Pφ

High-dose radiation and toxins (benzene) result in extrinsic damage to the bone marrow, while effects of moderate doses of drugs cause suppression of the marrow by altered metabolism of the pharmacologic agent. The production of toxic drug intermediates, with genetic inability for drug detoxification, may lead to marrow aplasia. Immune-mediated injury may also have a role, as certain cytokines, such as tumor necrosis factor and interferon, promote apoptosis. Cytotoxic T cells can also promote stem cell destruction.

TP

Clinical features of aplasia may have an insidious onset or may present acutely. Signs of anemia include weakness, lassitude, and malaise. The earliest signs of marrow aplasia usually result from bleeding and include epistaxis, petechial hemorrhages, easy bruising, and heavy menstruation (in women). Infections are an unusual initial presentation of aplastic anemia.

Dx

The bone marrow will exhibit sparse spicules, and examination will reveal either a very hypocellular marrow or an acellular marrow. Occasional mononuclear cells representing lymphocytes, stromal cells, and predominantly adipose tissue will be found in the marrow. Megakaryocytes, myeloid precursors, and erythroid precursors will be absent or markedly diminished. There will be no evidence of granulomas, infectious etiologies, or marrow infiltrative processes such as tumors. The history is extremely important in determining an etiology. A CT scan of the chest should be performed to look for a thymoma.

Pφ

The pathophysiology of pancytopenia secondary to acute leukemia is unclear but is probably related to a combination of suppression of normal hematopoiesis and replacement of bone marrow by leukemic cells.

TP

Patients present with gradual or abrupt onset of signs of leukopenia, anemia, and/or thrombocytopenia including weakness, fatigue, weight loss, and anorexia. Occasionally patients present with fever, easy bruising, lymphadenopathy, or bone pain. Physical examination may reveal sternal tenderness, splenomegaly, hepatomegaly, ecchymoses, poor dentition, and/or petechial hemorrhages. In patients with acute leukemia and pancytopenia, the blood counts and peripheral smear may reveal features of normocytic, normochromic anemia, anisopoikilocytosis, nucleated RBCs, hyposegmented and hypogranular neutrophils, low platelet count (<25,000/µL), and possibly rare immature forms including rare blasts. In aleukemic leukemia, no blasts or immature forms will be present, and bone marrow must be examined. Patients may have elevated serum LDH and uric acid concentrations.

Dx

Examination of the bone marrow will reveal a hypercellular marrow with 20% or more blasts (some may contain Auer rods) that stain or express myeloperoxidase, chloroacetate esterase, CD33, and CD15 (AML). Cytogenetics of myeloblasts may exhibit balanced chromosomal translocations including t(8;21), t(15;17), and inv(16). Immunohistochemical stains, flow cytometry, and enzyme cytochemistry are needed to differentiate lymphoblasts; acute lymphoblastic leukemia (B-lymphoblasts are PAS positive, and may express CD22, CD19, CD10, TdT, and Bcl-2).

Pφ

Megaloblastic anemias are disorders resulting from a deficiency of folic acid and/or vitamin B12 (cobalamin), resulting in impaired DNA synthesis. Folic acid is essential for the synthesis of purines, and a deficiency in cobalamin results in impaired ability to convert homocysteine to methionine, thereby inhibiting folic acid metabolism, and purine/DNA synthesis. This results in ineffective hematopoiesis with nuclear-cytoplasmic asynchrony. Etiologies for folic acid deficiency include (1) malabsorption (sprue, phenytoin, barbiturates), (2) impaired metabolism secondary to ethanol and drugs (methotrexate, trimethoprim), and (3) increased requirements (malignancy, pregnancy, hemolytic anemia). Cobalamin deficiencies may be secondary to malabsorption (partial or total gastrectomy, pernicious anemia, sprue, intestinal resection, blind-loop syndrome, and fish tapeworm infections) and inadequate intake.

TP

Patients present with signs of anemia and neurologic manifestations. Palpitations, vertigo, weakness, light-headedness, numbness of the extremities, irritability, and forgetfulness may be reported by patients. Physical examination may reveal tachycardia, pallor, and mildly icteric skin with mildly elevated serum total bilirubin concentrations, enlarged heart, rarely purpura if platelets are low, paresthesias of the extremities, diminished or increased reflexes, ataxia, diminished vibratory sense, dementia, and psychosis.

