Last reviewed: 8 Apr 2021
Last updated: 05 Mar 2020



History and exam

Other diagnostic factors

  • fatigue
  • shortness of breath
  • dizziness
  • splenomegaly
  • active infections
  • episodic dark urine (hemoglobinuria)
  • triggered by exposure to cold

Risk factors

  • autoimmune disorders
  • lymphoproliferative disorders
  • prosthetic heart valve
  • family origin in Mediterranean, Middle East, Africa, or Southeast Asia
  • family history of hemoglobinopathy or RBC membrane defects
  • paroxysmal nocturnal hemoglobinuria
  • recent exposure to cephalosporins, penicillins, quinine derivatives, or NSAIDs
  • recent exposure to naphthalene or fava beans
  • thermal injury
  • exceptional exertion
  • recent exposure to nitrites, dapsone, ribavirin, or phenazopyridine
  • recent paraquat ingestion
  • malaria
  • babesiosis
  • bartonellosis
  • leishmaniasis
  • Clostridium perfringens infection
  • Haemophilus influenzae type B infection
  • liver disease

Diagnostic investigations

1st investigations to order

  • CBC
  • MCHC
  • reticulocyte count
  • peripheral smear
  • unconjugated (indirect) bilirubin
  • LDH
  • haptoglobin
  • urinalysis

Investigations to consider

  • direct antiglobulin test (DAT or Coombs)
  • creatinine, BUN
  • LFTs
  • Donath-Landsteiner antibody
  • Hb electrophoresis
  • flow cytometry for CD55/CD59
  • glucose-6-phosphate dehydrogenase (G6PD) fluorescent spot test and spectrophotometry
  • ANA

Treatment algorithm


Associate Professor of Clinical Medicine

Department of Medicine

University of Virginia




JD declares that he has no competing interests.

Dr John Densmore would like to gratefully acknowledge Dr Michelle Loch, a previous contributor to this monograph. ML declares that she has no competing interests.

Peer reviewersVIEW ALL

Hematology Unit

Sant'Eugenio Hospital




PN declares that he has no competing interests.

Staff Hematologist-Oncologist

Hematologic Oncology and Blood Disorders

Cleveland Clinic

Associate Professor

Internal Medicine

Cleveland Clinic Lerner College of Medicine




AL declares that he has no competing interests.

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