A 65-year-old woman with systemic sclerosis and systemic lupus erythematosus developed acute kidney injury (AKI), Coombs-positive autoimmune hemolytic anemia and autoimmune thrombocytopenia; therefore, she was diagnosed with Evans syndrome (ES). Intravascular hemolysis was suggested as the cause of AKI based on the presence of acute tubular injury and trace hemosiderin deposits on the renal biopsy. The renal function, hemolytic anemia and thrombocytopenia were restored by an increased dose of glucocorticoids, hemodialysis, and plasma exchange. Although ES with severe hemolytic anemia is very rare, it is important to detect possible renal dysfunction when encountering patients with severe hemolysis.

Thrombotic microangiopathy (TMA) is a condition characterized by thrombocytopenia and microangiopathic hemolytic anemia (MAHA) with varying degrees of organ damage in the setting of normal International Normalized Ratio (INR) and activated Partial Thromboplastin Time (aPTT). Complement has been implicated in the etiology of TMA, which are classified as Primary TMA - when genetic and acquired defects in complement proteins are the primary drivers of TMA (complement-mediated TMA or atypical hemolytic uremic syndrome, aHUS) or Secondary TMA, when complement activation occurs in the context of other disease processes, such as infection, malignant hypertension, autoimmune disease, malignancy, transplantation, pregnancy and drugs. It is important to recognize that this classification is not absolute as genetic variants in complement genes have been identified in patients with secondary TMA, and distinguishing complement/genetic-mediated TMA from secondary causes of TMA can be challenging and lead to potentially harmful delays in treatment. In this review, we focus on data supporting the involvement of complement in aHUS and in secondary forms of TMA associated with malignant hypertension, drugs, autoimmune diseases, pregnancy and infections. In aHUS, genetic variants in complement genes are found in up to 60% of patients, whereas in the secondary forms the finding of genetic defects is variable, ranging from almost 60% in TMA associated with malignant hypertension to less than 10% in drug-induced TMA. Based on these findings, a new approach to management of TMA is proposed.

Vitamin B12 deficiency is seen in countries like India mainly because of predominantly vegetarian diet and is a significant health problem. Patients present with various neurological and hematological manifestations of megaloblastic anemia. In this case report, we present a 14-year-old girl child having a history of past blood transfusions and iron deficiency anemia currently presenting with severe anemia due to idiopathic autoimmune hemolytic anemia (AIHA) and later found to have concomitant vitamin B12 deficiency. On investigating, she had vitamin B12 deficiency, raised homocysteine and methylmalonic acid levels, positive Direct Coombs Test (DCT), and negative glucose-6-phoshphatase deficiency and osmotic fragility tests. Thyroid profile and tissue transglutaminase IgA (tTg-IgA) tests were negative. Antinuclear antibodies (ANA) and anti-double stranded DNA antibody (anti-dsDNA) serum immunoglobulin were also normal. Bone marrow showed megaloblastic anemia picture. Although AIHA and vitamin B12 deficiency anemia are not common, clinicians should have a high index of suspicion when patients present with hemolytic picture and severe megaloblastic anemia.

Immune-mediated hemolytic anemia (IMHA) is a life-threatening autoimmune disorder characterized by a self-mediated attack on circulating red blood cells. The disease occurs naturally in both dogs and humans, but is significantly more prevalent in dogs. Because of its shared features across species, dogs offer a naturally occurring model for studying IMHA in people. In this study, we used RNA sequencing of whole blood from treatment-naïve dogs to study transcriptome-wide changes in gene expression in newly diagnosed animals compared to healthy controls. We found many overexpressed genes in pathways related to neutrophil function, coagulation, and hematopoiesis. In particular, the most highly overexpressed gene in cases was a phospholipase scramblase, which mediates the externalization of phosphatidylserine from the inner to the outer leaflet of cell membranes. This family of genes has been shown to be critically important for programmed cell death of erythrocytes as well as the initiation of the clotting cascade. Unexpectedly, we found marked underexpression of many genes related to lymphocyte function. We also identified groups of genes that are highly associated with the inflammatory response and red blood cell regeneration in affected dogs. We did not find any genes that distinguished dogs that lived vs. those that died at 30 days following diagnosis, nor did we find any relevant genomic signatures of microbial organisms in the blood of affected animals. Future studies are warranted to validate these findings and assess their implication in developing novel therapeutic approaches for dogs and humans with IMHA.

