Paroxysmal Cold Hemoglobinuria Research Articles

Autoimmune hemolytic anemia with Donath–Landsteiner antibody: A rare case report

Abstract: Paroxysmal cold hemoglobinuria (PCH) is a rare autoimmune hemolytic anemia characterized by the abrupt onset of hemoglobinuria and anemia, typically following exposure to cold temperatures. The pathogenesis of PCH is primarily associated with the presence of a unique autoantibody known as the Donath–Landsteiner antibody, a biphasic hemolysin (immunoglobulin G) with specificity for P blood group antigens. This rare clinical entity can manifest at any age; however, in children, it typically follows a viral upper respiratory tract infection or immunization. We hereby report a rare case of PCH in a 3-year-old boy who presented at our hospital with severe anemia along with liver and renal dysfunction.

Autoimmune hemolytic anemia in children

Autoimmune hemolytic anaemia (AIHA) is an uncommon cause of antibody-induced hemolytic anemia in children. It is divided into three categories: warm AIHA, cold antibody AIHA and paroxysmal cold hemoglobinuria. The diagnostic work-up typically begins with a peripheral smear and a direct antiglobulin test. Further diagnostic approaches and pathogenesis of all three entities are discussed. Clinical trials are lacking for AIHA in children. First-line therapy for warm AIHA is corticosteroids and for cold antibody AIHA is rituximab. Data on other therapeutic agents is reviewed. Supportive care is an important aspect, particularly in cold AIHA and paroxysmal cold hemoglobinuria. Issues related to blood transfusion due to antibodies including the least incompatible blood are discussed. Tables and figures provide an overview of pathology, diagnosis and diagnostic algorithm.

Cold-antibody Autoimmune Hemolytic Anemia: its Association with Neoplastic Disease and Impact on Therapy.

Cold-antibody mediated autoimmune hemolytic anemia (cAIHA) is subclassified as cold agglutinin disease (CAD), secondary cold agglutinin syndrome (CAS), and paroxysmal cold hemoglobinuria (PCH). This review aims to address the occurrence of neoplastic disorders with these three entities and analyze the impact of such neoplasias on treatment for cAIHA. "Primary" CAD is a distinct clonal B-cell lymphoproliferative disorder in probably all cases, although not classified as a malignant lymphoma. CAS is secondary to malignant lymphoma in a minority of cases. Recent findings allow a further clarification of these differential diagnoses and the therapeutic consequences of specific neoplastic entities. Appropriate diagnostic workup is critical for therapy in cAIHA. Patients with CAD should be treated if they have symptomatic anemia, significant fatigue, or bothersome circulatory symptoms. The distinction between CAD and CAS and the presence of any underlying malignancy in CAS have essential therapeutic implications.

Challenges in the diagnosis and management of autoimmune hemolytic anemia: A case-based approach. Experience from a tertiary care hospital in the Haryana region.

Autoimmune hemolytic anemia (AIHA) is a rare immune disorder which occurs when antibodies are directed against self red blood cells (RBCs) leading to hemolysis. AIHA is widely classified as warm autoimmune hemolytic anemia, cold agglutinin syndrome, mixed AIHA, paroxysmal cold hemoglobinuria and rarely drug induced AIHA. The pathogenesis of AIHA is complex interplay between genetic predisposition, immune dysregulation and enviornmental triggers. A direct antiglobulin test can be used to assess the immunological origin of the hemolysis in order to diagnose AIHA after identifying laboratory and clinical symptoms of hemolysis. The objective is to understand underlying mechanism in AIHAs, and usage of targeted therapies to modulate specific components of the immune response. We are hereby presenting a case series of 11 clinically suspected cases of AIHA in collaboration with their clinical features, immuno-hematological and other laboratory parameters, Flow cytometric analysis of lymphocyte subset in relevant cases, underlying etiology as well as serological subtype are also included. Majority of the patients were categorized as secondary AIHA (7/11, 63.63%). Out of 11 cases 7 were serologically subtyped as warm AIHA (7/11, 63.63%) ,2 cases were DaaT negative AIHA (2/11;18.18%), 2 cases were characterized as mixed AIHA subtype (2/11, 18.18%). Accurate subtyping of AIHA requires a systematic immunohematological approach coupled with comprehensive evaluations of clinical, hematological, and biochemical parameters.

