Because over 95% of the cells in the bone marrow are progeny of hematopoietic stem cells, injury to these cells will result in a marked decrease in cellularity. Figure 4-1 compares a low-magnification view of normal bone marrow with that of bone marrow from a patient with severe aplastic anemia. In this specimen (Fig. 4-1B) it would be difficult to identify any cells of the erythroid, myeloid, or megakaryocyte lineages. The few cells that can be identified are a mix of lymphocytes, plasma cells, and marrow stroma that includes endothelial cells and fibroblasts.
Bone marrow biopsies. A) Normal. B) Patient with aplastic anemia. (Courtesy of Dr. Stanley Schreier, American Society of Hematology Image Bank.)
Marrow aplasia is thought to arise from genetic alterations in hematopoietic stem cells, either spontaneous mutations or mutations induced by an extrinsic insult such as a drug, toxin, or viral infection. As shown in Figure 4-2, the genetic damage may either directly impair the stem cell's capacity for proliferation and differentiation or indirectly affect hematopoiesis by the induction of neoantigen expression in the stem cell and its progeny, which then triggers immune destruction via recruitment of cytotoxic T lymphocytes.
Pathogenesis of marrow aplasia. Damage to the genome of stem cells may either cause defects that impair proliferation and differentiation or induce formation of neoantigens that trigger immune destruction. (Red Blood Cell and Bleeding Disorders. In: Kumar V, Abbas, AK, Fausto N, Aster JC, eds. Robbins Pathologic Basis of Disease. Philadelphia, U.S.A.: Elsevier; 2010: p. 663.)
The most frequent cause of bone marrow aplasia is iatrogenic, due either to drugs or radiation therapy. Patients with malignancies are commonly treated with chemotherapeutic agents designed to kill tumor cells. Many of these interfere with DNA replication or with other critical aspects of cell growth and are therefore toxic to normal cells in the body that are continuously proliferating. Foremost among these are hematopoietic cells and gastrointestinal epithelial cells. Accordingly, patients treated with many of the commonly used cancer chemotherapy agents or with therapeutic ionizing radiation often develop pancytopenia, owing to bone marrow suppression. The myelosuppression that is induced is predictable, dose-related, and reversible. In contrast, certain drugs such as the antibiotic chloramphenicol can induce irreversible aplastic anemia in an idiosyncratic manner, affecting only an extremely small fraction of exposed individuals.
In evaluating patients with aplastic anemia, it is important to elicit a thorough history of exposure to toxic chemicals, particularly hydrocarbons and other industrial solvents. The most frequent offender is benzene. Viral infections, particularly non-A, non-B, and non-C hepatitis, can occasionally cause severe, irreversible marrow aplasia. It is not known whether the damage to hematopoietic stem cells is a direct consequence of the infection or is immune mediated. This is an exceedingly rare complication, whereas mild and fully reversible cytopenias are commonly seen in a wide variety of viral infections.
Patients with marrow aplasia not due to drugs, toxins, or viral infection are deemed to have idiopathic aplastic anemia. This is a rare disorder with an incidence of about two new cases per million people per year. By comparison, the incidences of acute leukemia and multiple myeloma are each about 15-fold higher. As mentioned in the section on therapy on the following page, a substantial fraction of patients with idiopathic aplastic anemia respond to immunosuppressive agents, but the mechanism underlying the immune attack on hematopoietic stem cells has not been worked out.
Clinical Presentation and Diagnosis
The symptoms that bring these patients to the physician and the findings on physical examination are direct consequences of the severity of the cytopenias. Many patients present with progressive fatigue and pallor, owing to anemia. Others have petechiae or ecchymoses due to thrombocytopenia. Of most concern are patients who present with fever and symptoms and signs of acute bacterial infection, as a result of neutropenia. Of course many patients will have a combination of these clinical findings. The physical examination usually reveals pallor, petechiae, perhaps ecchymoses, and often findings directly related to bacterial infection such as an abscess or pneumonia. Lymph nodes and the spleen are not enlarged. A complete blood count usually will reveal marked pancytopenia. The average red cell size or volume (MCV) is often modestly increased, and the reticulocyte percentage and absolute reticulocyte count are very low. The white cell differential count shows neutropenia and monocytopenia, with relative preservation of lymphocyte numbers due to the long life spans of these cells. A bone aspirate and biopsy are essential for establishing the diagnosis. Histologic sections of a normal marrow generally reveal 35% to 50% cellularity (Fig. 4-1A), whereas in aplastic anemia the cellularity is usually below 10% (Fig. 4-1B).
Therapy, Clinical Course, and Prognosis
Once the diagnosis of aplastic anemia is made, attention should immediately focus on discontinuing any exposure to drugs or toxins that could be myelosuppressive. In the past, the treatment of aplastic anemia was entirely supportive: administration of red cell and platelet transfusions as needed to correct the anemia and prevent bleeding from thrombocytopenia, along with antibiotics to treat infections. Despite these interventions, the vast majority of patients with severe disease died, generally from overwhelming sepsis. Meticulous supportive care continues to be critically important. However, the majority of patients with severe aplastic anemia can now be brought into remission and many cured with either hematopoietic stem cell transplantation or immunosuppressive therapy.
