The choice of new treatments in autoimmune hemolytic anemia: how to pick from the basket?

Autoimmune hemolytic anemia (AIHA) is defined by increased erythrocyte turnover mediated by autoimmune mechanisms. While corticosteroids remain first-line therapy in most cases of warm-antibody AIHA, cold agglutinin disease is treated by targeting the underlying clonal B-cell proliferation or the classical complement activation pathway. Several new established or investigational drugs and treatment regimens have appeared during the last 1-2 decades, resulting in an improvement of therapy options but also raising challenges on how to select the best treatment in individual patients. In severe warm-antibody AIHA, there is evidence for the upfront addition of rituximab to prednisolone in the first line. Novel agents targeting B-cells, extravascular hemolysis, or removing IgG will offer further options in the acute and relapsed/refractory settings. In cold agglutinin disease, the development of complement inhibitors and B-cell targeting agents makes it possible to individualize therapy, based on the disease profile and patient characteristics. For most AIHAs, the optimal treatment remains to be found, and there is still a need for more evidence-based therapies. Therefore, prospective clinical trials should be encouraged.

Cold Agglutinin Detected in the Intraoperative Period: A Case of Coronary Bypass.

Cold agglutinin disease(CAD) is an autoimmune disease that occurs against erythrocyte antigens. It is usually idiopathic, but some infections can also be a trigger. CAD becomes active in the peripheral circulation at lower temperatures more easily when exposed to cold, causing hemolysis or agglutination. In this article, the management of a coronary bypass case with CA formation in intraoperative period is presented. A 46-year-old diabetic and hypertensive male patient had COVID-19 2 months ago. Cardiopulmonary bypass(CPB) was initiated with adequate heparinization, and the patient was cooled to 32degreeC. It was noticed that there were clots in the cardioplegia delivery line(+1degreeC). Agglutinations were observed in the autologous blood of the patient whose ACT values were normal. After CPB, the operation was completed without any problems and the patient was discharged on the 5th day with recovery. A diagnosis of CAD was made with the results of peripheral smear and immunologic tests. Determination of antibody concentration and thermal amplitude in the preoperative period in patients with CAD is very important. While preparing such patients for surgery, heating of room, patient, fluids, planning of normothermic CPB, and using warm cardioplegia are required. The relationship between CAD and COVID has started to take place in the literature. The patient we presented had a COVID 2 months ago, cold agglutinin may have been induced by COVID or may have arisen idiopathic. Considering that many people may have had a COVID nowadays, care should be taken especially in the perioperative period of cardiac surgery.Copyright © Telif hakki 2022 Gogus-Kalp-Damar Anestezi ve Yogun Bakim Dernegi Dergisi - Available online at www.gkdaybd.org.

Cold Agglutinin Detected in the Intraoperative Period: A Case of Coronary Bypass.

Cold agglutinin disease(CAD) is an autoimmune disease that occurs against erythrocyte antigens. It is usually idiopathic, but some infections can also be a trigger. CAD becomes active in the peripheral circulation at lower temperatures more easily when exposed to cold, causing hemolysis or agglutination. In this article, the management of a coronary bypass case with CA formation in intraoperative period is presented. A 46-year-old diabetic and hypertensive male patient had COVID-19 2 months ago. Cardiopulmonary bypass(CPB) was initiated with adequate heparinization, and the patient was cooled to 32degreeC. It was noticed that there were clots in the cardioplegia delivery line(+1degreeC). Agglutinations were observed in the autologous blood of the patient whose ACT values were normal. After CPB, the operation was completed without any problems and the patient was discharged on the 5th day with recovery. A diagnosis of CAD was made with the results of peripheral smear and immunologic tests. Determination of antibody concentration and thermal amplitude in the preoperative period in patients with CAD is very important. While preparing such patients for surgery, heating of room, patient, fluids, planning of normothermic CPB, and using warm cardioplegia are required. The relationship between CAD and COVID has started to take place in the literature. The patient we presented had a COVID 2 months ago, cold agglutinin may have been induced by COVID or may have arisen idiopathic. Considering that many people may have had a COVID nowadays, care should be taken especially in the perioperative period of cardiac surgery.Copyright © Telif hakki 2022 Gogus-Kalp-Damar Anestezi ve Yogun Bakim Dernegi Dergisi - Available online at www.gkdaybd.org.

