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Department of Pediatrics, Bicol Christian College of Medicine, Ago General Hospital, Lalitpur, Nepal

Address for Correspondence: Gautam Araya, Department of Pediatrics, Bicol Christian College of Medicine, Ago General Hospital, Rizal Street, Legaspi City, Lalitpur, Nepal. Email:

Keywords: DL-HA, antibody, bilirubin, fever, assay

Clinical Problem :
A 5-year-old male present to the emergency department with fever for 8 days and acute onset of dark coloured urine. There was no bleeding from any other site. Five days ago, he was prescribed amoxicillin-clavulanate for infection of the ear and suspected tonsillitis. On examination, his temperature was 103.6°F, heart rate was 90/min, respiratory rate was 18/min, oxygen saturation was 98% at room air. He had jaundice and pallor. Systemic examination was normal. Investigations showed initial hemoglobin 10.4 g/dL which decreased to 5.8 g/dL after 37 hours. Haptoglobin was 12 mg/dl and serum indirect bilirubin was 1.8 mg/dl. Peripheral blood smear showed erythrophagocytosis (Figure 1). He was suspected to have acute Donath -Landsteiner hemolytic anaemia (DL-HA). A prompt Donath-Landsteiner (DL) test was performed, which confirmed the presence of a DL antibody and thus our diagnosis.

Figure 1. Peripheral blood smear test showing erythrophagocytosis

How to treat this patient?

Discussion :
DL-HA represents 30-40% of autoimmune hemolytic anemia in children, that is generally self-limiting.1 Autoantibody responsible for DL-HA is a cold-reacting immunoglobulin known as, DL autoantibody, capable of causing severe hemolysis even when the titre detected is low.2 The DL autoantibody hold on tightly to red blood cell (RBC) surfaces during the peripheral circulation, where temperatures are cooler than 30°C in comparison to core body temperature.3 After attachment to RBC surface, the DL autoantibody activates the complement cascade, leading to RBC membrane perforation and intravascular hemolysis, hence the dark coloured urine.3 Complement activation and consequential hemolysis would become reality if binding RBCs travel to the core part of the body at a warmer temperature. Results of the direct antiglobulin test (DAT) with anti-C3 are likely to be positive, while negative for anti-IgG or anti-IgM.3 In contrast, in cold agglutinin disease (CAD) IgM is positive.3 The most prominent difference between DL-HA and CAD is this causative agent. Hence, a distinction must be established for proper diagnosis and treatment. Given that hemoglobinuria and personal history of travel to cold areas is not always present, diagnosis relies on lab testing.2 A peripheral smear is always essential for diagnosis of hemolytic anaemia and may reveal spherocytes, or rouleaux formation suggestive of warm autoimmune haemolysis.4 The best initial therapy for this patient is to keep him warm with gloves and warming blanket.4 Warm intravenous fluids and red blood cell transfusion are vital for treatment.4 If an underlying etiology is determined, it should be treated. The most likely etiology for this patient’s DL-HA is the history of a previous viral illness and initiation of amoxicillin-clavulanate (drug-induced immune hemolytic anaemia). Though corticosteroids represent the first-line treatment for patients with autoimmune hemolytic anaemia, about 30% of patients require second-line treatment.5 Plasmapheresis should only be used in severe cases, that are refractory to initial therapy.4

References :
  1. Eder AF. Review: acute Donath-Landsteiner hemolytic anemia. Immunohematology. 2005;21:56-62. Erratum in: Immunohematol. 2005;21:132.
  2. Emedicine. Donath-Landsteiner Hemolytic Anemia. Available at URL: Accessed on 28th Feb 2021
  3. Ogose T, Wakata Y, Kaneko M, Shinahara K, Takechi T, Kotani H. A case of recurrent paroxysmal cold hemoglobinuria with the different temperature thresholds of Donath-Landsteiner antibodies. J Pediatr Hematol Oncol. 2007;29):716-719.
  4. American Society of Hematology. Case Study: Four-Year-Old Male with Red Urine and Fever. Available from URL: Accessed on 5th March 2021.
  5. Lechner K, Jäger U. How I treat autoimmune hemolytic anemias in adults. Blood. 2010;116:1831-1838.

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