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The peripheral blood film and the red blood cell size distribution histogram were examined for evidence of red blood cell fragments in 2,350 subjects. To distinguish subjects with greater than or equal to 10 fragments/1,000 red blood cells (abnormal) from normal, examination of the blood film was 0.83 sensitive and 0.30 specific, whereas examination of the histogram was 0.97 sensitive and 0.87 specific. The most common causes of abnormal fragmentation were malignancy with cytotoxic chemotherapy and severe iron deficiency. In two subjects, an abnormal red blood cell fragmentation pattern was the clue to a spectrin mutant in subjects with an automated blood count previously evaluated as normal. The data suggest two conclusions: the red blood cell volume histogram appears more accurate than the peripheral blood film for routine identification of red blood cell fragments; and asymptomatic spectrin abnormality identifiable by abnormal histogram may be a relatively common disorder.

In four patients with cold agglutinins, erythrocyte mean corpuscular volume was increased. Erythrocyte volume histograms showed that in each case macrocytosis was due entirely to doublet erythrocytes counted as single cells. For two of the four patients, macrocytosis was reported intermittently, when the blood had been allowed to cool to room temperature during laboratory processing. For these two patients, macrocytosis due to doublet erythrocytes could be elicited in vitro proportionate to the degree of cooling of the blood and could be abolished to rewarming to 37 C. Two other patients had macrocytosis constantly during the acute illness. Otherwise unexplained macrocytosis may reflect cold agglutinin activity without overt hemolysis, particularly if the macrocytosis is intermittent.

New automated blood cell analyzers provide an index of red cell volume distribution width (RDW) or heterogeneity and a histogram display of red cell volume distribution. We have developed a classification of red cell disorders, based on mean corpuscular volume (MCV) or red cell size, heterogeneity, and histograms, to guide diagnosis from the peripheral blood analysis. The distinction of iron deficiency anemia from heterozygous thalassemia or the anemia of chronic disease and the detection of early iron and folate deficiency is improved. Red cell volume distribution histograms identify red cell fragmentation or agglutination, dimorphic populations, and artifactual counting of lymphocytes as red cells. We recommend the use of these new variables in the initial classification of anemia by the practicing physician.

We measured whole-blood mean platelet volume (MPV) and platelet count, determined by the Coulter Counter model S-Plus, in 683 normal subjects. There was nonlinear, inverse relation between MPV and platelet count throughout the normal range of platelet count: the change in MPV was most pronounced at the lower platelet counts. Because of this non-linear relation, "platelet-crit," the product of platelet count and MPV, was not constant, but varied directly with platelet count. Thus, the definition of "normal" values for MPV requires simultaneous reference to platelet count. In the whole blood of 13 patients, non-platelet cell fragments spuriously increased the automated platelet count. Seven patients with erythrocyte fragmentation had spuriously high MPV also: correct MPV and platelet count could be obtained from platelet rich plasma (PRP). In five patients with leukemic blast fragmentation, MPV remained spuriously low and platelet count spuriously high in PRP: only phase count allowed correct count. A patient with megakaryoblastic leukemia had megakaryoblast fragments confused for platelets.

We measured the complete blood cell count, including the index of RBC size heterogeneity (RBC distribution width [RDW]), in 181 subjects without anemia to determine whether RDW became abnormal earlier in the development of iron deficiency than did other variables. In 163 subjects selected only for otherwise normal blood cell counts, an increased RDW was 66% specific (48/73) and 100% sensitive (48/48) for decreased serum iron saturation. Stool guaiac testing was equally specific but less sensitive. In 13 subjects with polycythemia, as iron deficiency developed, RDW increased a minimum of four weeks before mean cell volume changed. In one apparently normal young woman, an abrupt isolated rise in RDW revealed a newly developed low serum transferrin saturation; all values remained normal during serial testing of four other normal subjects. We conclude that RDW is the part of the routine blood cell count that first becomes abnormal during the development of iron deficiency.