determinant of sepsis morbidity and mortality

Sepsis, the systemic inflammatory response to infection, is a leading cause of morbidity and mortality. The mechanisms of sepsis pathophysiology remain obscure but are likely to involve a complex interplay between mediators of the inflammatory and coagulation pathways. An improved understanding of these mechanisms should provide an important foundation for developing novel therapies. In this study, we show that sepsis is associated with a time-dependent increase in circulating levels of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) in animal and human models of sepsis. Adenovirus-mediated overexpression of soluble Flt-1 (sFlt-1) in a mouse model of endotoxemia attenuated the rise in VEGF and PlGF levels and blocked the effect of endotoxemia on cardiac function, vascular permeability, and mortality. Similarly, in a cecal ligation puncture (CLP) model, adenovirus–sFlt-1 protected against cardiac dysfunction and mortality. When administered in a therapeutic regimen beginning 1 h after the onset of endotoxemia or CLP, sFlt peptide resulted in marked improvement in cardiac physiology and survival. Systemic administration of antibodies against the transmembrane receptor Flk-1 but not Flt-1 protected against sepsis mortality. Adenovirus-mediated overexpression of VEGF but not PlGF exacerbated the lipopolysaccharide-mediated toxic effects. Together, these data support a pathophysiological role for VEGF in mediating the sepsis phenotype

Angiopoietin-1 and angiopoietin-2 as clinically informative prognostic biomarkers of morbidity and mortality in severe sepsis.

OBJECTIVE: To determine the utility of angiopoietin-1 and angiopoietin-2 as potentially novel biomarkers of morbidity and mortality in patients with severe sepsis. DESIGN: Multicenter longitudinal cohort study. SETTING: Three tertiary hospital intensive care units in Hamilton, Ontario, Canada. PATIENTS: A total of 70 patients with severe sepsis were enrolled within 24 hrs of meeting the inclusion criteria for severe sepsis and followed until day 28, hospital discharge, or death. INTERVENTIONS: Clinical data and plasma samples were obtained at intensive care unit admission for all 70 patients and then daily for 1 wk and weekly thereafter for a subset of 43 patients. Levels of angiopoietin-1 and angiopoietin-2 in stored plasma samples were measured and compared with clinical characteristics, including the primary outcomes of 28-day mortality and morbidity measured by the Multiple Organ Dysfunction score. MEASUREMENTS AND MAIN RESULTS: Lower angiopoietin-1 plasma levels (≤ 5.5 ng/mL) at admission were associated with increased likelihood of death (relative risk 0.49 [95% confidence interval of 0.25-0.98], p = .046). Lower angiopoietin-1 levels remained a significant predictor of 28-day mortality in a multiple logistic regression model (adjusted odds ratio of 0.282 [95% confidence interval of 0.086-0.93], p = .037). Analysis of serial data using linear mixed models confirmed that sepsis survivors had higher levels of angiopoietin-1 (p = .012) and lower daily levels of angiopoietin-2 (p = .022) than nonsurvivors. Furthermore, survivors had higher peak angiopoietin-1 levels (median 13 vs. 10 ng/mL, p = .019) and lower nadir angiopoietin-2 levels (median 2.8 vs. 6.2 ng/mL, p = .013) than nonsurvivors. A score incorporating angiopoietin-1 and angiopoietin-2 and three other markers of endothelial activation discriminated with high accuracy between fatal and nonfatal cases (c-index of 0.80 [95% confidence interval of 0.69-0.90], p < .001). Plasma levels of angiopoietin-2 correlated with clinical markers of organ dysfunction and molecular markers of endothelial cell activation. CONCLUSIONS: Angiopoietin-1 levels at admission and both angiopoietin-1 and angiopoietin-2 levels measured serially correlated with 28-day mortality in severe sepsis. Angiopoietin-2 levels also correlated with organ dysfunction/injury and a validated clinical sepsis score. These results suggest the use of angiopoietins as clinically informative biomarkers of disease severity and patient outcome in severe sepsis

Megakaryocyte apoptosis in immune thrombocytopenia

The mechanisms of platelet underproduction in immune thrombocytopenia (ITP) remain unknown. While the number of megakaryocytes is normal or increased in ITP bone marrow, further studies of megakaryocyte integrity are needed. Megakaryocytes are responsible for the production of platelets in the bone marrow, and they are possible targets of immune-mediated injury in ITP. Since the biological process of megakaryocyte apoptosis impacts platelet production, we investigated megakaryocyte DNA fragmentation as a marker of apoptosis from ITP bone marrow biopsies. Archived bone marrow biopsy specimens from ITP patients, bone marrow specimens from controls with normal platelet counts, and bone marrow specimens from thrombocytopenic controls with myelodysplastic syndrome (MDS) were evaluated. Sections were stained with anti-CD61 for megakaryocyte enumeration, and terminal deoxynucleotidyl transferase dUTP nick-end labeling was used as an apoptotic indicator. In ITP patients, megakaryocyte apoptosis was reduced compared to nonthrombocytopenic controls. Megakaryocyte apoptosis was similarly reduced in thrombocytopenic patients with MDS. These results suggest a link between megakaryocyte apoptosis and platelet production