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Consensus on the standardization of terminology in thrombotic thrombocytopenic purpura and related thrombotic microangiopathies. Accepted ArticleThis article is protected by copyright. All rights reserved. Running title: Terminology in TTP and TMAsKey words: ADAMTS-13 protein, human; thrombocytopenia; diagnosis, differential; thrombotic microangiopathy; thrombotic thrombocytopenic purpura Essentials• An international collaboration provides a consensus for clinical definitions.• This concerns thrombotic microangiopathies and thrombotic thrombocytopenic purpura (TTP).• The consensus defines diagnosis, disease monitoring and response to treatment.• Requirements for ADAMTS-13 are given. Abstract:Background Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are two important acute conditions to diagnose. Thrombotic Microangiopathy is a broad pathophysiological process that leads to microangiopathic hemolytic anemia, thrombocytopenia and involves capillary and small vessel platelet aggregates. The most common cause being disseminated intravascular coagulation (DIC), which may be differentiated by abnormal Accepted ArticleThis article is protected by copyright. All rights reserved. IntroductionThe elucidation of the pathophysiology of TTP and HUS, in the past 20 years, has transformed our understanding of the phenotypes, genotypes and therapies for these life-threatening conditions. Work on standardization has been addressed [1], but this document aims to develop robust criteria for future clinical use, studies and trials.Clinical and pathophysiologic features of TTP, atypical Hemolytic Uremic Syndrome (aHUS) and disorders with similar presentations, their investigation and subsequent management vary. This consensus document aims to rationalize and standardize definitions. Conditions often included in the initial differential diagnosis of TTP are discussed. Definitions for remission, refractory and relapsing disease are defined.ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) assays are central to diagnosis and are discussed. We therefore also describe the minimum requirements for validation of current and future assays. Methods:The development of this document involved key international, primarily clinical, experts in TTP and related TMAs. Accepted ArticleThis article is protected by copyright. All rights reserved.Hemostasis (ISTH) and American Society of Hematology (ASH) and all versions of the document have been reviewed and edited by the authors. Articles were identified by a computer-assisted search of the literature published in English using the National Library of Medicine PubMed database. The authors also undertook a focused review of the available literature. Where there was a lack of robust evidence, the international working group concluded a consensus-based approach was preferable. The conclusions are relevant to both children and adults. Thrombotic MicroangiopathyThe term TMA is a pathological term used to describe occlusive micro...

The efficacy of convalescent plasma for coronavirus disease 2019 (COVID-19) is unclear. Although most randomized controlled trials have shown negative results, uncontrolled studies have suggested that the antibody content could influence patient outcomes. We conducted an open-label, randomized controlled trial of convalescent plasma for adults with COVID-19 receiving oxygen within 12 d of respiratory symptom onset (NCT04348656). Patients were allocated 2:1 to 500 ml of convalescent plasma or standard of care. The composite primary outcome was intubation or death by 30 d. Exploratory analyses of the effect of convalescent plasma antibodies on the primary outcome was assessed by logistic regression. The trial was terminated at 78% of planned enrollment after meeting stopping criteria for futility. In total, 940 patients were randomized, and 921 patients were included in the intention-to-treat analysis. Intubation or death occurred in 199/614 (32.4%) patients in the convalescent plasma arm and 86/307 (28.0%) patients in the standard of care arm—relative risk (RR) = 1.16 (95% confidence interval (CI) 0.94–1.43, P = 0.18). Patients in the convalescent plasma arm had more serious adverse events (33.4% versus 26.4%; RR = 1.27, 95% CI 1.02–1.57, P = 0.034). The antibody content significantly modulated the therapeutic effect of convalescent plasma. In multivariate analysis, each standardized log increase in neutralization or antibody-dependent cellular cytotoxicity independently reduced the potential harmful effect of plasma (odds ratio (OR) = 0.74, 95% CI 0.57–0.95 and OR = 0.66, 95% CI 0.50–0.87, respectively), whereas IgG against the full transmembrane spike protein increased it (OR = 1.53, 95% CI 1.14–2.05). Convalescent plasma did not reduce the risk of intubation or death at 30 d in hospitalized patients with COVID-19. Transfusion of convalescent plasma with unfavorable antibody profiles could be associated with worse clinical outcomes compared to standard care.

