ZAP-70 mutation: a case with familial autoimmune haemolytic anaemia and immune deficiency.

Zeta-chain associated protein kinase 70 kDa (ZAP-70) deficiency is one of the rare immunodeficiency disorders due to autosomal recessive homozygous or compound heterozygous loss-of-function mutations in the ZAP-70 GENE In the literature, patients with ZAP-70 deficiency have been reported with a broad spectrum of clinical manifestations including recurrent respiratory infections (81.8%), cutaneous involvement (57.9%), lymphoproliferation (32.4%), autoimmunity (19.4%), enteropathy (18.4%) and increased risk of malignancies (8.1%). The most common immunological phenotype in those patients was low CD8+ T cell counts (97.9%) and normal non-functioning CD4+ T cell. Haematopoietic stem cell transplantation was applied as a curative treatment for this disorder.

[Sjögren's syndrome combined with cold agglutinin disease: A case report].

Sjögren's syndrome(SS)is a chronic autoimmune disease that affects exocrine glands, especially salivary and lacrimal glands. The main clinical manifestations are dry mouth and dry eyes, but also multi-organ and multi-system can be involved. Cold agglutinin disease(CAD)is an autoimmune disease characterized by red blood cell agglutination in the blood vessels of extremities caused by cold agglutinin at low temperature, resulting in skin microcirculation disturbance, or hemolytic anemia. Cold agglutinin disease is divided into two categories, primary cold agglutinin disease and secondary cold agglutinin disease. Primary cold agglutinin disease is characterized with cold agglutinin titer of 1 ∶4 000 or more and positive Coomb's test. However, the Coomb's test is not necessarily positive and the cold agglutinin titer is between 1 ∶32 and 1 ∶4 000 in secondary cold agglutinin disease. Here, we reported an elderly patient admitted to hospital due to fever. He was diagnosed with respiratory infection, but he showed incompletely response to the anti-infection treatment. Further laboratory tests showed the patient with positive ANA and anti-SSA antibodies. Additionally, the patient complained that he had dry mouth and dry eyes for 1 year. Schirmer test and salivate gland imaging finally confirmed the diagnosis Sjogren's syndrome. During the hospital stay, the blood clots were found in the anticoagulant tubes. Hemolytic anemia was considered as the patient had anemia with elevated reticulocytes and indirect bilirubin. In addition, further examination showed positive cold agglutination test with a titer of 1 ∶1 024, and cold agglutinin disease was an important type of cold-resistant autoimmune hemolytic anemia. Furthermore, the patient developed cyanosis after ice incubating at the tip of the nose. Hence, the patient was diagnosed as CAD and he was successfully treated with glucocorticoids instead of anti-infection treatments. Hence, the patient was diagnosed with SS combined with secondary CAD. SS combined CAD are rarely reported, and they are both autoimmune diseases. The abnormal function of B lymphocytes and the production of autoantibodies might be the common pathogenesis of them. Cold agglutinin disease can lead to severe hemolytic anemia, even life-threatening. In clinical practice, timely recognizing and dealing with CAD might promote the prognosis of the patient.

Co-Occurring Thrombotic Thrombocytopenic Purpura and Autoimmune Hemolytic Anemia in a Child Carrying the Pathogenic SHOC2 c.4A>G (p.Ser2Gly) Variant.

