Factors related to the development of high antibody titres against SARS-CoV-2 in convalescent plasma donors from the ConPlas-19 trial.

BACKGROUND AND OBJECTIVES: The efficacy of COVID-19 convalescent plasma (CP) associates with high titres of antibodies. ConPlas-19 clinical trial showed that CP reduces the risk of progression to severe COVID-19 at 28 days. Here, we aim to study ConPlas-19 donors and characteristics that associate with high anti-SARS-CoV-2 antibody levels. MATERIALS AND METHODS: Four-hundred donors were enrolled in ConPlas-19. The presence and titres of anti-SARS-CoV-2 antibodies were evaluated by EUROIMMUN anti-SARS-CoV-2 S1 IgG ELISA. RESULTS: A majority of 80.3% of ConPlas-19 donor candidates had positive EUROIMMUN test results (ratio ≥1.1), and of these, 51.4% had high antibody titres (ratio ≥3.5). Antibody levels decline over time, but nevertheless, out of 37 donors tested for an intended second CP donation, over 90% were still EUROIMMUN positive, and nearly 75% of those with high titres maintained high titres in the second sample. Donors with a greater probability of developing high titres of anti-SARS-CoV-2 antibodies include those older than 40 years of age (RR 2.06; 95% CI 1.24-3.42), with more than 7 days of COVID-19 symptoms (RR 1.89; 95% CI 1.05-3.43) and collected within 4 months from infection (RR 2.61; 95% CI 1.16-5.90). Male donors had a trend towards higher titres compared with women (RR 1.67; 95% CI 0.91-3.06). CONCLUSION: SARS-CoV-2 CP candidate donors' age, duration of COVID-19 symptoms and time from infection to donation associate with the collection of CP with high antibody levels. Beyond COVID-19, these data are relevant to inform decisions to optimize the CP donor selection process in potential future outbreaks.

High-titre methylene blue-treated convalescent plasma as an early treatment for outpatients with COVID-19: a randomised, placebo-controlled trial.

BACKGROUND: Convalescent plasma has been proposed as an early treatment to interrupt the progression of early COVID-19 to severe disease, but there is little definitive evidence. We aimed to assess whether early treatment with convalescent plasma reduces the risk of hospitalisation and reduces SARS-CoV-2 viral load among outpatients with COVID-19. METHODS: We did a multicentre, double-blind, randomised, placebo-controlled trial in four health-care centres in Catalonia, Spain. Adult outpatients aged 50 years or older with the onset of mild COVID-19 symptoms 7 days or less before randomisation were eligible for enrolment. Participants were randomly assigned (1:1) to receive one intravenous infusion of either 250-300 mL of ABO-compatible high anti-SARS-CoV-2 IgG titres (EUROIMMUN ratio ≥6) methylene blue-treated convalescent plasma (experimental group) or 250 mL of sterile 0·9% saline solution (control). Randomisation was done with the use of a central web-based system with concealment of the trial group assignment and no stratification. To preserve masking, we used opaque tubular bags that covered the investigational product and the infusion catheter. The coprimary endpoints were the incidence of hospitalisation within 28 days from baseline and the mean change in viral load (in log10 copies per mL) in nasopharyngeal swabs from baseline to day 7. The trial was stopped early following a data safety monitoring board recommendation because more than 85% of the target population had received a COVID-19 vaccine. Primary efficacy analyses were done in the intention-to-treat population, safety was assessed in all patients who received the investigational product. This study is registered with ClinicalTrials.gov, NCT04621123. FINDINGS: Between Nov 10, 2020, and July 28, 2021, we assessed 909 patients with confirmed COVID-19 for inclusion in the trial, 376 of whom were eligible and were randomly assigned to treatment (convalescent plasma n=188 [serum antibody-negative n=160]; placebo n=188 [serum antibody-negative n=166]). Median age was 56 years (IQR 52-62) and the mean symptom duration was 4·4 days (SD 1·4) before random assignment. In the intention-to-treat population, hospitalisation within 28 days from baseline occurred in 22 (12%) participants who received convalescent plasma versus 21 (11%) who received placebo (relative risk 1·05 [95% CI 0·78 to 1·41]). The mean change in viral load from baseline to day 7 was -2·41 log10 copies per mL (SD 1·32) with convalescent plasma and -2·32 log10 copies per mL (1·43) with placebo (crude difference -0·10 log10 copies per mL [95% CI -0·35 to 0·15]). One participant with mild COVID-19 developed a thromboembolic event 7 days after convalescent plasma infusion, which was reported as a serious adverse event possibly related to COVID-19 or to the experimental intervention. INTERPRETATION: Methylene blue-treated convalescent plasma did not prevent progression from mild to severe illness and did not reduce viral load in outpatients with COVID-19. Therefore, formal recommendations to support the use of convalescent plasma in outpatients with COVID-19 cannot be concluded. FUNDING: Grifols, Crowdfunding campaign YoMeCorono.

