Frequency of thrombocytopenia and heparin induced thrombocytopenia in patients receiving extracorporeal membrane oxygenation compared to cardiopulmonary bypass and the limited sensitivity of pre-test probability score

Objectives:To ascertain:i)the frequency of thrombocytopeniaand heparininducedthrombocytopenia (HIT), ii)positive predictive value (PPV) of the pre-test probability score (PTPS) in identifying HIT iii)clinical outcome of HITin adult patients receiving veno-venous (VV)-extracorporeal membraneoxygenation(ECMO)or veno-arterial (VA)-ECMO, comparedto cardiopulmonary bypass (CPB). Design: A single-centre, retrospective, observational cohort study from January 2016 to April 2018Setting: Tertiary referral centre for cardiac and respiratory failure Patients:Patients who received ECMOfor>48hrs or had CPB during specified period Interventions: None.Measurements and Main Results:Clinical and laboratory data were collected retrospectively. PTPS and HIT testing results were collected prospectively. Mean age (standard deviation) of the EMCO and CPB cohorts were 45.4 (±15.6) and 64.9 (±13), p< 0.00001.Median duration of CPB was 4.6 [2-16.5]hrs compared to 170.4[70-1008] hrson ECMO.Moderateand severethrombocytopenia were more common in ECMO compared to CPB throughout (p<0.0001).Thrombocytopenia increased in CPB patients on day2 but was 4normal in 83% compared to 42.3 % ofECMOpatients at day 10. Patients on ECMO also followed a similar pattern of platelet recoveryfollowing cessation of ECMO. The incidences of HIT in ECMO and CPB were 6.4% (19/298) and 0.6% (18/2998) respectivelyp<0.0001). There was no difference in prevalence of HIT in patients on VV-ECMO (9/156, 5.7%) vs VA-ECMO (11/142, 7.7%), p=0.81. The PPV of the PTPS in identifying HIT in patients post-CPB and on ECMO were 56.25% (18/32) and 25% (15/60) respectively. Mortalitywas not different with (6/19, 31.6%) or without (89/279, 32.2%) HIT in patients on ECMO,p=0.79. Conclusions Thrombocytopenia is already common at ECMO initiation. HIT is more frequent in both VV-and VA-ECMO compared to CPB. PPV of PTPSin identifying HIT was lower inECMO patients.HIT had no effect on mortality

Belgian clinical guidance on anticoagulation management in hospitalised and ambulatory patients with COVID-19

Objectives COVID-19 predisposes patients to thrombotic disease. The aim of this guidance document is to provide Belgian health-care workers with recommendations on anticoagulation management in COVID-19 positive patients. Methods These recommendations were based on current knowledge and a limited level of evidence. Results We formulated recommendations for the prophylaxis and treatment of COVID-related venous thromboembolism in ambulatory and hospitalised patients, as well as recommendations for the use of antithrombotic drugs in patients with prior indication for anticoagulation who develop COVID-19. Conclusions These recommendations represent an easy-to-use practical guidance that can be implemented in every Belgian hospital and be used by primary care physicians and gynaecologists. Of note, they are likely to evolve with increased knowledge of the disease and availability of data from ongoing clinical trials

The management of heart failure cardiogenic shock:an international RAND appropriateness panel