Dx

Review of blood cell counts and the peripheral smear will demonstrate a macrocytic anemia with a mean corpuscular volume (MCV) usually >100 fL with reduced platelet and leukocyte counts. RBC morphology reveals macrocytes, ovalocytes, nucleated RBCs with nuclear-cytoplasmic asynchrony, and basophilic stippling. Hypersegmented neutrophils (more than six lobes), when seen, are characteristic of megaloblastic anemia. There may be leukopenia and thrombocytopenia in some patients. Serum LDH concentrations may be markedly elevated with a flipped LDH pattern (LDH1 > LDH2). The anemia may be extremely severe for the clinical symptomatology. A bone marrow examination is indicated in the workup of a patient with suspicion of megaloblastic anemia and will reveal a hypercellular marrow with erythroid hyperplasia. Erythroid and myeloid precursors are large and exhibit immature-appearing nuclei compared to the cytoplasmic maturation (nuclear-cytoplasmic asynchrony). Megakaryocytes also show abnormal morphology. Cobalamin and/or folic acid serum concentrations are reduced (cobalamin <200 pg/mL, folic acid <4 ng/mL). Methylmalonic acid concentrations are elevated in cobalamin-deficient patients. Homocysteine concentrations are increased with both folate and cobalamin deficiency.

Pφ

Myelodysplastic syndromes (MDSs) are abnormal clonal hematopoietic stem cell lesions resulting in impaired cell differentiation and proliferation. They are due to a combination of cytogenetic abnormalities, mitochondrial dysfunction, oncogene activation, and loss of tumor suppressor genes resulting in disordered iron metabolism and ineffective hematopoiesis.

TP

About one-half of patients are asymptomatic, with the remainder presenting with fatigue, pallor, weakness, and dyspnea. A history of radiation, chemotherapy, Down syndrome, and Fanconi anemia may be seen in MDS. A family history of sideroblastic anemia and Fanconi anemia may be present. Physical examination may reveal pallor and increased heart rate indicative of anemia. CBC reveals a macrocytic anemia, pancytopenia, or isolated neutropenia or thrombocytopenia. Patients may have a monocytosis.

Dx

Evaluation reveals a dimorphic population of RBCs, large platelets that are deficient of granules, hypogranulated neutrophils with hyposegmented (two lobes) pseudo–Pelger-Huët cells, or ringed neutrophils and neutrophils with Döhle bodies. Rare myeloblasts may be found. Examination of the bone marrow may reveal a hypercellular or normocellular marrow; however, in 10% to 20% of cases the marrow is hypocellular. Ringed sideroblasts, erythroid megaloblastoid dysplastic maturation, disordered (dysplastic) maturation of megakaryocytes (micro-megakaryocytes, hypolobation, pawn ball megakaryocytes), and increased myeloblasts, but <20% of non-erythroid cells can be found. Marrow examination may show abnormal localized immature precursors (ALIPs) remote from bone trabeculae. Cytogenetics may show clonal chromosome abnormalities including trisomy 8, monosomy 5 or 7, and deletions of the long arms of chromosomes 20, 5, or 7 (20q-, 5q-, or 7q-).

Pφ

Myelofibrosis may be primary (agnogenic myeloid metaplasia [AMM]) or secondary to infiltrative diseases such as infections and metastatic malignancies (myelophthisic marrow). Because the marrow is replaced by fibrous tissue and possible infiltrative process of metastatic tumor or infection, there is loss of hematopoietic tissue with increase in extramedullary hematopoiesis (spleen and liver). When primary, there is neoplastic transformation of multipotent stem cells that stimulate (transforming growth factor-β and thrombopoietin) marrow non-neoplastic fibroblasts to produce excess collagen. Marrow failure eventually occurs with resultant pancytopenia.

TP

In early stages, patients are usually asymptomatic and are first diagnosed with splenomegaly or from an abnormal CBC. In the later stages, patients develop weight loss, hepatomegaly, malaise, and fever. In primary myelofibrosis, they may present with AML. Rarely, patients develop lymphadenopathy, splenic infarction, or secondary gout. Also, secondary myelofibrosis may be seen in patients exposed to toxins such as benzene and radiation.

Dx

Evaluation of the patient’s peripheral smear and bone marrow is required to make the diagnosis. Patients may exhibit anemia with or without thrombocytopenia and/or leukopenia. Platelet and leukocyte counts may even be increased. The peripheral smear may reveal nucleated RBCs, teardrop-shaped RBCs, and immature myelogenous cells including myelocytes, promyelocytes, and myeloblasts. Patients may have elevated serum LDH and uric acid concentrations. In patients with myelofibrosis the bone marrow aspirate usually produces a dry tap, requiring a biopsy for evaluation and diagnosis. The bone marrow biopsy will reveal increased marrow fibrous tissue and may exhibit a hypercellular marrow including trilineage hyperplasia. In secondary myelofibrosis, granulomas, osteomyelitis, Hodgkin and non-Hodgkin lymphoma, hairy cell leukemia, or metastatic carcinoma may be found.