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58 RED BLOOD CELL DISORDERS

58 RED BLOOD CELL DISORDERS
Harrison’s Manual of Medicine

58

RED BLOOD CELL DISORDERS

Hypoproliferative Anemias
Maturation Disorders
Anemia Due to RBC Destruction or Acute Blood Loss
Bibliography

Anemia is a common clinical problem in medicine. A physiologic approach to anemia diagnosis (outlined in Chap. 27) provides the most efficient path to diagnosis and management. Anemias arise either because RBC production is inadequate or RBC lifespan is shortened through loss from the circulation or destruction.
HYPOPROLIFERATIVE ANEMIAS
These are the most common anemias encountered in clinical practice. Usually the RBC morphology is normal and the reticulocyte index (RI) is low. Marrow damage, early iron deficiency, and decreased erythropoietin production or action may produce anemia of this type.
Marrow damage may be caused by infiltration of the marrow with tumor or fibrosis that crowds out normal erythroid precursors or by the absence of erythroid precursors (aplastic anemia) as a consequence of exposure to drugs, radiation, chemicals, viruses (e.g., hepatitis), or genetic factors, either hereditary (e.g., Fanconi’s anemia) or acquired (e.g., paroxysmal nocturnal hemoglobinuria). Most cases of aplasia are idiopathic. The tumor or fibrosis that infiltrates the marrow may originate in the marrow (as in leukemia or myelofibrosis) or be secondary to processes originating outside the marrow (as in metastatic cancer or myelophthisis).
Early iron-deficiency anemia (or iron-deficient erythropoiesis) is associated with a decrease in serum ferritin levels (<15 µg/L), moderately elevated total iron-binding capacity (>380 µg/dL), serum iron level <50 µg/dL, and an iron saturation of <30% but >10% (Fig. 58-1). RBC morphology is generally normal until iron deficiency is severe (see below).

FIGURE 58-1. Laboratory studies in the evolution of iron deficiency. Measurements of marrow iron stores, serum ferritin, and TIBC are sensitive to early iron-store depletion. Iron-deficient erythropoiesis is recognized from additional abnormalities in the SI, percent saturation of transferrin, the pattern of marrow sideroblasts, and the red blood cell protoporphyrin level. Finally, patients with iron-deficiency anemia demonstrate all of these same abnormalities plus an anemia characterized by microcytic hypochromic morphology. (From RS Hillman, CA Finchi: Red Cell Manual, 7th. ed, Philadelphia, Davis, 1996, with permission.)

Decreased stimulation of erythropoiesis can be a consequence of inadequate erythropoietin production [e.g., renal disease destroying the renal tubular cells that produce it or hypometabolic states (endocrine deficiency or protein starvation) in which insufficient erythropoietin is produced] or of inadequate erythropoietin action. The anemia of chronic disease is a common entity. It is multifactorial in pathogenesis: inhibition of erythropoietin production, inhibition of iron reutilization (which blocks the response to erythropoietin), and inhibition of erythroid colony proliferation by inflammatory cytokines (e.g., tumor necrosis factor, interferon-g). The laboratory tests shown in Table 58-1 may assist in the differential diagnosis of hypoproliferative anemias.

Table 58-1 Diagnosis of Hypoproliferative Anemias

MATURATION DISORDERS
These result from a defect in either hemoglobin synthesis, leading to cytoplasmic maturation defects and small red cells, or DNA replication, leading to nuclear maturation defects and large red cells. Defects in hemoglobin synthesis usually result from insufficient iron supply (iron deficiency), decreased globin production (thalassemia), or are idiopathic (sideroblastic anemia). Defects in DNA synthesis are usually due to nutritional problems (vitamin B12 and folate deficiency), toxic (methotrexate or other cancer chemotherapeutic agent) exposure, or intrinsic marrow maturation defects (refractory anemia, myelodysplasia).
Laboratory tests useful in the differential diagnosis of the microcytic anemias are shown in Table 58-2. Mean corpuscular volume (MCV) is generally 60 to 80 fL. Increased lactic dehydrogenase (LDH) and indirect bilirubin levels suggest an increase in RBC destruction and favor a cause other than iron deficiency. Iron status is best assessed by measuring serum iron, total iron-binding capacity, and ferritin levels. Macrocytic MCVs are >94 fL. Folate status is best assessed by measuring red blood cell folate levels. Vitamin B12 status is best assessed by measuring serum B12, homocysteine, and methylmalonic acid levels. Homocysteine and methylmalonic acid levels are elevated in the setting of B12 deficiency.

Table 58-2 Diagnosis of Microcytic Anemias

ANEMIA DUE TO RBC DESTRUCTION OR ACUTE BLOOD LOSS
BLOOD LOSS   Trauma, GI hemorrhage (may be occult) are common causes; less common are genitourinary sources (menorrhagia, gross hematuria), internal bleeding such as intraperitoneal from spleen or organ rupture, retroperitoneal, iliopsoas hemorrhage (e.g., in hip fractures). Acute bleeding is associated with manifestations of hypovolemia, reticulocytosis, macrocytosis; chronic bleeding is associated with iron deficiency, hypochromia, microcytosis.
HEMOLYSIS   Causes are listed in Table 58-3.

