David C. Dale MD, FACP1
Professor of Medicine
1University of Washington Medical Center
The author is a consultant for, receives research support from, and is a member of the speakers' bureau of Amgen, Inc.
Hematology deals with the normal functions and disorders of the formed elements in the blood (i.e., erythrocytes, leukocytes, and platelets) and the plasma factors governing hemostasis. The blood sustains life by transporting oxygen and essential nutrients, removing waste, and delivering the humoral and cellular factors necessary for host defenses. Platelets and coagulation factors, together with vascular endothelial cells, maintain the integrity of this system. Some hematologic disorders such as anemia, leukocytosis, and bleeding are quite common, occurring secondary to infectious, inflammatory, nutritional, and malignant diseases. Other disorders, including the hematologic malignancies, are far less common. This chapter presents the general principles for understanding the hematopoietic system [see other chapters under Hematology for a more detailed description of the pathophysiology of specific hematologic diseases and their treatment].
Hematopoiesis begins in the fetal yolk sac and later occurs predominantly in the liver and the spleen.1 Recent studies demonstrate that islands of hematopoiesis develop in these tissues from hemangioblasts, which are the common progenitors for both hematopoietic and endothelial cells.2 These islands then involute as the marrow becomes the primary site for blood cell formation by the seventh month of fetal development. Barring serious damage, such as that which occurs with myelofibrosis or radiation injury, the bone marrow remains the site of blood cell formation throughout the rest of life. In childhood, there is active hematopoiesis in the marrow spaces of the central axial skeleton (i.e., the ribs, vertebrae, and pelvis) and the extremities, extending to the wrists, ankles, and the calvaria. With normal growth and development, hematopoiesis gradually withdraws from the periphery. This change is reversible, however; distal marrow extension can result from intensive stimulation, as occurs with severe hemolytic anemias, long-term administration of hematopoietic growth factors, and hematologic malignancies. The term medullary hematopoiesis refers to the production of blood cells in the bone marrow; the term extramedullary hematopoiesis indicates blood cell production outside the marrow in the spleen, liver, and other locations.
ORGANIZATION OF HEMATOPOIETIC TISSUES
In its normal state, the medullary space in which hematopoietic cells develop contains many adipocytes and has a rich vascular supply [seeFigure 1].3 Vascular endothelial cells, marrow fibroblasts, and stromal cells are important sources of the matrix proteins that provide structure to the marrow space; these cells also produce the hematopoietic growth factors and chemokines that regulate blood cell production.4 The vascular endothelial cells also form an important barrier that keeps immature cells in the marrow and permits mature hematopoietic elements to enter the blood. The abundant adipocytes may influence hematopoiesis by serving as a localized energy source, by synthesizing growth factors, and by affecting the metabolism of androgens and estrogens.5 Marrow macrophages remove effete or apoptotic cells and clear the blood of foreign materials when they enter the marrow. Osteoblasts and osteoclasts maintain and remodel the surrounding cancellous bone and the calcified lattice, which crisscrosses the marrow space.3
Figure 1. The architecture of the bone marrow showing the various types of cells.
The thymus, lymph nodes, mucosa-associated lymphatic tissues, and the spleen have multiple hematopoietic functions. Early in development, they are major sites of hematopoiesis. In adulthood, they are principally sites of lymphocyte development, processing of antigens, development of effector T cells, and antibody production [see 6 Immunology/Allergy]. In leukemia and the myeloproliferative disorders, the size and cellular architecture of these tissues are deranged, leading to many of the clinical manifestations of these disorders [see 12:XVI Acute Leukemia and 12:XVII Chronic Myelogenous Leukemia and Other Myeloproliferative Disorders].
Hematopoietic Stem Cells
All cells of the hematopoietic system are derived from common precursor cells, the hematopoietic stem cells. These cells are difficult to identify, in part because they normally represent only about 0.05% of marrow cells. Through self-renewal, this population is maintained at a constant level. Through the use of monoclonal antibodies that recognize specific cell surface molecules expressed selectively on developing hematopoietic cells and other specialized techniques, the stem cells can now be separated from other marrow cells. With these methods, very primitive hematopoietic stem cells have been found to be positive for c-kit and thy-1 but negative for CD34, CD38, CD33, and HLA-DR. For clinical purposes, CD34+ progenitor cell populations, which contain stem cells and some more mature cells, are often used for hematopoietic stem cell transplantation [see 5:XI Hematopoietic Stem Cell Transplantation].