Chronic cold agglutinin disease after a third COVID-19 mRNA vaccination.

COVID-19 mRNA vaccines manufactured by Pfizer-BioNTech and Moderna have been approved in many countries, and have been administered since 2020. Recent reports of mRNA vaccination exacerbating autoimmune hematologic disorders, such as immune thrombocytopenia or autoimmune hemolytic anemia, have caught the attention of the general public, resulting in alarm over the risks of serious consequences. Meanwhile, in very rare cases, vaccination was reported to trigger new onset of hemolytic anemia. However, it remains unknown whether this was a transient reaction or a persistent event, because all cases reported to date were immediately treated with corticosteroids or rituximab. Here, we present a case of newly diagnosed cold agglutinin disease after a third COVID-19 mRNA vaccination. The patient was followed for 4 months without treatment and continued to exhibit high levels of cold agglutinin and aggregation of red blood cells. The present case indicates that the disease can become chronic, and provides insights into the pathogenesis and treatment strategies.

Cold agglutinin detected in the intraoperative period: a case of coronary bypass

Cold agglutinin disease(CAD) is an autoimmune disease that occurs against erythrocyte antigens. It is usually idiopathic, but some infections can also be a trigger. CAD becomes active in the peripheral circulation at lower temperatures more easily when exposed to cold, causing hemolysis or agglutination. In this article, the management of a coronary bypass case with CA formation in intraoperative period is presented. A 46-year-old diabetic and hypertensive male patient had COVID-19 2 months ago. Cardiopulmonary bypass(CPB) was initiated with adequate heparinization, and the patient was cooled to 32°C. It was noticed that there were clots in the cardioplegia delivery line(+1°C). Agglutinations were observed in the autologous blood of the patient whose ACT values were normal. After CPB, the operation was completed without any problems and the patient was discharged on the 5th day with recovery. A diagnosis of CAD was made with the results of peripheral smear and immunologic tests. Determination of antibody concentration and thermal amplitude in the preoperative period in patients with CAD is very important. While preparing such patients for surgery, heating of room, patient, fluids, planning of normothermic CPB, and using warm cardioplegia are required. The relationship between CAD and COVID has started to take place in the literature. The patient we presented had a COVID 2 months ago, cold agglutinin may have been induced by COVID or may have arisen idiopathic. Considering that many people may have had a COVID nowadays, care should be taken especially in the perioperative period of cardiac surgery. (English) [ FROM AUTHOR]

Incidentally discovered cold hemagglutinins within autologous blood bag and cardioplegia line in a patient with a recent history of COVID-19 undergoing coronary artery surgery.

INTRODUCTION: Cold agglutinin disease (CAD) is a rare autoimmune disorder characterized by destruction (hemolysis) of erythrocytes. In CAD, autoantibodies that cause agglutination at temperature of optimum +3-+4 ℃ degree cause symptoms. It is known that CAD often occurs after viral infections. Also, it has been reported in case reports that COVID-19 disease can cause CAD. CASE REPORT: 46-year-old male patient with a history of diabetes mellitus and hypertension presented to outpatient clinic in our department to have CABG surgery. He recovered from COVID-19 disease 1.5 months ago. Cardiopulmonary bypass was initiated and the cross-clamp was placed and antegrade Delnido cardioplegia solution was started to be given at +4 ℃. It was observed that the cardioplegia line was agglutinated. On the other hand, it was seen that the autologous blood taken by the anesthesiologist was also agglutinated and formed air bubbles and became unusable. X-clamp was removed and the heart rhythm recovered. The patient was consulted to hematology during postoperative intensive care follow-ups. The cold agglutinin test performed at of +4 ℃ was reported as positive. In this case, we associated the CAD with covid-19 for three main reasons. First one, the patient's complaints about CAD started after COVID-19 disease. Secondly, in the national health archive, the patient's pre-COVID-19 blood tests were completely normal but it was seen that LDH increased and RBC-HCT incompatibility started after COVID-19. As the third, when we search the literature, we have seen the COVID-19 related CAD in many case reports published by hematologists. CONCLUSION: With the rare cold agglutinin disease, it seems that we will encounter it more often after the COVID-19 pandemic. Except for deep hypothermia, the most important problem is seen during cardioplegia administration. Therefore, non-blood cardioplegia can be lifesaving.