BACKGROUND RASopathies involve mutations in genes that encode proteins participating in the RAS-mitogen-activated protein kinase pathway and are a collection of multisystem disorders that clinically overlap. Variants in the SHOC2 gene have been reported in Noonan-like syndrome, which include distinct facial features, short stature, congenital cardiac defects, developmental delays, bleeding disorders, and loose anagen hair. This report is of a 7-year-old girl with the c.4A>G (p.Ser2Gly) variant of the SHOC2 gene, consistent with Noonan-like syndrome, with loose anagen hair, presenting with thrombotic thrombocytopenic purpura and autoimmune hemolytic anemia. CASE REPORT The child had a medical history of 7 hospitalizations at our institution. At the age of 2 months, she underwent surgical correction for ventricular and atrial septal defects. At the age of 2 years, tonsil and adenoid removal surgery was performed, followed by surgery for otitis media at age 5 years. At 7 years, she was hospitalized for the simultaneous occurrence of thrombotic thrombocytopenic purpura and autoimmune hemolytic anemia. The patient displayed short stature and mild intellectual disability. Notable facial features included sparse hair, mild frontal bossing, and low-set ears. Antinuclear antibody levels demonstrated a significant gradual shift. Through trio whole-exome sequencing, a c.4A>G (p.Ser2Gly) variation in the SHOC2 gene was identified. CONCLUSIONS Given the clinical information and genetic testing results, the patient's condition appeared to closely be a type of RASopathy. This report has highlighted the importance of physical, developmental, and genetic testing in children presenting with dysmorphism, developmental delay, and hematological abnormalities.

Hematologic Abnormalities After COVID-19 Infection: A Case of Coombs-Negative Hemolytic Anemia and Thrombocytopenia.

The occurrence of hemolytic anemia in patients with active SARS-CoV-2 infection has been documented in medical literature. While relatively uncommon, there have been instances where this condition presents as a Coombs-negative hemolytic anemia. In this research study, we report a distinctive case of Coombs-negative hemolytic anemia and thrombocytopenia in a patient with a known history of COVID-19 infection. The patient demonstrated a favorable response to treatment involving the administration of steroids and intravenous immunoglobulin (IVIG) therapy. This case adds to the existing body of evidence regarding the hematological manifestations of SARS-CoV-2 infection, highlighting the importance of considering and managing hematological complications in patients with COVID-19.

Evaluating the prevalence of inborn errors of immunity in adults with chronic immune thrombocytopenia or Evans syndrome.

Inborn errors of immunity (IEIs) are monogenic disorders that predispose patients to immune dysregulation, autoimmunity, and infection. Autoimmune cytopenias, such as immune thrombocytopenia (ITP) and Evans syndrome (a combination of ITP and autoimmune hemolytic anemia), are increasingly recognized phenotypes of IEI. Although recent findings suggest that IEIs may commonly underlie pediatric ITP and Evans syndrome, its prevalence in adult patients with these disorders remains undefined. This study sought to estimate the prevalence of underlying IEIs among adults with persistent or chronic ITP or Evans syndrome using a next-generation sequencing panel encompassing >370 genes implicated in IEIs. Forty-four subjects were enrolled from an outpatient adult hematology clinic at a tertiary referral center in the United States, with a median age of 49 years (range, 20-83). Fourteen subjects (31.8%) had secondary ITP, including 8 (18.2%) with Evans syndrome. No cases of IEI were identified despite a high representation of subjects with a personal history of autoimmunity (45.5%) and early onset of disease (median age at diagnosis of 40 years [range, 2-77]), including 20.5% who were initially diagnosed as children. Eight subjects (18.2%) were found to be carriers of pathogenic IEI variants, which, in their heterozygous state, are not disease-causing. One case of TUBB1-related congenital thrombocytopenia was identified. Although systematic screening for IEI has been proposed for pediatric patients with Evans syndrome, findings from this real-world study suggest that inclusion of genetic testing for IEI in the routine work-up of adults with ITP and Evans syndrome has a low diagnostic yield.

[Novel therapeutic agents for hemolytic anemia].

In recent years, it has become clear that various diseases are caused by complement (related molecule) abnormalities (complementopathies) or are exacerbated by complement (complement-related diseases), and novel therapeutic agents targeting complement (anti-complement agents) are now being developed. Paroxysmal nocturnal hemoglobinuria (PNH) is a hematopoietic stem cell disorder characterized by complement-mediated intravascular hemolysis due to a deficiency of complement regulatory factors, making it a perfect candidate for anti-complement agents. In 2007, the anti-C5 monoclonal antibody eculizumab was approved for PNH, as the first anti-complement agent. The indications for eculizumab are expanding, and aggressive development is underway for new anti-complement agents, not only for PNH but also a variety of other diseases. In addition, the anti-C1s antibody sutimlimab was approved last year for the treatment of cold agglutinin disease, a form of autoimmune hemolytic anemia. This presentation overviews novel anti-complement agents for these hemolytic anemias.