Stem cells give rise to daughter cells, which undergo irreversible differentiation along various hematopoietic cell lineages [see Figure 2]. Many aspects of the earliest steps in this differentiation process are not well understood. With lineage commitment, however, differentiation, maturation, and release of cells to the blood come under the control of well-defined hematopoietic growth factors. In the early phases of differentiation, the regulatory roles played by these growth factors overlap. Later in development, some growth factors are lineage specific, meaning that they govern the maturation and deployment of single lineages. Erythropoietin (EPO) (erythrocytes), thrombopoietin (TPO) (platelets), granulocyte colony-stimulating factor (G-CSF) (neutrophils), and macrophage colony-stimulating factor (M-CSF) (monocytes) are the best-characterized lineage-specific factors.
Figure 2. The pattern for development of various types of blood cells in the bone marrow. (BFU-E—burst-forming unit-erythroid; CFU-GM—colony-forming unit-granulocyte-macrophage; CFU-mega—colony-forming unit-megakaryocyte; EPO—erythropoietin; EPOR—surface component of the erythropoietin receptor; FLT-3L—fms-like tyrosine kinase 3 ligand; G-CSFµgranulocyte colony-stimulating factor; GM-CSFµgranulocyte-macrophage colony-stimulating factor; IL—interleukin; M-CSF—macrophage colony-stimulating factor; TPO—thrombopoietin; SCF—stem cell factor)
Hematopoietic Growth Factors
The hematopoietic growth factors, also referred to as hematopoietic cytokines, are a family of glycoproteins produced in the bone marrow by endothelial cells, stromal cells, fibroblasts, macrophages, and lymphocytes; they are also produced at distant sites, from which they are transported to the marrow through the blood [see Table 1]. The naming of these factors is somewhat confusing. Erythropoietin and thrombopoietin derive part of their names from the Greek word poiesis, meaning “to make.” The colony-stimulating factors were first recognized because of their capacity to stimulate early hematopoietic cells to grow into clusters and large colonies in tissue culture systems. The term interleukin denotes factors that are produced by leukocytes and that affect other leukocytes. This is a large family of factors that predominantly govern lymphocytopoiesis, but many members also have broad effects on other lineages. The discovery of new growth factors and of the biologic consequences of deficiencies or excesses of these factors continues to evolve rapidly.
Table 1 Hematopoietic Growth Factors
Hematopoietic cells have distinctive patterns of expression of growth factor receptors, and the patterns evolve as the cells differentiate [seeFigure 2]. Each growth factor binds only to its specific receptor.6,7—It is now known that some growth factors share components of the receptor (e.g., interleukin-3 [IL-3], IL-5, and granulocyte-macrophage colony-stimulating factor [GM-CSF] share a common β chain of their receptor); specificity comes from other unique or private components of the receptor. Binding of the ligand to the receptor leads to a conformational change, activation of intracellular kinases, and, ultimately, the triggering of cell proliferation.8,9 For some growth factors, these pathways are well defined; for others, the pathways are still unclear [see Figure 3].
