A Case of Secondary Autoimmune Hemolytic Anemia Successfully Treated With Rituximab.

Secondary cold agglutinin autoimmune hemolytic anemia (AIHA) occurs most commonly due to infectious causes like Mycoplasma pneumonia and, more rarely, Epstein-Barr virus(EBV). Here we present a case of a 69-year-old female presenting with generalized weakness, who was found to have cold agglutinin hemolytic anemia. She unfortunately experienced some of the most severe complications of the disease including encephalopathy, hypoxia, and dry necrosis of peripheral extremities. Further investigation revealed an EBV infection, the rarest infectious cause of cold AIHA. She was started on steroids, the mainstay of treatment, but continued to worsen over the course of her extensive stay in the intensive care unit (ICU). Given the severity of the disease, the decision was made to use plasmapheresis and rituximab, the monoclonal antibody directed against CD20, as an experimental therapy. After adjunctive therapy was initiated, the patient began to clinically improve and ultimately made a full recovery. Rituximab is historically only effective in primary cold AIHA, but it appeared to elicit significant clinical improvement with our use in secondary cold AIHA. While there have been a handful of studies demonstrating its successful use in secondary cold AIHA, we propose that this medication be further studied to prevent the significant morbidity and mortality associated with the disease.

[Solid Tumors With Cold Agglutinins:Report of Two Cases and Literature Review].

Cold agglutinins(CA),autoantibodies against the antigen I or i on the surface of red blood cells,are mainly of IgM class,and the majority have κ light chains.They can lead to red blood cell agglutination at decreased body temperature and are usually associated with infections,drug reactions,autoimmune diseases,and hematological malignancies.However,solid tumors with CA are rare.We reported two cases of CA in the peripheral blood of patients with solid tumors.Peripheral complete blood cell count of the patients at admission showed reduced erythrocyte count and hematocrit,mismatching between erythrocyte count and hemoglobin,abnormally elevated levels of mean corpuscular hemoglobin and mean cell hemoglobin concentration.Peripheral blood smear showed erythrocyte aggregation.After the sample was preheated at 37 ℃ for 30 min,the reversibility of red blood cell aggregation was observed,and the erythrocyte parameters were corrected.

Cardiopulmonary bypass surgery-cold alert!

The term "cold agglutinin (CA)" refers to a group of disorders caused by anti-erythrocyte autoantibodies that preferentially bind RBCs at cold temperatures (4°C-18°C). CAs contribute to 10 to 15% of autoimmune hemolytic anemia. We report a case of CAs diagnosed intraoperatively during emergency mitral valve replacement.

Veno-venous extra-corporeal membrane oxygenation in a COVID-19 patient with cold-agglutinin haemolytic anaemia: A case report.

OVERVIEW: The use of extra-corporeal membrane oxygenation (ECMO) therapy to treat severe COVID-19 patients with acute respiratory failure is increasing worldwide. We reported herein the use of veno-venous ECMO in a patient with cold agglutinin haemolytic anaemia (CAHA) who suffered from severe COVID-19 infection. DESCRIPTION: A 64-year-old man presented to the emergency department (ED) with incremental complaints of dyspnoea and cough since one week. His history consisted of CAHA, which responded well to corticosteroid treatment. Because of severe hypoxemia, urgent intubation and mechanical ventilation were necessary. Despite deep sedation, muscle paralysis and prone ventilation, P/F ratio remained low. Though his history of CAHA, he still was considered for VV-ECMO. As lab results pointed to recurrence of CAHA, corticosteroids and rituximab were started. The VV-ECMO run was short and rather uncomplicated. Although, despite treatment, CAHA persisted and caused important complications of intestinal ischemia, which needed multiple surgical interventions. Finally, the patient suffered from progressive liver failure, thought to be secondary to ischemic cholangitis. One month after admission, therapy was stopped and patient passed away. CONCLUSION: Our case report shows that CAHA is no contraindication for VV-ECMO, even when both titre and thermal amplitude are high. Although, the aetiology of CAHA and its response to therapy will determine the final outcome of those patients.

