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Normal ranges for blood cell numbers are dependent on age, gender, and race.
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Because the bone marrow circulation connects with the general circulation, fluids and medications injected into the marrow are absorbed as rapidly as when administered intravenously.
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For major invasive procedures such as surgery, placement of arterial lines, or endotracheal tubes, platelet count should be maintained at 50,000/µL or greater.
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Since small amounts of oxygen (O 2 ) are dissolved in plasma, severely anemic patients with insufficient O 2 -carrying capacity in hemoglobin may benefit from O 2 administration.
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Blood growth factors and thrombopoietin-like molecules may be useful in some congenital and acquired cytopenias.
The hematopoietic system includes the bone marrow and, at different stages of fetal and postnatal development, the liver, spleen, lymph nodes, and thymus. The extensive use of red blood cell (RBC) or platelet transfusions and of antimicrobials in febrile neutropenic patients reflects the importance of the blood system in the pediatric intensive care unit (PICU) setting. This chapter reviews the anatomy and physiology of the hematopoietic system with a focus on the bone marrow to provide a basis for understanding the repercussions of hematologic abnormalities. Aspects that are of practical importance to the intensivist are emphasized.
Normal peripheral blood values
Within the peripheral circulation of healthy individuals, the number of each type of blood component is maintained within a narrow range. However, the normal ranges for RBCs and white blood cells (WBCs) vary considerably by age in the pediatric population. Adults and pubertal adolescents have approximately 8000 WBCs, including 5000 granulocytes, 2000 lymphocytes, 500 monocytes, 5 × 10 6 RBCs, and 150,000 to 400,000 platelets per microliter of whole blood. Hemoglobin and hematocrit values vary with gender such that median hemoglobin levels in pubertal males and females are 16 and 14 g/dL, respectively ( Table 86.1 ). Besides age, WBC values also are a function of ethnicity, so that healthy normal African-Americans (especially males) may have granulocyte counts less than 1500/μL (i.e., benign ethnic neutropenia). Normative values for Hispanics are less well established but have been reported to be closer to those of whites. Normal ranges for all blood cell types may vary to a small extent among laboratories. Production of RBCs, WBCs, and platelets is a function of the bone marrow under normal and stressed conditions.
| Age | Hb (g/dL) | HCT (%) | MCV (fL) | MCHC (g/dL RBC) | Reticulocytes | WBCs (×10 3 /mL) a | Platelets (10 3 /mL) a |
|---|---|---|---|---|---|---|---|
| 26–30 wk gestation b | 13.4 (11) | 41.5 (34.9) | 118.2 (106.7) | 37.9 (30.6) | — | 4.4 (2.7) | 254 (180–327) |
| 28 wk | 14.5 | 45 | 120 | 31.0 | (5–10) | — | 275 |
| 32 wk | 15.0 | 47 | 118 | 32.0 | (3–10) | — | 290 |
| Term c (cord) | 16.5 (13.5) | 51 (42) | 108 (98) | 33.0 (30.0) | (3–7) | 18.1 (9–30) | 290 |
| 1–3 days | 18.5 (14.5) | 56 (45) | 108 (95) | 33.0 (29.0) | (1.8–4.6) | 18.9 (9.4–34) | 192 |
| 2 wk | 16.6 (13.4) | 53 (41) | 105 (88) | 31.4 (28.1) | — | 11.4 (5–20) | 252 |
| 1 mo | 13.9 (10.7) | 44 (33) | 101 (91) | 31.8 (28.1) | (0.1–1.7) | 10.8 (4–19.5) | — |
| 2 mo | 11.2 (9.4) | 35 (28) | 95 (84) | 31.8 (28.3) | — | — | — |
| 6 mo | 12.6 (11.1) | 36 (31) | 76 (68) | 35.0 (32.7) | (0.7–2.3) | 11.9 (6–17.5) | — |
| 6 mo–2 y | 12.0 (10.5) | 36 (33) | 78 (70) | 33.0 (30.0) | — | 10.6 (6–17) | (150–350) |
| 2–6 y | 12.5 (11.5) | 37 (34) | 81 (75) | 34.0 (31.0) | (0.5–1.0) | 8.5 (5–15.5) | (150–350) |
| 6–12 y | 13.5 (11.5) | 40 (35) | 86 (77) | 34.0 (31.0) | (0.5–1.0) | 8.1 (4.5–13.5) | (150–350) |
| 12–18 y | |||||||
| Male | 14.5 (13) | 43 (36) | 88 (78) | 34.0 (31.0) | (0.5–1.0) | 7.8 (4.5–13.5) | (150–350) |
| Female | 14.0 (12) | 41 (37) | 90 (78) | 34.0 (31.0) | (0.5–1.0) | 7.8 (4.5–13.5) | (150–350) |
| Adult | |||||||
| Male | 15.5 (13.5) | 47 (41) | 90 (80) | 34.0 (31.0) | (0.8–2.5) | 7.4 (4.5–11) | (150–350) |
| Female | 14.0 (12) | 41 (36) | 90 (80) | 34.0 (31.0) | (0.8–4.1) | 7.4 (4.5–11) | (150–350) |
b Values are from fetal samplings.
c 1 mo, capillary hemoglobin exceeds venous: 1 h, 3.6-g difference; 5 days, 2.2-g difference; 3 wk, 1.1-g difference.
