Analyzing and modeling massive transfusion strategies and the role of fibrinogen-How much is the patient actually receiving?

BACKGROUND: Hemorrhage is a leading cause of preventable death in trauma, cardiac surgery, liver transplant, and childbirth. While emphasis on protocolization and ratio of blood product transfusion improves ability to treat hemorrhage rapidly, tools to facilitate understanding of the overall content of a specific transfusion strategy are lacking. Medical modeling can provide insights into where deficits in treatment could arise and key areas for clinical study. By using a transfusion model to gain insight into the aggregate content of massive transfusion protocols (MTPs), clinicians can optimize protocols and create opportunities for future studies of precision transfusion medicine in hemorrhage treatment. METHODS: The transfusion model describes the individual round and aggregate content provided by four rounds of MTP, illustrating that the total content of blood elements and coagulation factor changes over time, independent of the patient's condition. The configurable model calculates the aggregate hematocrit, platelet concentration, percent volume plasma, total grams and concentration of citrate, percent volume anticoagulant and additive solution, and concentration of clotting factors: fibrinogen, factor XIII, factor VIII, and von Willebrand factor, provided by the MTP strategy. RESULTS: Transfusion strategies based on a 1:1:1 or whole blood foundation provide between 13.7 and 17.2 L of blood products over four rounds. Content of strategies varies widely across all measurements based on base strategy and addition of concentrated sources of fibrinogen and other key clotting factors. DISCUSSION: Differences observed between modeled transfusion strategies provide key insights into potential opportunities to provide patients with precision transfusion strategy.

Quality of life and cost-effectiveness of convalescent plasma compared to standard care for hospitalized COVID-19 patients in the CONCOR-1 trial.

BACKGROUND: The CONvalescent Plasma for Hospitalized Adults With COVID-19 Respiratory Illness (CONCOR-1) trial was a multicenter randomized controlled trial assessing convalescent plasma in hospitalized COVID-19 patients. This study evaluates the cost-effectiveness of convalescent plasma and its impact on quality-of-life to provide insight into its potential as an alternative treatment in resource-constrained settings. METHODS: Individual patient data on health outcomes and resource utilization from the CONCOR-1 trial were used to conduct the analysis from the Canadian public payer's perspective with a time horizon of 30 days post-randomization. Baseline and 30-day EQ-5D-5L were measured to calculate quality-adjusted survival. All costs are presented in 2021 Canadian dollars. The base case assessed the EQ-5D-5L scores of hospitalized inpatients reporting at both timepoints, and a utility score of 0 was assigned for patients who died within 30 days. Costs for all patients enrolled were used. The sensitivity analysis utilizes EQ-5D-5L scores from the same population but only uses costs from this population. RESULTS: 940 patients were randomized: 627 received CCP and 313 received standard care. The total costs were $28,716 (standard deviation, $25,380) and $24,258 ($22,939) for the convalescent plasma and standard care arms respectively. EQ-5D-5L scores were 0.61 in both arms (p = .85) at baseline. At 30 days, EQ-5D-5L scores were 0.63 and 0.64 for patients in the convalescent plasma and standard care arms, respectively (p = .46). The incremental cost was $4458 and the incremental quality-adjusted life day was -0.078. DISCUSSION: Convalescent plasma was less effective and more costly than standard care in treating hospitalized COVID-19.

Fungal microbiota sustains lasting immune activation of neutrophils and their progenitors in severe COVID-19.

Gastrointestinal fungal dysbiosis is a hallmark of several diseases marked by systemic immune activation. Whether persistent pathobiont colonization during immune alterations and impaired gut barrier function has a durable impact on host immunity is unknown. We found that elevated levels of Candida albicans immunoglobulin G (IgG) antibodies marked patients with severe COVID-19 (sCOVID-19) who had intestinal Candida overgrowth, mycobiota dysbiosis and systemic neutrophilia. Analysis of hematopoietic stem cell progenitors in sCOVID-19 revealed transcriptional changes in antifungal immunity pathways and reprogramming of granulocyte myeloid progenitors (GMPs) for up to a year. Mice colonized with C. albicans patient isolates experienced increased lung neutrophilia and pulmonary NETosis during severe acute respiratory syndrome coronavirus-2 infection, which were partially resolved with antifungal treatment or by interleukin-6 receptor blockade. sCOVID-19 patients treated with tocilizumab experienced sustained reductions in C. albicans IgG antibodies titers and GMP transcriptional changes. These findings suggest that gut fungal pathobionts may contribute to immune activation during inflammatory diseases, offering potential mycobiota-immune therapeutic strategies for sCOVID-19 with prolonged symptoms.