Approximately five decades ago, alloimmunization to human leukocyte antigens (HLA) and platelet refractoriness were recognized as potentially serious complications of platelet transfusions. The mechanisms that result in stimulating immunity against blood products are still incompletely understood but are related to both the composition of the donor product transfused and the immune status of the recipient. Based on murine studies of platelet immunity, platelets are inherently immunogenic and there are at least two independent levels of immunoregulation against platelet transfusions. The first level resides within the recipient and is related to antigen processing/presentation events and CD8+ T cell-mediated immunosuppression. The second level relates to the donor product and includes donor antigen presenting cells (APC) levels as well as age-induced changes in donor APC and/or platelets. Implementation of pre-storage leukoreduction of cellular blood components led to a marked reduction in platelet alloimmunization and its dreaded complication, platelet refractoriness. Platelet refractoriness is usually managed by transfusion of matched platelets, selected according to one of the many published methods. It is unclear which of these methods is superior, and given the difficulty of obtaining a perfectly matched product, perhaps the most logical approach is to use a combination of selection strategies. This review discusses the various aspects of platelet alloimmunization and the clinical consequences that may result. It highlights how animal studies have shed light on the immune mechanisms responsible for allogeneic platelet immunity and immunomodulation and reviews relevant literature on clinical and laboratory manifestations of immune platelet refractoriness.

IMPORTANCE Excessive bleeding is a common complication of cardiac surgery. An important cause of bleeding is acquired hypofibrinogenemia (fibrinogen level <1.5-2.0 g/L), for which guidelines recommend fibrinogen replacement with cryoprecipitate or fibrinogen concentrate. The 2 products have important differences, but comparative clinical data are lacking.OBJECTIVE To determine if fibrinogen concentrate is noninferior to cryoprecipitate for treatment of bleeding related to hypofibrinogenemia after cardiac surgery. DESIGN, SETTING, AND PARTICIPANTSRandomized clinical trial at 11 Canadian hospitals enrolling adult patients experiencing clinically significant bleeding and hypofibrinogenemia after cardiac surgery (from February 10, 2017, to November 1, 2018). Final 28-day follow-up visit was completed on November 28, 2018.INTERVENTIONS Fibrinogen concentrate (4 g; n = 415) or cryoprecipitate (10 units; n = 412) for each ordered dose within 24 hours after cardiopulmonary bypass. MAIN OUTCOMES AND MEASURESPrimary outcome was blood components (red blood cells, platelets, plasma) administered during 24 hours post bypass. A 2-sample, 1-sided test for the ratio of the mean number of units was conducted to evaluate noninferiority (threshold for noninferiority ratio, <1.2). RESULTSOf 827 randomized patients, 735 (372 fibrinogen concentrate, 363 cryoprecipitate) were treated and included in the primary analysis (median age, 64 [interquartile range, 53-72] years; 30% women; 72% underwent complex operations; 95% moderate to severe bleeding; and pretreatment fibrinogen level, 1.6 [interquartile range, 1.3-1.9] g/L). The trial met the a priori stopping criterion for noninferiority at the interim analysis after 827 of planned 1200 patients were randomized. Mean 24-hour postbypass allogeneic transfusions were 16.3 (95% CI, 14.9 to 17.8) units in the fibrinogen concentrate group and 17.0 (95% CI, 15.6 to 18.6) units in the cryoprecipitate group (ratio, 0.96 [1-sided 97.5% CI, −ϱ to 1.09; P < .001 for noninferiority] [2-sided 95% CI, 0.84 to 1.09; P = .50 for superiority]). Thromboembolic events occurred in 26 patients (7.0%) in the fibrinogen concentrate group and 35 patients (9.6%) in the cryoprecipitate group. CONCLUSIONS AND RELEVANCEIn patients undergoing cardiac surgery who develop clinically significant bleeding and hypofibrinogenemia after cardiopulmonary bypass, fibrinogen concentrate is noninferior to cryoprecipitate with regard to number of blood components transfused in a 24-hour period post bypass. Use of fibrinogen concentrate may be considered for management of bleeding in patients with acquired hypofibrinogenemia in cardiac surgery.

