Donath-Landsteiner 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.

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.

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.

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.

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.

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.

Donath-landsteiner hemolytic anemia with erythrophagocytosis and platelet phagocytosis in peripheral smear: Rare findings

The Donath-Landsteiner (DL) hemolytic anemia or paroxysmal cold hemoglobinuria (PCH) is a rare subtype of autoimmune hemolytic anemia (AIHA). We report here a case of a 22-year-old young female who presented with acute onset shortness of breath. Routine hematological investigation revealed erythrophagocytosis and platelet phagocytosis by monocytes in peripheral blood smear, which are rarely reported in AIHA, especially the DL. The unusual blood smear findings directed the pathologists to initiate workup for hemolytic anemia that yielded positive results in direct Coombs test C3d (Complement) and direct DL test. The findings confirmed the case as DL hemolytic anemia. To the best of our knowledge, this is the first report of both erythrophagocytosis and platelet phagocytosis in peripheral blood smear in PCH.

Paroxysmal Cold Hemoglobinuria Successfully Treated with Complement Inhibition

Introduction: Paroxysmal cold hemoglobinuria (PCH) is a rare autoimmune hemolytic anemia (AIHA) that causes intravascular hemolysis and profound, sometimes life-threatening anemia. It most commonly occurs in children following viral infection, and presents with acute onset anemia, pallor, jaundice, and hemoglobinuria. PCH is caused by a biphasic immunoglobulin G (IgG) autoantibody that targets the P-antigen on red blood cells (RBCs) with complement fixation at low temperatures. Subsequent warming in the central circulation leads to complement activation and intravascular hemolysis. Management of PCH has been primarily supportive, with environmental warming to prevent autoantibody binding and transfusion with warmed packed red blood cells (PRBCs) as clinically indicated. Efficacy of corticosteroids has not been demonstrated. We report on successful treatment of PCH by complement blockade using a single dose of eculizumab. Case Description: We treated a previously healthy 4-year-old boy who presented with 5-day history of transient maculopapular rash, 3-day history of fatigue, thigh and abdominal pain, 2-day history of cough, chills, vomiting, diarrhea and high-grade fevers, and on the day of presentation, developed jaundice and dark urine. Hemoglobin (Hgb) level was 6.4 g/dL at a primary care visit. On admission, he was febrile, tachycardic, with scleral icterus and pallor, worsening anemia (Hgb 5.6 g/dL) which 1 hour later dropped to 4.5 g/dL, with reticulocytopenia, spherocytosis, and positive direct antiglobulin test (DAT). Initially he received methylprednisolone as empiric treatment for AIHA. Monospecific DAT was positive for C3d and negative for IgG, leading to suspicion of cold-antibody mediated AIHA (cAIHA). Due to hemoglobinuria consistent with intravascular hemolysis, PCH was suspected and a Donath-Landsteiner (DL) test was ordered. Despite environmental warming and azithromycin for potential Mycoplasma pneumoniae induced cold agglutinin syndrome, he developed worsening anemia (nadir Hgb 3.0 g/dL) with signs of shock including altered mental status, tachycardia, lactic acidosis, and high oxygen extraction, and continued transfusion requirement. On hospital day 4, we decided to treat him with eculizumab 600 mg intravenously. That afternoon, definitive testing for PCH with the DL test returned positive, confirming PCH diagnosis. Markers of hemolysis, including lactate dehydrogenase and bilirubin, decreased immediately following eculizumab administration. No further transfusion was required. Hgb levels stabilized, and reticulocyte counts increased daily. Steroids were discontinued on hospital day 6. Complete complement blockade following a single dose of eculizumab was confirmed on hospital day 7, with total complement level (CH50) reported as &lt;13.8 U/mL. The patient continued to improve and was discharged home on hospital day 15 with Hgb 6.6 g/dL, improving to 9.1 g/dL 6 days later. Diagnostic tests for infectious and toxin-mediated causes of PCH remained negative. He was given prophylaxis for encapsulated bacterial infections with penicillin VK, given increased risk of infection from ongoing complement blockade and his unvaccinated status. This was discontinued when CH50 levels normalized, 42 days after eculizumab administration. Discussion: To our knowledge, this is the first published observation of successful complement blockade for the treatment of PCH. Complement is a key effector of intravascular hemolysis in PCH. Eculizumab, an anti-C5 monoclonal antibody that blocks the terminal complement pathway, resulted in an efficient, complete, and sustained clinical improvement following a single dose. We observed no adverse effects. This case suggests a need for further investigation of complement-blockade, either at the terminal pathway or classical pathway level, in the treatment of this disease. Figure Disclosures Berentsen: Apellis: Consultancy, Honoraria; Alexion: Honoraria; Bioverativ, a Sanofi company: Consultancy, Honoraria; Janssen-Cilag: Honoraria; Mundipharma: Research Funding; True North Therapeutics: Consultancy, Honoraria. OffLabel Disclosure: Eculizumab for paroxysmal cold hemoglobinuria