Autoimmune Hemolytic Anemias: Classifications, Pathophysiology, Diagnoses and Management.

Autoimmune hemolytic anemias (AIHAs) are conditions involving the production of antibodies against one's own red blood cells (RBCs). These can be primary with unknown cause or secondary (by association with diseases or infections). There are several different categories of AIHAs recognized according to their features in the direct antiglobulin test (DAT). (1) Warm-antibody AIHA (wAIHA) exhibits a pan-reactive IgG autoantibody recognizing a portion of band 3 (wherein the DAT may be positive with IgG, C3d or both). Treatment involves glucocorticoids and steroid-sparing agents and may consider IVIG or monoclonal antibodies to CD20, CD38 or C1q. (2) Cold-antibody AIHA due to IgMs range from cold agglutinin syndrome (CAS) to cold agglutin disease (CAD). These are typically specific to the Ii blood group system, with the former (CAS) being polyclonal and the latter (CAD) being a more severe and monoclonal entity. The DAT in either case is positive only with C3d. Foundationally, the patient is kept warm, though treatment for significant complement-related outcomes may, therefore, capitalize on monoclonal options against C1q or C5. (3) Mixed AIHA, also called combined cold and warm AIHA, has a DAT positive for both IgG and C3d, with treatment approaches inclusive of those appropriate for wAIHA and cold AIHA. (4) Paroxysmal cold hemoglobinuria (PCH), also termed Donath-Landsteiner test-positive AIHA, has a DAT positive only for C3d, driven upstream by a biphasic cold-reactive IgG antibody recruiting complement. Although usually self-remitting, management may consider monoclonal antibodies to C1q or C5. (5) Direct antiglobulin test-negative AIHA (DAT-neg AIHA), due to IgG antibody below detection thresholds in the DAT, or by non-detected IgM or IgA antibodies, is managed as wAIHA. (6) Drug-induced immune hemolytic anemia (DIIHA) appears as wAIHA with DAT IgG and/or C3d. Some cases may resolve after ceasing the instigating drug. (7) Passenger lymphocyte syndrome, found after transplantation, is caused by B-cells transferred from an antigen-negative donor whose antibodies react with a recipient who produces antigen-positive RBCs. This comprehensive review will discuss in detail each of these AIHAs and provide information on diagnosis, pathophysiology and treatment modalities.

Significance of Donath-Landsteiner Antibody Test for Diagnoses of a Rare Case of Paroxysmal Cold Hemoglobinuria with Acute Renal Failure

Donath Landsteiner (DL) antibodies are biphasic IgG autoantibodies formed in response to a viral or bacterial infection and can induce paroxysmal cold hemoglobinuria (PCH), an autoimmune hemolytic anaemia. It is more frequently seen in children post-infective episodes and is transient and self-limiting in nature. We report a case of a 4.5-year-old male who presented with sudden intravascular hemolysis and AKI with a 2-weekold history of fever and acute viral hepatitis. AKI in PCH is a rarity, and the diagnoses of PCH could only be made correctly with the help of a DL antibody test, which helped with subsequent patient management and avoiding unnecessary treatment escalation.

Clinical and serological features in an 11-monthold infant with Paroxysmal cold hemoglobinuria

Clinical and serological features in an 11-monthold infant with Paroxysmal cold hemoglobinuria

Adenovirus-associated Paroxysmal Cold Hemoglobinuria as Chilly Month Hemolytic Crisis.

Adenovirus-associated Paroxysmal Cold Hemoglobinuria as Chilly Month Hemolytic Crisis.