Figure 3. A model of how hematopoietic growth factors interact with their receptors to initiate cell proliferation. (EPO—erythropoietin; JAK2—Janus kinase 2; SH2—Src homology 2; STAT5—signal transducer and activator of transcription 5)
Hematopoietic growth factors not only stimulate cell proliferation but also prolong cell survival; that is, they have antiapoptotic effects.10For some lineages, such as neutrophils and monocytes, growth factor receptors occur on fully mature cells; exposure of these cells to the factors primes the cells for an enhanced responsiveness to bacteria or other stimulators of their metabolic activity. Thus, for cells of the neutrophil lineage, the growth factors G-CSF and GM-CSF can stimulate early hematopoietic cell proliferation, increase the number of cells produced by the marrow, prolong the life span of these cells, and augment cell functions.11
The peritubular interstitial cells located in the inner cortex and outer medulla of the kidney are the primary site for erythropoietin production.12 In response to hypoxia, transcription of the erythropoietin gene in these cells increases, resulting in increased secretion of erythropoietin. The protein is then transported through the blood to the marrow to stimulate erythropoiesis. With renal failure, erythropoietin production is severely impaired. In infections and many chronic inflammatory conditions, the erythropoietin response is blunted, and erythropoietin levels are low.13
Erythropoietin is a glycosylated protein that modulates erythropoiesis by affecting several steps in red cell development. The most primitive identifiable erythroid cells, the burst-forming unit-erythroid cells (BFU-E), are relatively insensitive to erythropoietin. More mature cells, the colony-forming unit-erythroid cells (CFU-E), are very sensitive. Erythropoietin treatment prolongs survival of erythroid precursors, shortens the time between cell divisions, and increases the number of cells produced from individual precursors.14
Erythropoietin can be administered intravenously or subcutaneously for the treatment of anemia caused by inadequate endogenous production of erythropoietin.15,16 Treatment is maximally effective when the marrow has a generous supply of iron and other nutrients, such as cobalamin and folic acid.17 For patients with renal failure, who have very low erythropoietin levels, the starting dosage is 50 to 100 units S.C. three times a week. The most easily monitored immediate effect of increased endogenous or exogenous erythropoietin is an increase in the blood reticulocyte count. Normally, as red cell precursors mature, the cells extrude their nucleus at the normal blast stage. The resulting reticulocytes, identified by the supravital stain of their residual ribosomes, persist for about 3 days in the marrow and 1 day in the blood. Erythropoietin shortens the transit time through the marrow, leading to an increase in the number and proportion of blood reticulocytes within a few days.
In some conditions, particularly chronic inflammatory diseases, the effectiveness of erythropoietin can be predicted from measurement of the serum erythropoietin level by immunoassay.12,13 It may be cost-effective to measure the level before initiating treatment in patients with anemia attributable to suppressed erythropoietin production, such as patients with HIV infection, cancer, and chronic inflammatory diseases. Several studies have shown that erythropoietin treatment decreases the severity of anemia and improves the quality of life for patients with cancer.18 In patients with anemia caused by cancer and cancer chemotherapy, current guidelines recommend erythropoietin treatment if the hemoglobin level is less than 10 g/dl.19
The development of megakaryocytes from hematopoietic stem cells and the level of platelets in the blood are governed by thrombopoietin.20Thrombopoietin is produced primarily by the liver and is similar to erythropoietin in structure. However, thrombopoietin has broader biologic effects than erythropoietin, stimulating the proliferation and release of hematopoietic stem cells from the bone marrow and prolonging survival of these cells.24 Thrombopoietin signals through its specific receptor, called cMpL, expressed on hematopoietic cells. Plasma thrombopoietin levels are inversely related to the blood platelet count. Deficiencies in thrombopoietin cause thrombocytopenia, and excesses in thrombopoietin cause thrombocytosis. Recombinant human thrombopoietin and related molecules activating cMpL are being studied for treatment of thrombocytopenia of diverse causes. Thrombopoietin is not yet approved for clinical use.
Granulocyte Colony-Stimulating Factor
G-CSF is a glycosylated protein produced by monocytes, macrophages, fibroblasts, stromal cells, and endothelial cells throughout the body.21 It stimulates the growth and differentiation of neutrophils both in vitro and in vivo. G-CSF levels are normally very low or undetectable but increase with bacterial infections or after administration of bacterial endotoxin.11 G-CSF (the synthesized form is known as filgrastim or lenograstim) administration causes a dose-dependent increase in the blood neutrophil count in healthy persons. Studies in animals have shown that G-CSF deficiency causes neutropenia.22 As with erythropoietin, administration of G-CSF leads to an acceleration in the development of neutrophils in the bone marrow, with the neutrophils shifting at an earlier stage than normal from the marrow to the blood.23
G-CSF is used primarily to prevent severe neutropenia after cancer chemotherapy, for acceleration of neutrophil recovery after bone marrow transplantation, for mobilization of hematopoietic progenitor cells from the marrow to the blood in hematopoietic transplantation, and for the treatment of severe chronic neutropenia.24 The usual dosage is 5 µg/kg S.C. daily; higher doses are used to mobilize progenitor cells, and lower doses are used for long-term treatment of neutropenia. A formulation of G-CSF, in which G-CSF is conjugated to polyethylene glycol to reduce renal clearance and prolong the effects of the drug, is also available. Side effects of either form of G-CSF are principally musculoskeletal pain and headaches during the period of rapid marrow expansion soon after therapy is initiated. Other side effects are uncommon. The use of G-CSF to treat chemotherapy-induced febrile neutropenia is controversial.25
Granulocyte-Macrophage Colony-Stimulating Factor
GM-CSF is a glycosylated protein produced by many types of cells, including T cells. GM-CSF stimulates formation of neutrophils, monocytes, and eosinophils and may also enhance the growth of early cells of other lineages. In contrast to G-CSF, GM-CSF levels generally do not increase with infections or acute inflammatory conditions, and neutropenia does not result from deficiencies of GM-CSF.26 The marrow effects of G-CSF and GM-CSF are similar, but GM-CSF is less potent in elevating the blood neutrophil count.27 GM-CSF (the synthesized form is known as sargramostim or molgramostim) is approved in the United States for acceleration of marrow recovery after bone marrow transplantation or chemotherapy and for mobilization of progenitor cells from the marrow. The usual dosage of GM-CSF is 250 mg/m2/day S.C. The side effects of GM-CSF include bone and musculoskeletal pain, myalgias, and injection-site reactions.
