Idiopathic Autoimmune Hemolytic Anemia Research Articles

Mitigation of checkpoint inhibitor–induced autoimmune hemolytic anemia through modulation of purinergic signaling

AbstractImmune checkpoint inhibitors (ICPis) have revolutionized cancer immunotherapy but also can induce autoimmune hemolytic anemia (AIHA), a severe disease with high mortality. However, the cellular and molecular mechanism(s) of AIHA secondary to ICPi therapy (ICPi-AIHA) are unclear, other than being initiated through decreased checkpoint inhibition. Herein, we report ICPi-AIHA in a novel mouse model that shows similar characteristics of known human ICPi-AIHA (eg, autoantibodies, hemolysis, and increased mortality). During ICPi-AIHA, there is the simultaneous reduction of 2 regulatory T-cell populations (FoxP3+ and Tr1 [type 1 regulatory cells]) and an increase in inflammatory T helper cell 17 (TH17). Moreover, a novel CD39+CD73–FoxP3–CD25– CD4+ T-cell subset (ie, CD39 single positive [CD39SP]) emerges, and early increases in CD39SP predict AIHA development; CD39 is an ectonuclease that breaks down adenosine triphosphate (ATP). Additionally, we found that boosting ATPase activity by injecting recombinant apyrase mitigates AIHA development and significant CD39SP reductions, both suggesting a functional role for CD39 and demonstrating a novel therapeutic approach. Importantly, CD39SP are detectable in multiple mouse models developing AIHA and in patients with AIHA, demonstrating applicability to idiopathic and secondary AIHA. Highlighting broader autoimmunity relevance, ICPi-treated NZB mice experienced accelerated onset and severity of lupus, including AIHA. Moreover, ICPi treatment of healthy B6 animals led to detectable CD39SP and development of autoantibodies against multiple autoantigens including those on red blood cells and platelets. Together, our findings provide further insight into the cellular and molecular mechanisms of ICPi-AIHA, leading to novel diagnostic and therapeutic approaches with translational potential for use in humans being treated with ICPi.

Dermatomyositis following COVID-19 infection

IntroductionViruses have been shown to reveal autoimmune diseases like type1 diabetes and systemic connectivities like dermatomyositis (DM). Coronavirus disease 2019 (COVID-19) is best known for its respiratory symptoms but multiple systems could be affected in acute or post COVID-19 infection period. Clinical dermatomyositis following COVID-19 infection was exceptionally reported.ObservationWe report a case of a 61-year- woman with no medical history observed in March 2021 with bilateral edema. Doppler ultrasound demonstrated a superficial venous thrombosis of saphenous veins. The patient had a suspicious epidemiological history, and her chest CT scans showed lung damage similar to that caused by COVID-19. PCR test for Coronavirus confirmed the infection. She was treated by curative anticoagulation, steroids and oxygen therapy. Two months after her leaving, she was presented in internal medicine's department with pulmonary embolism despite good anti coagulation. Her PCR test for Coronavirus was negative. At her admission, she was complained of asthenia weight loss and pain in scapular and pelvic muscles. Physical examination revealed erythematous patches with edema in periorbital areas. Chest auscultation found bilateral basal lung crepitation. Bilateral proximal muscle weakness in upper and lower extremities was objectified. Oral examination found ulcerations in the lower gingiva. We found signs of arthritis in wrists and proximal interphalangeal joints. Biological tests showed anemia (hemoglobin =8.6 g/dl), accelerated erythrocyte sedimentation rate (65 mm H1) ; high C-reactive protein(119 mg/l)d biological myolysis and cytolydid (Creatinin kinase = 1052 U/l, LDH = 478 AST/ALT 238 U/l/119 U/l). Infectious investigations including HCV, HBV and HIV serology were negative. Thyroid function test was in normal range. Neoplastic research was negative. Immunologic analysis revealed positive antinuclear antibodies (ANA) with anti JO1 antibodies. Anti cardiolipin antibodies and kit-myositis were negatives. Electromyographic findings revealed inflammatory myositis. The patient was treated by high doses of steroids then progressively decreased. Good progress was noticed.ConclusionDermatomyositis is an inflammatory myopathy relatively rare. An elevation of its incidence was noticed during the pandemic period coinciding of corona virus [1]. Viral infections could induce autoimmunity and may be the eliciting event in the pathogenesis of myositis [2]. In our case, dermatomyositis is hypothetically linked to viral trigger on the background of genetic predisposition. The spectrum of complications following COVID-19 is broad but incidence is too rare including Idiopathic thrombocytopenic purpura, Guillain-Barré syndrome and autoimmune haemolytic anaemia recorded in 1, 5 and 7 patients respectively, 4–13 days following onset of COVID-19 symptoms. We assume that true dermatomyositis, triggered by COVID-19 may occur and the immunopathogenicity is via type 1 IFN pathway. Tanboon et al. commented that 58-year-old COVID-19 patient reported to have myositis may actually have dermatomyositis.