Paroxysmal Cold Hemoglobinuria in a 4-year-old Child

Paroxysmal Cold Hemoglobinuria is a rare cause of intravascular hemolysis presenting in children following an acute viral illness. It is usually self-limiting in nature. We present the details of a 4-year-old boy who presented with rapid onset intravascular hemolysis. Donath Landsteiner antibody test was positive and hemolysis resolved within two weeks of onset.

Donath-Landsteiner test

The Donath-Landsteiner (DL) test is a serologic test used to detect the presence of a biphasic hemolysin. This autoantibody is seen in patients with paroxysmal cold hemoglobinuria. The test relies on the characteristic cold binding of an IgG autoantibody with specificity to the P blood group antigen. This autoantibody causes complement-mediated red blood cell (RBC) lysis when warmed to body temperature. In this review, we describe the various methods for performing the DL test-namely a direct test, an indirect test, an indirect test with modifications such as the use of enzyme-treated RBCs and two stages, and an indirect antiglobulin DL test-and highlight the advantages and disadvantages of each. Our focus is on the indirect testing method as it is most commonly used in blood bank laboratories.

A case of paroxysmal cold hemoglobinuria that was difficult to diagnose owing to negative Donath–Landsteiner test

A case of paroxysmal cold hemoglobinuria that was difficult to diagnose owing to negative Donath–Landsteiner test

Clinical and Serological Characteristics of Cold Autoimmune Hemolytic Anemia with Concomitant Cold Agglutinin and Donath-Landsteiner Antibodies