COVID-19 and Immune-Mediated RBC Destruction.

OBJECTIVES: To summarize the epidemiologic, clinical, and laboratory characteristics of autoimmune hemolytic anemia (AIHA) secondary to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or vaccination. METHODS: We conducted a systematic review using standardized keyword search to identify all reports of SARS-CoV-2 infection or vaccination and AIHA across PubMed, Web of Science, Scopus, and Google Scholar through September 24, 2021. RESULTS: Fifty patients (mean [SD] age, 50.8 [21.6] years) diagnosed with coronavirus disease 2019 (COVID-19) and AIHA were identified. AIHA subtypes and number of patients were as follows: cold AIHA (n = 18), warm AIHA (n = 14), mixed-type AIHA (n = 3), direct antiglobulin test (DAT)-negative AIHA (n = 1), DAT-negative Evans syndrome (n = 1), Evans syndrome (n = 3), and subtype not reported (n = 10). Mean (SD) hemoglobin at AIHA diagnosis was 6.5 [2.8] g/dL (95% confidence interval, 5.7-7.3 g/dL). Median time from COVID-19 symptom onset to AIHA diagnosis was 7 days. In total, 19% (8/42) of patients with COVID-19-associated AIHA with reported outcomes were deceased. Four patients (mean [SD] age, 73.5 [16.9] years) developed AIHA following SARS-CoV-2 vaccination: Pfizer-BioNTech BNT162b2 vaccine (n = 2); Moderna mRNA-1273 vaccine (n = 1); undisclosed mRNA vaccine (n = 1). AIHA occurred after 1 dose in 3 patients (median, 5 days). CONCLUSIONS: SARS-CoV-2 infection and vaccination are associated with multiple AIHA subtypes, beginning approximately 7 days after infectious symptoms and 5 days after vaccination.

Cold agglutinin disease following SARS-CoV-2 and Mycoplasma pneumoniae co-infections.

SARS-CoV-2 and other respiratory co-infections may occur. As Mycoplasma pneumoniae and various viruses can cause cold agglutinin disease (CAD), the presence of CAD in COVID-19 patients should indicate the need of investigations for those pathogens.

Autoimmune hemolytic anemia: causes and consequences.

INTRODUCTION: Autoimmune hemolytic anemia (AIHA) is classified according to the direct antiglobulin test (DAT) and thermal characteristics of the autoantibody into warm and cold forms, and in primary versus secondary depending on the presence of associated conditions. AREAS COVERED: AIHA displays a multifactorial pathogenesis, including genetic (association with congenital conditions and certain mutations), environmental (drugs, infections, including SARS-CoV-2, pollution, etc.), and miscellaneous factors (solid/hematologic neoplasms, systemic autoimmune diseases, etc.) contributing to tolerance breakdown. Several mechanisms, such as autoantibody production, complement activation, monocyte/macrophage phagocytosis, and bone marrow compensation are implicated in extra-/intravascular hemolysis. Treatment should be differentiated and sequenced according to AIHA type (i.e. steroids followed by rituximab for warm, rituximab alone or in association with bendamustine or fludarabine for cold forms). Several new drugs targeting B-cells/plasma cells, complement, and phagocytosis are in clinical trials. Finally, thrombosis and infections may complicate disease course burdening quality of life and increasing mortality. EXPERT OPINION: Beyond warm and cold AIHA, a gray-zone still exists including mixed and DAT negative forms representing an unmet need. AIHA management is rapidly changing through an increasing knowledge of the pathogenic mechanisms, the refinement of diagnostic tools, and the development of novel targeted and combination therapies.