Penny-wise and pound-foolish: the challenges of preoperative anaemia management.

The timely correction of anaemia before major surgery is important for optimising perioperative patient outcomes. However, multiple barriers have precluded the global expansion of preoperative anaemia treatment programmes, including misconceptions about the true cost/benefit ratio for patient care and health system economics. Institutional investment and buy-in from stakeholders could lead to significant cost savings through avoided complications of anaemia and red blood cell transfusions, and through containment of direct and variable costs of blood bank laboratories. In some health systems, billing for iron infusions could generate revenue and promote growth of treatment programmes. The aim of this work is to galvanise integrated health systems worldwide to diagnose and treat anaemia before major surgery.

Incidence and Impact of a Single-Unit Red Blood Cell Transfusion: Analysis of The Society of Thoracic Surgeons Database 2010-2019.

BACKGROUND: As the adverse effects of blood transfusions are better understood, recommendations support single-unit red blood cell (RBC) transfusions (SRBCT). However, an isolated SRBCT across the entire index admission suggests even the single unit may be avoidable. We sought to identify the characteristics of cardiac surgery patients receiving an isolated SRBCT and analyze the impact on outcomes. METHODS: The Society of Thoracic Surgeons Adult Cardiac Surgery Database was queried for the period between January 1, 2010, and December 31, 2019. Patients aged >18 years undergoing isolated coronary artery bypass grafting or isolated aortic valve replacement were included. A total of 2,151,430 encounters were analyzed. RESULTS: Of the 847,442 patients (39.3%) receiving any RBC transfusion during their index admission, 206,555 (24.4%) received only 1 unit. Propensity-matching analysis determined SRBCT patients were significantly older (67.26 vs 64.02 years; odds ratio [OR], 1.02; P < .001), female (39.1% vs 17.8%; OR, 1.57; P < .001), non-White (18.2% vs 13.1%; OR, 0.81; P < .001), and had a smaller body surface area (1.94 vs 2.07 m2; OR, 0.20; P < .001). They also had higher mortality (1.4% vs 1.0%, P < .001), stroke (1.7% vs 1.2%, P < .001), prolonged ventilation (6.4% vs 3.4%, P < .001), renal failure (1.8% vs 0.9%, P < .001), and reoperations (1.3% vs. 0.5%, P < .001) than patients who received 0 RBCs. CONCLUSIONS: SRBCT is a common occurrence in adult cardiac surgery. This low-volume transfusion is strongly associated with higher morbidity, even after controlling for preoperative risk factors.

Blood utilization in liver transplantation (BUILT): A multidisciplinary survey of transfusion practices.

BACKGROUND: The purpose of this study was to survey liver transplant centers in the United States to assess baseline practices in blood utilization and identify opportunities for standardization to optimize blood use in these complex cases. STUDY DESIGN AND METHODS: Two surveys, one for transfusion medicine physicians and the other for anesthesiologists, were distributed to high-volume liver transplant centers. RESULTS: The response rate was 52% for both surveys. The majority of respondents (90%) indicated they issue a standardized number of blood products to start surgeries. The most common number of products issued before the start of cases were 10 red blood cells (RBC) and 10 plasma units with no platelets or cryoprecipitate. On average, fewer RBC (7.5) and plasma (7) units were transfused than issued. Decisions to transfuse RhD+ RBCs to RhD- patients and use antigen untested units in alloimmunized patients were mainly handled on a case-by-case basis. Many centers reported utilizing viscoelastic testing (97%) and cell salvage (97%). Most centers reported standardized, laboratory-based intraoperative transfusion goals for RBCs (65%) and fibrinogen replacement (52%) but lacked a standardized approach for plasma (55%) and platelets (58%). DISCUSSION: More blood products are issued during surgery than are transfused. Responses from anesthesiology providers suggest a broad consensus on practice. Almost all respondents use viscoelastic testing in the management of intraoperative coagulopathy, either alone or in combination with classical coagulation tests. The majority of programs do not transfuse clotting factor concentrates, including fibrinogen concentrate, prothrombin complex concentrates, and recombinant activated FVII, and do not use antifibrinolytics prophylactically.

Lessons learned from the CONCOR-1 trial.