IMPORTANCE Blood transfusion is one of the most frequently used therapies worldwide and is associated with benefits, risks, and costs. OBJECTIVE To develop a set of evidence-based recommendations for patient blood management (PBM) and for research. EVIDENCE REVIEWThe scientific committee developed 17 Population/Intervention/ Comparison/Outcome (PICO) questions for red blood cell (RBC) transfusion in adult patients in 3 areas: preoperative anemia (3 questions), RBC transfusion thresholds (11 questions), and implementation of PBM programs (3 questions). These questions guided the literature search in 4 biomedical databases (MEDLINE, EMBASE, Cochrane Library, Transfusion Evidence Library), searched from inception to January 2018. Meta-analyses were conducted with the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology and the Evidence-to-Decision framework by 3 panels including clinical and scientific experts, nurses, patient representatives, and methodologists, to develop clinical recommendations during a consensus conference in Frankfurt/Main, Germany, in April 2018.FINDINGS From 17 607 literature citations associated with the 17 PICO questions, 145 studies, including 63 randomized clinical trials with 23 143 patients and 82 observational studies with more than 4 million patients, were analyzed. For preoperative anemia, 4 clinical and 3 research recommendations were developed, including the strong recommendation to detect and manage anemia sufficiently early before major elective surgery. For RBC transfusion thresholds, 4 clinical and 6 research recommendations were developed, including 2 strong clinical recommendations for critically ill but clinically stable intensive care patients with or without septic shock (recommended threshold for RBC transfusion, hemoglobin concentration <7 g/dL) as well as for patients undergoing cardiac surgery (recommended threshold for RBC transfusion, hemoglobin concentration <7.5 g/dL). For implementation of PBM programs, 2 clinical and 3 research recommendations were developed, including recommendations to implement comprehensive PBM programs and to use electronic decision support systems (both conditional recommendations) to improve appropriate RBC utilization. CONCLUSIONS AND RELEVANCEThe 2018 PBM International Consensus Conference defined the current status of the PBM evidence base for practice and research purposes and established 10 clinical recommendations and 12 research recommendations for preoperative anemia, RBC transfusion thresholds for adults, and implementation of PBM programs. The relative paucity of strong evidence to answer many of the PICO questions supports the need for additional research and an international consensus for accepted definitions and hemoglobin thresholds, as well as clinically meaningful end points for multicenter trials.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a potentially fatal thrombotic microangiopathy caused by autoantibody-mediated severe deficiency of ADAMTS13. Standardized definitions of response, exacerbation, remission and relapse were initially proposed in 2003 and modified by the International Working Group (IWG) for TTP in 2017. These definitions, which have been widely used in clinical practice and research, are based primarily on the platelet count and are benchmarked against the timing of discontinuation of therapeutic plasma exchange (TPE). They do not incorporate ADAMTS13 activity or the temporizing effects of caplacizumab, a novel anti-von Willebrand factor (VWF) nanobody, on the platelet count. In light of these limitations, the IWG aimed to develop revised consensus outcome definitions that incorporate ADAMTS13 activity and the effects of anti-VWF therapy using an estimate-talk-estimate approach. The updated definitions distinguish clinical remission and clinical relapse (defined primarily by platelet count) from ADAMTS13 remission and ADAMTS13 relapse (defined by ADAMTS13 activity). The revised definitions of exacerbation and remission are benchmarked against not only the timing of discontinuation of TPE, but also of anti-VWF therapy. Retrospective validation of the revised definitions is described, though they remain to be prospectively validated. Clinical implications of the updated outcome definitions are also discussed and an example of their application to clinical practice is provided in order to highlight their clinical relevance.

The frequency of WHO bleeding varies depending on the method used to assign grade. Adjudication to assign bleeding grade resulted in significant disagreement when two adjudicators were used.