A rare cause of Acquired Hemolytic Anemia in a child; Donath-Landsteiner antibody

Abstract Introduction/Objective INTRODUCTION: The Donath-Landsteiner (DL) antibody is known to cause paroxysmal cold hemoglobinuria (PCH), a rare form of intravascular hemolytic anemia which is precipitated by an IgG biphasic hemolysin with specificity to the P blood group antigen and most commonly reported in children. The DL test is a serologic test specifically examines, the biphasic nature of the antibody activity. Methods/Case Report CASE PRESENTATION: A 4-year-old previously healthy boy presented at an academic medical center with rhinorrhea and nasal congestion. His family reported that his urine became darker almost coke colored after his symptoms started. His initial vitals; temperature of 37.1 C, heart rate of 140, blood pressure of 122/87 and O2 saturation of 96% on room air. Laboratory investigations showed a hemoglobin level of 4.2 g/dL, hematocrit level of 12.5%, platelets count of 229 K/uL, indirect bilirubin of 6.2mg/dL, haptoglobin <30 mg/dL, LDH >1800 U/L. Direct antiglobulin test was positive with complement only. Thermal Amplitude and indirect Donath-Landsteiner tests were both positive. Respiratory viral panel was positive for Rhinovirus. The antibody screen was negative, and the patient was provided supportive care including as needed RBC transfusion, warming of fluids and body. By day day 9 patient Hgb stabilized, LDH, bilirubin and haptoglobin normalized and his urine turned yellow color and was discharged in stable condition. Results (if a Case Study enter NA) NA Conclusion CONCLUSIONS PCH is classified as a cold autoimmune hemolytic anemia caused by an IgG antibody that sensitizes RBCs at cold temperatures by attaching complement to the RBCs, causing intravascular hemolysis upon rewarming. The DL test for PCH involves in vitro testing for hemolysis with the patient's serum, washed group-O cells expressing the P antigen, and fresh normal serum. To prevent autoadsorption of the antibody and hemolysis, blood should be collected in prewarmed tubes that do not contain anticoagulants and kept at 37°C during the collection procedure. A high index of suspicion especially in pediatric population should be maintained after a viral infection. The treatment is usually supportive.

A Single Center Experience for Clinical Evaluation of Paroxysmal Cold Hemoglobinuria and Donath-Landsteiner Testing

Introduction: Paroxysmal cold hemoglobinuria (PCH) is a rare form of autoimmune hemolytic anemia (AIHA), mainly affecting children. The diagnosis and management is challenging due to similarities to other causes for AIHA and limited availability to Donath-Landsteiner (DL) testing. Methods: In this single-center retrospective study, we aimed to characterize the clinical presentation and outcomes of PCH patients, defined as having positive Donath-Landsteiner antibodies, compared to a cohort of AIHA patients. Results: DL-positive patients were observed to have higher lactose dehydrogenase levels and lower reticulocyte counts compared to DL-negative patients, although this was not statistically significant. We also observed that using steroids in DL-positive patients did not significantly impact their recovery. Conclusions: Our findings support the limited published data on PCH patients and further prompt prompting larger multicenter studies to further characterize these patients so that they are more readily identified, especially in centers where DL antibody testing is not readily available.