Faced with an evolving pandemic and a lack of clarity of the role of convalescent plasma for patients with COVID-19, the CONCOR-1 trial was launched. In 14 months the trial was designed, launched, completed, and submitted for publication. In total, 72 sites in three countries served by four blood suppliers randomised 940 patients. Many enablers facilitated the trial including: three study principal investigators to distribute the trial workload, diverse steering committee members, an international data safety monitoring committee, multiple statisticians and methodologists, virtual meeting platforms, REDCap data platform, pausing of non-COVID-19 trials, rapid approval pathways for institutional review boards and regulators, centralised institutional review boards in many locations, restriction of use of convalescent plasma to trial participants and the incredible dedication by research personnel. In future pandemics, we need to be prepared for rapid launch of trials. The protocols, consent forms, data collection tools, and procedures need to be in draft form ready for use at all times. We were well-prepared for blood shortages but should have anticipated the need to conduct trials with convalescent plasma. In this short article, we detail our lessons learned to inform researchers faced with the next pandemic pathogen.

Distinct Laboratory Test Result Profiles Between SARS-CoV-2 and Seasonable Influenza Infected Patients.

OBJECTIVE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza viruses are contagious respiratory pathogens with similar symptoms but require different treatment and management strategies. This study investigated the differences in laboratory test result profiles between SARS-CoV-2 and influenza infected patients upon presentation to emergency department (ED). METHODS: Laboratory test results and demographic information from 723 influenza positive (2018/1/1 to 2020/3/15) and 1,281 SARS-CoV-2 positive (2020/3/11 to 2020/6/30) ED patients were retrospectively analyzed. The dataset was randomly divided into a training/validation set (2/3) and a test set (1/3) with the same SARS-CoV-2/influenza ratio. Four machine learning models in differentiating the laboratory profiles of RT-PCR confirmed SARS-CoV-2 and influenza positive patients were evaluated. The Shapley Additive Explanations technique was employed to visualize the impact of laboratory tests on the overall differentiation. Furthermore, the model performance was also evaluated in a new test dataset including 519 SARS-CoV-2 ED patients (2020/12/1 to 2021/2/28) and the previous influenza positive patients (2018/1/1 to 2020/3/15). RESULTS: A laboratory test result profile consisting of 15 blood tests, together with patient age, gender, and race can discriminate the two types of viral infections using a random forest (RF) model. The RF model achieved an area under the receiver operating characteristic curve (AUC) of 0.90 in the test set. Among the profile of 15 laboratory tests, the serum total calcium level exhibited the greatest contribution to the overall differentiation. Furthermore, the model achieved an AUC of 0.81 in a new test set. CONCLUSION: We developed a laboratory tests-based RF model differentiating SARS-CoV-2 from influenza, which may be useful for the preparedness of overlapping COVID-19 resurgence and future seasonal influenza.

Rapid detection of SARS-CoV-2 variants of concern by single nucleotide polymorphism genotyping using TaqMan assays.

We evaluated the performance of SARS-CoV-2 TaqMan real-time reverse-transcription PCR (RT-qPCR) assays (ThermoFisher) for detecting 2 nonsynonymous spike protein mutations, E484K and N501Y. Assay accuracy was evaluated by whole genome sequencing (WGS). Residual nasopharyngeal SARS-CoV-2 positive samples (N = 510) from a diverse patient population in New York City submitted for routine SARS-CoV-2 testing during January-April 2020 were used. We detected 91 (18%) N501Y and 101 (20%) E484K variants. Four samples (0.8%) were positive for both variants. The assay had nearly perfect concordance with WGS in the validation subset, detecting B.1.1.7 and B.1.526 variants among others. Sensitivity and specificity ranged from 0.95 to 1.00. Positive and negative predictive values were 0.98-1.00. TaqMan genotyping successfully predicted the presence of B.1.1.7, but had significantly lower sensitivity, 62% (95% CI, 0.53, 0.71), for predicting B.1.526 sub-lineages lacking E484K. This approach is rapid and accurate for detecting SARS-CoV-2 variants and can be rapidly implemented in routine clinical setting.

Vitamin K antagonist reversal strategies: Systematic review and network meta-analysis from the AABB.

BACKGROUND: Anticoagulation requires urgent reversal in cases of life-threatening bleeding or invasive procedures. STUDY DESIGN AND METHODS: Network meta-analysis for comparing the safety and efficacy of warfarin reversal strategies including plasma and prothrombin complex concentrates (PCCs). RESULTS: Seven studies including 594 subjects using reversal agents plasma, 3-factor-PCC (Uman Complex and Konyne), and 4-factor-PCC (Beriplex/KCentra, Octaplex, and Cofact) met inclusion criteria. Compared with plasma, patients receiving Cofact probably have a higher rate of international normalized ratio (INR) correction (risk difference [RD] 499 more per 1000 patients, 95% confidence interval [CI], 176-761, low certainty[LC]); higher reversal of bleeding (323 more per 1000 patients, 11-344 more, LC); and fewer transfusion requirements (0.96 fewer units, 1.65-0.27 fewer, LC). Patients receiving Beriplex/KCentra probably have a higher rate of INR correction (476 more per 1000 patients, 332-609 more, LC); higher reversal of bleeding (127 more per 1000 patients, 43 fewer to 236 more); and similar transfusion requirements (0.01 fewer units, 0.31 fewer to 0.28 more, high/moderate certainty). Patients receiving Octaplex probably have a higher rate of INR correction (RD 579 more per 1000 patients, 189-825 more, LC). CONCLUSIONS: PCCs probably provide an advantage in INR reversal compared to plasma. There was no added risk of adverse events with PCCs.