Historically, the first patients treated with stem cell transplantation were those with aplastic anemia. The initial results were sufficiently encouraging that this therapy was extended to patients with other hematologic disorders (discussed in Chapter 26). During the last 30 years, advances in transplantation regimens and supportive care have produced higher rates of engraftment and lower incidences of graft-versus-host disease and opportunistic infections, leading to a marked improvement in disease-free survival. Currently, about 75% of patients age 20 or younger receiving stem cells from HLA-matched sibling donors go into long-term, stable hematologic remissions and can be considered cured. In patients older than 40, this figure drops to about 40%. The results are less impressive with transplants from unrelated donors.
Patients who lack a suitable stem cell donor or who are too old to undergo transplantation are treated with immunosuppressive therapy, generally consisting of a combination of a calcineurin inhibitor such as cyclosporine and antithymocyte or antilymphocyte globulin. The fact that nearly three-fourths of patients with idiopathic aplastic anemia respond suggests that immune-mediated destruction of hematopoietic progenitors plays a major role in its pathogenesis (Fig. 4-2). Compared with stem cell transplantation, immunosuppressive therapy is less expensive and has less immediate toxicity. However, remissions are less stable and nearly a third of patients eventually develop a clonal hematologic disorder such as myelodysplasia, acute leukemia, or paroxysmal nocturnal hemoglobinuria. These dreaded late complications are much less often seen in patients treated with stem cell transplantation.
Rarely, a patient may present with severe anemia and virtual absence of reticulocytes but normal platelet, white cell, and differential counts. As shown in Figure 4-3, the bone marrow reveals normal cellularity and normal megakaryocytes and myeloid precursors but a virtual absence of erythroid precursors. An immune-mediated pathogenesis is suggested by the presence of thymoma (a tumor of thymic epithelial cells), lymphoma, or an autoimmune disorder in about a third of patients, as well as frequent and long-lasting responses to immunosuppressive therapy. On rare occasions, pure red cell aplasia can occur in a patient treated with recombinant erythropoietin, due to development of an autoantibody that inactivates both the pharmacologic erythropoietin and the patient's endogenous erythropoietin.
Bone marrow aspirate smear of a patient with pure red cell aplasia. Note the absence of erythroid precursor cells. (Courtesy of Dr. Peter Maslak, American Society of Hematology Image Bank.)
Acute, transient suppression of erythropoiesis can be caused by infection with parvovirus B19, which has specific tropism for erythroid precursor cells. In normal individuals, parvovirus B19 infection causes an erythemic rash (fifth disease) and no more than a modest drop in hemoglobin levels. However, patients with underlying chronic hemolytic anemias such as sickle cell disease develop a sudden and marked drop in hemoglobin, owing to a combination of acute suppression of erythropoiesis and ongoing rapid destruction of circulating red cells.
Bone marrow failure can be encountered in newborns and infants as a feature of a number of rare genetic disorders, many with complex phenotypes. Here we will consider only two: Fanconi anemia, the most often encountered and best characterized of the congenital causes of bone marrow failure, and Diamond-Blackfan anemia, a congenital disorder that closely parallels acquired pure red cell aplasia.
This rare, autosomal recessive disorder has an incidence of about three per one million births. Fanconi anemia is characterized by progressive bone marrow failure along with a heterogeneous group of congenital anomalies, particularly abnormal skin pigmentation (café au lait spots), short stature, and skeletal, gonadal, and renal defects. Figure 4-4A shows a patient lacking a thumb, a relatively common skeletal defect in Fanconi anemia. Affected individuals have a defect in one or another of the components of a multiprotein complex that plays a key role in DNA repair. About 10% of patients with Fanconi anemia develop acute myeloid leukemia. Patients may enter prolonged remissions following stem cell transplantation.
Hand abnormalities, Fanconi anemia. A) Radiograph of the hand of a child with Fanconi anemia, showing the absence of the thumb. B) Radiograph of the hand of a child with Diamond-Blackfan anemia, showing a triphalangeal thumb.
Diamond-Blackfan anemia is a rare disorder (about five per million births) that is both genetically and clinically heterogeneous. Anemia is usually detected either at birth or within the first year of life but occasionally may appear later in life. Affected babies often have underlying skeletal (particularly thumb [Fig. 4-4B]), renal, craniofacial, or cardiac anomalies. Short stature is common. Similar to that in acquired pure red cell aplasia, the bone marrow in Diamond-Blackfan anemia has a paucity of erythroid precursors, whereas myeloid precursors and megakaryocytes are normal, giving rise to normal peripheral white cell and platelet counts. Like children with Fanconi anemia, those with Diamond-Blackfan anemia are at increased risk of developing malignancies. About half of children with the Diamond-Blackfan anemia clinical phenotype are heterozygotes with a mutation in one of the proteins of the small or large ribosome subunit. In addition, red cells of affected individuals often have markedly increased activity of adenosine deaminase, an enzyme in the purine salvage pathway, which can be used to support the diagnosis. It is not yet clear how either the defect in a ribosomal protein or the enhanced adenosine deaminase activity contributes to the pathogenesis and clinical phenotype. Nor is it clear why most patients respond to steroid therapy.