We report the case of an 82-year old male patient admitted in our medical intensive care unit for diffuse skin lesions, three days after the onset of ceftriaxone for bilateral pneumonia without microbiological documentation. The patient concomitantly exhibited diffuse skin lesions compatible with livedo and neurological and hemodynamic failure. Biological analysis revealed acute hemolytic anemia. Warming of patient, red blood-cells transfusion and high-doses corticosteroids were initiated and ceftriaxone was stopped. Despite these therapeutics, the patient exhibited multiple organ failure and died. The main suspected triggering factor of this acute and fatal hemolytic anemia was ceftriaxone administration considering (i)the delay between cephalosporin administration and symptoms, (ii)the worsening of livedo and acrocyanosis a few hours after meningeal ceftriaxone doses and (iii) fatal evolution. Cephalosporin-induced autoimmune hemolytic anemia is a rare and serious cause of livedo that should be suspected in patients exhibiting livedo and acute hemolytic anemia within hours/days following cephalosporin administration.

The characteristics of autoimmune cytopenias (AICP) associated with Hodgkin lymphoma (HL) are not thoroughly defined. We retrospectively assessed the clinical features of HL-associated AICPs in 563 HL patients diagnosed over a period of 28 years. We identified 8 cases of autoimmune hemolytic anemia (AIHA) and 8 cases of autoimmune thrombocytopenia among 14 patients altogether. Four (26%) AICPs were present at lymphoma diagnosis, while 11 (74%) cytopenias occurred during follow-up after first-line therapy. The overall incidence of HL-associated AICPs was 2.8%. Nine (75%) cytopenias responded to intravenous steroids. Seven (46%) AICPs led to the diagnosis of HL, indicated a relapse, or revealed secondary malignancies. AIHAs and AICPs altogether were more likely to develop in patients with advanced-stage HL (p = 0.010 and p < 0.004, respectively). HL patients experiencing AICPs had an increased short-term (1-year) mortality compared to the general HL population (p < 0.022). The 5-year OS of HL patients with concurrent AICPs at diagnosis was inferior compared to HL patients developing AICPs during follow-up (p = 0.005), and to HL patients without AICPs (p < 0.001). Patients with HL-associated AICPs appear to have a particular disease-related profile. The association of HL and AICPs may increase short-term mortality, while patients with concurrent AICPs at HL diagnosis have a dismal prognosis.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease, with multisystemic involvement. Hemoglobin E/beta-thalassemia (HbE/beta-thalassemia) is the genotype responsible for approximately one-half of all severe beta-thalassemia worldwide. When beta-thalassemia and SLE coexist, SLE seems to have a more severe course. Here we report a 32-year-old female who presented with dizziness and fatigue was found to have severe hemolytic anemia with thrombocytopenia. Upon further evaluation, she was diagnosed with HbE/beta-thalassemia and SLE, which is a very rare association. In SLE patients, anemia usually results from the disease itself, but it is important to think of other coexisting conditions like thalassemia.

We report a case of primary sclerosing cholangitis (PSC) with autoimmune hemolytic anemia (AIHA). A 47-year-old woman was diagnosed with PSC. One year later, she was admitted to our hospital for jaundice and fatigue. Magnetic resonance cholangiopancreatography (MRCP) showed worsening of the biliary stricture, and rapidly progressive anemia developed simultaneously. Based on the various laboratory findings, she was diagnosed with AIHA. The administration of prednisolone improved not only the anemia but also the biliary stricture. This case is impactful, as there are few case reports of PSC with AIHA. In addition, we were able to observe the changes in imaging findings using MRCP over time.

