The proerythroblasts, called also pronormoblasts or rubriblasts, are the earliest precursors of erythropoiesis. They range from 15 to 22 im in size and do not yet contain hemoglobin. They typically have a darkly basophilic, often shadowy cytoplasm that sometimes shows pseu-dopodia. The nucleus has a dense, finely honeycombed chromatin structure (Fig. 4 a - c). Most proerythroblasts have several (at most five) indistinct pale blue nucleoli, which disappear as the cell matures. Like all erythropoietic cells, proery-throblasts tend to produce multinucleated forms. Typically there is a perinuclear clear zone, which is found to contain minute granules on phase contrast examination. Hemoglobin first appears adjacent to the nucleus and produces a flaring of the perinuclear clear zone, later expanding to occupy the whole cell and heralding a transition to the polychromatic forms. Meanwhile the nucleus undergoes a characteristic structural change: the nucleoli disappear while the chromatin becomes coarser and acquires typical erythro-blastic features.
A continuum exists from the proerythroblasts to the basophilic erythroblasts (macroblasts) (Fig. 4d). These cells tend to be smaller than proerythroblasts (8-15 im in diameter). The nu-clear-cytoplasmic ratio is shifted in favor of the cytoplasm. The polychromatic erythroblasts show a coexistence of basophilic material with a greater abundance of hemoglobin. The nucleus appears coarse and smudgy, and there is partial clumping of the nuclear chromatin.
As development progresses, the cell loses more of its basophilic cytoplasm and further diminishes in size (7 -10 im in diameter), gradually entering the stage of the orthochromatic normoblast (Fig. 4e). The nuclear- cytoplasmic ratio is further shifted in favor of the cytoplasm, which acquires an increasingly red tinge ultimately matching that of the mature erythrocyte. Supravital staining of the youngest erythrocytes reveals a network of strands (see p. 8) called the "substantia reticulofilamentosa" of the reticulocytes. Staining with brilliant cresyl blue causes the aggregation or precipitation of ribonucleo-proteins. It takes four days for the cells to pass through the four maturation stages. The clumplike erythroblastic nucleus then condenses to a streaklike, featureless, homogeneous mass. Some authors subdivide the normoblasts into ba-sophilic, polychromatic, and orthochromatic forms according to their degree of maturity, while others use the terms rubricyte (basophilic normoblast) and metarubricyte (orthochromatic normoblast). Such fine distinctions are unnecessary for the routine evaluation of marrow smears, however. Normoblasts are incapable of dividing. The nucleus is expelled through the cell membrane.
Particularly when erythropoiesis is increased, examination of the smear will reveal nests or islands of erythroblasts with central reticulum cells whose cytoplasm is in close contact (metabolic exchange) with the surrounding erythroblasts (Fig. 4 f).
The morphologic evaluation of erythrocytes is based on the following criteria:
- Hemoglobin: concentration, distribution
- Distribution in the smear
Hypochromic erythrocytes (Fig. 5 b) in iron deficiency anemia. The cells, which have normal diameters, are conspicuous for their paucity of hemoglobin, which may form only a thin peripheral rim (anulocytes).
Poikilocytes (Fig. 5 c) are dysmorphic erythro-cytes of variable shape that occur in the setting of severe anemias. Their presence indicates a severe insult to the bone marrow. Teardrops and pear shapes are particularly common and are not specific for osteomyelosclerosis or -fibrosis.
Microspherocytes (Fig. 5 d) are smaller than normal erythrocytes (diam. 3-7 im) but are crammed with hemoglobin and have a greater thickness, giving them an approximately spherical shape. They are typical of congenital hemoly-tic jaundice (spherocytic anemia) but also occur in acquired hemolytic anemias.
Elliptocytes (ovalocytes) (Fig. 5 e) result from an inherited anomaly of erythrocyte shape that is usually innocuous but may be linked to a propensity for hemolytic anemia (elliptocytic anemia).