Table 58-3 Classifications of Hemolytic Anemias

1.   Intracellular RBC abnormalities—most are inherited enzyme defects [glucose-6-phosphate dehydrogenase (G6PD) deficiency >> pyruvate kinase deficiency], hemoglobinopathies, sickle cell anemia and variants, thalassemia, unstable hemoglobin variants.
G6PD deficiency leads to episodes of hemolysis precipitated by ingestion of drugs that induce oxidant stress on RBCs. These include antimalarials (chloroquine), sulfonamides, analgesics (phenacetin), and other miscellaneous drugs (Table 58-4).

Table 58-4 Drugs Causing Hemolysis in Subjects Deficient in G6PD

Sickle cell anemia is characterized by a single amino acid change in b globin (valine for glutamic acid in the 6th residue) that produces a molecule of decreased solubility, especially in the absence of O2. Although anemia and chronic hemolysis are present, the major disease manifestations relate to vasoocclusion from misshapen sickled RBCs. Infarcts in lung, bone, spleen, retina, brain, and other organs lead to symptoms and dysfunction (Table 58-5).

Table 58-5 Clinical Manifestations of Sickle Cell Anemia

2.   Membrane abnormalities (rare)—spur cell anemia (cirrhosis, anorexia nervosa), paroxysmal nocturnal hemoglobinuria, hereditary spherocytosis (increased RBC osmotic fragility, spherocytes), hereditary elliptocytosis (causes mild hemolytic anemia).
3.   Immunohemolytic anemia (positive Coombs’ test, spherocytes). Two types: (a) warm antibody (usually IgG)—idiopathic, lymphoma, chronic lymphocytic leukemia, SLE, drugs (e.g., methyldopa, penicillins, quinine, quinidine, isoniazid, sulfonamides); and (b) cold antibody—cold agglutinin disease (IgM) due to Mycoplasma infection, infectious mononucleosis, lymphoma, idiopathic; paroxysmal cold hemoglobinuria (IgG) due to syphilis, viral infections.
4.   Mechanical trauma (macro- and microangiopathic hemolytic anemias; schistocytes)—prosthetic heart valves, vasculitis, malignant hypertension, eclampsia, renal graft rejection, giant hemangioma, scleroderma, thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome, DIC, march hemoglobinuria (e.g., marathon runners).
5.   Direct toxic effect—infections (e.g., malaria, Clostridium welchii toxin, toxoplasmosis).
6.   Hypersplenism (pancytopenia may be present).
LABORATORY ABNORMALITIES   Elevated reticulocyte index, polychromasia and nucleated RBCs on smear; also spherocytes, elliptocytes, schistocytes, target, spur, or sickle cells may be present depending on disorder; elevated unconjugated serum bilirubin and LDH, elevated plasma hemoglobin, low or absent haptoglobin; urine hemosiderin present in intravascular but not extravascular hemolysis, Coombs’ test (immunohemolytic anemias), osmotic fragility test (hereditary spherocytosis), hemoglobin electrophoresis (sickle cell anemia, thalassemia), G6PD assay (best performed after resolution of hemolytic episode to prevent false-negative result).

TREATMENT
General Approaches The acuteness and severity of the anemia determine whether transfusion therapy with packed RBCs is indicated. Rapid occurrence of severe anemia (e.g., after acute GI hemorrhage resulting in Hct < 25%, following volume repletion) is an indication for transfusion. Hct should increase 3 to 4% [Hb by 10 g/L (1 g/dL)] with each unit of packed RBCs, assuming no ongoing losses. Chronic anemia (e.g., vitamin B12 deficiency), even when severe, may not require transfusion therapy if the pt is compensated and specific therapy (e.g., vitamin B12) is instituted.

1.
Iron deficiency: find and treat cause of blood loss, oral iron (e.g., FeSO4 300 mg tid)

2.
Folate deficiency: common in malnourished, alcoholics; folic acid 1 mg PO qd (5 mg qd for pts with malabsorption)

3.
Vitamin B12 deficiency: can be managed either with parenteral vitamin B12 100 µg IM qd for 7 d, then 100–1000 µg IM per month or 2 mg oral crystalline vitamin B12 per day

4.
Anemia of chronic disease: treat underlying disease; in uremia use recombinant human erythropoietin, 50–150 U/kg tiw; role of erythropoietin in other forms of anemia of chronic disease is less clear; response more likely if serum erythropoietin levels are low

5.
Sickle cell anemia: hydroxyurea (antisickling) 10–30 mg/kg/d PO, treat infections early, supplemental folic acid; painful crises treated with oxygen, analgesics, hydration, and hypertransfusion; consider allogeneic bone marrow transplantation in pts with increasing frequency of crises

6.
Thalassemia: transfusion to maintain Hb > 90 g/L (> 9 g/dL), folic acid, prevention of Fe overload with deferoximine chelation; consider splenectomy and allogeneic bone marrow transplantation

7.
Aplastic anemia: antithymocyte globulin ± cyclosporine, bone marrow transplantation in young pts with a matched donor

8.
Autoimmune hemolysis: glucocorticoids, sometimes immunosuppressive agents, danazol, plasmapheresis, rituximab

9.
G6PD deficiency: avoid agents known to precipitate hemolysis.

Bibliography

For a more detailed discussion, see Adamson JW et al: Chaps. 105–110, pp. 660–701, in HPIM-15.

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