A New Murine Model of Primary Autoimmune Hemolytic Anemia (AIHA).

Loss of humoral tolerance to red blood cells (RBCs) can lead to autoimmune hemolytic anemia (AIHA), a severe, and sometimes fatal disease. Patients with AIHA present with pallor, fatigue, decreased hematocrit, and splenomegaly. While secondary AIHA is associated with lymphoproliferative disorders, infections, and more recently, as an adverse event secondary to cancer immunotherapy, the etiology of primary AIHA is unknown. Several therapeutic strategies are available; however, there are currently no licensed treatments for AIHA and few therapeutics offer treatment-free durable remission. Moreover, supportive care with RBC transfusions can be challenging as most autoantibodies are directed against ubiquitous RBC antigens; thus, virtually all RBC donor units are incompatible. Given the severity of AIHA and the lack of treatment options, understanding the cellular and molecular mechanisms that facilitate the breakdown in tolerance would provide insight into new therapeutics. Herein, we report a new murine model of primary AIHA that reflects the biology observed in patients with primary AIHA. Production of anti-erythrocyte autoantibodies correlated with sex and age, and led to RBC antigen modulation, complement fixation, and anemia, as determined by decreased hematocrit and hemoglobin values and increased reticulocytes in peripheral blood. Moreover, autoantibody-producing animals developed splenomegaly, with altered splenic architecture characterized by expanded white pulp areas and nearly diminished red pulp areas. Additional analysis suggested that compensatory extramedullary erythropoiesis occurred as there were increased frequencies of RBC progenitors detectable in the spleen. No significant correlations between AIHA onset and inflammatory status or microbiome were observed. To our knowledge, this is the first report of a murine model that replicates observations made in humans with idiopathic AIHA. Thus, this is a tractable murine model of AIHA that can serve as a platform to identify key cellular and molecular pathways that are compromised, thereby leading to autoantibody formation, as well as testing new therapeutics and management strategies.

Diagnostic algorithm for classification and characterization of direct antiglobulin test-negative autoimmune hemolytic anemia with 1-year clinical follow-up.

Approximately 5%-10% of autoimmune hemolytic anemia (AIHA) cases are negative for direct antiglobulin test (DAT). We previously reported a classification system for untreated patients with DAT-negative AIHA by quantifying levels of red blood cell (RBC)-bound IgG. This study investigated the clinical utility of a novel diagnostic algorithm with a comprehensive classification system and characterized each subgroup in DAT-negative AIHA. We assessed 637 patients with undiagnosed hemolytic anemia using our diagnostic algorithm and classification system, which was based on RBC-bound IgG levels and results of column method-DAT before and after washing RBCs. Patients were diagnosed with DAT-negative AIHA with 97% sensitivity and 84% specificity when the laboratory tests were performed before treatment and classified into the following six categories: tube DAT-negative, low-affinity IgG, double DAT-negative, IgA- or IgM-positive, low-affinity IgM, and s/o non-AIHA. The first three types were major conditions and accounted for 76% of DAT-negative AIHA cases. Based on multivariate analyses of idiopathic DAT-negative AIHA (n=71), platelet count and albumin concentration were significant factors for survival at 1-year follow-up. The low-affinity IgG group showed the highest platelet count and albumin levels, better response to steroids, and higher 1-year survival rate than those in other groups. Our classification included DAT-negative, IgA-driven, and warm-IgM AIHA categories, which were atypical forms of AIHA with the severe onset and increased risk of relapse. When treating a patient with DAT-negative hemolysis, atypical AIHA should be considered and tested in reference laboratories, especially before treatment.

Disease-modifying treatments for primary autoimmune haemolytic anaemia.