Basophilic stippling (Fig. 5 f) of erythrocytes is a sign of increased but abnormal regeneration. It is particularly common in lead poisoning. The normal prevalence of basophilic stippling is 0 - 4 erythrocytes per 10,000
Polychromatic erythrocytes (Fig. 5 g) (diam. 7 -8 im), Cabot rings. Polychromasia occurs when mature erythrocytes show increased staining with basic dyes (violet stain) in addition to hemoglobin staining. It is usually associated with reti-culocytosis. Polychromasia occurs in red cells that still have a relatively high RNA content and in which hemoglobin synthesis is not yet complete. It is especially common in chronic hemolytic anemias. The variable staining of the erythrocytes is also termed anisochromia. Cabot rings are remnants of spindle fibers and are a product of abnormal regeneration (see also Fig. 46c).
Megalocytes (Fig. 5 h) are very large, mostly oval erythrocytes that are packed with hemoglobin (> 8 im in diameter). They occur predominantly in megaloblastic anemias (see sect. 5.2.3)
Erythrocytes (Fig. 6 a) containing nuclear remnants in the form of Howell-Jolly bodies, which are observed after splenectomy and in cases of splenic atrophy. Chromatin dust, like the Ho-well-Jolly bodies, consist of nuclear remnants.
Target cells (Mexican hat cells) (Fig. 6 b) are distinguished from anulocytes by the deeper staining of their central zone and peripheral rim. They are particularly common in hemoglobin abnormalities, occurring also in other hemolytic anemias, severe iron deficiency, and after splenectomy.
Acanthocytes or "burr cells" (Fig. 6 c) are distinguished by their jagged surface, which usually is deeply clefted. Acanthocytes are seen in a rare hereditary anomaly, A-b-lipoproteinemia. They are also a feature of uremia and hepatic coma, where large numbers of these cells are considered a poor prognostic sign. Acanthocyte formation has also been linked to the use of alcohol and certain drugs.
Sickle cells (drepanocytes) (Fig. 6 d). Sickle-shaped erythrocytes occasionally form spontaneously, but sickling is consistently induced by oxygen withdrawal in the sickle cell test (see p. 5). It signifies a common hemoglobinopathy, HbS disease (sickle cell anemia), which affects blacks almost exclusively. Red cell sickling also occurs in the less common HbC disease.
Knizocytes (triconcave erythrocytes) (Fig. 6 e)
occur mainly in hemolytic anemias. The affected erythrocyte appears to have a "handle."
Stomatocytes (Fig. 6 f) have a slitlike central lu-cency. They are found in the very rare hereditary stomatocytosis and in other anemias.
Schizocytes (fragmentocytes) (Fig. 6 g) result from the fragmentation of erythrocytes, consisting either of a fragmented red cell or a fragment detached from such a cell. They resemble bits of broken egg shell. They may be caused by increased mechanical hemolysis (turbulence from artificial heart valves) or by increased intravascular coagulation (e.g., in hemolytic uremic syndrome) as fast-flowing red cells are sliced apart by fibrin filaments.
Siderocytes (Fig. 6 h) are erythrocytes that contain iron granules detectable with iron staining. They are a common feature of severe hemolytic anemias, lead poisoning, and pernicious anemia. Siderocytes containing coarse iron granules, which may encircle the nucleus (see Fig. 60), are pathognomonic for sideroachrestic anemias. Normal blood contains 0.5-l siderocyte per 1000 red cells.
Left: At the center is a siderocyte containing several large iron granules and two sideroblasts also containing coarse iron granules, which normally are very small and difficult to see.
Right: At the center are three erythrocytes with numerous gray-violet granules that contain iron (Pappenheimer bodies). This is a clear-cut pathologic finding that is rarely observed.
Reticulocytes (Fig. 6 i) in various stages of maturity. The more filamentous reticula are characteristic of younger cells (brilliant cresyl blue stain, see p. 8).
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