SARS-CoV-2/COVID-19 pandemic: first wave, impact, response and lessons learnt in a fully integrated Regional Blood and Tissue Bank. A narrative report.

BACKGROUND: The COVID-19 pandemic is placing blood and tissue establishments under unprecedented stress, putting its capacity to provide the adequate care needed at risk. Here we reflect on how our integrated organisational model has faced the first impact of the pandemic and describe what challenges, opportunities and lessons have emerged. MATERIALS AND METHODS: The organisational model of the Catalan Blood and Tissue Bank (Banc de Sang i Teixits, BST) is described. The new scenario was managed by following international recommendations and considering the pandemic in a context of volatility, uncertainty, complexity, and ambiguity (VUCA), allowing rapid measures to be taken. These aimed to: ensure donor safety, promote proper responses to patients' needs, ensure the health and well-being of personnel, and prepare for future scenarios. RESULTS: The BST has adapted its activities to the changes in demand. No shortage of any product or service occurred. Donor acceptance, safety and wellbeing were maintained except for tissue donation, which almost completely stopped. To support the health system, several activities have been promoted: large-scale convalescent plasma (CP) production, clinical trials with CP and mesenchymal stromal cells, massive COVID-19 diagnoses, and participation in co-operative research and publications. Haemovigilance is running smoothly and no adverse effects have been detected among donors or patients. DISCUSSION: Several elements have proven to be critical when addressing the pandemic scenario: a) the early creation of a crisis committee in combination with technical recommendations and the recognition of a VUCA scenario; b) identification of the strategies described; c) the integrated donor-to-patient organisational model; d) active Research and Development (R&D); and e) the flexibility of the staff. It is essential to underline the importance of the need for centralised management, effective contingency strategies, and early collaboration with peers.

Relationship between the ABO blood group and COVID-19 susceptibility, severity and mortality in two cohorts of patients.

BACKGROUND: Several articles reported the existence of an association between ABO blood groups and COVID-19 susceptibility. Group A and group O individuals showed a higher and lower risk, respectively, of becoming infected. No association was observed between ABO groups and mortality. To verify this association, we performed a retrospective study of two cohorts of patients with different demographic and clinical characteristics. MATERIAL AND METHODS: A total of 854 regular blood donors were recruited for convalescent plasma donation after recovering from a mild COVID-19 infection, and a group of 965 patients more severely affected who were transfused during hospitalisation were also included. We also investigated the potential role of the different risk factors on patient outcome and death. To eliminate the confounding effect of risk factors on mortality, a propensity score analysis was performed. RESULTS: Blood group A and blood group O COVID-19 blood donors showed a higher and lower risk, respectively, for acquiring COVID-19. In contrast, this association was not found in the group of patients transfused during hospitalisation, probably due to the great differences in demographic and clinical characteristics between the two groups. Regarding severity, age was one of the most significant risk factors. ABO blood groups were also seen to represent important risk factors for COVID-19 severity and mortality. Mortality risk in group A individuals was significantly higher than in group O individuals (OR: 1.75, 95% CI: 1.22-2.51). DISCUSSION: The association between the ABO blood groups and the susceptibility to acquire COVID-19 infection was confirmed in the group of blood donors. ABO blood groups were also associated to COVID-19 severity and mortality in the group of patients transfused during hospitalisation. Therefore, blood groups A and O are two important factors to be considered when evaluating the prognosis of patients with COVID-19.

[Diagnostic and therapeutic guidelines of thrombotic microangiopathies of the Spanish Apheresis Group]. / Guía diagnóstica y terapéutica de las microangiopatías trombóticas del Grupo Español de Aféresis.