Solid Tumors With Cold Agglutinins:Report of Two Cases and Literature Review / 中国医学科学院学报

Cold agglutinins(CA),autoantibodies against the antigen I or i on the surface of red blood cells,are mainly of IgM class,and the majority have κ light chains.They can lead to red blood cell agglutination at decreased body temperature and are usually associated with infections,drug reactions,autoimmune diseases,and hematological malignancies.However,solid tumors with CA are rare.We reported two cases of CA in the peripheral blood of patients with solid tumors.Peripheral complete blood cell count of the patients at admission showed reduced erythrocyte count and hematocrit,mismatching between erythrocyte count and hemoglobin,abnormally elevated levels of mean corpuscular hemoglobin and mean cell hemoglobin concentration.Peripheral blood smear showed erythrocyte aggregation.After the sample was preheated at 37 ℃ for 30 min,the reversibility of red blood cell aggregation was observed,and the erythrocyte parameters were corrected.

Survival in autoimmune hemolytic anemia remains poor, results from a nationwide cohort with 37 years of follow-up.

INTRODUCTION: Autoimmune hemolytic anemia (AIHA) is considered a chronic disease, with an overall good prognosis. However, recent reports indicate pre-mature mortality. Causes of death have not been evaluated previously. METHODS: In a nationwide setting, we identified all patients with warm type AIHA or cold agglutinin disease (CAD), and age-sex-matched comparators from Denmark, 1980-2016. We estimated overall survival and cause-specific mortality from anemia, infection, cardiovascular causes, hematological or solid cancer, bleeding, or other causes, using cumulative incidence proportions. RESULTS: We identified 1460 patients with primary AIHA, 1078 with secondary AIHA, 112 with CAD, and 130 801 comparators. One-year survival and median survival were, 82.7% and 9.8 years for primary AIHA, 69.1% and 3.3 years for secondary AIHA, and 85.5% and 8.8 years for CAD. Prognosis was comparable to the general population only in patients with primary AIHA below 30 years. In all other age and subgroups, the difference was considerable. Cumulated cause-specific mortality at 1 year was increased among patients versus comparators. DISCUSSION: All groups of autoimmune hemolytic anemia are associated with increased overall and cause-specific mortality compared to the general population. This probably reflects unmet needs in both treatment and follow-up programs.

Anemia hemolítica autoinmune desencadenada por SARS-CoV-2 Reporte de un caso / SARS-CoV-2-Induced Autoimmune Hemolytic Anemia: Case Report

Resumen Infection by SARS-CoV-2 virus is not solely limited to the common clinical presentation of acute respiratory distress syndrome, mainly because a wide spectrum of clinical manifestation has been observed. These presentations include, but are not limited to, neurological, cardiovascular, throm- boembolic, hematologic, and autoimmune presentations. Within this wide spectrum, cases of autoimmune hemolytic anemia due to SARS-CoV-2 infection are rising. This is why primary care physicians should be ready to identify this clinical entity appropriately.

Abstract Infection by SARS-CoV-2 virus is not solely limited to the common clinical presentation of acute respiratory distress syndrome, mainly because a wide spectrum of clinical manifestation has been observed. These presentations include, but are not limited to, neurological, cardiovascular, throm- boembolic, hematologic, and autoimmune presentations. Within this wide spectrum, cases of autoimmune hemolytic anemia due to SARS-CoV-2 infection are rising. This is why primary care physicians should be ready to identify this clinical entity appropriately.

Cold Reactive Proteins in Cardiovascular Surgery.

Background: According to the literature, Cryoglobins, Cold Agglutinins, Donath-Landsteiner antibodies, and Cryofibrinogen arethe 4 types of Cold-Reactive proteins described. Objective: The aim of the study was to show the role of these proteins cardiovascular surgery. Case presentation: A 57-year-old male patient with a history of myocardial infarction 6 years ago, heavy smoker until 1 year ago, with diabetes, was admitted to the hospital for a surgical confrontation of coronary disease. He reports that for1-month symptoms are deteriorating (NYHA III). The history of the patient does not include either hematopoietic system or connective tissue diseases or recent viral infection. Angiographic control showed total obstruction of the small branch. The patient underwent median sternotomy. Suspension of the left sternum. Mobilization of the left internal mammary artery. Concomitant reception of left great saphenous vein. Intubation of ascending aorta and right atrium - vena cava with acatheter of two steps. He was extubated at the 10th post-surgical hour. Smooth post-surgical progression, with no signs of brain, myocardial or renal failure. The patient was discharged on the 5th post-surgical day. Conclusion: Independently of the technique that is used, the systemic temperature must be maintained duringthe cardiopulmonary bypass above the temperature threshold activity of the cold-reactiveproteins.