IL-11 (oprelvekin) is a pleiotropic cytokine that is expressed by, as well as active in, many tissues. IL-11 acts synergistically with other growth factors, including thrombopoietin, to stimulate megakaryocyte development and platelet formation. The Food and Drug Administration approved it for use in the prevention of severe thrombocytopenia and for patients who need platelet transfusions after chemotherapy. The usual dosage is 50 mg/kg/day S.C. Its side effects include edema, tachycardia, and dyspnea.
Other Growth Factors
Several other hematopoietic growth factors have potential clinical uses. IL-3 acts at an early phase in hematopoiesis to stimulate cell proliferation; however, it has relatively little effect on peripheral counts. Stem cell factor (SCF) and fms-like tyrosine kinase 3 (FLT-3) ligand are other early-acting factors under investigation. M-CSF is a selective factor for monocytes and macrophage formation. IL-5 is a selective factor that is similar to M-CSF but with regard to the generation of eosinophils.
It is presumed that normally, hematopoietic cell formation is governed by combinations of factors, released in a cascade, that closely coordinate the development of these cells. The details of how this process occurs, however, are not yet clear. Numerous laboratory and clinical studies have investigated combinations of factors, but the therapeutic benefit of using multiple growth factors is not yet proved.
DYNAMICS OF HEMATOPOIESIS
In the marrow, blood cells develop in two phases, the proliferative and the maturational phases. During cell proliferation, the precursors of blood cells normally undergo cell division at intervals of about 18 to 24 hours. In the maturational phase, cell division ceases, but final features are added before the cells enter the blood. During this phase, erythrocytes normally lose all their nuclear material, acquire their biconcave shape, and develop their final content of enzymes necessary for maintaining the biconcave shape and resisting destruction by oxidative stress. Normally, it takes 7 to 10 days for erythrocytes to develop from their early precursors, but this process can be accelerated by erythropoietin therapy.
Neutrophils acquire most of their granules (known as the primary, secondary, and tertiary granules), which are necessary for their microbicidal activities, during the proliferative phase. During maturation, their nuclear chromatin condenses, the glycogen content of the cytoplasm increases, and the surface properties governing the circulation, adherence, and migration to tissues are added.28 Neutrophils reach a fully mature state in the marrow before they are released into the blood. These mature marrow cells are called the marrow neutrophil reserve. Quantitatively, this neutrophil pool is substantially larger—probably five to 10 times larger—than the total circulating supply of neutrophils. Normally, it takes 10 to 14 days for blood neutrophils to develop from early precursors, but this process is accelerated in the presence of infections and by treatment with G-CSF or GM-CSF [see 5:VII Nonmalignant Disorders of Leukocytes].
Platelets form from the breaking apart of the cytoplasm of the fully mature megakaryocytes, which are also derived from hematopoietic stem cells.20 Megakaryocytes undergo reduplication of their nuclear chromatin without cell division, which results in the production of extremely large cells. When marrow damage occurs from chemotherapeutic agents and after hematopoietic transplantation, the megakaryocytes are often the slowest cells to recover, and thrombocytopenia is often the last cytopenia to resolve.