Background: Observational data suggest that the subset of patients with heart failure related CS (HF-CS) now predominate critical care admissions for CS. There are no dedicated HF-CS randomised control trials completed to date which reliably inform clinical practice or clinical guidelines. We sought to identify aspects of HF-CS care where both consensus and uncertainty may exist to guide clinical practice and future clinical trial design, with a specific focus on HF-CS due to acute decompensated chronic HF. Methods: A 16-person multi-disciplinary panel comprising of international experts was assembled. A modified RAND/University of California, Los Angeles, appropriateness methodology was used. A survey comprising of 34 statements was completed. Participants anonymously rated the appropriateness of each statement on a scale of 1 to 9 (1–3 as inappropriate, 4–6 as uncertain and as 7–9 appropriate). Results: Of the 34 statements, 20 were rated as appropriate and 14 were rated as inappropriate. Uncertainty existed across all three domains: the initial assessment and management of HF-CS; escalation to temporary Mechanical Circulatory Support (tMCS); and weaning from tMCS in HF-CS. Significant disagreement between experts (deemed present when the disagreement index exceeded 1) was only identified when deliberating the utility of thoracic ultrasound in the immediate management of HF-CS. Conclusion: This study has highlighted several areas of practice where large-scale prospective registries and clinical trials in the HF-CS population are urgently needed to reliably inform clinical practice and the synthesis of future societal HF-CS guidelines

PEAR1 is not a major susceptibility gene for cardiovascular disease in a Flemish population

Background: Platelet Endothelial Aggregation Receptor 1 (PEAR1), a membrane protein highly expressed in platelets and endothelial cells, plays a role in platelet contact-induced activation, sustained platelet aggregation and endothelial function. Previous reports implicate PEAR1 rs12041331 as a variant influencing risk in patients with coronary heart disease. We investigated whether genetic variation in PEAR1 predicts cardiovascular outcome in a white population. Methods: In 1938 participants enrolled in the Flemish Study on Environment, Genes and Health Outcomes (51.3% women; mean age 43.6years), we genotyped 9 tagging SNPs in PEAR1, measured baseline cardiovascular risk factors, and recorded Cardiovascular disease incidence. For SNPs, we contrasted cardiovascular disease incidence of minor-allele heterozygotes and homozygotes (variant) vs. major-allele homozygotes (reference) and for haplotypes carriers vs. non-carriers. In adjusted analyses, we accounted for family clusters and baseline covariables, including sex, age, body mass index, mean arterial pressure, the total-to-HDL cholesterol ratio, smoking and drinking, antihypertensive drug treatment, and history of cardiovascular disease and diabetes mellitus. Results: Over a median follow-up of 15.3years, 238 died and 181 experienced a major cardiovascular endpoint. The multivariable-adjusted hazard ratios of eight PEAR1 SNPs, including rs12566888, ranged from 0.87 to 1.07 (P 650.35) and from 0.78 to 1.30 (P 650.15), respectively. The hazard ratios of three haplotypes with frequency 6510% ranged from 0.93 to 1.11 (P 650.49) for mortality and from 0.84 to 1.03 (P 650.29) for a cardiovascular complications. These results were not influenced by intake of antiplatelet drugs, nonsteroidal anti-inflammatory drugs, or both (P-values for interaction 650.056). Conclusions: In a White population, we could not replicate previous reports from experimental studies or obtained in patients suggesting that PEAR1 might be a susceptibility gene for cardiovascular complications

A large retrospective assessment of voriconazole exposure in patients treated with extracorporeal membrane oxygenation

Background: Voriconazole is one of the first-line therapies for invasive pulmonary aspergillosis. Drug concentrations might be significantly influenced by the use of extracorporeal membrane oxygenation (ECMO). We aimed to assess the effect of ECMO on voriconazole exposure in a large patient population. Methods: Critically ill patients from eight centers in four countries treated with voriconazole during ECMO support were included in this retrospective study. Voriconazole concentrations were collected in a period on ECMO and before/after ECMO treatment. Multivariate analyses were performed to evaluate the effect of ECMO on voriconazole exposure and to assess the impact of possible saturation of the circuit’s binding sites over time. Results: Sixty-nine patients and 337 samples (190 during and 147 before/after ECMO) were analyzed. Subtherapeutic concentrations (<2 mg/L) were observed in 56% of the samples during ECMO and 39% without ECMO (p = 0.80). The median trough concentration, for a similar daily dose, was 2.4 (1.2–4.7) mg/L under ECMO and 2.5 (1.4–3.9) mg/L without ECMO (p = 0.58). Extensive inter-and intrasubject variability were observed. Neither ECMO nor squared day of ECMO (saturation) were retained as significant covariates on voriconazole exposure. Conclusions: No significant ECMO-effect was observed on voriconazole exposure. A large proportion of patients had voriconazole subtherapeutic concentrations