Thrombotic microangiopathies (TMA) are disorders defined by the presence of a microangiopathic hemolytic anemia (with the characteristic hallmark of schistocytes in the peripheral blood smear), thrombocytopenia and organ malfunction of variable intensity. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are the most important forms of TMA and, without the adequate treatment, they are associated with high morbimortality. In recent years, significant advances in the knowledge of the pathophysiology of TMA have occurred. Those advances have allowed us to move from a syndromic diagnosis with a similar treatment to all entities to the search of etiologic diagnosis which would lead to a specific treatment, finally leading to a better outcome of the patient. This document pretends to summarize the current status of knowledge of the pathophysiology of TMA and the therapeutic options available, and to offer a diagnostic and therapeutic practical tool to the professionals caring for the patients.

[Thrombotic thrombocytopenic purpura]. / Púrpura trombótica trombocitopénica.

Thrombotic thrombocytopenic purpura (TTP) is the most extensive and dangerous intravascular platelet clumping disorder. For more than a half-century after its initial recognition, mortality was near 100% and the etiology totally obscure. Then, in the late 1970s to early 1980s, empiric, but successful, therapy with plasma exchange was followed by sudden laboratory insight into pathophysiology. The most important finding was the identification of a novel metalloprotease, named ADAMTS13, which is involved in the regulation of the size of von Willebrand factor. Inherited or acquired deficiencies of ADAMTS13 impair von Willebrand factor cleavage, leading to the disseminated formation of platelet-rich thrombi in the microcirculation and to symptoms of end-organ ischemia. Treatment with plasma exchange, available for more than 20 years, has dramatically altered the course of disease in adults with TTP. Long term follow-up has revealed increasing frequencies of relapse that require new therapeutic alternatives for these patients.

The epidemiology of blood component transfusion in Catalonia, Northeastern Spain.

BACKGROUND: Epidemiologic information on blood component usage can help improve the utilization of transfusion resources. STUDY DESIGN AND METHODS: Crosssectional survey in 2007 that included every hospital in Catalonia. Clinical data of blood recipients, including the four-digit International Classification of Diseases, 9th Revision, Clinical Modification codes and the indication for transfusion, were prospectively collected according to an established protocol. RESULTS: In total, 19,148 red blood cell (RBC) units, 1812 platelet (PLT) doses, and 3070 plasma units, transfused into 8019 patients (median age, 71 years; 52% males), were surveyed. Half the RBC units were used by patients older than 70 years. Specific diagnosis and procedures with the highest RBC use were lower limb orthopedic surgery (10.6% of all units) and gastrointestinal hemorrhage (6%). Therapeutic plasmapheresis (8.1%) and heart valve surgery (7.2%) were the procedures with the highest plasma use. Oncohematology patients accounted for 73% of transfused PLTs, more that two-thirds being administered for hemorrhage prophylaxis. Acute hemorrhage was the most common indication for RBC and plasma transfusion. Among all blood recipients, 80% received only RBCs and 6.9% received only plasma and/or PLTs, without concomitant RBCs. The population transfusion incidence rates were 35 RBC units, three PLT doses, and 6 plasma units per 1000 population-year. Demographic changes anticipate a 30% increase in RBC transfusion by year 2030. CONCLUSIONS: These results allow for identification of blood uses that are susceptible to improvement, help appraise the expected yield of blood safety measures, and will assist in planning the future blood supply.

Methylene blue-photoinactivated plasma versus quarantine fresh frozen plasma in thrombotic thrombocytopenic purpura: a multicentric, prospective cohort study.

Plasma exchange (PE) with plasma infusion is the treatment of choice for thrombotic thrombocytopenic purpura (TTP) but doubts remain as to whether all kinds of plasma are equally effective. A multicentric cohort study was conducted to compare methylene blue-photoinactivated plasma (MBPIP) with quarantine fresh frozen plasma (qFFP) in the treatment of TTP. One hundred and two episodes of idiopathic TTP were included; MBPIP was used in 63 and qFFP in 39. The treatment schedule consisted of daily PE and costicosteroids, and the main end-point was remission status on day 8. Patients treated with MBPIP required more PEs (median: 11 vs. 5, P = 0.002) and a larger volume of plasma (median: 485 ml/kg vs. 216 ml/kg, P = 0.007) to achieve a remission, and presented more recrudescences while on PE therapy (29 of 63 vs. 8 of 39, P = 0.02) than those receiving qFFP. After adjustment for possible confounding factors, the use of MBPIP was associated with a lower likelihood of remission on day 8 [Odds ratio (OR): 0.17; 95% confidence interval (CI): 0.06-0.47] and a higher risk of recrudescence while on treatment (OR: 4.2; 95% CI: 1.6-10.8). In conclusion, MBPIP is less effective than qFFP in the treatment of TTP.

