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The nine abnormal red cells depicted on the cover show the amazing plasticity of the red cell. Consider the membrane reorganization required to maintain these deviations from a biconcave disk.

In veins, the shear rate is low, and normal red cells remain close to a biconcave disk shape. They, also, may overlap tightly at very low flow rates into stacks (rouleaux). When subjected to increased shear rates in the arterial circulation, rouleaux would be dispersed and the red cells deform. At high flow velocities the red cell tends to elongate parallel to the direction of flow. The cytoplasm moves in what has been considered eddy flow. This eddy flow results from the shear flow of the blood being transmitted to the cytoplasm through a motion of the membrane around the elongated red cell, called tank-tread motion or tank-treading. In a blood capillary with diameters smaller than their own diameter, red cells are folded.

The markedly deformed red cells shown on the cover image were each found in the blood of a patient with a red cell disease (eg, hemoglobin SS, beta-thalassemia, or another red cell disorder). After enucleation, red cells leave the marrow through very narrow, temporary, apertures in the marrow sinus wall that separates hematopoietic cords from the marrow sinus network requiring marked deformation upon egress. Red cells navigate the confinements of capillary dimensions, squeeze through the inter-endothelial cell spaces of the splenic sinus walls, and navigate other physical constraints. Abnormal red cells may be shunted around those constricted dimensions.

The shapes of seven of the nine images approximate an animal form, if one’s imagination is permitted to operate. In the upper-left corner is a slightly deformed (thickened edge) discocyte and in its biconcavity rests a triangular-shaped extremely small microcytic, but the latter, strikingly, retains its biconcavity. The other images are that of a simulated dinosaur (aka Erythrosurus Rochesteriensis), an octopus (although with more than eight limbs), a severely deformed red cell with a retained concavity and a large hole perforating its cytoplasm, a flying goose, a snail, dancing penguins, a shark, and a duckling, each with their own irregularities requiring extraordinary membrane adaptations. Several have para-crystallization of hemoglobin SS as a deforming force (eg, shark shape).

The distortions that can be maintained by abnormal red cells are extraordinary to consider and certain patterns, discerned on a careful examination of the blood film can be, and frequently are, important diagnostic clues to the nature of the underlying disease. In the absence of a crystallizing hemoglobin or a mutant gene that results in a membrane protein misconfiguration, it is possible that acquired alterations in the spectrin-based membrane protein network is altered so as to maintain abnormal bends and distortions of the red cell surface.

These images and those in Plates 1 and 2 were captured by Patricia A. Santillo, Senior Technologist, Electron Microscopy Laboratory, Hematology Unit at the University of Rochester Medical Center and have been used with permission from Lichtman’s Atlas of Hematology. www.accessmedicine.com

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Plate 1. The alphabet made of poikilocytes from a single patient with sickle cell anemia and B-thalassemia trait. Note the electron dense areas in the cells that are in the patient who is homozygous for hemoglobin S, as a reflection of the para-crystallization of that hemoglobin in a low oxygen environment (venous blood). The patient with B-thalassemia trait from whom many of these cells were imaged was a physician whose family arrived to the United States originally from the United Kingdom with no apparent recent Mediterranean heritage. As a result of Rome’s invasion of Britain on several occasions between 55 B.C.E. and 43 A.D., troops from current Italy, Spain, Egypt, and Syria garrisoned there married local Britons. (Reproduced with permission from Lichtman MA, Shafer MS, Felgar RE, et al: Lichtman’s Atlas of Hematology 2016. New York, NY: McGraw Hill; 2017.)

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Plate 2. Paul Alfred Weiss (1898-1989) was an American cell and neurobiologist who had emigrated from Austria and specialized in morphogenesis, cell development, and differentiation. He encouraged cross-disciplinary interactions among scientist and was elected to the National Academy of Sciences. He was one of the earliest scientists to propose that the cell microenvironment (né stroma) had important influences on the parenchymal cells it held in its grasp as highlighted in this aphorism he coined, here spelled out with misshapen red cells. (Reproduced with permission from Lichtman MA, Shafer MS, Felgar RE, et al: Lichtman’s Atlas of Hematology 2016. New York, NY: McGraw Hill; 2017.)

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