Rate and duration of hospitalisation for acute pulmonary embolism in the real-world clinical practice of different countries : Analysis from the RIETE registry

publishersversionPeer reviewe

Genetic Variation in the Platelet Endothelial Aggregation Receptor 1 Gene Results in Endothelial Dysfunction

We gratefully acknowledge our Amish liaisons and field workers and the extraordinary cooperation and support of the Amish community, without which these studies would not have been possible. We also acknowledge Dr. Alan Shuldiner for his impactful insights and guidance.Platelet Endothelial Aggregation Receptor 1 (PEAR1) is a newly identified membrane protein reported to be involved in multiple vascular and thrombotic processes. While most studies to date have focused on the effects of this receptor in platelets, PEAR1 is located in multiple tissues including the endothelium, where it is most highly expressed. Our first objective was to evaluate the role of PEAR1 in endothelial function by examining flow-mediated dilation of the brachial artery in 641 participants from the Heredity and Phenotype Intervention Heart Study. Our second objective was to further define the impact of PEAR1 on cardiovascular disease computationally through meta-analysis of 75,000 microarrays, yielding insights regarding PEAR1 function, and predictions of phenotypes and diseases affected by PEAR1 dysregulation. Based on the results of this meta-analysis we examined whether genetic variation in PEAR1 influences endothelial function using an ex vivo assay of endothelial cell migration. We observed a significant association between rs12041331 and flow-mediated dilation in participants of the Heredity and Phenotype Intervention Heart Study (P = 0.02). Meta-analysis results revealed that PEAR1 expression is highly correlated with several genes (e.g. ANG2, ACVRL1, ENG) and phenotypes (e.g. endothelial cell migration, angiogenesis) that are integral to endothelial function. Functional validation of these results revealed that PEAR1 rs12041331 is significantly associated with endothelial migration (P = 0.04). Our results suggest for the first time that genetic variation of PEAR1 is a significant determinant of endothelial function through pathways implicated in cardiovascular disease.Yeshttp://www.plosone.org/static/editorial#pee

'Refeeding a heart': an echocardiographic follow-up

status: publishe

A human platelet receptor protein microarray identifies the high affinity immunoglobulin E receptor subunit α (FcεR1α) as an activating platelet endothelium aggregation receptor 1 (PEAR1) ligand

Genome-wide association studies to identify loci responsible for platelet function and cardiovascular disease susceptibility have repeatedly identified polymorphisms linked to a gene encoding platelet endothelium aggregation receptor 1 (PEAR1), an “orphan” cell surface receptor that is activated to stabilize platelet aggregates. To investigate how PEAR1 signaling is initiated, we sought to identify its extracellular ligand by creating a protein microarray representing the secretome and receptor repertoire of the human platelet. Using an avid soluble recombinant PEAR1 protein and a systematic screening assay designed to detect extracellular interactions, we identified the high affinity immunoglobulin E (IgE) receptor subunit α (FcεR1α) as a PEAR1 ligand. FcεR1α and PEAR1 directly interacted through their membrane-proximal Ig-like and 13th epidermal growth factor domains with a relatively strong affinity (K(D) ∼ 30 nm). Precomplexing FcεR1α with IgE potently inhibited the FcεR1α-PEAR1 interaction, and this was relieved by the anti-IgE therapeutic omalizumab. Oligomerized FcεR1α potentiated platelet aggregation and led to PEAR1 phosphorylation, an effect that was also inhibited by IgE. These findings demonstrate how a protein microarray resource can be used to gain important insight into the function of platelet receptors and provide a mechanistic basis for the initiation of PEAR1 signaling in platelet aggregation