BackgroundThe two major types of cold autoimmune hemolytic anemias are cold agglutinin disease (CAD) and paroxysmal cold hemoglobinuria (PCH). In CAD, the cold agglutinin is usually IgM with anti-I specificity. In PCH, the Donath-Landsteiner (DL) antibody is a cold reacting IgG with anti-P specificity. In this study, we describe the clinical and serological characteristics of patients with autoimmune hemolytic anemia positive for both cold agglutinin and DL antibodies.MethodsOn review of our immunohematology reference laboratory database, we identified patients over a 16-year period (January 2000- March 2016) with the following: i) age ≥18 years, ii) hemoglobin (Hb) <12g/dL, iii) positive direct antiglobulin test (DAT) with hemolysis (increased lactate dehydrogenase/low serum haptoglobin/ elevated indirect bilirubin), and iv) tested for both CAD and DL antibodies. We classified the patients into 3 cohorts. Cohort 1 included patients positive for both cold agglutinin (titer ≥1:64) and DL antibodies. Cohort 2 consisted of patients with DL antibody but no cold agglutinin (titer <1:64), while Cohort 3 was comprised of patients with cold agglutinin but no DL antibody. We evaluated the clinical response based on the GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) criteria (Barcellini W, et al . Blood 2014) defined as i) complete (CR): hemoglobin ≥12 g/dL with normalization of at least one previously abnormal hemolytic marker; ii) partial (PR): hemoglobin 10-12 g/dL with hemolysis; or iii) none (NR): if any of the above criteria were not met.ResultsSeven patients had cold autoimmune hemolytic anemia with concomitant cold agglutinin and DL antibodies (Cohort 1). The clinical and serological characteristics are described in table 1. The median age at diagnosis was 68 years (range: 59-78) and the median hemoglobin at onset was 10.3 g/dL (range: 8.2-10.6). Six had red cell agglutination in the blood smear. Two patients had a recent history of infection (1 with Mycoplasma pneumoniae and 1 with upper respiratory tract infection). The median follow-up was 4.8 months (range: 1.0-166.4). Five patients received steroid/other immunosuppressants and two were managed conservatively. The clinical response to treatment was CR in 28.6% patients, PR in 42.9%, and NR in 14.3%. In comparison, Cohort 2 had a 20% CR, 20% PR and 40% NR, while Cohort 3 had a 50% CR, 25% PR and 25% NR, respectively.ConclusionOur study is the first series describing patients with cold autoimmune hemolytic anemia with concomitant cold agglutinin and DL antibodies. In terms of clinical response, patients with negative DL antibodies and cold agglutinin titers >1:64 had better response (50% CR, Cohort 3) to immunosuppressants compared to patients with positive DL antibody (20-30% CR, Cohorts 1 and 2). Large scale studies may be warranted to determine the treatment strategies among patients with concomitant DL and high cold agglutinin titers. [Display omitted] DisclosuresKay:Agios: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Tolero Corporation: Research Funding; Gilead: Research Funding. Winters:Fresenius Kabi USA: Consultancy; Eliaz Therapeutics Inc: Membership on an entity's Board of Directors or advisory committees; Sanofi Inc: Other: Moderated opinion leader's forum; Wiley Blackwell: Employment; Regional Health Inc: Consultancy; Mayo Clinic: Employment; Grifols International SA: Consultancy.

A Novel Case of Direct Antiglobulin Test-Negative Intravascular Hemolysis in a Patient with Smoldering Myeloma