Warm and Cold Autoimmune Hemolytic Anemia in the Setting of COVID-19 Disease.

Known associations with autoimmune hemolytic anemia (AIHA) include lymphoproliferative neoplasms, autoimmune conditions, and viral infections. There are a few case reports that implicate a potential relationship between COVID-19 and either warm or cold AIHA. We present the case of combined warm and cold AIHA in the setting of COVID-19. A 51-year-old male with no known past medical history presented with weakness and jaundice. Initial workup revealed white blood cells 41.4, hemoglobin 3.1, platelets 343, total bilirubin 5.3, direct bilirubin 1.6, and COVID-19 positive. Direct antiglobulin test (DAT) found IgG and C3 antibodies and pathology revealed cold agglutinins, consistent with both warm and cold AIHA. He received a total of five blood transfusions and was started on prednisone 1 mg/kg daily with a gradual taper over months. Hemolysis labs normalized within two weeks after discharge although antibodies remained positive 70 days after admission. Our patient presented with IgG and C3 antibodies as well as cold agglutinins, consistent with both warm and cold AIHA. To our knowledge, this is the first case of both warm and cold AIHA presenting simultaneously in COVID-19 infection. Unlike most cases in the existing literature, this patient had no history of underlying hematologic malignancy and both warm and cold AIHA.

[Feasibility of Preheating at 41 ℃ to Correct Red Blood Cell Parameters in the Presence of High-titer Cold Agglutinins].

Objective To explore the feasibility of preheating in 41 ℃ water bath for 30 minutes to correct the red blood cell parameters in the specimens containing high-titer cold agglutinins(CAs). Methods Two specimens containing high-titer CAs were selected during work,and the parameters of complete blood count at room temperature or after preheating in 37 ℃ or 41 ℃ water bath were compared.The smears were stained,and the distribution of red blood cells was observed with a microscope.Further,74 specimens without CAs were collected for complete blood count,and then the test results at room temperature and after preheating at 41 ℃ were compared. Results At room temperature,the specimens containing high-titer CAs showed significantly reduced red blood cell count(RBC)and hematocrit(HCT),abnormally increased mean corpuscular hemoglobin(MCH)and mean cell hemoglobin concentration(MCHC),abnormal percents of hemoglobin(HGB)and RBC,and aggregation of a large number of red blood cells.After being preheated at 37 ℃ for a certain time,the specimens demonstrated obviously improved parameters while still aggregation of a small number of red blood cells.After being preheated at 41 ℃ for 30 minutes,the specimens showed significantly increased RBC,normal HCT,MCH,and MCHC,and evenly distributed red blood cells.The 74 specimens without CAs showed the comparability was ≥80% between room temperature and preheating at 41 ℃ for 30 minutes or 60 minutes. Conclusion We can preheat the specimens containing high-titer CAs in a water bath at 41 ℃ to obtain accurate red blood cell parameters.

Prospective validation of an automatic reflex test for identifying spurious elevations of mean corpuscular haemoglobin concentration due to the presence of cold agglutinins.

Cold agglutinins (CA) in blood may cause false reduction in red blood cell (RBC) count and false increases of RBC indices, such as mean corpuscular haemoglobin concentration (MCHC). Preheating at 37 °C for 2 h is used to overcome this problem. We previously proposed the integration in a total laboratory automation (TLA) setting of a customized reflex test in the presence of MCHC >385 g/L for identifying spurious elevations due to CA. Here, we prospectively evaluate this approach after its introduction in our clinical practice. We evaluated 73 consecutive blood samples from 34 adult patients. Short heating (<1 min) at 41 °C using the reticulocyte channel of Sysmex XN-9000 platform was followed by calculation of optical parameters by the instrument software to ensure quick solution of the CA-dependent problems. After the reflex test in the reticulocyte channel, MCHC dropped below 385 g/L in 50 samples. The reflex markedly corrected the RBC number in eight samples obtained from three patients with CA condition. Two samples from markedly anaemic patients had low blood haemoglobin and RBC count before and after reflex. The remaining 13 samples were obtained from 12 patients, most of whom were on antiretroviral therapy or suffered severe electrolyte disorders, known conditions associated to increased MCHC. The implementation of the proposed automatic reflex by reticulocyte channel on the Sysmex XN-9000 platform in a TLA setting may solve the problem of spuriously high MCHC due to RBC agglutination for CA in a few minutes instead of waiting hours for sample preheating.