Red blood cell alloimmunization in myelodysplastic syndromes: Associations with sex, DAT-positivity, and increased transfusion needs.

BACKGROUND: Many patients with myelodysplastic syndromes (MDS) need repeated red blood cell transfusions which entails a risk of immunization and antibody formation. Associations between alloantibodies, autoantibodies and increased transfusion requirements have been reported, but their relationship remains unclear. In this study, we analyzed factors potentially associated with red blood cell alloimmunization, as well as changes in transfusion intensity and post-transfusion hemoglobin increments. METHODS: In a retrospective cohort study, we linked Swedish MDS patients diagnosed between 2003 and 2017 to transfusion and immunohematology data. Potentially associated factors were analyzed using Cox proportional hazards regression. The transfusion rate after detected alloimmunization was analyzed using a fixed effects Poisson regression. Post-transfusion hemoglobin increments before and after alloimmunization were compared using a mixed effects regression. RESULTS: Alloantibodies following MDS diagnosis were detected in 50 out of 429 patients (11.7%). Female sex and a positive direct antiglobulin test (DAT) were independently associated with alloimmunization, with hazard ratios of 2.02 (95% confidence interval [CI] 1.08-3.78) and 9.72 (95% CI, 5.31-17.74), respectively. The transfusion rate following alloimmunization was increased with an incidence rate ratio of 1.33 (95% CI, 0.98-1.80) and the post-transfusion hemoglobin increment after alloimmunization was 1.40 g/L (95% CI, 0.52-2.28) lower per red blood cell unit (p = .002) compared to before alloimmunization, in multivariable analyses. DISCUSSION: Alloimmunization against blood group antigens was associated with sex, DAT-positivity, increased transfusion needs, and lower post-transfusion hemoglobin increments. These findings warrant further investigation to evaluate the clinical significance of up-front typing and prophylactic antigen matching in patients with MDS.

Total arch replacement for an aortic arch aneurysm with cold agglutinin disease after rituximab and plasmapheresis.

BACKGROUND: Cold agglutinin disease can lead to significant complications, especially for patients undergoing arch repair requiring hypothermic circulatory arrest. Rituximab and plasmapheresis are treatments for cold agglutinin disease. However, its use in patients with Stanford type A dissection has not been reported. Therefore, after consultation with hematologists, we used rituximab and plasmapheresis before mild hypothermic aortic arch surgery to maintain the body temperature above the thermal altitude. CASE PRESENTATION: This report describes an 86-year-old male patient with acute type A aortic dissection who received outpatient treatment for rheumatoid arthritis and a 55-mm thoracic aortic aneurysm. The patient was scheduled to undergo urgent surgery for a type A intramural hematoma and progressive aortic aneurysm; however, laboratory test results indicated blood clotting and cold agglutinin. Consequently, urgent surgery was rescheduled. After consulting with hematologists, rituximab was initiated 3 months before surgery, and plasmapheresis was performed 2 days before surgery for cold agglutinin disease. Under mild hypothermia conditions, total arch replacement using the frozen elephant trunk technique was performed while maintaining cerebral and lower body perfusion. The postoperative course was uneventful. On postoperative day 42, the patient was discharged without any neurological deficits. CONCLUSIONS: This case involving total arch replacement with mild hypothermia for an aortic arch aneurysm with cold agglutinin disease after rituximab treatment and plasmapheresis resulted in a successful outcome.

Detection of red cell alloantibody prior to overflow phenomenon in a case of warm AIHA secondary to Chronic Lymphocytic Leukemia and Myasthenia Gravis: A case report.