Primary autoimmune haemolytic anaemia (AIHA) is an autoantibody mediated condition characterised by a variable disease course. A myriad of immunomodulatory agents have been employed but there is a paucity of evidence to support their use or compare their effectiveness. To determine the effects of various disease-modifying treatment modalities in people with AHIHA. We searched MEDLINE (Ovid) (1946 to 2021), Embase (Ovid) (1974 to 2021), Latin American and Caribbean Health Sciences Literature (LILACS) (1982 to 2021), and the Cochrane Library (CENTRAL). Clinical trial registries and relevant conference proceedings were also reviewed. Records were included as of 7 March 2021. We did not impose any language restrictions. Randomised controlled trials (RCTs) comparing immunosuppressive or immunomodulatory treatments against no treatment, placebo, or another immunosuppressive or immunomodulatory treatment, for people of all age with idiopathic AIHA. We used standard methodological procedures expected by Cochrane. The prioritisedpre-defined outcomes includedcomplete haematological response at 12 months, frequency of adverse events at two, six and 12 months, partial haematological response at 12 months, overall survival at six and 12 months, relapse-free survival (RFS) at six and 12 months, red blood cel (RBC) transfusion requirement after treatment at 12 months, and quality of life (QOL) as measured by validated instruments at 12 months. Based on data availability, we were only able to perform meta-analysis on frequency of complete haematological response. Two trials were included, enrolling a total of 104 adult participants (96 randomised) with warm AIHA in the setting of tertiary referral centres, both comparing the effectiveness between rituximab (375 mg/m2 weekly for four weeks, or 1000 mg for two doses two weeks apart) plus glucocorticoid (prednisolone 1.5 or 1mg/kg/day with taper) and glucocorticoid monotherapy. The average age of participants in the two trials were 67 and 71, respectively. One of the included studies had good methodological quality with low risk of bias, whereas the other study had high risk of performance and detection bias due to lack of blinding.Compared with glucocorticoid alone, adding rituximab may result in a large increase of complete response at 12 months (n = 96, risk ratio (RR) 2.13, 95% confidence interval (CI) 1.34 to 3.40, GRADE: low-certainty evidence). Rates of adverse effects at prespecified time-points were not reported. Limited data on partial haematological response were reported. The evidence is very uncertain about the effect of adding rituximab to glucocorticoids on partial haematological response at 12 months (n = 32; study = 1; RR 3.00, 95% CI 0.13 to 68.57; GRADE very low-certainty evidence). RBC transfusion need at 12 months was reported in one study, with four participants (mean number of packed red cell units 4.0 ± 2.82) from the rituximab group and five participants from the placebo (corticosteroid only) (mean number of packed red cell units 5.6 ± 4.15) group requiring transfusion, indicating very uncertain evidence about the effect of adding rituximab to glucocorticoids (n = 32, RR 0.80, 95% CI 0.26 to 2.45, GRADE very low-certainty evidence). The other study did not report transfusion requirement at prespecified time points but reported no difference in transfusion requirement between the two groups when comparing responders from enrolment to end of response or to the end of study follow-up (34 units versus 30 units, median [range]: 0 [1 to 6] versus 0 [1 to 5], P = 0·81). Overall survival and RFS rates at prespecified time-points were not explicitly reported in either study. Data on QOL were not available. Available literature on the effectiveness of immunomodulatory therapy for primary AIHA is restricted to comparison between rituximab plus glucocorticoid and glucocorticoid alone, in patients with newly diagnosed warm AIHA, calling for need for additional studies. The current result suggests that combinatory therapy with rituximab and glucocorticoid may increase the rate of complete haematological response over glucocorticoid monotherapy.

Hepatic Pseudolymphoma: Case Report and Review

Purpose: Hepatic Pseudolymphoma or Reactive Lymphoid Hyperplasia is a rare benign neoplasia characterized by a polyclonal lymphocytes proliferation gathered in nodes with an active germinal center. It`s pathophysiology is uncertain though it is clearly related to inflammatory or infectious diseases, collagen disorders and malignancy. Diagnosis is often difficult due to its similarities to malignant tumors. If diagnostic is confirmed, a conservative approach may be applied. Method: A 57 years old woman with a history of lung adenocarcinoma T1a surgically managed by a left inferior lobectomy in 2015. That same year the patient develops an idiopathic autoimmune hemolytic anemia treated with steroids. During follow-up dissociated cholestasis is detected with elevation of hepatic enzymes. Primary Biliary Cholangitis was suspected. Imaging studies (RMI, US) show an 18mm hypervascular nodule between liver segments II and III. Core Needle Biopsy is performed showing polymorphic lymphoid infiltrations, polyclonal lymphocytes B and T, and germinal center cells, findings compatible with hepatic pseudolymphoma or low grade lymphoma. Results: Segment III hepatectomy was performed, without postoperative complications. Patient was discharged 2 days after surgery. Studies confirm hepatic pseudolymphoma. After 54 months follow up no recurrence has been detected. Conclusion: Hepatic Pseudolymphoma is a rare (less than 70 published cases) benign disease, often associated to autoimmune disorders, malignancy or collagen disorders. Treatment of this pathology could be conservative, but the difficulties regarding differential diagnosis (malignancy) makes surgical approach often required. If diagnostic is confirmed, a conservative approach may be applied.

Common variable immunodeficiency with granulomatous-lymphocytic interstitial lung disease and preceding neurological involvement: a case-report