[The "Seville" Consensus Document on Alternatives to Allogenic Blood Transfusion. Sociedades españolas de Anestesiología (SEDAR), Medicina Intensiva (SEMICYUC), Hematología y Hemoterapia (AEHH), Transfusión sanguínea (SETS) Trombosis y Hemostasia (SETH)]. / Documento «Sevilla¼ de Consenso sobre Alternativas a la Transfusión de Sangre Alogénica.

The Consensus Document on Alternatives to Allogenic Blood Transfusion (AABT) has been drawn up by a panel of experts from 5 scientific societies. The Spanish Societies of Anesthesiology (SEDAR), Critical Care Medicine and Coronary Units (SEMICYUC), Hematology and Hemotherapy (AEHH), Blood Transfusion (SETS) and Thrombosis and Hemostasis (SETH) have sponsored and participated in this Consensus Document. Alternatives to blood transfusion have been divided into pharmacological and non-pharmacological, with 4 modules and 12 topics. The main objective variable was the reduction of allogenic blood transfusions and/or the number of transfused patients. The extent to which this objective was achieved by each AABT was evaluated using the Delphi method, which classifies the grade of recommendation from A (supported by controlled studies) to E (non-controlled studies and expert opinion). The experts concluded that most of the indications for AABT were based on middle or low grades of recommendation, "C", "D", or "E", thus indicating the need for further controlled studies.

[Oral iron and folic acid supplements in a preoperative autologous blood collection program: a randomized study]. / Suplementos de hierro oral y ácido fólico en un programa de transfusión autóloga con predepósito: estudio aleatorizado.

BACKGROUND AND OBJECTIVE: We evaluated the capacity of oral iron with or without oral folic acid administration to improve the accomplishment of our scheduled preoperative autologous blood collection program in patients with baseline hemoglobin > 115 g/l. PATIENTS AND METHOD: Patients were enrolled in a randomized trial. The control group received no vitamin supplements. The iron group received 105 mg of elemental iron daily p.o. The and iron+folate group received 105 mg of elemental iron daily and 5 mg of folic acid daily p.o. RESULTS: Eighty-six percent of patients in the control group, 86% of patients in the iron group and 87% of patients in the iron+folate group accomplished our preoperative autologous blood collection program. CONCLUSION: In our study, neither oral iron nor folic acid supplements enhanced the accomplishment of our preoperative autologous blood collection program in patients with baseline hemoglobin > 115 g/l.

Use of polyethylene glycol for performing autologous adsorptions.

BACKGROUND: Our reference adsorption procedure is to autoadsorb serum with ZZAP-pretreated patients' red cells (RBCs), although it is time-consuming. The aim of this study was to evaluate the use of polyethylene glycol (PEG) for performing autologous adsorption procedures without pretreatment of patients' RBCs. STUDY DESIGN AND METHODS: Equal volumes of patient's plasma, patient's RBCs, and PEG were mixed. This mixture was incubated for 15 minutes at 37 degrees C, and the adsorbed plasma-PEG mixture was immediately harvested to proceed to the antiglobulin test with anti-immunoglobulin G. The ZZAP-adsorption procedure was performed in our reference laboratory. RESULTS: Thirty-one samples were detected with warm autoantibodies in pretransfusion testing. A total number of 58 autologous adsorption procedures were performed with PEG in 870 minutes (mean, 28 min) and alloantibodies were detected in 4 (13%) cases (anti-E in 2 cases and anti-E + K in 2 cases). Our reference laboratory performed a total number of 61 adsorption procedures with ZZAP in 3660 minutes (mean, 118 min) and detected the same alloantibodies specificities. CONCLUSION: The PEG autologous adsorption procedure is an efficient method of enhancing autoantibody adsorption and alloantibody detection and decreasing the labor-intensive testing required by the presence of serum warm autoantibodies in pretransfusion samples.