Anemia due to inadequate erythropoiesis without factor deficiency may be classified in several ways. One system is based on the mechanism involved, including (1) marrow failure to incorporate adequate supplies of hematopoietic raw materials (e.g., iron) into red blood cell (RBC) precursors, (2) failure to release mature RBCs from the marrow, or (3) destruction of RBC precursors in the marrow. From a clinical point of view, it is easier to divide production-defect anemias into two categories: those due to a hypoplastic bone marrow and those with normally cellular marrow that are associated with certain systemic diseases.
Conditions that produce a hypoplastic marrow affect the bone marrow directly either by actual replacement or by toxic depression of RBC precursors. Bone marrow examination is the main diagnostic or confirmatory test.
Replacement of marrow by fibrosis. This condition, commonly termed myelofibrosis, is usually idiopathic and leads to a clinical syndrome called myeloid metaplasia. The peripheral blood picture is similar in many ways to that of chronic myelogenous leukemia. Many include this condition with the myeloproliferative syndromes.
Replacement of marrow by neoplasm. The types of tumors most commonly metastatic to bone marrow, the laboratory abnormalities produced, and the main hematologic findings are described in Chapter 33. The anemia of neoplasia is usually normocytic and normochromic. Iron deficiency anemia secondary to hemorrhage may be present if the tumor has invaded or originated from the gastrointestinal (GI) tract. Besides extensive marrow replacement (myelophthisic anemia), neoplasia may produce anemia with minimal bone involvement or even without any marrow metastases; in these patients, there seems to be some sort of toxic influence on the marrow production and release mechanism. In occasional cases of widespread neoplasm, a hemolytic component (shortened RBC life span) has been demonstrated.
Multiple myeloma is a neoplasm of plasma cells that is difficult to distinguish for classification purposes from leukemia on one hand and malignant lymphoma on the other. Myeloma initially or eventually involves the bone marrow and produces a moderate normocytic-normochromic anemia. Despite proliferation of plasma cells in the bone marrow, appearance of more than an occasional plasma cell in the peripheral blood is very uncommon. Peripheral blood RBCs often display the phenomenon of rouleau formation, a piling up of RBCs like a stack of coins. This is not specific for myeloma and is most often associated with hyperglobinemia.
Aplastic anemia. Aplastic anemia is defined as peripheral blood pancytopenia (decrease in RBCs, white blood cells [WBCs], and platelets below population reference range) due to below-normal numbers and function of bone marrow cell precursors without cytologic marrow abnormality or marrow replacement by fibrosis or malignancy. Among the various etiologies are agents that predictably damage the bone marrow (e.g., radiation, certain chemicals such as benzene, and certain cytotoxic antitumor drugs). Another category, sometimes called idiosyncratic or acquired aplastic anemia, includes medications or chemicals that ordinarily do not produce cytopenia. Effects of some medications in this group are dose-related (e.g., chloramphenicol) and in others occur completely unpredictably. A third category of aplasia appears to have some autoimmune component. This includes aplasia (usually temporary) that uncommonly occurs in association with certain viral infections (e.g., parvovirus B-19, Epstein-Barr, rubella, herpes zoster-varicella) and a permanent type rarely seen in non-A, non-B (type C) hepatitis virus infection. A fourth category, probably related to category 3, might include aplasia associated with pregnancy or thymoma (the latter most often affecting RBCs only). The aplastic“crisis” of sickle cell anemia might also fit here. Some of these temporary aplastic crises may be due to parvovirus B-19 infection. A fifth category includes congenital diseases in which aplasia appears with varying frequency, of which the best known are Fanconi’s syndrome and the Diamond-Blackfan syndrome. Finally, some investigators create a more controversial category into which they place certain conditions involving bone marrow that frequently, but not always, develop into typical hematopoietic malignancies. Even more controversial is the status of other hematopoietic or nonhematopoietic malignancies that affect bone marrow function without actual marrow involvement.
About 50% (in some reports, up to 70%) of aplastic anemia cases are unexplained or the cause is unproven. To make matters even more difficult, in some cases marrow aplasia may develop days or weeks after beginning treatment or exposure to the causative agent; and in some cases it may appear some time after exposure has ceased (in the case of radiation, even years later). Also, certain other conditions, such as hypersplenism, megaloblastic anemia, or marrow replacement by tumor, can simulate aplastic anemia.
A great variety of drugs and chemicals have been reported to cause idiosyncratic reactions. The effects range from pancytopenia to any combination of single or multiple blood element defects. Bone marrow aspiration usually shows a deficiency in the particular cell precursor involved, although, especially with megakaryocytes, this is not always true. Patients most often recover if they can be supported long enough, although a considerable number die of superimposed infection.
The drugs most often implicated in idiosyncratic reaction aplastic change are listed here according to blood element defect:
Pancytopenia. Chloramphenicol (Chloromycetin), phenylbutazone (Butazolidin), indomethacin, mephenytoin (Mesantoin), gold preparations, nitrogen mustard compounds (e.g., busulfan [Myleran]) and other antileukemic drugs. In addition, chloramphenicol may produce the“gray syndrome” in premature infants and newborns.
Leukopenia. Chlorpromazine (Thorazine), promazine (Sparine), phenylbutazone, thiouracil, antileukemic drugs, sulfonamides.
Thrombocytopenia. Quinidine, nitrofurantoin (Furadantin), sulfonylureas, chlorothiazide.
Aplastic anemia is most often normocytic-normochromic. Reticulocyte counts are usually low (although they sometimes are slightly elevated if the patient is in a recovery phase). About one third of aplastic anemia patients have a macrocytic peripheral blood smear.
As noted, bone marrow aspiration is usually essential for diagnosis and can be used to follow any response to therapy. However, certain problems are associated with this method of diagnosis and must be taken into account. A false impression of marrow hypocellularity may be produced by hemodilution of the marrow specimen, by aspiration at a place that has unusually large amounts of fatty tissue, and by poor slide preparation technique. An occasional completely dry puncture may occur in normal persons due to considerable variability in the bone marrow distribution. Therefore, the diagnosis should never be made on the basis of a single failure to obtain marrow. Also, a bone marrow biopsy specimen, or at least a clot section (clotted marrow aspirate, processed as an ordinary histologic specimen), is more reliable than a smear for estimating cellularity. This is especially true for megakaryocytes. On the other hand, a smear is definitely more valuable for demonstrating abnormal morphology. Both can usually be done at the same time.
Certain conditions may be associated with episodes of transient bone marrow RBC hypoplasia. These include congenital spherocytosis, sickle cell anemia, and RBC hypoplasia associated with thymoma. Aplastic pancytopenia may occur in paroxysmal nocturnal hemoglobinuria, either preceding onset of the disease or after onset as a transient episode.
Pancytopenia in children may be caused by Fanconi’s anemia or Diamond-Blackfan congenital hypoplastic anemia. Fanconi’s anemia is an autosomal recessive disorder characterized by pancytopenia and congenital abnormalities such as short stature, web neck, cleft lip, mental retardation, and renal anomalies. More than 10% of peripheral blood lymphocytes display chromosome abnormalities. Anemia may appear in children up to age 10 years with the disease. Diamond-Blackfan syndrome also has an autosomal recessive inheritance pattern and displays congenital anomalies, but it consists of pure RBC aplasia, and onset of anemia occurs either at birth or by age 6 months.
In children, apparent aplastic anemia or pancytopenia must be differentiated from acute leukemia.