BackgroundCommon variable immunodeficiency (CVID) is a group of heterogeneous primary immunodeficiencies characterised by a dysregulated and impaired immune response. In addition to an increased susceptibility to infection, it is also associated with noninfectious autoimmune and lymphoproliferative complications. CVID is rarely associated with neurological complications. Pulmonary involvement is more common, and patients can develop an interstitial lung disease known as granulomatous-lymphocytic interstitial lung disease (GLILD).Case presentationA 50-year-old Caucasian female with a history of Evans syndrome (idiopathic thrombocytopaenic purpura and autoimmune haemolytic anaemia) and hypogammaglobulinaemia initially presented to the neurology clinic with marked cerebellar ataxia and headaches. Following extensive investigation (which included brain biopsy), she was diagnosed with neuro-sarcoidosis and her symptoms resolved following treatment with immunosuppressive therapy. Over the following 10 years, she was extensively investigated for recurrent pulmonary infections and abnormal radiological findings, which included pulmonary nodules, infiltrates and splenomegaly. Subsequently, she was referred to an immunology clinic, where immunoglobulin replacement treatment was started for what was ultimately considered to be CVID. Shortly afterwards, evaluation of her clinical, radiological and histological findings at a specialist interstitial lung disease clinic led to a diagnosis of GLILD.ConclusionCVID is a condition which should be suspected in patients with immunodeficiency and recurrent infections. Concomitant autoimmune disorders such as haemolytic anaemia and immune thrombocytopenia may further support the diagnosis. As illustrated in this case, there is a rare association between CVID and inflammatory involvement of the neurological system. Respiratory physicians should also suspect CVID with associated GLILD in patients with apparent pulmonary granulomatous disease and recurrent infections. In addition, this case also highlights the challenge of diagnosing CVID and its associated features, and how the definitive exclusion of other pathologies such as malignancy, mycobacterial infection and lymphoma is required as part of this diagnostic process.

First report of expansion of CD4+/CD28 null T-helper lymphocytes in adult patients with idiopathic autoimmune hemolytic anemia

CD28 null T helper (Th) cells are rare in healthy individuals, but they are increased in various inflammatory and immune-mediated diseases. In this study, we determined the size of the CD4+/CD28 null T lymphocyte compartment in the peripheral blood of 40 autoimmune hemolytic anemia (AIHA) patients (idiopathic and secondary) and 20 healthy control subjects, using tri-color flow cytometry. The frequency and absolute count of CD4+/CD28 null T helper (Th) cells was significantly higher in idiopathic AIHA patients, compared to healthy controls (p = 0.001 and 0.001, respectively) and to patients with secondary AIHA (p = 0.04 and 0.01, respectively). The percentage of CD4+/CD28 null Th cells was also negatively correlated to the hemoglobin (Hb) level (p = 0.03). These findings demonstrate, for the first time, the expansion of this phenotypically-defined population of T lymphocytes in patients with idiopathic AIHA and indicate that it likely plays an etiological role in the development of this disease. However, establishing the use of this marker for diagnosis or monitoring treatment of such patients needs further studies.

Partial Splenic Artery Embolization for Idiopathic Warm Autoimmune Hemolytic Anemia Refractory to Medical Therapy

Purpose: While Partial Splenic Artery Embolization (PSAE) is a useful procedure that has been performed for a variety of indications including trauma and hypersplenism, it has only been rarely described as a treatment for Idiopathic Warm Autoimmune Hemolytic Anemia. Previous reports in the literature are limited to case reports in situations that include the patient being a poor surgical candidate, the inability to transfuse blood during surgery because of autoantibodies, and a patient's refusal of blood products on religious grounds. Materials and Methods: A case report describing the case of a 27-year-old male diagnosed with idiopathic warm Autoimmune Hemolytic Anemia treated successfully with partial splenic artery embolization (PSAE) as a bridging therapy to definitive surgical splenectomy. Results: The patient's pre-procedure hemoglobin was 2.1 g/dl. The first hemoglobin post-procedure was 4.5 g/dl. After embolization, the patient remained in the inpatient setting for eight days for close observation. During the inpatient hospitalization the patient's hemoglobin continued to trend upwards until it stabilized around 6 g/dl. Inpatient laboratory workup also showed increasing haptoglobin, and decreasing LDH. After discharge, the patient developed persistent pain two months post-procedure. An elective splenectomy was scheduled three months after the embolization procedure to address the persistent pain. Six months' post embolization procedure and three months postoperatively, the patient is doing well clinically with a hemoglobin of 14 g/dl. Conclusion: In conclusion, this case demonstrates the utility of a Partial Splenic Artery Embolization (PSAE) as an acute life-saving intervention for poor surgical candidates with idiopathic warm Autoimmune Hemolytic Anemia (AIHA) refractory to medical therapy.

PSY25 FACTORS BEHIND AUTOIMMUNE HEMOLYTIC ANEMIA

The mechanism of autoimmune hemolytic anemia (AIHA) is the production of antibodies by the body against its own red blood cells. In most cases, the cause of AIHA cannot be determined (idiopathic autoimmune hemolytic anemia), and it’s frequently associated with other diseases, or caused by certain substances get into the human body.

