Paeds · haematology-oncology-and-transfusion
Haemolytic anaemia: diagnostic approach
Also known as Haemolytic anaemia · Haemolysis workup · Coombs test interpretation · Direct antiglobulin test approach · Autoimmune haemolytic anaemia workup
Fellowship guide to the systematic diagnostic approach to haemolytic anaemia in infants, children and adolescents. Covers recognising haemolysis from reticulocytes, lactate dehydrogenase, haptoglobin and unconjugated bilirubin; splitting immune from non-immune causes with the direct antiglobulin test; and the morphological and confirmatory tests that distinguish hereditary spherocytosis, glucose-6-phosphate dehydrogenase deficiency, sickle cell disease, thalassaemia and microangiopathic haemolysis.
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Target exams
Red flags
- Rapidly falling haemoglobin with pallor, tachycardia and poor perfusion signalling acute severe haemolysis
- Dark red or cola-coloured urine indicating intravascular haemolysis with haemoglobinuria
- Acrocyanosis or Raynaud-type change on cold exposure suggesting cold agglutinin disease
- Petechiae or bleeding accompanying haemolysis in Evans syndrome or thrombotic microangiopathy
- Sudden drop in reticulocytes in a child with chronic haemolysis signalling parvovirus B19 aplastic crisis
- Splenomegaly with cytopenias and jaundice suggesting decompensated chronic haemolysis or an underlying haematological malignancy
- Neurological change with haemolysis and thrombocytopenia raising thrombotic thrombocytopenic purpura
Life stages
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Clinical exam formats
Board mappings
- Recognises jaundice, pallor and splenomegaly as clues to haemolysis
- Orders reticulocyte count, lactate dehydrogenase, haptoglobin and bilirubin to confirm haemolysis
- Uses the direct antiglobulin test to separate immune from non-immune haemolysis
- Applies a structured algorithm to DAT-negative haemolysis
- Selects confirmatory tests for hereditary spherocytosis, G6PD deficiency and haemoglobinopathies
- Identifies pitfalls of enzyme assay timing and the pseudo-hyperkalaemia of delayed sampling
- Confirming haemolysis with the core laboratory panel
- Interpreting the direct antiglobulin test and blood film together
- Differential diagnosis of DAT-negative haemolytic anaemia
- Bedside assessment of a pale jaundiced school-age child
- Communication of a stepwise diagnostic plan to the family
- Counselling about hereditary spherocytosis and the role of splenectomy
- Level 1: Recognises the clinical features of haemolysis
- Level 2: Investigates haemolytic anaemia systematically
- Level 3: Interprets the direct antiglobulin test and confirmatory membrane tests
- Haemolysis markers: reticulocytes, LDH, haptoglobin, unconjugated bilirubin
- Warm versus cold autoimmune haemolytic anaemia
- Diagnostic tests for hereditary spherocytosis and G6PD deficiency
- History-taking from a child with intermittent jaundice
- Communication of a haemolysis diagnostic pathway
- Structured examination of a child with anaemia and splenomegaly
- Diagnostic approach to haemolytic anaemia in children
- Direct antiglobulin test interpretation
- Confirmatory testing for inherited haemolytic anaemias
- Systematic evaluation of suspected haemolysis
- Appropriate selection and timing of confirmatory tests
- Recognition of haemolytic emergencies requiring urgent transfusion
- Canadian approach to the haemolysis workup
- Newborn screening and haemoglobinopathy confirmation
- Choosing between osmotic fragility and flow cytometric membrane tests
Overview & Definition
Haemolytic anaemia is anaemia produced by a shortened red cell lifespan: the bone marrow cannot keep up with the rate of destruction. The central diagnostic task is not to name every cause at once, but to move through three ordered questions. Is the anaemia really haemolytic? Is it immune or non-immune? And which specific mechanism is responsible? Answering these in sequence is what separates a focused workup from a scattergun battery of tests. [2]
The first question is settled by a small panel of indirect haemolysis markers. A raised reticulocyte count, a raised lactate dehydrogenase, a low or absent haptoglobin, and a raised unconjugated bilirubin together confirm that red cells are being destroyed faster than they are made. These markers are cheap, rapid, and available in every hospital laboratory, and they anchor every subsequent decision. [2]
The second question is settled by a single test, the direct antiglobulin test. A positive result points the clinician toward antibody-mediated destruction and a search for an immune trigger. A negative result redirects the workup toward the inherited and microangiopathic causes, guided by the blood film. The third question is settled by morphology and a handful of targeted confirmatory assays. [3]
References11ShowHide
- [1]Scheckel CJ, Go RS Autoimmune Hemolytic Anemia: Diagnosis and Differential Diagnosis. Hematol Oncol Clin North Am, 2022.PMID 35282951
- [2]Siddon AJ, Tormey CA The chemical and laboratory investigation of hemolysis. Adv Clin Chem, 2019.PMID 30797470
- [3]Zantek ND, Koepsell SA, Tharp DR Jr, et al. The direct antiglobulin test: a critical step in the evaluation of hemolysis. Am J Hematol, 2012.PMID 22566278
- [4]Bass GF, Tuscano ET, Tuscano JM Diagnosis and classification of autoimmune hemolytic anemia. Autoimmun Rev, 2014.PMID 24418298
- [5]Blackall D, Dolatshahi L Autoimmune Hemolytic Anemia in Children: Laboratory Investigation, Disease Associations, and Treatment Strategies. J Pediatr Hematol Oncol, 2022.PMID 35235549
- [6]Zhang C, Charland D, O'Hearn K, et al Childhood autoimmune hemolytic anemia: A scoping review. Eur J Haematol, 2024.PMID 38894537
- [7]Bolton-Maggs PH, Langer JC, Iolascon A, Tittensor P, King MJ Guidelines for the diagnosis and management of hereditary spherocytosis--2011 update. Br J Haematol, 2012.PMID 22055020
- [8]King MJ, Garçon L, Hoyer JD, et al ICSH guidelines for the laboratory diagnosis of nonimmune hereditary red cell membrane disorders. Int J Lab Hematol, 2015.PMID 25790109
- [9]Wu Y, Liao L, Lin F The diagnostic protocol for hereditary spherocytosis-2021 update. J Clin Lab Anal, 2021.PMID 34689357
- [10]Luzzatto L, Nannelli C, Notaro R Glucose-6-Phosphate Dehydrogenase Deficiency. Hematol Oncol Clin North Am, 2016.PMID 27040960
- [11]Brandow AM, Liem RI Advances in the diagnosis and treatment of sickle cell disease. J Hematol Oncol, 2022.PMID 35241123