Laboratory Interventions to Eliminate Unnecessary Rapid COVID-19 Testing During a Reagent Shortage.

OBJECTIVES: In the fall of 2020, US medical centers were running out of rapid coronavirus disease 2019 (COVID-19) tests. The aim of this study is to evaluate the impact of an intervention to eliminate rapid test misutilization and to quantify the effect of the countermeasures to control rapid test ordering using a test utilization dashboard. METHODS: Interventions were made to preserve a severely limited supply of rapid diagnostic tests based on real-time analysis of a COVID-19 test utilization dashboard. This study is a retrospective observational study evaluating pre- and postintervention rates of appropriate rapid test use, reporting times, and cost/savings of resources used. RESULTS: This study included 14,462 severe acute respiratory syndrome coronavirus 2 reverse transcriptase polymerase chain reaction tests ordered during the study period. After the intervention, there was a 27.3% decrease in nonconforming rapid tests. Rapid test reporting time from laboratory receipt decreased by 1.47 hours. The number of days of rapid test inventory on hand increased by 39 days. CONCLUSIONS: Performing diagnostic test stewardship, informed by real-time review of a test utilization dashboard, was associated with significantly improved appropriate utilization of rapid diagnostic COVID-19 tests, improved reporting times, implied cost savings, and improved reagent inventory on hand, which facilitated the management of scarce resources during a pandemic.

Viscoelastic Testing and Factor Concentrate Therapy to Reduce Bleeding and Transfusions in the Surgical Separation of Ischiophagus Twins: A Case Report.

The surgical procedure to separate conjoined twins represents a rare and major challenge. One of the most feared perioperative scenarios is the presence of coagulopathy secondary to bleeding. We present a case of the surgical separation of ischiopagus tetrapus twins using a patient blood management strategy encompassing a tranexamic acid infusion, intraoperative viscoelastic testing, and early fibrinogen supplementation to reduce bleeding and transfusions. This approach allowed early detection and treatment of acquired hypofibrinogenemia, which resulted in minimal exposure to blood products. This case reflects the increasing clinical interest in early avoidance of fibrinogen deficiency in complex noncardiac pediatric surgery.

Coagulopathy and hemostasis management in patients undergoing liver transplantation: Defining a dynamic spectrum across phases of care.

Patients with acute and chronic liver disease present with a wide range of disease states and severity that may require liver transplantation (LT). Physiologic alterations occur that are dynamic throughout all phases of perioperative care, creating complex management scenarios that necessitate multidisciplinary clinical care. Specifically, alterations in hemostasis in liver disease can be pronounced and evolve with disease progression over time. Recent studies and society guidance address this emerging paradigm and offer recommendations to assist with hemostatic management in patients with liver disease. However, patients undergoing LT are unique and diverse, often with unstable disease that requires specialized approaches. Our aim is to provide a focused review of hemostatic management of the LT patient, distinguish unique aspects of the three main phases of care (before LT, perioperative, and after LT), and identify knowledge gaps and critical areas of future research.

System-wide transcriptome damage and tissue identity loss in COVID-19 patients.

The molecular mechanisms underlying the clinical manifestations of coronavirus disease 2019 (COVID-19), and what distinguishes them from common seasonal influenza virus and other lung injury states such as acute respiratory distress syndrome, remain poorly understood. To address these challenges, we combine transcriptional profiling of 646 clinical nasopharyngeal swabs and 39 patient autopsy tissues to define body-wide transcriptome changes in response to COVID-19. We then match these data with spatial protein and expression profiling across 357 tissue sections from 16 representative patient lung samples and identify tissue-compartment-specific damage wrought by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, evident as a function of varying viral loads during the clinical course of infection and tissue-type-specific expression states. Overall, our findings reveal a systemic disruption of canonical cellular and transcriptional pathways across all tissues, which can inform subsequent studies to combat the mortality of COVID-19 and to better understand the molecular dynamics of lethal SARS-CoV-2 and other respiratory infections.