Abstract No. 397 Partial splenic artery embolization for idiopathic warm autoimmune hemolytic anemia refractory to medical therapy

Abstract No. 397 Partial splenic artery embolization for idiopathic warm autoimmune hemolytic anemia refractory to medical therapy

Warm antibody autoimmune hemolytic anemia in pregnancy: A case report

Introduction. Warm autoimmune hemolytic anemia is the presence of warm autoantibodies against red blood cell with or without complement activation. The presence of warm autoantibodies on the red blood cells is detected by direct antiglobulin test with polyspecific and immunoglobulin G reagents. Antibodies removed from the red blood cells tested by indirect antiglobulin test show panagglutination with a panel of red blood cells. Case Report. We report a rare case of idiopathic warm autoimmune hemolytic anemia in a 26-year-old woman in the early pregnancy. Warm autoimmune hemolytic anemia was mild, so during monitoring the risk to the fetus was assessed as low. The fetal status was assessed every four weeks. The noninvasive Doppler examination of the fetal middle cerebral artery revealed no fetal anemia. The last control before childbirth was done in the 38 week of pregnancy and the fetal direct antiglobulin test was 4+ and indirect antiglobulin test was 2+. The newborn presented with warm autoantibody immunoglobulin G, and positive direct antiglobulin test (3+). The infant was breastfed for nine months after birth. The direct antiglobulin tests were positive (3+) in both mother and child over the following 12 months. Conclusion. In case of warm autoimmune hemolytic anemia, the main purpose is to stop hemolysis and correct anemia in pregnant women, but it is also necessary to monitor the fetal condition in order to detect fetal hemolytic anemia as early as possible.

Anti tissue transglutaminase antibody in idiopathic autoimmune haemolytic anemia

BackgroundIn idiopathic autoimmune haemolytic anaemia (AIHA haemolytic antibodies are directed to every type of red cellsWestern blot studies have shown antibody positivity towards red cell anion channel complex which also includes band 4.2 a protein with similarities to tissue trans glutaminase. ObjectiveEvaluation of AIHA for anti tissue transglutaminase antibody (Anti tTG). Materials & methodsTwenty three AIHA patients were tested along with routine hamatogical work up, for a series of auto antibodies and red cell eluates and serum from the patents were tested against solubilised group O red cell ghosts on western blot. Other ancillary investigations were done to rule out complications and secondary causes of haemolysis. Results11/23 patients (48%) were positive for anti tTG, Four, 3 and 8,7 patients were positive for anti thyroid, anti b2 glycoprotein, lupus anticoagulant and ANA respectively. One patient with anti tTG had biopsy proven celiac disease. Three patient developed DVT and all of them were lupus anticoagulant as well as b2 gp-1 antibody positive.17 had become Coombs test negative on treatment while 21/23 had positive western blot test. Discussion & conclusionThere is strong association of anti tTG antibody with idiopathic AIHA. Aetiological association of this finding needs exploration.

Successful treatment of severe idiopathic mixed autoimmune hemolytic anemia with bortezomib and intravenous immunoglobulin

Introduction: Autoimmune hemolytic anemia (AIHA) is a rare and diverse group of acquired hemolytic anemias which results from increased destruction of red blood cells (RBCs) due to autoantibodies directed against antigens on the RBC surface. Currently, there are no clearly defined evidence-based guidelines on the management of AIHA, and current treatment options are based on small retrospective studies, case reports, as well as expert experiences and recommendations. We report a case of severe idiopathic mixed AIHA that responded to a combination of steroids, intravenous immunoglobulin (IVIG) and bortezomib. Case Report: A 25-year-old African American female presented with jaundice, shortness of breath, and abdominal pain. She had splenomegaly on examination and initial work-up was significant for severe anemia (hemoglobin, 3.3 g/dl) and hyperbilirubinemia (total bilirubin, 26.7 mg/dl; direct bilirubin, 21.9 mg/dl). Direct antiglobulin test (DAT) was microscopically positive for anti-IgG and anti-C3d, and cold autoantibodies were identified. An extensive workup for a possible secondary cause of her anemia was non-revealing. She was sequentially treated with prednisone, IVIG, and bortezomib. Marked response was noted as evidenced by improvement in the hemoglobin from a nadir of 3.2 g/dl on admission to 10.1 at discharge. Patient has remained clinically in remission since then. Conclusion: The first line treatment for warm AIHA (w-AIHA) includes glucocorticoids and transfusion of least incompatible RBCs. Steroids are rarely necessary or effective in cold agglutinin AIHA in which case high dose IVIG and plasmapheresis have been used albeit with inconsistent results. Bortezomib is an inhibitor of the 26S proteasome and is approved for the treatment of multiple myeloma. It has been reported to have some activity in rituximabresistant cold agglutinin disease (CAD) due to its activity against the CD20-negative plasma cell compartment that may be responsible for IgG anti-RBC autoantibody production.