High Thermal Amplitude Red Blood Cell Agglutinating Cold Type Autoantibodies in a Case of Severe Acute Respiratory Syndrome Coronavirus 2 Pneumonia and Multiorgan Failure.

A 48-year-old man diagnosed with multiorgan failure and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia developed anemia and polyclonal cold agglutinins that reacted at 37 °C. He recovered after a 2-month hospitalization where he received intensive care support. Cold agglutinins resolved after 2 weeks of supportive care. As red blood cell (RBC) cryptic antigens and warm type autoimmune hemolysis have been recently described in coronavirus disease 2019 (COVID-19) patients, we believe this mechanism may also give rise of clinically detectable cold immunoglobulin M (IgM) autoantibodies. Given the thermal amplitude of this particular agglutinin we believe it is possible that in vivo RBC agglutination could contribute to disease severity.

Resolution of serologic problems due to cold agglutinin mediated autoimmune hemolytic anemia and its transfusion decision.

BACKGROUND: Autoimmune hemolytic anemia (AIHA) is a rare disease characterized by hemolysis caused by autoantibodies against erythrocyte surface antigen. These antibodies can be classified as warm, cold, or mixed types. METHODS: We report two cases of cold agglutinin disease (CAD), which were eventually diagnosed owing to blood group discrepancy. Resolution was achieved after washing the red blood cells (RBCs) with warm saline and absorbing the autoantibodies at 4°C with the washed RBCs. We also assessed the patient's condition and discussed the strategy of blood transfusion. RESULTS: The first case occurred after postoperative chemotherapy for rectal cancer, and the other manifested with anemia from the outset. Direct antiglobulin tests were positive and revealed autoantibodies against C3d only. Cold agglutinin titration was performed, and the titers of both were 1:1024. Eventually, the patient's condition stabilized without blood transfusion. CONCLUSION: The serological discrepancies observed in the blood transfusion department can successfully guide blood transfusion decisions in cases of CAD.

Cryoglobulins, Cryofibrinogens, and Cold Agglutinins in Cold Urticaria: Literature Review, Retrospective Patient Analysis, and Observational Study in 49 Patients.

Introduction: Cryoproteins, such as cryoglobulins, cryofibrinogens and cold agglutinins, precipitate at low temperatures or agglutinate erythrocytes and dissolve again when warmed. Their pathogenetic and diagnostic importance in cold urticaria (ColdU) is unclear. In this study, we aimed to characterize the prevalence of cryoproteins in patients with ColdU. Methods: We conducted 3 analyses: i) a systematic review and meta-analysis of published data using an adapted version of the Joanna Briggs Institute's critical appraisal tool for case series, ii) a retrospective analysis of 293 ColdU patients treated at our Urticaria Center of Reference and Excellence (UCARE) from 2014 to 2019, and iii) a prospective observational study, from July 2019 to July 2020, with 49 ColdU patients as defined by the EAACI/GA2LEN/EDF/UNEV consensus recommendations. Results: Our systematic review identified 14 relevant studies with a total of 1151 ColdU patients. The meta-analyses showed that 3.0% (19/628), 1.1% (4/357) and 0.7% (2/283) of patients had elevated levels of cryoglobulins, cryofibrinogens and cold agglutinins, respectively. Our retrospective analyses showed that cryoproteins were assessed in 4.1% (12/293) of ColdU patients. None of 9 ColdU patients had cryoglobulins, and one of 5 had cold agglutinins. In our prospective study, none of our patients had detectable cryoglobulins (0/48) or cryofibrinogens (0/48), but 4.3% (2/46) of patients had cold agglutinins (without any known underlying autoimmune or hematological disorder). Conclusion: Our investigation suggests that only very few ColdU patients exhibit cryoproteins and that the pathogenesis of ColdU is driven by other mechanisms, which remain to be identified and characterized in detail.