There are important differences in the dynamics or kinetics of erythrocytes, platelets, and leukocytes in the blood. For instance, neutrophils have a blood half-life of only 6 to 8 hours; essentially, a new blood population of neutrophils is formed every 24 hours.28 Erythrocytes last the longest by far: the normal life span is about 100 days. These differences partially account for why neutrophils and their precursors are the predominant marrow cells, whereas in the blood, erythrocytes far outnumber neutrophils. Similarly, the short half-life and high turnover rate of neutrophils account for why neutropenia is the most frequent hematologic consequence when bone marrow is damaged by drugs or radiation. Finally, transfusion of erythrocytes and platelets is feasible because of their relatively long life span, whereas the short life span of neutrophils has greatly impeded efforts to develop neutrophil transfusion therapy.
Clinical Manifestations of Hematologic Disorders
The following signs and symptoms are frequently observed in patients with hematologic diseases.
WEAKNESS, FATIGUE, AND PALLOR
Weakness and fatigue are common complaints of patients with anemia, especially if it is of recent onset, such as anemia caused by recent blood loss or acute hemolysis.29 Anemia that develops gradually, particularly in inactive persons, may cause only fatigue. Fatigue is a very common complaint of patients with infections, inflammatory diseases, and malignancies. Other common causes of fatigue include chronic lung diseases, congestive heart failure, endocrine disorders, and depression.
Pallor is recognized by examining the conjunctiva, mucous membranes, nail beds, and palmar creases—tissues lacking melanin pigmentation. The World Health Organization has developed a simple clinical scale to measure pallor for diagnosing anemia when blood counts are not available. The sensitivity and specificity of this scale vary between 70% and 90%, depending on the population and severity of the anemia.30,31 Other causes of pallor include edema (including myxedema) and vasoconstriction caused by cold temperatures, hemorrhage, hypoglycemia, or shock.
Pain, particularly bone pain, is an important marker of hematologic disease. Pain is usually generalized in patients with acute leukemia and multiple myeloma, but most frequently, it is felt in the back or pelvis. With metastatic breast, colon, or lung cancer, the pain is more often localized and asymmetrical. In sickle cell disease, severe bone pain and pain in many other tissues occur with vascular obstruction and infarction caused by obstruction of blood flow by the aggregation of abnormal cells [see 5:IV Hemoglobinopathies and Hemolytic Anemias]. Bone pain mimicking these disorders occurs with marrow expansion in response to treatment with hematopoietic growth factors.
FATIGUE, PHARYNGITIS, AND FEVER
Fatigue, pharyngitis, and fever are a frequently observed sequence in patients with acutely developing neutropenia, occurring as an idiosyncratic or toxic reaction to many drugs. In cases of severe neutropenia, cough and respiratory symptoms, perianal pain and tenderness, or acute abdominal pain often occurs and necessitates immediate medical assessment [see 5:VII Nonmalignant Disorders of Leukocytes].
MOUTH ULCERS, GINGIVITIS, AND CERVICAL ADENOPATHY
Mouth ulcers, gingivitis, and cervical adenopathy are common problems of patients with chronic neutropenia [see 5:VII Nonmalignant Disorders of Leukocytes]. Gingivitis is a serious problem, often leading to periodontal disease and tooth loss.
PERIANAL PAIN, INFLAMMATION, AND BLEEDING
Hemorrhoids are the most common cause of perianal discomfort. Patients with neutropenia readily develop pain and cellulitis in this area. Hemorrhoids, inflammatory bowel disease, and cancer commonly cause rectal bleeding.
LYMPHADENOPATHY AND SPLENOMEGALY
Lymphadenopathy is a common presentation of infectious, inflammatory, and hematologic diseases, particularly the lymphomas and leukemias [see Table 2]. Lymphadenopathy may occur without associated symptoms, but often, fatigue and intermittent fever (e.g., Pel-Ebstein fever) occur. In contrast to acute infectious diseases leading to tender lymphadenopathy, in most hematologic disorders the lymph nodes and spleen are nontender, with a soft to rubbery consistency. Splenomegaly is often more difficult to detect than lymphadenopathy; most of the diseases causing lymphadenopathy can also cause splenic enlargement.
Table 2 Causes of Lymphadenopathy42
BLEEDING AND BRUISING
Bleeding occurs as a consequence of thrombocytopenia, deficiencies of coagulation factors, or both [see 5:XIII Hemorrhagic Disorders]. Thrombocytopenia usually presents as petechial bleeding that is first observed in the lower extremities. Coagulation factor deficiencies more often cause bleeding into the gastrointestinal tract or joints. Intracranial bleeding, however, can occur with a deficiency of platelets or coagulation factors and can be catastrophic.
