A CBC shows extreme poikilocytosis with microspherocytes, an elevated reticulocyte count, a positive osmotic fragility test, and red cells lysing upon heating. Which diagnosis is most likely?

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Extreme membrane instability of red cells leads to severe shape variation and high fragility, which is the hallmark of hereditary pyropoikilocytosis. This condition is a membrane-skeletal defect often due to mutations affecting spectrin or related proteins, causing red cells to become highly fragile and take on many abnormal shapes. The extreme poikilocytosis with microspherocytes seen on the smear reflects the membrane’s inability to maintain normal biconcave shape, producing fragmented and spherical forms.

The elevated reticulocyte count shows the bone marrow mounting a response to ongoing hemolysis. The osmotic fragility test being positive indicates that the red cells rupture more easily in hypotonic solutions because their membranes are unstable. Even more characteristic is the heating test: these cells lyse at much lower temperatures than normal, demonstrating thermal fragility that is classic for pyropoikilocytosis.

Together, these findings point to a hereditary red cell membrane disorder with pronounced thermal and osmotic fragility, making hereditary pyropoikilocytosis the most likely diagnosis. Sideroblastic anemia and thalassemia would usually present with different red cell morphologies and aren’t defined by this pattern of osmotic and heat fragility. G6PD deficiency causes acute oxidative hemolysis rather than this combination of extreme poikilocytosis and heat/osmotic fragility.