Use of the reticulocyte channel warmed to 41 °C of the XN-9000 analyzer in samples with the presence of cold agglutinins

ABSTRACT Objectives The purpose of this study was to compare data obtained from the reticulocyte channel (RET channel) heated to 41 °C with those obtained from impedance channel (I-Channel) at room temperature in the samples with the mean corpuscular hemoglobin concentration (MCHC) < 370 g/L and in samples with the MCHC > 370 g/L, in the presence of cold agglutinins. Methods In this study, 60 blood samples (group 1) with the MCHC < 370 g/L (without cold agglutinins) and 78 blood samples (group 2) with the MCHC > 370 g/L (with cold agglutinins) were used to compare the two analytical channels of the XN-9000 analyzer in different preanalytical conditions. The parameters evaluated in both groups were the following: red blood cell (RBC), hemoglobin (HGB), hematocrit (HCT), mean cell volume (MCV), RBC-most frequent volume (R-MFV), mean hemoglobin concentration (MCH) and mean cellular hemoglobin concentration (MCHC). Results The results of this study showed an excellent correlation with both channels of the XN-9000 analyzer in samples with and without cold agglutinins, except for the MCHC. The bias between the values obtained in the I-channel and those obtained in the RET channel of both groups was insignificant and remained within the limits of acceptability, as reported by Ricos et al. for all considered parameters, except for MCHC. Conclusions The presence of cold agglutinins in blood samples can be detected by a spurious lowering of the RBC count and by a spurious increase in the MCHC. The RET channel represents a great opportunity to correct the RBC count in a rapid manner without preheating. However, neither methodology can completely solve the residual presence of cold agglutinins in all samples, despite the MCHC values being < 370 g/L.

Transient Cold Agglutinins in a Patient With COVID-19.

Coronavirus disease 2019 (COVID-19) infection has been associated with various complications such as acute respiratory distress syndrome, acute kidney failure, myocardial infection, and thromboembolism. Cold agglutinin syndrome (CAS) has been associated with other viral infections such as Epstein-Barr virus (EBV), but there have been only a few reports of cold agglutination associated with COVID-19. In this report, we describe a case of transient cold agglutinin elevation in a COVID-19-infected patient. A 61-year-old man with hypertension, diabetes mellitus, and end-stage renal disease (ESRD) presented with shortness of breath, cough, and lethargy for five days. A clinical diagnosis of COVID-19 infection was made. The COVID-19 RNA qualitative real-time polymerase-chain-reaction (PCR) assay tested positive. During the hospital stay, he had progressive dyspnea requiring intubation and mechanical ventilation. During the third week of hospital stay, an acute drop in the hemoglobin (Hb) level to 4.5 g/dl (baseline Hb: 9 g/dl) was observed. The workup for acute anemia revealed a positive result for cold agglutinins, direct antibody test (C3d), and agglutination of the red blood cells were apparent on the peripheral blood smear. Further, cold agglutinin titers peaked during the third week of the onset of illness and significantly declined during the fifth week. These observational findings indicate that cold agglutinin titers might correlate with the disease activity.

A renewed understanding of anti-human globulin reagents: interference constraints using an optimization method in pretransfusion compatibility tests.

Anti-human globulin (AHG) reagents are widely applied in pretransfusion compatibility tests. The accuracy of detection with AHG reagents is mainly affected by irregular antibodies or cold agglutinins in blood samples, which are related to the human complement system. Although much has been written about various types and applications of AHG reagents, their characteristics, interference factors and optimal selection in pretransfusion compatibility tests still need to be further clarified. Here, we review clinical practice and basic studies that describe each AHG reagent, summarize the advantages and disadvantages of using different AHG reagents in the presence of cold agglutinins or complement-fixing antibodies, explore the potential mechanisms by which the complement system influences detection with AHG reagents and address the question of how to optimally select AHG reagents for clinically significant antibody detection.

