1028 SECTION IX Pediatric Critical Care Hematology and Oncology and granulocyte colony stimulating factor (G CSF) suffer from severe anemia, thrombocytopenia, or neutropenia, respectively The list of[.]
1028 S E C T I O N I X Pediatric Critical Care: Hematology and Oncology 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.13 Characteristics of specific hematopoietic growth factors, discussed in the following sections, are summarized in Table 86.2 Erythropoiesis On its way toward RBC maturation (see Fig 86.2), the hematopoietic stem cell gives rise to an erythrocyte/megakaryocyte progenitor cell that may differentiate into burst-forming units-erythroid (BFU-E) and colony forming units-erythroid (CFU-E), which are identifiable experimentally on the basis of growth characteristics in culture These phases of development, which involve amplification of cell number, are extensively reviewed elsewhere.14 As noted earlier, the proerythroblast is the earliest morphologically identifiable precursor and presumably is the successor to the CFU-E The subsequent sequence of RBC production normally takes to days in the marrow and involves multiple cell divisions with increasing differentiation, characterized chiefly by globin messenger RNA, cytoplasmic synthesis of hemoglobin, and, ultimately, extrusion of the RBC nucleus The enucleated cell is large and, because it contains residual RNA, stains deeply by the Wright-Giemsa technique (i.e., polychromatophilic macrocyte) Normally, at this stage, the erythrocyte is released into the circulation, where it is recognized as a reticulocyte Because reticulocytes lose their RNA within 24 to 30 hours, their quantitation provides a rough estimate of the rate of erythropoiesis during the past 24 hours In newborns younger than week of age, reticulocytes in the blood can comprise more than 5% of the total RBCs At any older age, the normal reticulocyte count is less than 2% The absolute reticulocyte count can be calculated from this uncorrected reticulocyte count by multiplying the latter by the RBC count (normally approximately 106/µL) Sometimes, a corrected reticulocyte count is used as determined by multiplying the reticulocyte percentage by the observed hematocrit divided by the normal hematocrit If the corrected reticulocyte count is less than 1%, one must suspect bone marrow failure or insufficiency The rate of erythropoiesis can be more accurately measured by ferrokinetic studies, but these are not available in most clinical settings The proportion of erythroid precursors in a bone marrow aspirate also provides a more convenient estimate of total erythropoiesis that is valid if a cellular specimen is obtained and if granulopoiesis is normal In the older child or adult, erythroid precursors normally are one-third as plentiful as myeloid precursors (i.e., the myeloid/erythroid ratio is about 3:1) Approximately 10% of erythroid precursors not produce circulating RBCs (ineffective erythropoiesis) Maturation of RBC precursors is regulated by a number of humoral and nutritional factors Epo appears to act predominantly by increasing proliferation of CFU-E (see Table 86.2 and Fig 86.2) Its production is stimulated by hypoxemia or acute hemorrhage During fetal development, it is mainly produced in the liver, but this site shifts later to the juxtamedullary region in the kidneys Thus, renal dysfunction may result in a normochromic normocytic anemia Humoral factors less well characterized than Epo that are derived from multiple sources (spleen cells, peripheral blood monocytes, and mononuclear bone marrow cells) appear to act at an earlier stage of differentiation to amplify the number of progenitors committed to Epo responsiveness Among these are burst-promoting activity, which enhances production and TABLE Recombinant Hematopoietic Growth Factors and Their Clinical Uses 86.2 CSF Target Clinically Available SCF HSC, mast cells No IL-3 HSC No Dosagea Epo Erythroid progenitors Yes Epoietin 50 U/kg/dose IV times/wk G-CSF Granulocytes and their precursors, for hemotherapy-induced suppression, severe congenital neutropenia, peripheral stem cell harvest, drug-induced neutropenia Yes Filgrastim mg/kg/d IV or SC Pegfilgrastim 1.5–6.0 mg (weight based) SC 24 h after chemotherapy GM-CSF Phagocytes and their precursors, dendritic cells, for autologous stem cell transplantation, enhanced antigen presentation, drug-induced neutropenia Yes Sargramostim 250 µg/m2/d IV or SC M-CSF Monocytes and their precursors No Megakaryocytes, for immune thrombocytopenic purpura, aplastic anemia Yesb Tpo a a Eltrombopag 25 or 50 mg daily (starting dose) Romiplostim mg/kg/d IV Variable Check formulary for specific indications and dosing The