INTRODUCTION: Defects in the lymphoid system have been linked to immune dysregulation, which might explain why lymphoid neoplasms and immunological disorders tend to occur concurrently. Chronic Lymphocytic Leukemia (CLL), characterised by the accumulation of dysfunctional lymphocytes, is associated with autoimmune cytopenias such as autoimmune haemolytic anaemia (AIHA). Detection of underlying alloantibody in warm AIHA, is challenging for any transfusion medicine specialist. This report highlights the significance of overflow phenomenon in detection of alloantibody in a case of warm AIHA secondary to CLL and myasthenia gravis. CASE REPORT: A 56-year-old male with a history of myasthenia gravis and thymoma progressed to B-cell CLL presented with severe anaemia and thrombocytopenia leading to multiple red blood cell (RBC) transfusions in the last two months. Clinical profile and laboratory workup suggested features of AIHA, and subsequent immunohaematological workup hinted towards an impending overflow phenomenon due to differential reactivity pattern observed between serum and eluate with antibody screen/identification panel. The eluate was pan-reactive with an antibody screen/ identification panel, while the serum showed a discrete anti-C alloantibody pattern. A compatible and antigen-negative RBC unit was successfully transfused, followed by medical management. DISCUSSION: The overflow phenomenon in AIHA depends on antibody titre and its affinity for RBC antigens. In the index case, the impending 'overflow or spillover' of autoantibodies into the patient's serum allowed us to detect underlying alloantibody without performing allogeneic adsorption and transfuse antigen-negative and crossmatch compatible PRBC unit. CONCLUSION: This case emphasises the significance of understanding the overflow phenomenon in AIHA as it can guide a transfusion medicine specialist in the early detection and identification of underlying alloantibodies, which is crucial for appropriate transfusion management in AIHA. However, early presentation and timely workup, along with a high level of suspicion, is crucial to identify this phenomenon.

A case of renal vein thrombosis associated with autoimmune hemolytic anemia and eosinophilic granulomatous polyangiitis.

Only a few cases of renal vein thrombosis (RVT) occurring in patients with vasculitis have been reported. RVT associated with vasculitis and hemolytic anemia has not been reported yet. We describe here a patient with RVT complicated by pulmonary embolism, autoimmune hemolytic anemia, and eosinophilic granulomatous polyangiitis. A 69-year-old Japanese man who had been treated with corticosteroids was referred to our department for severe proteinuria (4.32 g/gCr). Abdominal ultrasonography showed bilateral RVT, and contrast-enhanced computed tomography showed bilateral pulmonary embolism. Therefore, the patient was diagnosed with RVT complicated by pulmonary embolism. Anticoagulation therapy with heparin followed by apixaban was started. Thereafter, the D-dimer concentration decreased from 8.3 to 1.2 µg/mL, and urinary protein excretion improved to 0.62 g/gCr. Renal function was unchanged with an estimated glomerular filtration rate of 68.8 mL/minute/1.73 m2. The thrombi in both renal veins and pulmonary arteries gradually regressed. Clinicians should be aware of this complication when worsening proteinuria is observed during steroid therapy in patients with autoimmune hemolytic anemia and eosinophilic granulomatous polyangiitis.

[Association of giant cell hepatitis and autoimmune hemolytic anemia in infancy]. / Óriássejtes hepatitis és autoimmun haemolyticus anaemia társulása kisdedkorban.

Giant cell hepatitis associated with autoimmune hemolytic anemia (GCH-AIHA) is a rare disorder with unfavorable prognosis, affecting infants and young children. The mortality rate is high, complications of acute liver failure, sepsis, or liver transplantation can be responsible for fatal outcomes. An 18-month-old child who was diagnosed previously with autoimmune hemolytic anemia, developed acute hepatitis and acute liver failure concomitant to the relapse of the disease. GCH-AIHA is characterized by Coombs positive hemolytic anemia and progressive liver injury, histologically defined by widespread giant cell transformation. Liver biopsy was performed to establish the diagnosis, histological examination confirmed the presence of multinuclear, giant cell hepatocytes. Corticosteroid and azathioprine treatment were started. As a result of subsequent rituximab treatment and intravenous immunoglobulin therapy, acute liver failure and anemia gradually resolved. The exact background of the association of the two entities is still unknown, an autoimmune mechanism is suspected. Conventional immunosuppressive treatment with corticosteroid and azathioprine seems to be ineffective in most cases, therefore second- and third-line therapies are required. Since the introduction of the anti-CD20 rituximab therapy, the prognosis of GCH-AIHA has improved significantly. Orv Hetil. 2023; 164(36): 1432-1436.