Steroid-Refractory Paroxysmal Cold Hemoglobinuria in a 6-Year-Old Male

Background Paroxysmal Cold Hemoglobinuria (PCH) is a rare autoimmune hemolytic anemia (AIHA) that is often seen as a sequela of viral upper respiratory tract infections and immunizations in children. It is characterized by a positive Coombs test with a biphasic auto anti-P IgG known as the “Donath-Landsteiner antibody,” which sensitizes red cells and fixes complement at 0-4°C, and hemolyzes red cells near body temperature. The mainstay treatment of PCH includes cold avoidance, intravenous hydration, and supportive blood transfusions. Glucocorticoids may be used in the setting of significant hemolysis, with debated efficacy. We present a case of steroid-refractory PCH in a 6-year-old boy secondary to human rhinovirus/enterovirus. Methods Patient clinical data was abstracted from the electronic medical record. Blood bank testing was performed through the in-house blood bank. Donath-Landsteiner testing was performed at a reference laboratory. Findings A 6-year-old male with a history of mild upper respiratory tract infection 1 week prior presented to the emergency department with abdominal pain, dark urine, and jaundice. Initial laboratory evaluation uncovered anemia with hemoglobinuria, hyperbilirubinemia, elevated LDH, and decreased haptoglobin, raising concerns for acute hemolytic anemia (Table 1). Follow-up blood bank testing revealed a cold autoantibody. Viral PCR was positive for human rhinoenterovirus. Despite supportive therapy through intravenous fluids and warming, the patient's anemia worsened significantly (Hgb 5.1g/dL) and packed red blood cell (pRBC) transfusion was required. Methylprednisolone 0.8 mg/kg IV twice daily was initiated as empiric therapy for autoimmune hemolysis without significant improvement. Blood was sent for Donath-Landsteiner antibody testing at a reference laboratory and revealed a bi-phasic hemolysin consistent with paroxysmal cold hemoglobinuria. The patient required an additional pRBC transfusion and was discharged after 4 days inpatient. Conclusion Our case supports a growing body of evidence that finds steroid therapy inefficacious in the treatment of hemolysis in the setting of PCH.

Severe Acute Kidney Injury in Children as a Rare Complication of Paroxysmal Cold Hemoglobinuria.

Paroxysmal cold hemoglobinuria (PCH) is a rare condition in childhood characterized by complement-mediated premature destruction of red blood cells. PCH is associated with intravascular hemolysis causing hemoglobinuria, which may result in acute kidney injury of various severity. We aimed to retrospectively analyze clinical and laboratory features of children with PCH-associated acute kidney injury received at tertiary Pediatric Hematology and Nephrology Center, University Motol Hospital, Prague, Czech Republic during the period 2016 to 2022. We present here 3 children with PCH-associated acute kidney failure requiring renal replacement therapy. We highlight the association of PCH with kidney disease. Renal parameters and urine examination should be regularly tested in all children with PCH.

A single center experience for clinical evaluation of paroxysmal cold hemoglobinuria and Donath-Landsteiner testing.

Paroxysmal cold hemoglobinuria (PCH) is a rare form of autoimmune hemolytic anemia (AIHA), mainly affecting children. The diagnosis and management are challenging due to similarities to other causes for AIHA and limited availability to Donath-Landsteiner (DL) testing. In this single-center retrospective study, we aimed to characterize the clinical presentation and outcomes of PCH patients, defined as having positive Donath-Landsteiner antibodies, compared to a cohort of AIHA patients. DL-positive patients were observed to have higher lactate dehydrogenase levels and lower reticulocyte counts compared to DL-negative patients, although this was not statistically significant. We also observed that using steroids in DL-positive patients did not significantly impact their recovery. Our findings support the limited published data on PCH patients and further prompt larger multicenter studies to further characterize these patients so that they are more readily identified, especially in centers where DL antibody testing is not readily available.

Is Splenectomy still the best treatment for Autoimmune hemolytic anemia

Introduction:
 Autoimmune hemolytic anemia (AIHA) is an acquired, heterogeneous group of diseases that includes AIHA with warm type antibodies, cold agglutinin disease (CAD), mixed type AIHA, paroxysmal cold hemoglobinuria, and atypical AIHA.
 Currently CAD is defined as chronic, clonal lymphoproliferative disease, while presence of cold agglutinin in gastrointestinal tract is known as cold agglutinin syndrome. AIHA is mediated by autoantibodies against red blood cells (RBCs), these antibodies cause premature destruction of erythrocytes. The pathogenesis of AIHA is complex and still not yet fully understood.
 Aim of study:
 The purpose of the study was to review the literature on the treatment options for Autoimmune Hemolytic Anemia
 Materials and methods: A systemic review was conducted using PubMed, ScienceDirect, Google Scholar databases. The search strategy was based on following terms: Aiha, splenectomy autoimmune anemia, aiha treatment,
 Results and Conclusions:
 Based on the review of the medical literature, we believe that Splenectomy is no longer the most effective method of treating any type of AIHA and the Rituximab treatment presented by us seems to be safer and definitely less burdensome for the patient.
 Of course, splenectomy is still used in AIHA - but nowadays it is more limited due to the very high effectiveness of the described non-surgical treatment