▪Objectives:1. Describe a case of severe DAT-negative intravascular hemolysis in plasma cell dyscrasia.2. Discuss a potential novel mechanism of light-chain mediated hemolysis.A 34-year old woman was admitted to hospital with fatigue and severe iron deficiency anemia (hemoglobin 47 g/dL, MCV 59 fL, ferritin 2 mcg/L). Her medical history included a presumptive diagnosis of paroxysmal nocturnal hemoglobinuria (PNH) from five years prior. She was transfused 2 units of red cells, started on oral iron and folate, and was discharged symptom-free with a hemoglobin of 71 g/dL. She returned three days later with abdominal pain, dark urine, and evidence of intravascular hemolysis. She was admitted for empiric treatment of PNH with high-dose glucocorticoids and therapeutic enoxaparin for presumed intra-abdominal thrombosis. Her flow cytometry, including granulocytes, was negative for PNH. Her direct antiglobulin test (DAT) was negative for IgG antibodies but positive for C3 complement. A thorough hemolysis workup was negative, including schistocytes and Donath Landsteiner testing. ADAMTS13 testing was uninterpretable due to high plasma free hemoglobin.Despite corticosteroids, brisk hemolysis continued with 10 units of RBCs required over 5 days to maintain a stable hemoglobin. Plasma free hemoglobin reached 1147 mg/L, prompting therapeutic plasmapheresis for renal protection by the end of day 5. She deteriorated clinically after her first plasmapheresis with acute confusion (GCS 10) and lactic acidosis. She was empirically treated for seizure with levetiracetam. CT and MRI scans of her brain and lumbar puncture were normal. Her consciousness improved with daily plasmapheresis. A bone marrow biopsy performed on day twelve of glucocorticoid therapy found monoclonal plasma cell proliferation of 15% with marked lambda light chain predominance (20:1) (Figure 1). Repeat bone marrow biopsy 3 months post-steroid therapy still revealed 10% clonal plasma cells.Hemolysis can be a rare presentation of plasma cell dyscrasia. Case reports of both autoimmune hemolytic anemia and microangiopathic hemolytic anemia associated with multiple myeloma exist. In our case, there was no evidence of a microangiopathic process, making thrombotic thrombocytopenic purpura (TTP) or atypical hemolytic-uremic syndrome (aHUS) unlikely. DAT was negative for IgG but did demonstrate C3 complement molecules bound to red cells. No previous case reports of complement-mediated hemolysis and multiple myeloma were found on literature review.We report the first in vivo association between complement-mediated hemolysis and plasma cell dyscrasia. Complement pathways bridge the innate and acquired immune systems by helping select cells to be targeted by the acquired immune system. The alternative complement pathway does not require an antigen-antibody interaction to become active; rather, it is controlled by direct binding of complement and regulated by cofactor molecules. Jokiranta et al. (J Immunol 1999) identified a monoclonal Ig-lambda dimer that efficiently activated the alternative pathway of complement, triggering complement molecules to enhance hemolysis of serum in vitro. This "miniautoantibody" specifically bound and blocked the function of complement factor H, inhibiting enzymatic inactivation of fluid-phase C3b with uncontrolled activation of the alternative pathway. It is possible that the relative immune dysfunction in this patient's plasma cell dyscrasia led to a disturbance in the alternate complement pathway, perhaps due to dimerization of abnormal lambda light chains, resulting in complement-mediated intravascular hemolysis. Glucocorticoids and plasmapheresis may have helped manage hemolysis in this case.By diagnostic criteria, this patient has smoldering myeloma, with urine monoclonal protein (1.2 g/24 hours), clonal bone marrow plasma cells (10-15%), and absence of myeloma-defining events. We have elected to manage her as such, with close observation. Further work-up performed for her plasma cell dyscrasia included a normal MRI of spine and pelvis. Over a year later, there has been no recurrence of hemolysis. Consideration will be given to treatment if she progresses to overt multiple myeloma. [Display omitted] DisclosuresSandhu:Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.

Paroxysmal cold hemoglobinuria in an elderly patient: A rare case with poor prognosis

Introduction: Paroxysmal cold hemoglobinuria (PcH) is a very rare type of cold-mediated autoimmune hemolytic anemia causing direct intravascular hemolysis and hemoglobinuria, typically after exposure to cold. the reaction is caused by an IgG antibody known as DonathLandsteiner (D-L), which binds specifically to the P antigen of red blood cells at low temperatures, leading to complement activation and red cell lysis. case report: We report a case of rare occurrence of acute syphilitic paroxysmal cold hemoglobinuria in an elderly female with evidence of intravascular hemolysis complicated with peripheral gangrene and multiple organ dysfunctions. conclusion: the prognosis of PcH associated with syphilis is usually considered excellent and benign. However, we encountered a syphilitic PcH in an elderly female with a grave prognosis who passed away within five months after her first episode. based on our case experience, we recommend that acute episodes of PcH in an elderly patient should be treated in a closely monitored setting with high dose of steroids and warm blankets.

Paroxysmal cold hemoglobinuria caused by an IgM‐class Donath–Landsteiner antibody

We report on a 4-year-old boy who developed paroxysmal cold hemoglobinuria (PCH) following the first dose of a seven-valent pneumococcal conjugate vaccine. He was admitted because of dark urine after exposure to cold air. Laboratory tests indicated anemia, increased serum indirect bilirubin and lactate dehydrogenase, and decreased serum haptoglobin. Donath-Landsteiner (D-L) test was positive. The D-L antibody belonged to the IgM class and exhibited anti-P specificity. Symptoms and signs subsided after supportive care without any medication. Although PCH is often associated with viral or bacterial infection and is caused by IgG-class D-L antibodies with anti-P specificity, this case was unique because a D-L antibody of the IgM class with anti-P specificity caused PCH after immunization with a pneumococcal vaccine.

