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H. Al-Samkari et al.
mRNA processing.38 Additional mutations in other regions involved in PKLR gene expression may also play a role in the pathogenesis of PKD.39 In addition to lack of diagnosis, patients with only one identifiable mutation in PKLR may be excluded from clinical trials, which use the presence of two mutated PKLR alleles for eligibility. This is what
occurred in the case described above: the patient described clearly has a clinical and enzymatic diagnosis of PKD, but standard exome sequencing-based genetic test- ing has failed to elucidate her genotype. Such patients with high suspicion of PKD as the cause of chronic hemo- lysis (e.g. persistently low PK enzyme activity) should be
Figure 3. Our consensus, stepwise approach to laboratory workup of a patient with chronic hemolytic anemia. The initial workup includes hemolysis testing per- formed routinely. The second-pass workup is intended to rule out relatively common inherited entities (including hemoglobinopathies not identified in the initial workup) as well as paroxysmal nocturnal hemoglobinuria, particularly relevant if the patient presents in adulthood. The third-pass workup allows for identification of pyruvate kinase deficiency and red cell membrane abnormalities not diagnosed in prior steps. If this three-step workup is unrevealing, additional testing is recom- mended to diagnose particularly rare inherited and acquired causes of hemolytic anemia. The diagnostician may narrow or broaden the workup at each step as appropriate and as testing is available; for example, molecular PKLR and KLF1 testing can be reasonably performed earlier in the workup. Additionally, the clinician should be aware that many specialized tests are poorly standardized between laboratories. aDeficiency may result in a hemolytic picture due to ineffective erythro- poiesis; folate may be low in chronic hereditary anemias due to rapid cell turnover. bAllows identification of most hemoglobinopathies. TTP: thrombotic thrombotic thrombocytopenic purpura; DIC: disseminated intravascular coagulopathy; PNH: paroxysmal nocturnal hemoglobinuria; DAT: direct antiglobulin test; ADAMTS13: a disintegrin and metalloproteinase with thrombospondin motifs 13.
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haematologica | 2020; 105(9)