Epstein-Barr Virus-induced Paroxysmal Cold Hemoglobinuria in a 17-Year-old Male.

Paroxysmal cold hemoglobinuria is a rare autoimmune hemolytic anemia seen almost exclusively in children under 5 years of age after a viral illness. It is mediated by a biphasic polyclonal autoantibody against red blood cells, which causes severe hemolysis that typically self-resolves within 2 weeks without recurrence. While laboratory identification of the aforementioned antibody, the Donath Landsteiner antibody, would confirm this diagnosis, a negative test does not rule out this condition in the appropriate clinical context. We report on the rare occurrence of a severe presentation of paroxysmal cold hemoglobinuria in a 17-year-old male with Epstein-Barr virus infection.

Energy Trial in Warm Autoimmune Hemolytic Anemia (wAIHA): Design of a Phase 2/3 Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of Nipocalimab, an FcRn Blocker

Background: Warm autoimmune hemolytic anemia (wAIHA) is a rare condition characterized by the premature destruction of red blood cells (RBCs) mainly in the presence of pathogenic immunoglobulin G (IgG) autoantibodies that preferentially bind to RBCs at 37°C, resulting in extravascular hemolysis of these RBCs in the spleen (or liver). Patients with wAIHA can experience acute or chronic worsening of anemia, increased risk of thromboembolic events, and premature death. Innovative targeted therapies that address the underlying pathogenesis of wAIHA are needed, as there is currently no approved treatment for this disease. Nipocalimab is a high affinity, fully human, aglycosylated, effectorless IgG1 monoclonal antibody that targets the neonatal Fc receptor (FcRn) to lower circulating IgG levels, including pathogenic autoantibodies. Nipocalimab is being evaluated across multiple IgG-mediated diseases. A completed phase 2 study in patients with generalized myasthenia gravis demonstrated rapid, durable total serum IgG and pathogenic IgG autoantibody reductions and meaningful clinical response [Guptill J, et al. AAN 2021. Presentation 2157]. Aim: Describe the rationale and study design of ENERGY, an ongoing, adaptive, phase 2/3 multicenter, randomized, double-blind, placebo-controlled study that will evaluate the efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics of nipocalimab compared with placebo in patients with wAIHA (NCT04119050). Methods: Subjects ≥18 years of age who have been diagnosed with primary or secondary wAIHA and are currently receiving treatment for wAIHA or have previously received treatment for wAIHA will be included in the study. Subjects with cold antibody AIHA, cold agglutinin syndrome, mixed type (i.e., warm and cold) AIHA, or paroxysmal cold hemoglobinuria will be excluded. Stable doses of corticosteroids or immunosuppressants will be allowed. Approximately 111 patients will be randomized 1:1:1 to receive nipocalimab at two different dose schedules or placebo. Following completion of 24 weeks of double-blind treatment, patients may enter an open-label extension period to receive nipocalimab for 144 weeks with a follow-up period of 6 weeks after last assessment. Results: ENERGY will include approximately 160 sites across 19 countries, including Brazil, Canada, China, Czech, Egypt, France, Germany, Greece, Hungary, Japan, Israel, Malaysia, Netherlands, Italy, Poland, South Korea, Spain, the United Kingdom, and the United States. The primary endpoint is percentage of participants achieving durable response of improvement in hemoglobin (Hgb). The secondary endpoints include change from baseline in the total score from the Functional Assessment of Chronic Illness Therapy-Fatigue Scale, corticosteroid dose reduction from baseline, and normalization of hemolytic markers. Conclusion/Summary: The results of ENERGY have the potential to identify a novel treatment option to address the significant unmet needs of patients with wAIHA. Enrollment is ongoing in this clinical trial.

