Endothelial Dysfunction Criteria in Critically Ill Children: The PODIUM Consensus Conference

OBJECTIVES To review, analyze, and synthesize the literature on endothelial dysfunction in critically ill children with multiple organ dysfunction syndrome and to develop a consensus biomarker-based definition and diagnostic criteria. DATA SOURCES Electronic searches of PubMed and Embase were conducted from January 1992 to January 2020, using a combination of medical subject heading terms and key words to define concepts of endothelial dysfunction, pediatric critical illness, and outcomes. STUDY SELECTION Studies were included if they evaluated critically ill children with endothelial dysfunction, evaluated performance characteristics of assessment/scoring tools to screen for endothelial dysfunction, and assessed outcomes related to mortality, functional status, organ-specific outcomes, or other patient-centered outcomes. Studies of adults or premature infants (≤36 weeks gestational age), animal studies, reviews or commentaries, case series with sample size ≤10, and non-English language studies with the inability to determine eligibility criteria were excluded. DATA EXTRACTION Data were abstracted from each eligible study into a standard data extraction form along with risk of bias assessment. DATA SYNTHESIS We identified 62 studies involving 84 assessments of endothelial derived biomarkers indirectly linked to endothelial functions including leukocyte recruitment, inflammation, coagulation, and permeability. Nearly all biomarkers studied lacked specificity for vascular segment and organ systems. Quality assessment scores for the collected literature were low. CONCLUSIONS The Endothelial Subgroup concludes that there exists no single or combination of biomarkers to diagnose endothelial dysfunction in pediatric multiple organ dysfunction syndrome. Future research should focus on biomarkers more directly linked to endothelial functions and with specificity for vascular segment and organ systems.

The algorithm of decision-making in administration of anticoagulant therapy due to COVID‑19. Review

There is a hypothesis that on its late complicated stages, coronavirus disease of 2019 (COVID‑19) represents an endothelial disease. According to Peter’s Libbi data (2020), the endothelial monolayer measures up to 7000 m2 in surface area. The endothelial functions include anticoagulant, antiplatelet, anti‑inflammatory, vasomotion, and structure. The aim of the review was to figure out COVID‑19 logistics from the standpoint of its pathogenesis, in particular its thrombotic complications, to summarize data on the choice of an anticoagulant, its dose and duration of use. COVID‑19 is a new disease with the lack of evidence‑based data, however, its per‑syndrome analysis results in conclusion that the most part of acute and post‑COVID complications refer to thromboembolic ones. According to the recommendations of the European Society of Cardiology on diagnostic and treatment of thromboembolism, the need for thromboembolism prevention is defined in case of respiratory failure, installed intravenous catheters, infection (specifically pneumonia), bed rest, elderly age, etc. The adherence to evidence‑based recommendations will allow one to administer rational anticoagulation therapy without harm to a patient. It concerns both patients, who are on anticoagulant therapy at hospital admission, and those who requires its new administration. The following questions are mostly frequent arising in doctors: How one should manage a patient with active bleeding, or platelet levels < 25 · 109/ L, or with congenital abnormality of coagulation? What types of blood chemistry should be considered when administering anticoagulant? What therapy should be administered at discharge? Compliance with clear anticoagulation algorithms will prevent thromboembolic complications, further damage to organs and systems, and significant bleeding.

THE RELATIONSHIP BETWEEN INFLAMMATION MARKERS AND MAGNESIUM/PHOSPHATE RATIO WITH ENDOTEL FUNCTION IN PERIPHERAL ARTERY DISEASE

Objective: In our study, it was aimed to evaluate the relationship between neutrophil/lymphocyte, monocyte/high-density lipoprotein and magnesium/phosphate ratios with endothelial functions in patients with peripheral artery disease. Methods: Sixty patients followed up with peripheral arterial disease were included in this study. Endothelial functions of the patients were evaluated by flow-mediated vasodilation test. Pearson correlation analysis was used to evaluate the relationship between magnesium/phosphate, neutrophil/lymphocyte, monocyte/high-density lipoprotein ratios with percent change in flow-mediated vasodilation. Results: 48.3% of the participants are male and 51.7% are female. The mean age of the patients were 66.85±11.08 years. The mean radial artery basal diameter was 0.24±0.02 cm in the flow-mediated vasodilatation test and after the test the mean radial artery diameter was 0.27±0.02 cm(p<0.001). In the flow-mediated dilatation test predicting endothelial functions, the percentage change in arterial diameter was positively correlated with the Magnesium/phosphate ratio (r=-0.326, p=0.011), and negatively correlated with the Neutrophil/lymphocyte ratio and monocyte/high-density lipoprotein ratio (respectively r= -0.411, p=0.001; r=-0.530, p=0.001). Conclusion: Magnesium/phosphate ratio, neutrophil/lymphocyte ratio and monocyte/high-density lipoprotein ratio can be used to predict endothelial dysfunction in patients with peripheral artery disease.