thrombopoietin receptor agonists romiplostim and eltrombopag are approved for pediatric use in aplastic anemia and immune thrombocytopenia purpura CSF, Colony-stimulating factor; Epo, erythropoietin; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; HSC, hematopoietic stem cells; IL, interleukin; IV, intravenous; M-CSF, macrophage colony-stimulating factor; SC, subcutaneous; SCF, stem cell factor; Tpo, thrombopoietin b CHAPTER 86 Structure and Function of the Hematopoietic Organs proliferation of BFU-E Within the marrow, normal RBC maturation requires both folate and vitamin B12 A deficiency of either results in abnormal nucleic acid synthesis and the production of an abnormal precursor, the megaloblast Iron is required for hemoglobin synthesis; deficiency results in poorly hemoglobinized (hypochromic) small (microcytic) RBCs Compared with the 120-day life span of normal RBCs in older individuals, the RBC life span in the term newborn is about 60 days Greater prematurity is associated with even shorter RBC life spans, reflecting decreased membrane stability and vulnerability to oxidative stress Removal of RBCs from the circulation is not a random process Senescent RBCs are removed selectively from the circulation by the macrophages of the reticuloendothelial system Although this is primarily a function of the spleen (see the following section), asplenic patients with normal RBCs accomplish this process in the liver and other sites and not exhibit a prolonged life span In patients with some types of hemolytic anemias who undergo therapeutic splenectomy, the RBC life span increases but not to normal levels The primary function of the circulating RBC is to carry oxygen (O2) from the lungs to the tissues Hemoglobin must be packaged within the RBC membrane to prolong its plasma half-life Interference with the reversible binding of O2 by Hb can occur by several mechanisms, including (1) methemoglobinemia, the inability to maintain ionic iron within the Hb molecule in the reduced (ferrous, Fe11) state; (2) the presence of abnormal hemoglobins, among which are the methemoglobins, which have an abnormal affinity for O2; (3) age- or disease-related differences in the percentage of structurally normal HbF, which has a high affinity for O2; and (4) changes in the microenvironment that alter the intracellular concentration of 2,3-diphosphoglycerate (2,3-DPG), which decreases hemoglobin affinity for O2 The oxyhemoglobin interaction also is complicated by the Bohr effect (at a lower pH, Hb binds O2 with less affinity) independent of 2,3-DPG concentration Patients with severe acidosis have low concentrations of 2,3-DPG, which results in an O2 dissociation curve that shifts to the left However, the in vivo curve may be normally placed because the Bohr effect counterbalances the reduction in RBC 2,3DPG If metabolic acidosis is rapidly corrected, the prompt rise in blood pH is reflected in a proportional increase in O2 affinity (the Bohr effect) However, there is a lag of several hours before the RBC 2,3-DPG increases to normal During this time, there is a shift to the left in both the in vivo and in vitro O2 dissociation curves This phenomenon may compromise tissue oxygenation in patients who have diminished cardiovascular reserves Premature infants with respiratory failure may have a leftshifted O2 affinity curve because of the high levels of HbF and an acidosis-induced decrease in 2,3-DPG levels Exchange transfusions with fresh adult blood have been found to reduce mortality, perhaps by providing blood with “normal” O2 affinity.15 Other reasons for impaired O2 delivery are decreased RBC mass (anemia, which leads to a compensatory increase in 2,3-DPG) and decreased blood flow, either because of vascular anatomic abnormalities or increased blood viscosity (e.g., in sickle cell disease) In addition to Hb-bound O2, the O2 dissolved in plasma (which normally amounts to less than 2% of the total O2 carried in the blood) increases linearly with increases in partial pressure of O2 (PO2) For this reason, very anemic patients (e.g., Hb g/dL) who have insufficient Hb with which to carry O2 may benefit from administration of O2 Extensive research into the design of artificial blood has focused both on “red blood” (repackaged Hb from senescent RBCs or of Hb produced with 1029 genetic engineering) and “white blood” or perfluorocarbons (emulsions that dissolve large amounts of O2), but their use remains investigational For now, RBC transfusions ameliorate anemia acutely; otherwise, Epo may be used to elevate Hb over several weeks (see also Chapter 91) Although antibody-mediated Epo-associated pure RBC aplasia is infrequent,16 familiarity with possible Epo