[Diagnosis of non-autoimmune hemolysis in the adult]

The diagnosis of hemolysis is still based on straightforward biochemical parameters: haptoglobin (the most sensitive), lactate dehydrogenase (LDH), and unconjugated bilirubin. Anemia is not always present. Reticulocyte counts typically exceed 120×10⁹/L, except in cases of associated vitamin deficiency or during the very early phase of acute hemolysis. When the Direct Antiglobulin Test is negative, a non-autoimmune cause of hemolysis should be considered. A thorough history, careful physical examination, and meticulous review of the peripheral blood smear help to rule out major emergencies such as malaria, thrombotic microangiopathy, severe infections, delayed hemolytic transfusion reaction, or toxic hemolysis. In the absence of a mechanical valve or other intravascular device that could induce hemolysis, second-line laboratory tests should be pursued: hemoglobin phenotyping, eosin-5'-maleimide (EMA) binding test, screening for paroxysmal nocturnal hemoglobinuria (PNH), and enzymatic assays. These tests usually lead to the diagnosis of most corpuscular non-autoimmune hemolytic anemias, including hemoglobinopathies (such as sickle cell disease, thalassemia syndromes, hemoglobin C disease, or unstable hemoglobins), membranopathies (such as hereditary spherocytosis or stomatocytosis), and enzyme deficiencies. The diagnosis of rare causes of hemolysis should be considered at a later stage or in specific contexts, such as alcoholism (Zieve's syndrome), advanced cirrhosis (spur cell anemia), or acute hemolysis in a young patient (Wilson's disease).