A 71-year-old male with a life-threatening recurrence of hemolytic anemia, thrombocytopenia, and acute kidney injury after pembrolizumab therapy: a case report.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. However, their use has been restricted in patients with preexisting autoimmune diseases due to concerns about increased risk of immune-related adverse events (irAEs). CASE PRESENTATION: We present a case of a patient with stage IV lung adenocarcinoma and a history of complement-mediated autoimmune hemolytic anemia in remission. After receiving a single dose of pembrolizumab, the patient experienced life-threatening recurrent hemolytic anemia, de novo thrombocytopenia, diarrhea, myocarditis, and acute kidney injury. Laboratory tests confirmed the diagnosis of Evan's syndrome, with positive PAIgG and direct antiglobulin test. Treatment with intravenous methylprednisolone at a dose of 2 mg/kg resulted in a favorable response, with resolution of symptoms and rapid recovery of kidney function. The probable cause of pre-renal hypoperfusion (evidenced by a BUN-to-creatinine ratio of 48.1) leading to acute tubular injury was attributed to pembrolizumab-induced diarrhea. CONCLUSIONS: This case illustrates a life-threatening recurrence of complement-mediated autoimmune hemolytic anemia induced by ICIs. Clinicians should carefully consider the expected efficacy and potential toxicity before initiating ICIs therapy in patients with preexisting autoimmune diseases. Additionally, the occurrence of acute kidney injury during ICIs therapy adds complexity and requires careful differential diagnosis.

Severe autoimmune hemolytic anemia complicating hereditary spherocytosis treated successfully with glucocorticoids and cyclosporine: a case report.

BACKGROUND: Severe autoimmune hemolytic anemia complicating hereditary spherocytosis is life threatening and has not been described in a case report. Here, we report a case in which this intractable disease was treated successfully with glucocorticoids and cyclosporine. CASE PRESENTATION: A 25-year-old female patient with hereditary spherocytosis developed severe autoimmune hemolytic anemia after respiratory syncytial virus infection. Her hemoglobin level was 26 g/L and various anti-red blood cell antibodies were detected in her serum, making blood matching difficult. Glucocorticoid monotherapy was ineffective. With the addition of cyclosporine (50 mg/12 h), the patient's hemoglobin level increased significantly and the symptoms associated with anemia were greatly relieved. CONCLUSION: In patients with severe autoimmune hemolytic anemia, especially when the presence of multiple anti-red blood cell antibodies and alloantibodies interferes with blood matching, a glucocorticoid-cyclosporine regimen may be tried.

A case of cold agglutinin syndrome associated with chronic lymphocytic leukaemia harbouring mutations in CARD11 and KMT2D.

Cold agglutinin disease (CAD) is a rare cold autoimmune haemolytic anaemia (cAIHA) caused by IgM antibodies recognizing I antigens on erythrocytes. cAIHA is now mainly classified into two types: primary CAD and cold agglutinin syndrome (CAS). CAS develops in association with the underlying disease, which is most commonly malignant lymphoma. Recent studies have identified gene mutations in CARD11 and KMT2D in a high proportion of patients with CAD, which has led to recognition of CAD as an indolent lymphoproliferative disorder. We herein report a case of cAIHA without lymphocytosis or lymphadenopathy in whom bone marrow was infiltrated by a small population of clonal lymphocytes (6.8%) expressing cell surface markers consistent with chronic lymphocytic leukaemia (CLL). Whole-exome sequencing of bone marrow mononuclear cells revealed mutations in the CARD11 and KMT2D genes. This patient also had somatic hypermutation with overrepresentation of IGHV4-34, which is prevalent in CLL harbouring the KMT2D mutation. These observations suggest that CAS caused by early-phase CLL could be misinterpreted as primary CAD.