What are the Current Indications and Contraindications for a Splenectomy?

Splenectomy can treat conditions characterized by hemolysis or thrombocytopenia caused by autoantibodies or splenic reticuloendothelial function, as well as disorders characterized by massive splenomegaly and hypersplenism with cytopenias, such as hereditary spherocytosis, transfusion-dependent thalassemia, immune thrombocytopenia, autoimmune hemolytic anemia, splenic marginal zone lymph Splenectomy is no longer used for Hodgkin disease staging and is typically avoided in autoimmune lymphoproliferative syndrome, hereditary stomatocytosis or xerocytosis, cold agglutinin disease, paroxysmal cold hemoglobinuria, Gaucher disease, and cirrhosis-related hypersplenism.

Peripheral smear reckons the nature of IgM cold agglutinins: A case‐based study asserting the role of thermal amplitude and clonality

Peripheral smear reckons the nature of IgM cold agglutinins: A case‐based study asserting the role of thermal amplitude and clonality

Neutrophilic erythrophagocytosis in a child with paroxysmal cold hamoglobinuria.

A 3-year-old previously healthy male child presented to the emergency department with a 2-day history of fatigue, jaundice, and dark-brown colored urine following a week of vomiting and fever. There was no significant past medical, drug or family history. Clinical examination was normal apart from jaundice and mildly enlarged spleen on physical examination, confirmed on ultrasonography. Blood tests revealed hemoglobin of 57 g/L, haptoglobin of <0.2 g/L bilirubin of 80 μmol/L, lactate dehydrogenase of 1902 U/L, and C-reactive peptide of 126 mg/L. Direct antiglobulin test was strongly positive for C3d only. Donath–Landsteiner (D-L) antibody positivity was not demonstrated. Urine examination revealed hemoglobinuria. Viral swabs were negative for COVID-19, respiratory syncytial virus (RSV), influenza A&B, and serology did not demonstrate recent infection by cytomegalovirus, Epstein–Barr virus, or parvovirus B19. Blood cultures were negative. These results were consistent with auto-immune hemolytic anemia of intravascular type. His peripheral blood smear (shown in the panel) revealed features of hemolytic anemia with polychromasia, red cell agglutination, and spherocytosis. In addition to this, neutrophilic erythrophagocytosis (Figure 1, blue arrows) can be seen, which is typical in paroxysmal cold hemoglobinuria (PCH), though it can occasionally be seen in other conditions such as myelodysplasia [1]. A diagnosis of PCH was reached and patient was treated according to the standard protocols with warmed blood transfusions and folic acid. He required multiple transfusions during the first 2 weeks of presentation. He was discharged from the hospital once his hemoglobin stabilized. We continued to monitor his condition as an outpatient for few weeks and his hemoglobin showed a consistent upward trend, completely resolving within 2 weeks of discharge. Although PCH is a rare disorder, it is one of the most common causes of autoimmune hemolytic anemia in children [2]. Historically, it was often associated with chronic Syphilis infection and patients would experience paroxysms of hemolysis on exposure to cold; however, nowadays, it almost always occurs as acute transient anemia in children after some form of viral illness. As a result, bouts of hemolysis on exposure to cold are now rarely demonstrated [2]. Symptoms are normally transient and require no specific treatment other than supportive measures like transfusion support. Immunosuppression with steroids has not proven to be effective [2]. PCH is classically diagnosed following demonstration of a D-L antibody. This specialized test is performed in reference laboratories in the United Kingdom. The D-L antibody is a biphasic, usually IgG antibody, that binds with the “P” antigen on red cells at low temperature and causes complement-mediated lysis in red cells coated with C3 on rewarming [3]. Difficulty in maintaining the correct temperature during sample collection and handling will lead to a falsely negative result [3], and it is the most likely reason for this result in this case. A negative D-L antibody test should not dissuade the clinician from a diagnosis of PCH when the clinical features and other tests are otherwise supportive. The authors declare they have no conflicts of interest. The authors received no specific funding for this work. Written consent was obtained from the patient's guardian. Data are available upon reasonable request from the corresponding author.