Indications for splenectomy in a tertiary care hospital in South India

Background: Splenectomy is a surgical treatment for a wide range of diseases including symptomatic splenomegaly, autoimmune, malignant, hereditary and congenital disorders, splenic injury/rupture secondary to blunt trauma to abdomen. By far the two most common atraumatic indications for splenectomy are malignancy and haematological autoimmune disorders, such as Idiopathic Thrombocytopenic Purpura (ITP) and Autoimmune Hemolytic Anemia (AIHA). Methods: We did a retrospective study in a tertiary care hospital, of all patients undergoing splenectomy over a 5-year period to describe the indications for splenectomy. Results: 186 patients under went splenectomy, both emergency and elective (Open or Laparoscopic – conventional and hand-assisted). Most common indication was hematological in 153 patients, of which ITP-70 (37.6%) was the highest. Non-hematological indications were secondary to splenic cyst or abscess, neuroendocrine tumour of the pancreas, hydatid cyst of spleen. Emergency splenectomy was done for blunt trauma to abdomen, and grade 5 injury was commonly encountered. Among all, 16 (8.6%) patients had spleniculi. Conclusion: In patients with hematological disorders, splenectomy must be undertaken only after anticipating both, short- and long-term risks and potential benefits to the patient.

An Unusual Case of Autoimmune Hemolytic Anemia-Thinking Outside the Box for Management

A 27 year old male with no significant past medical history presented to an outside hospital for chief complaints of nausea/vomiting, epigastric pain, and acute jaundice. Initial laboratory workup revealed a hemoglobin of 5.5 g/dl, normal WBC and platelet count, elevated direct bilirubin (10 mg/dl), elevated lactate dehydrogenase (969 IU/L), low haptoglobin (<8 mg/dl), a peripheral smear showing rare polychromasia and spherocytes, and positive direct antiglobulin test (DAT: BS +, IgG +, C3d -) with presence of warm autoantibodies. All infectious disease testing was negative. Initial CT abdomen showed a normal sized spleen. The patient was diagnosed with idiopathic warm autoimmune hemolytic anemia and was treated with pulsed steroids, one dose of Rituximab, and transfused with up to 13 units of packed red blood cells. The patient did not respond to medical treatment, and after one week, the patient was transferred to our institution for escalation of care.At our institution, the patient presented with similar symptoms. Due to lack of response to packed red blood cell transfusions, As the patient continued a downtrend in the hemoglobin despite continued transfusion support, Transfusion Medicine advised to only transfuse phenotypically matched, least incompatible, packed red blood cells for significantly symptomatic anemia or hemodynamic instability. High dose steroid were continued and IVIG, Cytoxan and Vincristine were added to his warm autoimmune hemolytic anemia (WAIHA) therapy. Despite these efforts, the patient's hemoglobin continued to decrease despite an additional 9 RBC units transfused at our institution, reaching a hemoglobin nadir of of 2.1 g/dL. In addition, the patient developed thrombocytopenia, NSTEMI, and left lower quadrant pain accompanied by bloody bowel movements. A repeat CT scan of the abdomen was performed, which revealed an enlarged spleen with a span of 16.5 cm in its maximum dimension. Due to concerns for splenic infarction and/or rupture, and since the patient was not a candidate for surgery, partial splenic artery embolization was performed. Thirty percent residual viable spleen remained. Within hours post embolization, a dramatic increase in hemoglobin was observed without any additional transfusion support. Shortly after splenic embolization the patient developed severe left upper quadrant abdominal pain with a peri-splenic fluid measuring slightly greater than simple fluid attenuation on CT which was managed medically. After close observation the patient was discharged home 2 weeks after admission. At home the patient was doing well with the exception of persistent left upper quadrant pain. He had no clinical or laboratory signs of recurrent hemolysis. Three months post discharge, due to persistent left upper quadrant pain and presence of a splenic cyst, the patient underwent a laparoscopic splenectomy that was performed without complications. During this hospitalization, in preparation for surgery, compatibility testing showed no autoantibodies. However new clinically significant alloantibodies were identified.Hypersplenism and/or reticulocytopenia are infrequent complications of a warm autoimmune hemolytic anemia, constituting a life threatening complication that may not respond to standard therapy and may not qualify for surgical intervention. The above patient did not improve with any medical therapies and displayed a decreasing trend in hemoglobin that was accompanied by increasing lactate levels and NSTEMI. Splenic embolization achieved a dramatic response that was maintained through follow up. Due to recurrent pain from the embolization, the patient eventually received a splenectomy once he was stable. Four months after initial presentation, post infusion of 4 doses of Rituxan and steroid therapy, the autoantibodies were not detectable. However, the patient developed 3 alloantibodies post multiple transfusions. DisclosuresNo relevant conflicts of interest to declare.