Structure of the bone marrow
Hematopoiesis refers to production of RBCs, granulocytes (neutrophils, eosinophils, basophils), monocytes, lymphocytes, platelets, and their stem, progenitor, and precursor cells. During embryogenesis and fetal development, hematopoiesis shifts from the yolk sac (primitive hematopoiesis) to the liver and, after the 20th week of gestation, to the bone marrow (definitive hematopoiesis). Although extramedullary erythropoiesis may persist for several weeks after birth, hematopoiesis takes place almost entirely in the bone marrow in the term infant.
Grossly, two types of bone marrow can be recognized in normal individuals: yellow marrow, so called because of the predominance of adipocytes, and red marrow, in which blood cells and hematopoiesis predominate. In disease states such as starvation, white marrow also can be seen, consisting predominantly of stromal cells and intercellular matrix. Red marrow proportionately is a much greater component of body weight and volume in the infant than in the adult ( Fig. 86.1 ). Early in life, red marrow is contained in the medullary cavities of the long bones, which gradually fill with fat such that, by late puberty, the adult distribution of hematopoiesis (sternum, pelvis, vertebrae, cranium, ribs, epiphyses of long bones) is achieved. That the degree of hematopoiesis in a given bone varies with age is an important consideration in selecting a site for bone marrow aspiration or biopsy. Although the anterior and posterior iliac crests can be used at any age to provide representative samples of active marrow, the tibia can be used only until the age of 2 years. In disease states characterized by excessive destruction of blood cells, such as thalassemia major, hematopoiesis may increase twofold to eightfold. Sites of normal medullary hematopoiesis may expand—resulting, for example, in frontal bossing of the skull. Extramedullary hematopoiesis, particularly in the liver and spleen, may develop as a compensatory response to excessive destruction of blood (e.g., hemolytic anemias) or replacement of the bone marrow with collagen (e.g., primary or secondary myelofibrosis).
Microscopically, the marrow is a network of vascular channels (sinuses) separating “hematopoietic islands” of hematopoietic cells, fat, and rare osteoblasts and osteoclasts (which are important for bone remodeling). , The vasculature and cells are joined by a reticulin (fiber) network, or scaffolding. By light microscopy, bone marrow aspirate specimens demonstrate hematopoietic elements. However, a bone marrow biopsy provides a more accurate measure of marrow architecture and cellularity. Reticulin can be seen by light microscopy using specific histochemical stains. Increased reticulin is characteristic of either primary or secondary myelofibrosis.
The blood vessels that feed the marrow are branches of those that feed the surrounding bone. , Large central arteries run longitudinally within the marrow and send radial branches that penetrate the endosteum and form capillaries in the Haversian and Volkmann canals of the bony cortex. These capillary systems drain into the bone marrow sinuses, which, in turn, drain into a central sinus or vein. Because the marrow circulation connects with the general circulation in this fashion, fluids and medication injected into bone marrow are absorbed as rapidly as through intravenous (IV) routes. Unlike peripheral veins, intramedullary vessels supported by their bony shell do not collapse in shock. Therefore, intraosseous (usually tibial or iliac crest) infusion can be used when peripheral IV access is not available (see also Chapter 14 ). It is also noteworthy that the connection between the marrow and general circulation provides the mechanism by which fat from bone marrow may embolize to the lung after osseous trauma or fracture or in patients with acute chest syndrome from sickle cell anemia. Marrow embolization has not been demonstrated to be a problem in the case of intraosseous infusion.
Function of the bone marrow: Hematopoiesis
RBCs, granulocytes (neutrophils, eosinophils, basophils), monocytes (and their tissue forms, macrophages), megakaryocytes, and lymphocytes develop from a self-renewing pluripotent hematopoietic stem cell ( Fig. 86.2 ). Stem cells look like small lymphocytes and are not usually distinguishable from them by microscopy. They constitute less than 1% of the nucleated cells in the normal marrow. Immunophenotyping provides rapid identification of cell lineage and stage of development. , Hematopoietic stem cells are defined by the cell surface expression of the CD34 antigen. The “trilineage myeloid” stem cell (erythroid, granulocyte, megakaryocyte) has been designated the colony forming unit-stem (CFU-S; in humans, CD34 + cells) on the basis of murine bone marrow culture assays and experiments in which the spleens of lethally irradiated mice infused with donor marrow cells are found to contain colonies, each consisting of precursors of RBCs, granulocytes, monocytes, and megakaryocytes. Lymphopoiesis appears to depend on a separate progenitor cell, a common lymphoid progenitor cell derived from CD34 + stem cells.
