Harmonizing Definitions for Diagnostic Criteria and Prognostic Assessment of Transplantation-Associated Thrombotic Microangiopathy: A Report on Behalf of the European Society for Blood and Marrow Transplantation, American Society for Transplantation and Cellular Therapy, Asia-Pacific Blood and Marrow Transplantation Group, and Center for International Blood and Marrow Transplant Research DOI Creative Commons
Michelle Long Schoettler, Enric Carreras, Byung‐Sik Cho

et al.

Transplantation and Cellular Therapy, Journal Year: 2022, Volume and Issue: 29(3), P. 151 - 163

Published: Nov. 25, 2022

Transplantation-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized complication of hematopoietic cell transplantation (HCT) associated with significant morbidity and mortality. However, TA-TMA a clinical diagnosis, multiple criteria have been proposed without universal application. Although some patients self-resolving disease, others progress to multiorgan failure and/or death. Poor prognostic features also are not uniformly accepted. The lack harmonization diagnostic markers has precluded multi-institutional studies better understand incidence outcomes. Even current interventional trials use different criteria, making it challenging interpret the data. To address this urgent need, American Society for Transplantation Cellular Therapy, Center International Bone Marrow Transplant Research, Asia-Pacific Blood Transplantation, European nominated representatives expert panel tasked reaching consensus on criteria. reviewed literature, generated statements regarding using Delphi method, identified future directions investigation. Consensus was reached 4 key concepts: (1) can be diagnosed laboratory or tissue biopsy kidney gastrointestinal tissue; however, required; (2) modified Jodele additional definitions anemia thrombocytopenia. when ≥4 following 7 occur twice within 14 days: anemia, defined as achieve transfusion independence despite neutrophil engraftment; hemoglobin decline by ≥1 g/dL new-onset dependence; thrombocytopenia, platelet engraftment, higher-than-expected needs, refractory transfusions, ≥50% reduction in baseline count after full lactate dehydrogenase (LDH) exceeding upper limit normal (ULN); schistocytes; hypertension; soluble C5b-9 (sC5b-9) ULN; proteinuria (≥1 mg/mg random urine protein-to-creatinine ratio [rUPCR]); (3) any at increased risk nonrelapse mortality should stratified high-risk TA-TMA: elevated sC5b-9, LDH ≥2 times ULN, rUPCR mg/mg, dysfunction, concurrent grade II-IV acute graft-versus-host disease (GVHD), infection (bacterial viral); (4) all allogeneic pediatric autologous HCT recipients neuroblastoma screened weekly during first 100 days post-HCT. Patients risk-stratified, those offered participation trial TA-TMA-directed therapy if available. We propose that these stratification used data registries, prospective studies, practice across international settings. This will facilitate investigation populations diverse race, ethnicity, age, indications, characteristics. As widely used, we expect continued refinement necessary. Efforts identify more specific biomarkers top priority field. Finally, impact treatment, particularly setting highly morbid complications, such steroid-refractory GVHD infection, critically needed.

Language: Английский

Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination DOI Open Access
Nina Haagenrud Schultz,

Ingvild Hausberg Sørvoll,

Annika E. Michelsen

et al.

New England Journal of Medicine, Journal Year: 2021, Volume and Issue: 384(22), P. 2124 - 2130

Published: April 9, 2021

We report findings in five patients who presented with venous thrombosis and thrombocytopenia 7 to 10 days after receiving the first dose of ChAdOx1 nCoV-19 adenoviral vector vaccine against coronavirus disease 2019 (Covid-19). The were health care workers 32 54 years age. All had high levels antibodies platelet factor 4-polyanion complexes; however, they no previous exposure heparin. Because cases occurred a population more than 130,000 vaccinated persons, we propose that represent rare vaccine-related variant spontaneous heparin-induced refer as vaccine-induced immune thrombotic thrombocytopenia.

Language: Английский

Citations

1387
The COVID-19 puzzle: deciphering pathophysiology and phenotypes of a new disease entity DOI Creative Commons
Marcin F. Osuchowski, Martin Sebastian Winkler, Tomasz Skirecki

et al.