Use of the reticulocyte channel warmed to 41°C of the XN-9000 analyzer in samples with the presence of cold agglutinins.

OBJECTIVES: The purpose of this study was to compare data obtained from the reticulocyte channel (RET channel) heated to 41°C with those obtained from impedance channel (I-Channel) at room temperature in the samples with the mean corpuscular hemoglobin concentration (MCHC)<370g/L and in samples with the MCHC>370g/L, in the presence of cold agglutinins. METHODS: In this study, 60 blood samples (group 1) with the MCHC<370g/L (without cold agglutinins) and 78 blood samples (group 2) with the MCHC>370g/L (with cold agglutinins) were used to compare the two analytical channels of the XN-9000 analyzer in different preanalytical conditions. The parameters evaluated in both groups were the following: red blood cell (RBC), hemoglobin (HGB), hematocrit (HCT), mean cell volume (MCV), RBC-most frequent volume (R-MFV), mean hemoglobin concentration (MCH) and mean cellular hemoglobin concentration (MCHC). RESULTS: The results of this study showed an excellent correlation with both channels of the XN-9000 analyzer in samples with and without cold agglutinins, except for the MCHC. The bias between the values obtained in the I-channel and those obtained in the RET channel of both groups was insignificant and remained within the limits of acceptability, as reported by Ricos et al. for all considered parameters, except for MCHC. CONCLUSIONS: The presence of cold agglutinins in blood samples can be detected by a spurious lowering of the RBC count and by a spurious increase in the MCHC. The RET channel represents a great opportunity to correct the RBC count in a rapid manner without preheating. However, neither methodology can completely solve the residual presence of cold agglutinins in all samples, despite the MCHC values being < 370g/L.

Feasibility of Preheating at 41 ℃ to Correct Red Blood Cell Parameters in the Presence of High-titer Cold Agglutinins / 中国医学科学院学报

Objective To explore the feasibility of preheating in 41 ℃ water bath for 30 minutes to correct the red blood cell parameters in the specimens containing high-titer cold agglutinins(CAs). Methods Two specimens containing high-titer CAs were selected during work,and the parameters of complete blood count at room temperature or after preheating in 37 ℃ or 41 ℃ water bath were compared.The smears were stained,and the distribution of red blood cells was observed with a microscope.Further,74 specimens without CAs were collected for complete blood count,and then the test results at room temperature and after preheating at 41 ℃ were compared. Results At room temperature,the specimens containing high-titer CAs showed significantly reduced red blood cell count(RBC)and hematocrit(HCT),abnormally increased mean corpuscular hemoglobin(MCH)and mean cell hemoglobin concentration(MCHC),abnormal percents of hemoglobin(HGB)and RBC,and aggregation of a large number of red blood cells.After being preheated at 37 ℃ for a certain time,the specimens demonstrated obviously improved parameters while still aggregation of a small number of red blood cells.After being preheated at 41 ℃ for 30 minutes,the specimens showed significantly increased RBC,normal HCT,MCH,and MCHC,and evenly distributed red blood cells.The 74 specimens without CAs showed the comparability was ≥80% between room temperature and preheating at 41 ℃ for 30 minutes or 60 minutes. Conclusion We can preheat the specimens containing high-titer CAs in a water bath at 41 ℃ to obtain accurate red blood cell parameters.

Cold agglutinin syndrome as a complication of Covid-19 in two cases.

BACKGROUND: Cold agglutinins are autoantibodies against RBC antigens, leading to hemolysis at less-than-physiological temperatures through complement fixation. Production can be triggered by infections, resulting in secondary cold agglutinin syndrome (CAS). This syndrome has been classically described in the setting of Mycoplasma pneumoniae infection, as well as with several viral pathogens. CASES: Here, we present two cases of cold agglutinins identified in the context of Covid-19 in critically ill patients treated at our institution. Each case was characterized by little in-vivo hemolysis, but these antibodies complicated laboratory assessment and renal replacement therapy. Management included anticoagulation and warming of dialysis circuit. CONCLUSIONS: Despite minimal in-vivo hemolysis, these antibodies are of clinical significance given their implications for laboratory assessment and renal replacement therapy, particularly with the frequency of multi-organ system dysfunction associated with severe Covid-19.