Thrombotic thrombocytopenic purpura (TTP) is a rare but life-threatening microangiopathic hemolytic anemia characterized by thrombocytopenia, hemolytic anemia, and ischemic organ damage. It is mainly caused by an autoreactive antibody directed at ADAMTS13. Immunotherapy is frequently associated with autoimmune complications in patients with cancer, but only three cases of TTP have been reported, none implicating single treatment with the anti-programmed cell death receptor 1 ligand antibody nivolumab. We present the first identified and reported case of nivolumab-associated TTP in a 51-year-old woman with stage IIIc anal carcinoma who achieved complete response following chemoradiation and received adjuvant nivolumab as part of a randomized clinical trial. Twelve weeks into treatment, she presented with dark urine, progressive fatigue, and headache. TTP diagnosis was based on laboratory evidence of hemolytic anemia, thrombocytopenia, and ADAMTS13 activity of 9% associated with an inhibitor. She was treated with daily plasma exchange and oral prednisone and responded well to treatment, with platelet counts over 100 K/cmm within 4 days. We reviewed and summarized data from all reported cases of TTP associated with cancer immunotherapy. We provide guidance on identification and management of this devastating hematologic complication, focusing on the importance of early recognition, as most patients achieve complete recovery with appropriate treatment. KEY POINTS: Thrombotic thrombocytopenic purpura (TTP) was originally excluded from previous reviews of hematologic immune-related adverse events; however, several cases have been reported in the past 2 years in patients treated with either single agent or combination of cytotoxic T-lymphocyte-associated antigen 4 and the programmed cell death receptor 1 (PD-1) or the PD-1 ligand inhibitors. Although rare, TTP is a life-threatening condition that could be challenging to diagnose, and early recognition is key as delayed treatment is associated with significant increase in mortality. The pathophysiology of immunotherapy-induced TTP is likely related to autoimmune inhibition of ADAMTS13; the addition of prednisone and rituximab to urgent plasmapheresis appears to be effective and should be part of the up-front management for these patients.

Drug-induced immune hemolytic anemia (DIIHA) is a rare condition with an increasing incidence associated with the frequent use of certain drugs. An 85-year-old woman with lung adenocarcinoma prescribed alectinib complained of dyspnea on exertion at our hospital. Based on her laboratory tests results on admission, we focused on the clinical course of anemia and hemolysis progression after alectinib administration. The patient's anemia and hemolysis gradually improved after discontinuation of alectinib, leading to a diagnosis of alectinib-induced IHA, presented here as the first case encountered in a patient with lung adenocarcinoma. Furthermore, we discuss the importance of correlating clinical laboratory findings in DIIHA.

Autoimmune manifestations after allogeneic hematopoietic stem cell transplantation (AHSCT) are rare and poorly understood due to the complex interplay between the reconstituting immune system and transplant-associated factors. While autoimmune manifestations following AHSCT have been observed in children with graft-versus-host disease (GvHD), an alloimmune process, they are distinct from the latter in that they are generally restricted to the hematopoietic compartment, i.e., autoimmune hemolytic anemia, thrombocytopenia, and/or neutropenia. Autoimmune cytopenias in the setting of ASHCT represent a donor against donor immune reaction. Non-hematologic autoimmune conditions in the post-AHSCT setting have been described and do not currently fall under the GvHD diagnostic criteria, but could represent alloimmunity since they arise from the donor immune attack on the antigens that are shared by the donor and host in the thyroid, peripheral and central nervous systems, integument, liver, and kidney. As in the non-transplant setting, autoimmune conditions are primarily antibody mediated. In this article we review the incidence, risk factors, potential pathophysiology, treatment, and prognosis of hematologic and non-hematologic autoimmune manifestations in children after AHSCT.

IgG4 related disease (IgG4-RD) is a rare and relatively new group of systemic inflammatory diseases characterized by inflammatory, fibrotic or sclerotic involvement of one or more organs accompanied by increased IgG4plasma cells tissue infiltration andusually elevated serum IgG4(IgG4 > 1.35g/l, normal range 0.08-1.40 g/l) level. Histopathological findings are crucial for the diagnostics of this disease. The authors present a case report of a patient with IgG4 associated disease manifested by a rare combination of autoimmune hemolytic anemia and pulmonary involvement.