The Lancet Respiratory Medicine, Journal Year: 2021, Volume and Issue: 9(6), P. 622 - 642

Published: May 7, 2021

The zoonotic SARS-CoV-2 virus that causes COVID-19 continues to spread worldwide, with devastating consequences. While the medical community has gained insight into epidemiology of COVID-19, important questions remain about clinical complexities and underlying mechanisms disease phenotypes. Severe most commonly involves respiratory manifestations, although other systems are also affected, acute is often followed by protracted complications. Such complex manifestations suggest dysregulates host response, triggering wide-ranging immuno-inflammatory, thrombotic, parenchymal derangements. We review intricacies pathophysiology, its various phenotypes, anti-SARS-CoV-2 response at humoral cellular levels. Some similarities exist between failure origins, but evidence for many distinctive mechanistic features indicates constitutes a new entity, emerging data suggesting involvement an endotheliopathy-centred pathophysiology. Further research, combining basic studies, needed advance understanding pathophysiological characterise immuno-inflammatory derangements across range phenotypes enable optimum care patients COVID-19.

Language: Английский

Citations

479
Systemic complement activation is associated with respiratory failure in COVID-19 hospitalized patients DOI Creative Commons
Jan Cato Holter, Søren Erik Pischke, Eline de Boer

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2020, Volume and Issue: 117(40), P. 25018 - 25025

Published: Sept. 17, 2020

Significance The new SARS-CoV-2 pandemic leads to COVID-19 with respiratory failure, substantial morbidity, and significant mortality. Overactivation of the innate immune response is postulated trigger this detrimental process. complement system a key player in immunity. Despite few reports local activation, there lack evidence that degree systemic activation occurs early patients, whether associated failure. This study shows number products are systemically, consistently, long-lastingly increased from admission during hospital stay. Notably, terminal sC5b-9 complex was Thus, inhibition an attractive therapeutic approach for treatment COVD-19.

Language: Английский

Citations

377
Understanding COVID-19-associated coagulopathy DOI Open Access
Edward M. Conway, Nigel Mackman, Ronald Q. Warren

et al.

Nature reviews. Immunology, Journal Year: 2022, Volume and Issue: 22(10), P. 639 - 649

Published: Aug. 5, 2022

Language: Английский

Citations

256
Current and novel biomarkers of thrombotic risk in COVID-19: a Consensus Statement from the International COVID-19 Thrombosis Biomarkers Colloquium DOI Open Access
Diana A. Gorog, Robert F. Storey, Paul A. Gurbel

et al.

Nature Reviews Cardiology, Journal Year: 2022, Volume and Issue: 19(7), P. 475 - 495

Published: Jan. 13, 2022

Language: Английский

Citations

254
The state of complement in COVID-19 DOI Open Access
Behdad Afzali, Marina Noris, Bart N. Lambrecht

et al.

Nature reviews. Immunology, Journal Year: 2021, Volume and Issue: 22(2), P. 77 - 84

Published: Dec. 15, 2021

Language: Английский

Citations

229
Increased complement activation is a distinctive feature of severe SARS-CoV-2 infection DOI Creative Commons
Lina Ma, Sanjaya Kumar Sahu, Marlene Cano

et al.

Science Immunology, Journal Year: 2021, Volume and Issue: 6(59)

Published: May 13, 2021

Complement activation has been implicated in the pathogenesis of severe SARS-CoV-2 infection. However, it remains to be determined whether increased complement is a broad indicator critical illness (and thus, no different COVID-19). It also unclear which pathways are contributing COVID-19, and if associated with certain features infection, such as endothelial injury hypercoagulability. To address these questions, we investigated plasma from patients COVID-19 prospectively enrolled at two tertiary care centers: Washington University School Medicine (n=134) Yale (n=49). We compared our non-COVID cohorts: (a) hospitalized influenza (n=54), (b) admitted intensive unit (ICU) acute respiratory failure requiring invasive mechanical ventilation (IMV, n=22). demonstrate that circulating markers elevated those non-COVID-19 failure. Further, results facilitate distinguishing who higher risk worse outcomes ICU admission, or IMV. Moreover, indicate enhanced alternative pathway most prevalent (i.e., angiopoietin-2) well hypercoagulability thrombomodulin von Willebrand factor). Our findings identify distinctive feature provide specific targets may utilized for prognostication, drug discovery personalized clinical trials.