Incidental Hepatic Splenosis in a Male with Microhematuria

Hepatic splenosis is a rare entity which involves imbedding of native splenic tissue into liver parenchyma. This typically occurs after abdominal trauma, splenic laceration, or splenectomy. A 35 year old Russian male with history of obesity presented to Urology for evaluation given history of a solitary kidney. Urinalysis showed evidence of microhematuria and subsequent urine cytology showed a highly atypical cell. An abdominal MRI without contrast was done for further evaluation. A 3.4 cm x 5.0 cm T1 hypointense, T2 hyperintense mass in the right hepatic lobe was seen (figure 1). Additional history revealed splenectomy and nephrectomy after trauma in 1984. He denied blood transfusions, intravenous drug use, or sexual promiscuity. He admitted to a 6 year period of heavy alcohol use in his twenties. Labs revealed normal LFTs and negative viral hepatitis B and C serologies. Tumor markers CEA, AFP, and Ca 19-9 were not elevated. An abdominal MRI with contrast was done to better evaluate the lesion. It showed an unchanged lobulated 3.4 cm x 5.0 cm mass in hepatic segment 8 with arterial enhancement and patchy areas of washout (figure 1). The differential included hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma, focal nodular hyperplasia, sarcoma, and metastatic disease from testicular cancer. There was particular concern for HCC given arterial enhancement with washout. An ultrasound guided biopsy was done for diagnosis. Pathology of the mass showed red and white pulp of splenic tissue surrounded by normal appearing hepatocytes (figure 2). Approximately 80% of patients with hepatic splenosis have a history of splenectomy. The interval time between splenectomy and hepatic splenosis is 25 years. The pathogenesis is believed to be from hematogenous spread or direct seeding of splenic tissue onto exposed serosal surfaces at the time of trauma or splenectomy. Technetium-99m-labeled heat denatured red blood cell scintigraphy or supraparamagnetic iron oxide enhanced MRI are non-invasive tests that can confirm the diagnosis. Hepatic splenosis does not require resection unless the patient has evidence of idiopathic thrombocytopenic purpura or autoimmune hemolytic anemia. Although hepatic splenosis is a rare entity, it can mimic malignancy and lead to invasive testing and surgery. It is important to consider this diagnosis in patients with history of splenectomy and characteristic imaging in order to prevent unnecessary medical intervention.2423_A Figure 1 No Caption available.2423_B Figure 2 No Caption available.

Anemia hemolítica autoinmune por anticuerpos calientes secundaria a hipertiroidismo. Revisión de la literuatura

La anemia hemolítica autoinmune (AHAI) es un trastorno con autoanticuerpos dirigidos contra los glóbulos rojos lo que acorta su supervivencia. Su etiología es diversa, puede ser idiopática o secundaria a consumo de medicamentos o a enfermedades autoinmunes. La fisiopatología exacta sigue sin estar clara en los casos en que se ha descrito secundaria a enfermedad tiroidea, siendo la mayoría de los pacientes hipertiroideos en el momento del diagnóstico de AHAI. Presentamos un caso con antecedente de AHAI idiopática con múltiples exacerbaciones, que ingresa por síntomas sugestivos de tirotoxicosis vs tormenta tiroidea, manejado con metimazol, propanolol, corticoides y colestiramina. Se concluye que el paciente desarrolló una AHAI secundaria a un hipertiroidismo, por lo que es importante evaluar las causas secundarias y realizar un seguimiento estricto debido al componente autoinmune de su enfermedad.

Disease-modifying treatments for primary autoimmune haemolytic anaemia

Background Primary autoimmune haemolytic anaemia (AIHA) is an autoantibody mediated condition characterised by a variable disease course. A myriad of immunomodulatory agents have been employed but there is a paucity of evidence to support their use or compare their effectiveness. Objectives To determine the effects of various disease-modifying treatment modalities in people with AHIHA. Search methods We searched MEDLINE (Ovid) (1946 to 2021), Embase (Ovid) (1974 to 2021), Latin American and Caribbean Health Sciences Literature (LILACS) (1982 to 2021), and the Cochrane Library (CENTRAL). Clinical trial registries and relevant conference proceedings were also reviewed. Records were included as of 7 March 2021. We did not impose any language restrictions. Selection criteria Randomised controlled trials (RCTs) comparing immunosuppressive or immunomodulatory treatments against no treatment, placebo, or another immunosuppressive or immunomodulatory treatment, for people of all age with idiopathic AIHA. Data collection and analysis We used standard methodological procedures expected by Cochrane. The prioritised pre-defined outcomes included complete haematological response at 12 months, frequency of adverse events at two, six and 12 months, partial haematological response at 12 months, overall survival at six and 12 months, relapse-free survival (RFS) at six and 12 months, red blood cel (RBC) transfusion requirement after treatment at 12 months, and quality of life (QOL) as measured by validated instruments at 12 months. Based on data availability, we were only able to perform meta-analysis on frequency of complete haematological response. Main results Two trials were included, enrolling a total of 104 adult participants (96 randomised) with warm AIHA in the setting of tertiary referral centres, both comparing the effectiveness between rituximab (375 mg/m2 weekly for four weeks, or 1000 mg for two doses two weeks apart) plus glucocorticoid (prednisolone 1.5 or 1mg/kg/day with taper) and glucocorticoid monotherapy. The average age of participants in the two trials were 67 and 71, respectively. One of the included studies had good methodological quality with low risk of bias, whereas the other study had high risk of performance and detection bias due to lack of blinding. Compared with glucocorticoid alone, adding rituximab may result in a large increase of complete response at 12 months (n = 96, risk ratio (RR) 2.13, 95% confidence interval (CI) 1.34 to 3.40, GRADE: low-certainty evidence). Rates of adverse effects at prespecified time-points were not reported. Limited data on partial haematological response were reported. The evidence is very uncertain about the effect of adding rituximab to glucocorticoids on partial haematological response at 12 months (n = 32; study = 1; RR 3.00, 95% CI 0.13 to 68.57; GRADE very low-certainty evidence). RBC transfusion need at 12 months was reported in one study, with four participants (mean number of packed red cell units 4.0 ± 2.82) from the rituximab group and five participants from the placebo (corticosteroid only) (mean number of packed red cell units 5.6 ± 4.15) group requiring transfusion, indicating very uncertain evidence about the effect of adding rituximab to glucocorticoids (n = 32, RR 0.80, 95% CI 0.26 to 2.45, GRADE very low-certainty evidence). The other study did not report transfusion requirement at prespecified time points but reported no difference in transfusion requirement between the two groups when comparing responders from enrolment to end of response or to the end of study follow-up (34 units versus 30 units, median [range]: 0 [1 to 6] versus 0 [1 to 5], P = 0·81). Overall survival and RFS rates at prespecified time-points were not explicitly reported in either study. Data on QOL were not available. Authors' conclusions Available literature on the effectiveness of immunomodulatory therapy for primary AIHA is restricted to comparison between rituximab plus glucocorticoid and glucocorticoid alone, in patients with newly diagnosed warm AIHA, calling for need for additional studies. The current result suggests that combinatory therapy with rituximab and glucocorticoid may increase the rate of complete haematological response over glucocorticoid monotherapy.