EFFICACY AND SAFETY OF NIPOCALIMAB, AN FCRN BLOCKER, IN WARM AUTOIMMUNE HEMOLYTIC ANEMIA (WAIHA): ENERGY PHASE 2/3 STUDY DESIGN

Warm autoimmune hemolytic anemia (wAIHA) is characterized by the destruction of red blood cells (RBCs) by pathogenic autoantibodies which bind to RBCs and lead to their clearance in the spleen and liver. Patients with wAIHA can experience acute worsening of anemia, which can be a medical emergency, and have an increased risk of thromboembolic events and premature death. Nipocalimab is a fully human, aglycosylated, effectorless IgG1 monoclonal antibody that blocks the IgG binding site on the neonatal Fc receptor (FcRn) with high affinity. FcRn, which is expressed in endothelial cells, is responsible for recycling IgG into the circulation and for the relatively long half-life of IgG antibodies compared to other Igs. It is expected that nipocalimab, by blocking IgG binding to FcRn, will prevent IgG recycling and lower pathogenic IgG autoantibodies that cause many autoantibody diseases, including wAIHA. Nipocalimab has been studied in multiple phase 1 studies in healthy subjects and in a completed phase 2 study in subjects with Generalized Myasthenia Gravis (gMG). Treatment with nipocalimab was associated with rapid and durable total serum IgG and pathogenic IgG autoantibody reduction and meaningful clinical response. Here we share the rationale and study design for an adaptive, phase 2/3 multicenter, randomized, double-blind, placebo-controlled study in patients with wAIHA whose aim is to evaluate the efficacy, safety, tolerability, PK, and PD of nipocalimab compared with placebo (NCT04119050). Male or female subjects ≥18 years of age who have been diagnosed with primary or secondary wAIHA and have not experienced a sufficient response or have not tolerated currently available treatments will be included in the study. Subjects with cold antibody AIHA, cold agglutinin syndrome, mixed type (i.e., warm and cold) AIHA, or paroxysmal cold hemoglobinuria will be excluded. Participants will be randomized 1:1:1 to receive nipocalimab at two different dose schedules or placebo. Following completion of 24 weeks of double-blind treatment, participants may enter an open-label extension period to receive nipocalimab. The primary endpoint is percentage of participants achieving durable response of improvement in hemoglobin (Hgb). The main secondary endpoints are change from baseline in the total score from the FACIT-Fatigue Scale, number of participants who attain normal lactate dehydrogenase, normal haptoglobin, and normal indirect bilirubin levels at a minimum of 3 consecutive visits after baseline. ENERGY is a phase 2/3 study that will evaluate the efficacy and safety of nipocalimab in wAIHA. ENERGY is currently enrolling globally. IM received research support from Alexion, Annexon, Incyte, Kezar, Momenta, Rigel, and Sanofi; and served as a consultant for Apellis, Janssen, Momenta, Novartis, Rigel, and Sanofi. BF is a consultant of Alexion, Amgen, Janssen, Momenta, and Novartis. DC is an employee of Janssen Global Services, LLC, which is a wholly owned subsidiary of Johnson & Johnson, and may own stock or stock options in Johnson & Johnson; was an employee of Momenta. AMBP is an employee of Janssen Latin America, which is a wholly owned subsidiary of Johnson & Johnson, and may own stock or stock options in Johnson & Johnson. MHJ was an employee of Momenta.