Atypical hemolytic uremic syndrome (aHUS) is a rare cause of thrombotic microangiopathy (TMA), characterized by microangiopathic hemolytic anemia, consumptive thrombocytopenia, and multisystem end organ involvement, most commonly affecting the kidney. Diagnosis is clinical, after exclusion of other TMA causes. Primary aHUS arises from genetic abnormalities, resulting in uncontrolled complement activity, while a variety of clinical scenarios cause secondary aHUS, including infection, pregnancy, malignancy, autoimmune disease, and medications. They can also induce a temporary complement deregulation with an overlap between both scenarios, which can make differential diagnosis difficult. Primary aHUS can be sporadic or familial and is associated with a high rate of progression to ESRD. Many aHUS patients relapse in the native or transplanted kidneys, leading to kidney failure. The introduction of eculizumab has changed the prognosis of aHUS, by inducing hematologic remission, improving or stabilizing kidney functions, and preventing graft failure. The early institution of appropriate therapy can prevent multiorgan damage, so is essential to recognize and differentiate the TMA syndromes. Eculizumab is considered now the first-line treatment, and it is recommended lifelong therapy. However, the high cost of therapy has led to make efforts to develop precise complement functional and genetic studies that help physicians to determine the appropriate duration of eculizumab therapy. Nowadays, more studies are needed to select candidates to adjustment of therapy.

Higher levels of D-dimer, LDH, and ferritin, all have been associated with the poor prognosis of COVID-19. In a disease where there are acute inflammation and compromised oxygenation, we investigated the impact of initial hemoglobin (Hgb) levels at Emergency Department (ED) triage on the severity and the clinical course of COVID-19. We conducted a cross-sectional study on 601 COVID-19 patients in a COVID-19 national referral center between 13 and 27 June 2020. All adult patients presented at our hospital that required admission or hotel isolation were included in this study. Patients admitted to the intensive care unit (ICU) had a lower initial Hgb than those admitted outside the ICU (12.84 g/dL vs. 13.31 g/dL, p = 0.026) and over the course of admission; the prevalence of anemia (Hgb < 12.5 g/dL) was 65% in patients admitted to ICU, whereas it was only 43% in non-ICU patients (odds ratio of 2.464, 95% CI 1.71-3.52). Anemic ICU patients had a higher mortality compared with non-anemic ICU patients (hazard ratio = 1.88, log-rank p = 0.0104). A direct agglutination test (DAT) for all anemic patients showed that 14.7% of ICU patients and 9% of non-ICU patients had autoimmune hemolytic anemia (AIHA). AIHA patients had significantly longer length of hospital stay compared with anemic patients without AIHA (17.1 days vs. 14.08 days, p = 0.034). Lower Hgb level at hospital presentation could be a potential surrogate for COVID-19 severity.

Biphasic squamoid alveolar renal cell carcinoma (BSARCC) is a recently described kidney cancer entity with <60 published cases so far. Some unique features of BSARCC include distinct squamoid and alveolar morphology forming glomeruloid configurations and 2 types of tumor cells with different immunoprofiles. Although the mechanism is unknown, neutrophils and cellular materials engulfed by larger tumor cells (described as "emperipolesis") are observed in all reported cases including the current one. In this article, we report a case of a 70-year-old man who presented with an incidental renal mass during workup for immunoglobulin M monoclonal gammopathy of unknown significance and cold agglutinin autoimmune hemolytic anemia. A detailed pathologic evaluation and immunohistochemical studies revealed BSARCC colliding with atypical CD5+ monoclonal B-cells.

IgG4-related disease (IgG4-RD) is a rare autoimmune fibrosis disease characterized by elevated serum IgG4 and tissues as well as organs infiltrated with IgG4-positive cells, resulting in swelling and damage.It is currently treated as first-line treatment with glucocorticoids. Autoimmune hemolytic anemia (AIHA) is also a relatively rare disease that caused by autoreactive erythrocyte antibodies. Although both are autoimmune-related diseases, they rarely overlap. The relationship between them is not clear. A case of IgG4-RD combined with AIHA is reported. The patient has shortness of breath, cough, and sputum after physical activity. Physical examination showed appearance of anemia, yellow staining of skin and sclera, palpable neck and multiple swollen lymph nodes. Laboratory examination, bone marrow biopsy, and lymph node biopsy confirmed the diagnosis. Therefore, clinicians should develop ideas and raise awareness of such diseases.