Strong Association of Celiac Disease Serology with Idiopathic Autoimmune Hemolytic Anemia from Western India

▪Idiopathic autoimmune hemolytic anemia (AIHA) may be associated with positive autoimmune serology and some of the patients develop autoimmune disorder, malignancy on long follow up.There are no cohort studies on AIHA from India with long follow up. As AIHA has no known etiology and different populations of the world differ in their genetic makeup, environment background, it is likely that underlying conditions associated with AIHA will also vary in different countries with different population characteristics.Present study evaluates association of autoimmune markers along with follow up of a cohort of 21 well characterized AIHA patients from Gujarat, a western state of India.The cohort comprises of 2 men and 19 women aged between 20-72 years (Mean 36 years), followed up for a varying period of 6 month to 25 years (Mean 41/2years) after the diagnosis. AIHA was diagnosed by classical criteria of clinical presentation with severe weakness with feeling of being unwell, pallor and yellow discoloration coupled with laboratory parameters showing low hemoglobin (3.7-7.2 g/dL), high serum bilirubin level ( 2.1-3.8 mg/dl) , high reticulocyte count (5-69%) and strong direct anti human globulin(AHG) test coupled with absence of any other disease on detailed biochemical, flow cytometry (PNH, clonal disorders excluded) and other relevant imaging studies. Bone marrow examination was done in all patients. Splenomegaly of varying degree was present in 16/21 (78%) of the patients.All patients except 3/21 (14%) received red cell transfusions following the diagnosis as the Hb levels were very low. Best cross matched red cells were provided along with high dose prednisolone (1 mg/kg body weight). One of the patients, a 32 year old lady presented with intense hemolysis, hepatosplenomegaly, lymphadenopathy and hemophagocytosis in peripheral blood and in the marrow. After their stabilization the patients were tested for several autoimmune markers e.g. ANA, Anti ds-DNA, Antiparietal Cell, Antithyroid, AntiCardiolipin, Anti-β2glycoprotein, anti-tissue transglutaminase antibody IgA and lupus anticoagulants. 11/21 patients became AHG negative within one year, however they continued to show positive reaction by western blot test.7/21 (34%) positive for LA screening test (3 confirmed by platelet neutralization (14%), 2/21 positive for anti-β2 glycoprotein antibody. Anticardiolipin antibody and antiparietal cell antibody was negative in all. 4/21 were positive for antithyroid antibody and one of them needed thyroxine. 7/21 (34%) were ANA positive (6/7 anti dsDNA positive), one of them went on to develop SLE. One patient with LA positivity developed DVT in left leg and portal vein thrombosis.Most striking association in our cohort was seen with anti-transglutaminase antibody IgA, 8/21 (38%) were strongly positive for the antibody and 6/21 (28%) were in the borderline range. Hence 66% of our cohort had abnormal serology for celiac disease. AIHA in all our patients were well controlled 16/21 (78%) with steroid and azathioprine only, 4/21 underwent (18%) splenectomy. Single patient presenting with extensive hemophagocytosis and immune hemolytic anemia received weekly courses of Rituximab (375mg/m2), 4 cycles and her Hb was stabilized.Association of Celiac disease marker with AIHA in a large majority of patients needs further exploration. Western blot can be used when AHG tests become negative during follow up. DisclosuresNo relevant conflicts of interest to declare.