A defining feature of hematopoietic stem cells—even when they are introduced into the peripheral blood, as in stem cell transplantation—is their ability to home to the bone marrow. This homing occurs via chemoattractants such as stromal cell–derived factor-1 and its cognate receptor CXCR4 on the stem cell as well as through interactions between various stem cell adhesion molecules and their ligands on stroma and endothelial cells. Another defining feature of the stem cell is its plasticity. Provocative studies have shown that stem cells isolated from the bone marrow can be driven to differentiate into muscle, liver, cardiac, or neuronal tissue. In addition, differentiated cells may be isolated from patients and be reprogrammed to become an induced pluripotent stem cell (iPSC) through transient expression of stem cell transcription factors. These observations have raised the possibility that bone marrow may be a convenient source of stem cells for stem cell engineering and tissue replacement, which may be ethically less challenging than obtaining stem cells from embryos or fetuses. Although the clinical applications to nonhematologic tissues remain distant, the use of hematopoietic stem cells to replace a diseased marrow is a common practice (i.e., stem cell transplantation; see also Chapter 93 ).
CFU-S or CD34 + cells are found rarely in peripheral blood. They are found more commonly following growth factor–induced mobilization in adult stem cell donors or from placental cord blood; both are alternative sources of stem cells for transplantation. The first morphologically identifiable precursor cells are the proerythroblast, myeloblast, monoblast, megakaryoblast, and lymphoblast. These committed precursors and their terminally differentiated counterparts sit within the hematopoietic islands. Megakaryocytes (which make up fewer than 1% of hematopoietic cells) generally are located next to marrow sinusoids and shed proplatelets (elongated fragments of megakaryocyte cytoplasm) directly into the lumen, which quickly become platelets. Erythroblasts also are produced near the walls of the vascular sinuses in clusters with macrophages called erythroblast islets . As the erythroblasts develop, they extrude their nuclei, which are phagocytosed by the macrophages. During severe stress-induced erythropoiesis (e.g., hypoxia and severe hemolytic anemia) or when the marrow space is disrupted by tumor cell infiltration, circulating nucleated RBCs may be observed. In contrast, granulocytes (the most numerous cell type found in the bone marrow), monocytes, and lymphocytes are produced throughout the marrow away from vascular sinuses. Mature WBCs are motile and migrate to the sinuses, where they enter into the circulation.
Under normal conditions, the rate of production of each cell type equals the rate of destruction. The life span of mature RBCs in adults is 100 to 120 days, and 5 × 10 4 RBCs/ µL are produced daily to maintain hemoglobin (Hb) values. The average platelet life span is 7 to 10 days so that approximately 2 × 10 4 platelets/µL are produced daily. Granulocytes have the shortest life span, with estimates from hours to up to 5.4 days; production occurs at a rate of 10 4 cells/ µL per day. Production rates of different lymphocyte subsets vary, but some T and B lymphocytes are long-lived and can survive for years.
Regulators of hematopoiesis: Growth factors
The mechanisms that regulate the steady state of blood counts are incompletely understood. The number of committed progenitor cells that differentiate in any time period is dependent on feedback from humoral regulators that are produced within the marrow microenvironment (including its stromal cells) and by extramedullary sources (including T cells, macrophages, endothelial cells, and fibroblasts). These hematopoietic growth factors are cytokines. Many of the cytokines have overlapping functions. However, gene targeting in the mouse (“knockout mouse”) of cytokines or their cognate receptors has identified the essential nonredundant functions for several hematopoietic growth factors. Mice deficient in erythropoietin (Epo), thrombopoietin (Tpo), and granulocyte colony-stimulating factor (G-CSF) suffer from severe anemia, thrombocytopenia, or neutropenia, respectively.
The list of cytokines and small molecules that regulate hematopoiesis and their clinical application continue to grow. Chemical modification of Epo and G-CSF (filgrastim, Neupogen) has resulted in two longer-acting forms, darbepoetin alpha and pegfilgrastim (Neulasta, Neulasta-Onpro), respectively. Their primary advantage is longer half-lives, allowing them to be administered much less frequently. Two pharmacologic thrombopoietins, romiplostim (NPlate) and eltrombopag (Promacta), have been approved by the US Food and Drug Administration (FDA) for use in adults and children with chronic immune thrombocytopenic purpura (ITP) and in adults with thrombocytopenia secondary to chronic hepatitis. Eltrombopag also has been approved for frontline treatment of severe aplastic anemia in all age groups. Both drugs have been used in phase II clinical trials in pediatrics. Characteristics of specific hematopoietic growth factors, discussed in the following sections, are summarized in Table 86.2 .
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