toxicity should accompany its use Granulopoiesis As shown in Fig 86.2, in addition to BFU-E, CD341 stem cells (otherwise known as CFU-S) also give rise to several other distinct cell populations The best characterized of these are the CFU-GM (also known as granulocyte macrophage progenitor cell, which in turn generates both CFU-G [granulocyte colony-forming units] and CFU-M [monocyte-macrophage colony-forming units]) and the CFU-Eos (eosinophil colony-forming units) As with the CFU-E, these are not morphologically recognizable and probably masquerade in the bone marrow as small lymphocytes They are identified on the basis of growth characteristics in in vitro bone marrow culture assays Subsequent stages of granulocytic (neutrophilic, eosinophilic, and basophilic) and monocytic differentiation can be visualized by routine histochemical stains of bone marrow aspirates and characterized by flow cytometry.17 In the neutrophilic polymorphonuclear (PMN) series, the transition from myeloblast to mature PMN involves an overall decrease in cell size; coarsening, indentation, and, ultimately, separation of nuclear chromatin, with loss of nuclear chromatin, with loss of nucleoli; and replacement of azurophilic granules (whose contents include myeloperoxidase [MPO]), prominent in promyelocytes, by the specific granules (containing a number of secretory factors important for neutrophil function but not MPO) in mature PMNs Other structural changes during the course of PMN maturation include the disappearance of certain surface antigens, which can be identified by specific monoclonal antibodies, and the appearance of receptor sites for complement (C3) and for the Fc portion of the immunoglobulin molecule These stages in development are accompanied by functional changes, including increases in cell motility, responsiveness to chemoattractants, deformability, and phagocytic capabilities Parallel morphologic and functional changes occur with eosinophilic granulocyte differentiation It is noteworthy that the peroxidase in eosinophil granules is different from that in neutrophils or monocytes so that congenital deficiencies of myeloperoxidase in the latter cells leave eosinophil function intact The blood basophil (which histologically is similar to the tissue mast cell) also is presumed to arise in the bone marrow from the CFUGM In contrast to the CFU-Eos, there is no evidence as yet for a separate basophil CFU DNA labeling studies have demonstrated the kinetics of neutrophil development within the bone marrow There is a mitotic pool (myeloblast and myelocyte) that allows for amplification of cell number and a storage or reserve pool (metamyelocyte and PMN) that in older children and adults contains roughly 100 times the number of granulocytes normally found in the peripheral blood.3 This reserve is mobilized and leads to mature neutrophilia at times of stress (e.g., sepsis, exercise, tachycardia, and pregnancy) or on administration of pharmacologic doses of corticosteroids or exposure to endotoxin In neonates, the storage pool is only two to three times the circulating pool of PMNs and can be depleted, for example, by overwhelming sepsis.18 Sepsis-related neutropenia may be due to apoptosis of 1030 S E C T I O N I X Pediatric Critical Care: Hematology and Oncology neutrophils and their progenitors as well as a block in their maturation.19 In neonates, sepsis can result in neutropenia due to their limited granulocyte reserves Thus, sepsis results in either neutropenia or neutrophilia Eosinophilic granulocytes also have mitotic and storage pools in the marrow that are about 300 times that seen in the periphery After less than a week, they are released from the marrow in response to hypoxia and eosinophilic factors (e.g., heparin, histamine) In contrast to their effects on neutrophils, corticosteroids and epinephrine block mobilization of eosinophils from the marrow The effect of epinephrine can be blocked by propranolol, suggesting mediation by b-adrenergic receptors Little is known about basophil development in the bone marrow Monocyte development is closely related to myelopoiesis, but also is poorly understood However, there does not appear to be a monocyte storage pool The mature neutrophil escapes from the marrow into the circulation by migration through reversible gaps between the endothelial cells lining the sinuses and capillaries Factors known to influence this process include chemoattractants, such as products of the serum complement system and bacterial metabolites Those factors noted previously that mobilize the storage pool may cause an egress of less mature granulocytes with a resultant “shift to the left” in the peripheral blood Once in the