Red Cell Inclusions


  • Red blood cell (RBC) inclusions include:
    • Those visible by Wright-Giemsa staining:
      • Nucleated RBC
      • Howell–Jolly bodies (nuclear fragments)
      • Pappenheimer bodies (iron-containing autophagosomes)
      • Cabot rings (mitotic spindle remnants)
      • Basophilic stippling (aggregates of ribosomes)
      • Hb C crystals
      • Parasites
    • Those visible by other stains:
      • Iron stains:
        • Siderosomes (iron-containing inclusions)
        • Confirmation of Pappenheimer bodies 
      • Intravital stains:
        • Heinz bodies (denatured globin)
        • HbH inclusions
    • Most RBC inclusions are found in young RBCs (reticulocytes).
    • The inclusions represent nuclear or cytoplasmic remnants.
    • They must be distinguished from:
      • Stain precipitate
      • Bubbles
      • Dirt on slide
      • Overlying platelets

Nucleated red blood cells

  • Represents the presence of normoblasts in the peripheral blood, typically at orthochromatophilic stage of maturation. 
  • Typically enumerated and reported as number of nucleated red blood cells (nRBCs) per 100 white blood cells. 
  • Not necessary to distinguish the exact stage of maturation in the peripheral blood. The term nRBC encompasses all normoblasts circulating in the peripheral blood, regardless of maturation stage.
  • Compared with a lymphocyte, the nRBC has:
    • Pinkish cytoplasmic color
    • Lower N:C ratio
    • Dark purple chromatic color
    • Coarse condensation of chromatin (pyknotic)
  • Physiologically present at birth, generally disappear within 3-5 days.
  • May be seen in:
    • Bone marrow replacement processes including:
      • Metastatic tumor
      • Marrow infiltration with leukemia/lymphoma
      • Marrow fibrosis
      • Marrow granulomas
    • Rapid RBC production, for example hemolytic anemias

Howell-Jolly Bodies

  • Spherical, dark purple with Wright’s stain, vary widely in size and usually eccentrically located in the cell.
  • Compared with Pappenheimer body:
    • Larger
    • Rounder 
    • Do not form tight clusters in pairs or tetrads
  • Nuclear remnants or the result of abnormal mitosis in which a single chromosome fails to participate in the interphase nucleus and becomes detached:
    • The likelihood of the latter happening increases if the nucleus contains > 4N number of chromosomes prior to cell division as occurs in megaloblastic anemia. 
  • Normally the spleen removes any Howell-Jolly body, hence their presence in the setting of asplenia. 
  • Seen in:
    • Hyposplenism
    • Asplenism
    • Severe hemolytic anemia
    • Megaloblastic anemia

Basophilic Stippling

  • Consists of multiple, uniform, evenly distributed fine or coarse dark dots (granules) scattered within the cytoplasm of RBCs.
  • Two types of basophilic stippling:
    • Course:
      • RBC has variably sized (up to large) basophilic ‘granular’ discolorations across its entire cytoplasm on a Wright-stained film.
      • Never a normal finding; suggests impaired hemoglobin synthesis.
      • Seen in:
        • Thalassemia
        • Lead poisoning
        • Myelodysplastic syndrome
        • Sideroblastic anemia 
        • Congenital dyserythropoietic anemia
    • Fine:
      • RBC has small, uniform, punctate basophilic dots across its entire cytoplasm, on a Wright-stained film.
      • Associated with reticulocytosis; usually found in red cells that are larger and more polychromatophilic (purple) compared with neighboring non-stippled RBCs.
      • Of no clinical consequence.
  • Stippled cells are created when reticulocytes from patients with incomplete RNA degeneration (or abnormal ribosomes) are dried slowly or stained supravitally with new methylene blue:
    • The RNA-containing ribosomes of reticulocytes aggregate during these processes and thus become visible as stippling.
    • In lead poisoning and thalassemia, the altered reticulocyte ribosomes have a greater propensity to aggregate, forming larger granules (coarse stippling). 

Pappenheimer bodies

  • Pappenheimer bodies, or siderotic granules, appear in Wright-stained preparations as small, irregular basophilic (purple) coccoid granules < 1 um in diameter, sometimes clustered, and generally located near the cell periphery.
  • Compared with basophilic stippling, Pappenheimer bodies occupy only one portion or region of the RBC.
  • Compared with Howell-Jolly bodies, Pappenheimer bodies are:
    • Smaller
    • Less round, more angular
    • Form tight clusters in pairs or tetrads
  • Wright Giemsa stains the protein matrix of the granules, while Prussian blue stains the nonheme iron component.
  • Cells containing Pappenheimer bodies are termed siderocytes.
  • Created when autophagosomes in RBCs digest abnormal iron-containing mitochondria.
  • The autophagosomes are normally discharged from the cytoplasm or removed by the pitting action of the spleen.
  • Seen in anemias which have in common a defect of incorporation of iron into the hemoglobin molecule.
  • Observed in:
    • Asplenia
    • Megaloblastic anemia
    • Thalassemia
    • Hemolytic anemia
    • Sideroblastic anemia
    • Congenital dyserythropoietic anemia

Cabot Rings

  • Appear as thread-like red or purple loops which may be single, double, or twisted as a figure-of-eight:
  • Seen in:
    • Megaloblastic anemia
    • Severe anemia
    • Leukemia
    • Lead poisoning
    • Other causes of dyserythropoiesis
InclusionCompositionAppearance on WG stainClinical Conditions
nRBCDNASingle, dark purple nucleus, agranular cytoplasm with varying degrees pf hemoglobinization (pinkess)Newborn. severe stress reaction, myelofibrosis; thalassemia, hemolytic anemia, MDS
Howell-Jolly bodyDNARound blue granules, 1 um diameter, at cell periphery, usually single, may be multipleHypo/asplenia, severe hemolytic anemia, megaloblastic anemia
Basophilic stippling (coarse)Precipitate of ribosomesPunctate blue granulesThalassemia, lead poisoning, MDS, sideroblastic anemia, congenital dyserythropoietic anemia
Pappenheimer bodiesIron-containing autophagosomeBlue-purple granules, < 1 um diameter, at cell periphery; may form doublets, iron stain positive, DNA stain negativeAsplenia, megaloblastic anemia, thalassemia, hemolytic anemias, congenital dyserythropoietic anemia
Cabot ringsRemnants of mitotic spindleRed-purple thread-like ringsMegaloblastic anemia, severe anemia, leukemia, lead poisoning, other causes of dyserythropoiesis
ParasitesVarious parasitesVariable appearanceMalaria, babesiosis


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