Thrombosis can be either venous or arterial [see 5:XIV Thrombotic Disorders]. With venous thrombosis, swelling, tenderness, and pain beyond the obstruction usually occur, and embolization to the lungs is a frequent concern. Venous thrombosis usually occurs after inactivity or obstruction of venous flow or with imbalances of coagulation factors. On the other hand, arterial thrombosis usually occurs because of abnormalities of the arterial wall from atherosclerosis or acute vascular injury, as in thrombotic thrombocytopenic purpura, or from thrombocytosis in the myeloproliferative disorders.
The following basic tests are widely used to diagnose hematologic disorders.
COMPLETE BLOOD CELL COUNTS
CBCs are routinely performed in most laboratories through the use of an electronic particle counter, which determines the total white blood cell and platelet counts and calculates the hematocrit and hemoglobin levels from the erythrocyte count and the dimensions of the red cells. Abnormalities in the CBC are described in other Hematology chapters [see also the Normal Laboratory Values section].
PERIPHERAL BLOOD SMEARS
Peripheral blood smears usually stain with Wright stain. When examined by light microscopy, they reveal the size and shape of blood cells, which allows an estimate to be made of the amount of hemoglobin in erythrocytes. Differential leukocyte counts, enumerating the number of neutrophils, monocytes, lymphocytes, eosinophils, and basophils, are made by manually counting cells on the blood smears or by using an automated cell counter [see the Normal Laboratory Values section]. The morphology of the leukocytes often provides a clue for the diagnosis of leukemia and for recognizing some disorders of leukocytes that lead to susceptibility to infections [see 5:VII Nonmalignant Disorders of Leukocytes].
Reticulocyte counts are useful for evaluating the marrow response to anemia [see the Normal Laboratory Values section]. Normally, during their first 24 to 36 hours in the circulation, young red cells contain residual ribosomal RNA, which precipitates with certain dyes such as methylene blue. An increase in the proportion or absolute number of reticulocytes occurs a few days after significant blood loss or in response to red blood cell destruction in hemolytic anemias. Low reticulocyte counts in chronic anemia suggest either an endogenous erythropoietin deficiency or a marrow abnormality.
BONE MARROW EXAMINATION
Hematopoietic cells of the bone marrow can be removed by aspiration or by needle biopsy. In adults, the best site is the posterior iliac crest, with the patient in a prone position [see Figure 4]. Under special circumstances and in children, other sites can be used, such as the anterior iliac crest, the sternum, or the long bones. With local anesthesia and sterile technique, the patient experiences only transient pain. Bleeding or infection at the injection site is quite uncommon. The aspirate yields cells for morphologic examination, and differential counts reveal the ratio of myeloid cells to erythroid cells (M:E ratio) [see the Normal Laboratory Values section]. A biopsy reveals the cellularity of the marrow at the site sampled. Biopsies are particularly useful for examination of the marrow for infiltrative cells (e.g., in lymphomas or carcinomas involving the marrow) and for diagnosing leukemia, characterized by the marrow's being so densely packed with cells that none of the bone marrow can be aspirated. Biopsies take longer for interpretation because they must be decalcified and stained before examination.
Figure 4. Bone marrow aspirate and biopsy procedure. (a) The posterior iliac crest is the usual site for sampling; (b) the needle is placed through the skin to the marrow space; (c) the marrow sample is aspirated; and (d) the biopsy sample is carefully removed.
Radionuclide scanning (e.g., using technetium-99m) reveals the extent of the hematopoietic tissue in the marrow because the phagocytic cells of the marrow take up the radiolabeled particles. Marrow scanning is sometimes used to determine the extensiveness of the hematopoietic tissue; more often, it is useful in determining whether there are localized areas of increased uptake resulting from infection or a malignancy that has metastasized to the marrow. Computed tomography and ultrasonography are useful in determining the size of lymph nodes and the spleen, but they are not particularly useful for marrow examination. The marrow is seen well with magnetic resonance imaging. This technique is principally used to look for infiltrative processes in the marrow space, such as those that occur in malignancies and infections.
Figures 1,2,3,4 Seward Hung.
Editors: Dale, David C.; Federman, Daniel D.