periphery, approximately half of the polymorphs adhere to the endothelium of blood vessels as the marginating pool while the other half actually circulate Stress and epinephrine release the marginating cells and therefore double the absolute granulocyte count Eosinophils have a similar arrangement of circulating and marginating cells, whereas the marginating pool of monocytes is three times that of the circulating pool The life span of the neutrophil once in the periphery may be as long as 5.4 days but can be hours in the presence of inflammation, fever, or infection Neutrophils are irreversibly removed from the circulation into the liver, lungs, bowel, or bladder, back to the bone marrow, or to sites of infection where they contribute to the acute inflammatory response Their extravascular half-life also is on the order of hours Although the circulating half-life of eosinophils is comparable to that of neutrophils, eosinophils can persist in the tissues for many days Under pathologic conditions, eosinophils may cycle back and forth between the tissues and circulation Monocytes also have a circulating half-life measured in hours Once in the tissues, however, they mature into macrophages Their precise functions depend on the organ of residence; for example, in the liver they are identified as Kupffer cells and in the lung as alveolar macrophages Macrophages may be “polarized” by cytokines or ligands for the Toll-like receptors into two categories: either an antiinflammatory (M1) or a proinflammatory (M2) macrophage The CSFs that regulate myelopoiesis are diverse, and their biological specificities may overlap.20 Cytokines such as interleukin (IL)-1, tumor necrosis factor, granulocyte-macrophage colonystimulating factor (GM-CSF), and G-CSF expand the PMN precursor compartment and mobilize them by promoting their diapedesis from the marrow and vascular endothelium Endotoxin promotes the host inflammatory response by stimulating endothelial cells, macrophages, and fibroblasts to produce cytokines Both GM-CSF and G-CSF prime PMNs for enhanced phagocytosis and superoxide production in vitro, modulate cell surface expression of adhesion receptors, inhibit apoptosis, and promote antibody-dependent cellular cytotoxicity However, GM-CSF inhibits chemotaxis, whereas G-CSF promotes it G-CSF acts only on the granulocytic lineage GM-CSF affects macrophages and eosinophils, which accounts for side effects of eosinophilia and, at high doses, capillary leak syndrome when administered as sargramostim (Leukine) Because of stickiness and margination along vascular endothelium, a transient drop in O2 saturation may occur within minutes after administration GM-CSF can result in transient fever Bone pain may occur with administration of either drug as marrow production increases WBCs must be monitored, generally twice a week; G-CSF typically is discontinued when the absolute neutrophil count exceeds 1500/µL, even though the number of circulating PMNs then often decreases Multiple trials have demonstrated the efficacy of growth factors in decreasing the time interval of profound neutropenia or length of antibiotic coverage and hospitalization; however, their use has not changed overall survival Clinical uses of G-CSF and GM-CSF are summarized in Table 86.2 Although nonhematopoietic tumor cell lines can display receptors for GM-CSF or G-CSF, administration of these drugs has not led to an appreciated increase in relapse or progressive disease There has been concern that erythropoiesisstimulating agents might stimulate cancer growth.21 These agents can be given to patients with myeloid leukemias or myelodysplastic syndromes (MDSs) without adverse effects Based on adult studies, the FDA now warns that erythropoiesisstimulating agents may lead to serious cardiovascular and stroke events when the hemoglobin is greater than 11 g/dL and may lead to tumor progression and decreased survival As in the case of RBC and platelet development, normal myelopoiesis also requires the presence of vitamin and mineral growth factors Hallmarks of megaloblastic anemia (as in vitamin B12 and folate deficiencies) include macrocytosis with increased mean corpuscular volumes (MCVs), and hypersegmented PMNs The hypochromic microcytic anemia of copper deficiency is characteristically associated with neutropenia This can be seen with malabsorption states, zinc excess, and with inadvertent omission of copper supplementation in hyperalimentation fluids Copper deficiency can lead to blood cell dysplasias characteristic of MDS and with intracytoplasmic vacuole in RBCs and myeloid marrow precursors.22 Among the nonlymphoid WBCs, clinical sequelae of quantitative or qualitative deficiencies