Aplastic anemia is one of a group of hypoproliferative disorders in which there is cellular depletion and a reduced production of all blood cells, pancytopenia. Discovered in 1888 by Dr. Paul Ehrlich, this syndrome is usually idiopathic but thought to be a result of two possible mechanisms: an antibody directed against an antigen on stem cells or an immune mechanism that is at play, in which T lymphocytes suppress stem cell pro-liferation.23 Several situations seem to predispose an individual to an aplastic episode:
Clinical characteristics of this syndrome include a decreased marrow cellularity, pancytopenia, and reticu-locytopenia. Aplastic anemia is an insidious process, and the syndrome progresses in a slow but orderly fashion with symptoms reflective of the depressed cellular elements. When red cells significantly deplete, patients will show fatigue, heart palpitations, and dyspnea. As platelets deplete, ecchymosis and mucosal bleeds develop and white count depletion leads to infections. In many cases, the peripheral smear shows lymphocy-tosis. Treatment for this normochromic normocytic anemia includes transfusion support and steroids, with a few patients recovering spontaneously.
Occasionally, stem cell transplantation is used to treat severe aplastic anemia presentation.24
Characterized by Dr. Fanconi in 1927, Fanconi's anemia is a rare autosomal recessive disorder affecting physical characteristics as well as bone marrow development. Over 400 cases have been reported worldwide, and there is a database, the International Fanconi Anemia Registry, that provides current information concerning this disorder. There are numerous chromosomal abnormalities in this disorder, as well as defective DNA repair and many chromosomal breaks.25 The bone marrow often shows a macrocytic process with thrombocyto-
106 Part II • Red Cell Disorders penia and leukopenia, developing before red cell depletion. Hemoglobin F values are increased. The physical characteristics of a Fanconi's anemia patient reveal short stature, hyperpigmentation on the trunk and neck, microcephaly, broad nose, and structural abnormalities of the kidney.26 Life span is shortened with a mean survival of 16 years, and these individuals have a tendency toward the development of leukemia and other cancers. Treatment is supportive as complications from aplasia develop. The only curative therapy is a bone marrow transplant.
Diamond-Blackfan anemia, discovered in 1938 by Dr. Diamond and Dr. Blackfan, shows dominant and recessive inheritance patterns. This congenital hypoplastic disorder is usually diagnosed in early infancy; 80% of individuals are severely anemic by age 6 months.27 Several physical abnormalities have been observed, including short stature, low birth weight, head and facial abnormalities, and a tendency for children with Diamond-Blackfan anemia to look more like each other than family members. The bone marrow is usually lacking in red cell precursors with a slightly decreased number of leukocytes. The average hemoglobin is 7 g/dL and hemoglobin F is increased. Treatment includes steroids and transfusional support with careful attention to the possibility of hemosiderosis. Twenty-five percent of patients spontaneously recover.28
The rare hemolytic anemia paroxysmal nocturnal hemoglobinuria (PNH) is notable because the increased susceptibility of the red cells to complement lysis is directly related to a clonal membrane defect. Classically, red cells are destroyed while patients sleep because of their increased sensitivity to complement lysis, and upon arising the patient notices bloody urine or hemo-globinuria. PNH occurs because of a somatic mutation in the hematopoietic stem cells designated as phos-phatidylinositol glycan class A (PIGA). The X-linked mutation PIGA is essential for the synthesis of the glyco-sylphosphatidylinositol (GPI)-anchored proteins present in all cell lines. As a result of this mutation, nine cell surface proteins are missing from cells.29 Two proteins in particular, CD55 decay accelerating factor and CD59 membrane inhibitor, offer protection to red cells against lysis by complement. Therefore, intravascular lysis is a primary manifestation of red cells missing these proteins. The intensity of lysis in the form of hemoglo-
binuria has been described by patients as having urine samples that range in color from strong tea to tar.
PNH patients have a variable presentation with an unexpected onset in 30% of cases. Marrow failure is part of the clinical picture, yet its onset and its prevalence are not yet fully appreciated.30 Patients may have a mild to severe anemia. Most are pancytopenic with reticulocyte levels that are elevated but not appropriate with respect to the level of anemia. Neutropenia is always present, but there is usually the absence of stainable iron due to continued lysis. Many patients have a tendency toward thrombosis, especially in unusual sites like the dermal vessels, brain, liver, and abdomen.31 In these patients, anticoagulant therapy may need to be considered, because thrombosis can account for considerable mortality. Treatment for patients with PNH includes transfusion support and, in selected younger patients, bone marrow transplant.32 Iron therapy may also be included once the patient's iron status has been assessed. A new drug, eculixumab, blocks complement activity by binding to C5 and thus preventing hemolysis. This new monoclonal antibody treatment is well tolerated and has been effective in clinical trials in improving hemolysis and relieving symptoms.33 Screening procedures usually employed in the diagnosis of PNH are the sugar water test, the Ham's test, and flow cytometry
In the sugar water test, a 50% solution of the patient's washed EDTA red cells are mixed with ABO/Rh-compatible serum and sugar solution is added. The solutions are incubated for 30 minutes and then cen-trifuged. The percent hemolysis is determined by spec-trophotometer. Normal cells show less than 5% hemolysis and suspect cells will show between 10% and 80% hemolysis.
The Ham's Test
The Ham's test is used to confirm a diagnosis of PNH. The patient's serum is acidified using 0.2N HCl. A 50% solution of the patient's cells is added to tubes containing the patient's acidified serum, unacidified serum, and normal ABO-compatible serum. A normal red cell control is run. Normal red cells will not hemolyze, but cells from patients with PNH will hemolyze with acidified serum from the patient and from normal ABO-compatible serum (Fig. 7.11).
(Note: These tests are rarely performed in the laboratory, because so few individuals have PNH, but they are simple and direct and yield some value.)
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