Are Patients With Autoimmune Cytopenias at Higher Risk of COVID-19 Pneumonia? The Experience of a Reference Center in Northern Italy and Review of the Literature.

During COVID-19 pandemic the care of onco-hematologic and autoimmune patients has raised the question whether they are at higher risk of infection and/or worse outcome. Here, we describe the clinical course of COVID-19 pneumonia in patients with autoimmune cytopenias (AIC) regularly followed at a reference center in Northern Italy. The study period started from COVID-19 outbreak (February 22, 2020) until the time of writing. Moreover, we provide a review of the literature, showing that most cases reported so far are AIC developed during or secondary to COVID-19 infection. At variance, data about AIC pre-existing to COVID infection are scanty. The 4 patients here described (2 autoimmune hemolytic anemias, AIHA, 1 Evans syndrome, and 1 immune thrombocytopenia) with COVID-19 pneumonia belong to a large cohort of 500 AIC patients, making this study nearly population-based. The observed frequency (4/501; 0.7%) is only slightly superior to that of the general population admitted to hospital/intensive care unit (0.28/0.03%, respectively) in Lombardy in the same period of observation. All cases occurred between March 21 and 25, whilst no more AIC were recorded later on. Although different in intensity of care needed, all patients recovered from COVID-19 pneumonia, with apparently no detrimental effect of previous/current immunomodulatory treatments. AIHA relapse occurred in two patients, but promptly responded to therapy. With limitations due to sample size, these results suggest a favorable outcome and a lower-than-expected incidence of COVID-19 pneumonia in patients with previously diagnosed AIC, and allow speculating that immunomodulatory drugs used for AIC may play a beneficial rather than a harmful effect on COVID-19 infection.

Cold agglutinin disease and autoimmune hemolytic anemia with pulmonary embolism as a presentation of COVID-19 infection.

BACKGROUND: Lymphopenia, thrombocytopenia, and elevated D-dimer and ferritin levels are frequently reported in patients with severe coronavirus disease 2019 (COVID-19). Here we report a case of cold agglutinin disease (CAD), autoimmune hemolytic anemia (AIHA), and pulmonary embolism as a presentation of COVID-19 infection. CASE REPORT: A 51-year-old African-American woman presented to the emergency room with fever and shortness of breath. She was tachycardic, febrile, and had an oxygen saturation of 88% on room air. Laboratory studies showed hemoglobin (Hb) 5.1 g/dL, D-dimer 4.55 µg/mL, and C-reactive protein 12.3 mg/dL. Computed tomography scan of the chest showed acute pulmonary embolism involving the bilateral lower lobe segmental branches. Her influenza test was negative, but her SARS-CoV-2 test returned positive. Due to severe anemia, she was not started on any anticoagulation. Haptoglobin was low. Direct antiglobulin test returned positive for anticomplement and negative for anti-immunoglobulin G. Cold agglutinin titer was 80. Mycoplasma, Epstein-Barr virus, parvovirus, human immunodeficiency viruses, and acute hepatitis screen were negative. Abdominal and pelvic computed tomography showed a normal liver and spleen without lymphadenopathy. Peripheral blood smear showed red blood cell agglutination. On Day 2, she became hypoxic requiring 6 L oxygen. Since her Hb remained stable, she was started on low-intensity unfractionated heparin. Inflammatory markers subsequently improved and she was weaned off oxygen. Her Hb remained stable at 9 g/dL and she was discharged home. After 2 weeks, her Hb increased to 11 g/dL. CONCLUSION: As exemplified in this case report, COVID-19 infection can lead to thromboembolism, CAD, and AIHA and it should be recognized as a potential etiology to such rare diseases.