Leukocyte adhesion is governed by endolysosomal two pore channel 2 (TPC2)

In response to pro-inflammatory challenges including pathogenic attack and tissue damage, the endothelial cell surface is rearranged to present leukocyte-engaging cell surface receptors. The initial contact needed for leukocyte tethering and rolling is mediated via adhesion demand-driven exocytosis of Weibel-Palade bodies (WPB) that contain the leukocyte receptor P-selectin together with the stabilizing co-factor CD63. We found that diminished expression of the endolysosomal non-selective cation channel TPC2 or inhibition of TPC2-mediated Ca2+-release via trans-Ned 19 led to reduced endolysosomal Ca2+ efflux, and blocked transfer of CD63 from late endosomes/lysosomes (LEL) to WPB, and a concomitant loss of P-selectin on the endothelial cell surface. Accordingly, P-selectin-mediated leukocyte recruitment to trans-Ned 19-treated HUVEC under flow was significantly reduced without disturbing VWF exocytosis. Our findings establish the endolysosome-related TPC2 Ca2+ channel as a key element in the maintenance of proper endothelial functions and a potential pharmacological target in the control of inflammatory leukocyte recruitment.

The Evaluation of Flow Mediated Dilatation and Blood Parameters in Raynaud Phenomenon

Introduction: Raynaud phenomenon (RP) is a multifactorial disorder. If any underlying disease cannot be detected responsible for RP then it considered as primary RP (pRP). We aimed to investigate the differences between laboratory markers and impaired endothelial function in pRP. Material and Methods: Forty-two pRP patients included as study and control groups were created from 30 healthy individuals. The endothelial function was evaluated with flow-mediated dilatation (FMD) of the brachial artery. The blood samples were obtained both groups and white blood cell [WBC], hemoglobin, platelet, mean platelet volume [MPV], creatinine, alanine aminotransferase [ALT], aspartate aminotransferase[AST], D-dimer, fibrinogen, albumin, fibrinogen to albumin ratio [FAR], Neutrophil to Lymphocyte ratio [NLR], D-dimer to albumin ratio [DDAR] and monocyte chemo-attractant protein-1 [MCP-1]. Obtained blood parameters and FMD values were compared between groups. Results: The groups were found as similar in regards to age, gender, smoking history (p<0.05). There was no difference between the two groups in regards to hemoglobin, platelet, MPV, creatinine, ALT, D-dimer, albumin, FAR, NLR, DDAR levels (p<0.05). AST levels were slightly higher in pRP group (p=0.027). Markedly increased WBC, fibrinogen, MPV and MCP-1 values were detected in pRP group (p=0.000). Additionally, higher abnormal FMD responses were detected in pRP group (p=0.000). There was a direct correlation between abnormal FMD response and serum MCP-1 values in patients with pRP (R: 0.308, R2: 0.095, p: 0.044). Conclusion: It seems to be that MCP-1 levels are higher in patients with pRP and increased values of MCP-1 levels seem to be related to impaired endothelial functions

Is the Importance of Magnesium in Chronic Kidney Disease Underappreciated?

Magnesium (Mg) is one of the most important cations in the organism, essential for regulating vascular tone, cardiac rhythm, and endothelial functions. In patients with advanced stage chronic kidney disease (CKD) Mg deficit was associated in various studies with vascular calcifications and increased cardiovascular morbidity and mortality. Patients with CKD frequently have hyperparathyroidism, parathormone (PTH) being an important risk factor for vascular calcifications. Increased serum Mg levels inhibit PTH secretion and stimulate left ventricular hypertrophy, while low serum Mg levels stimulate PTH secretion. Correcting Mg de deficiency results in reduced cardiovascular mortality in these patients.