A case study of a child with chronic hemolytic anemia due to a Donath–Landsteiner positive, IgM anti‐I autoantibody

In children, paroxysmal cold hemoglobinuria (PCH) is generally considered an acute self-limited autoimmune hemolytic anemia caused by an IgG biphasic auto-anti-P antibody identified by the Donath-Landsteiner (D-L) test. We report a case of a 5-year-old female with a chronic hemolytic anemia. The etiology of the hemolysis appears to be an unusual D-L positive, IgM antibody with specificity for the I antigen. The clinical course is described and a discussion of PCH and the D-L antibody is presented. We also discuss intravenous immunoglobulin infusions as a therapy for children with this form of severe chronic autoimmune hemolytic anemia.

Failure of eculizumab to correct paroxysmal cold hemoglobinuria

Dear Editor, Paroxysmal cold hemoglobinuria (PCH) is a rare cause of intravascular hemolytic anemia in which an antibody against the P antigen develops and hemolysis ensues via a pathway involving thermally dependent complement binding. Previously an association of syphilis due to crossreactivity of antibody, PCH has since predominantly become a disease of childhood following varicella-zoster virus infection. The childhood form is typically acute, selflimiting, and steroid-responsive. Rare cases of PCH in adults have been described in association with chronic lymphocytic leukemia and lymphoma but never previously with myeloma [1]. We describe a case of steroid-refractory PCH in a patient with myeloma that was only partially corrected with eculizumab, a monoclonal antibody against C5 complement. A 51-year-old Nigerian man with Stage III ISS IgA kappa multiple myeloma in very good partial response following treatment with bortezomib, thalidomide, cyclophosphamide, and dexamethasone was admitted to our hospital with severe hemolytic anemia. At admission, lactate dehydrogenase (LDH) was elevated at 543 U/L (100–200 U/L); bilirubin, 164 μmol/L (<20 μmol/L); and hemoglobin was 60 g/L (125–175 g/L). Initial transfusion requirement were 2 to 4 U of red blood cells per day to achieve a target hemoglobin 60–80 g/L. PCH was diagnosed with the Donath–Landsteiner test following positive urinary hemosiderin on day 21 of admission. No complement C3 was detected on his red cells at diagnosis. Blood film was significant for rosette formation of erythrocytes around neutrophils and erythrophagocytosis by neutrophils (Fig. 1). Syphilis serology and cerebrospinal fluid treponemal PCR were negative. Being refractory to oral prednisolone and cyclophosphamide (1 g/m), he received standard induction with eculizumab 600 mg weekly for 4 weeks [2]. Urinary hemosiderin became negative by day 36; however, hemolysis continued albeit at reduced rate, and was finally controlled following a single dose of intravenous cyclophosphamide 4 g/m. The patient became transfusionindependent 31 days post high-dose cyclophosphamide and hemoglobin returned to normal reference range (136 g/L) at 10 weeks, with normalization of LDH at 9 weeks. This is the first reported case of eculizumab use for treatment of PCH. Failure of eculizumab to control hemolysis in this patient suggests that extravascular clearance of red cells in PCH may be induced by earlier components of complement and opsonization with anti-P antibodies. Moreover, the observation of neutrophil erythG. P. Gregory (*) : S. Opat :H. Quach : J. Shortt :H. Tran Department of Clinical Hematology, Monash Medical Centre, Clayton, VIC, Australia e-mail: g.gregory@alfred.org.au

Detection and Significance of Donath-Landsteiner Antibodies in a 5-year-old Female Presenting With Hemolytic Anemia

Donath-Landsteiner (DL) antibodies are immunoglobulins formed in response to a viral, bacterial, or spirochete infection and are capable of inducing Paroxysmal Cold Hemoglobinuria (PCH), an autoimmune hemolytic anemia. In the past, PCH was most commonly associated with syphilitic infections; however, now it is more frequently identified as a sequela in pediatric patients with upper respiratory infections. The authors present a case of a 5-year-old female who presented with hemolytic anemia and was subsequently diagnosed with PCH.