Language: Английский

Citations

198
Immune dysregulation and immunopathology induced by SARS-CoV-2 and related coronaviruses — are we our own worst enemy? DOI Creative Commons
Lok-Yin Roy Wong, Stanley Perlman

Nature reviews. Immunology, Journal Year: 2021, Volume and Issue: 22(1), P. 47 - 56

Published: Nov. 26, 2021

Human coronaviruses cause a wide spectrum of disease, ranging from mild common colds to acute respiratory distress syndrome and death. Three highly pathogenic human — severe coronavirus (SARS-CoV), Middle East SARS-CoV-2 have illustrated the epidemic pandemic potential coronaviruses, better understanding their disease-causing mechanisms is urgently needed for rational design therapeutics. Analyses patients revealed marked dysregulation immune system in cases infection, there ample evidence that aberrant responses are typified by impaired induction interferons, exuberant inflammatory delayed adaptive responses. In addition, various viral proteins been shown impair interferon signalling induce inflammasome activation. This suggests disease associated with mediated both dysregulated host active interference. Here we discuss our current involved each these scenarios. this Perspective, Lok-Yin Roy Wong Stanley Perlman consider how 2 (SARS-CoV-2) related able drive immunopathology. They provide an overview coronavirus-derived molecules interfere key innate responses, including pathways complement, NF-κB activation, as well activation immunity.

Language: Английский

Citations

164
Innate immunological pathways in COVID-19 pathogenesis DOI
Søren R. Paludan, Trine H. Mogensen

Science Immunology, Journal Year: 2022, Volume and Issue: 7(67)

Published: Jan. 7, 2022

Coronavirus disease 2019 (COVID-19) is a characterized by profound dysregulation of the innate immune system. This knowledge has emerged from large body single-cell omics studies patients with COVID-19, which have provided one most detailed cellular atlases human ever. However, we are only beginning to understand immunological pathways that govern host defense and immunopathology in COVID-19. In this review, discuss emerging understanding how SARS-CoV-2 host-derived molecules activate specific pattern recognition receptors elicit protective interferon responses pathological cytokine responses, particular focus on acute infection lung pathophysiology critical addition, these modulated virus-host interactions stress-sensing pathways. In-depth mechanisms will likely uncover molecular targets for treatment COVID-19 other viral infections. it reveal fine balance between beneficial versus causing responses.

Language: Английский

Citations

164
Endothelium Infection and Dysregulation by SARS-CoV-2: Evidence and Caveats in COVID-19 DOI Creative Commons
I Bernard, Daniel Limonta, Lara K. Mahal

et al.

Viruses, Journal Year: 2020, Volume and Issue: 13(1), P. 29 - 29

Published: Dec. 26, 2020

The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by the acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) poses a persistent threat to global public health. Although primarily illness, extrapulmonary manifestations COVID-19 include gastrointestinal, cardiovascular, renal and neurological diseases. Recent studies suggest that dysfunction endothelium during may exacerbate these deleterious events inciting inflammatory microvascular thrombotic processes. controversial, there is evidence SARS-CoV-2 infect endothelial cells binding angiotensin-converting enzyme 2 (ACE2) cellular receptor using viral Spike protein. In this review, we explore current insights into relationship between infection, due ACE2 downregulation, pulmonary extra-pulmonary immunothrombotic complications in severe COVID-19. We also discuss preclinical clinical development therapeutic agents targeting SARS-CoV-2-mediated dysfunction. Finally, present replication primary human lung cardiac cells. Accordingly, striving understand parameters lead patients, it important consider how direct infection contribute process.

Language: Английский

Citations

160