of neutrophils have been particularly well studied Systemic or mucocutaneous bacterial infections (gram-positive and gram-negative organisms) are frequent They occur with an incidence that increases with the degree and duration of neutropenia and in the presence of indwelling catheters, intravascular lines, and endotracheal tubes Recommendations for prevention of infections in neutropenia include strict handwashing, changing sites of percutaneous lines as often as every 48 hours, and use of recombinant CSFs in limited situations as noted previously The use of prophylactic antibiotics and reverse isolation is controversial and will vary among centers and divisions within centers In addition to clearing bacteria and fungi, monocytes secrete a variety of inflammatory cytokines Megakaryocyte and Platelet Production The CD341 stem cell gives rise to a committed megakaryocyte progenitor, the CFU-Mega (see Fig 86.2) identifiable in in vitro clonogenic assays and by the presence of platelet glycoprotein surface antigens Unlike RBC and granulocyte differentiation, in CHAPTER 86 Structure and Function of the Hematopoietic Organs which cell division keeps up with mitosis, the next phase of development of megakaryocytes is characterized by endoreduplication, a process of mitosis without cell division that leads to increased DNA content up to a ploidy of 32N (where 2N is a diploid cell) With increasing ploidy comes increased cell volume, degree of nuclear lobulation, and granules containing factors that influence platelet function A system of “demarcation membranes” identified by electron microscopy separates the megakaryocyte cytoplasm into several thousand anucleate platelets, which are shed into the lumens of the marrow sinusoids The entire process takes about days Although megakaryocytes can be visualized on bone marrow aspirates and biopsy specimens, their quantitation by these techniques is approximate and correlates only loosely with platelet production Factors controlling platelet shedding have not been studied extensively With exceptions, however, large platelets or megathrombocytes (increased mean platelet volume) are seen in thrombocytopenia caused by increased platelet destruction Normal platelet volume occurs more frequently in thrombocytopenia resulting from decreased platelet production Some platelets move directly from the marrow to the blood, where they remain; others go temporarily to the spleen, which possibly contributes to their further maturation Normally, onethird of the total body platelet mass is sequestered there, although the number can go as high as 90% in pathologic states Once in the peripheral blood, platelets have a life span of about 10 days Chromium studies, useful to assess platelet life span, have severe limitations in estimating the extent of organ-specific uptake of platelets and response to splenectomy Tpo is the critical growth factor for the production of platelets.23 Whereas IL-3, GM-CSF, Epo, IL-11, and IL-6 stimulate CFU-Mega growth in vitro, in contrast to romiplostim and eltrombopag, none of these factors has proved to be effective in increasing platelet counts Tpo potently stimulates the expression of CFU-Mega and megakaryocytes, resulting in an increased platelet mass Because knockout mice have been created that lack the gene for the Tpo receptor but still produce some platelets, other cytokines must contribute to platelet production These factors, such as IL-3 and IL-11, most likely synergize with Tpo Although iron-deficiency anemia is often associated with thrombocytosis, increases in Epo may not be the immediate mechanism and not all disease states associated with elevated Epo levels are characterized by increased platelet number As with the other cell lines, megakaryopoiesis is also dependent on vitamins; severe megaloblastic anemia may be associated with thrombocytopenia and bizarre platelet and megakaryocyte morphology Spontaneous bleeding is unlikely unless there are fewer than 20,000/ µL normally functioning platelets However, for major invasive procedures, such as surgery or placement of arterial lines or endotracheal tubes, the platelet count should be maintained at a level of more than 50,000/ µL or even 100,000/ µL The minimum platelet count for performing a spinal tap is less clear, but most clinicians would ask that the platelet count be at least 30,000/mL Other indications for platelet transfusions are discussed in Chapter 91 In the rare patient with idiopathic thrombocytopenic purpura and intracranial hemorrhage, optimum control of bleeding requires cooperation among neurosurgery, general surgery, hematology, and intensive care clinicians and some combination of splenectomy, high-dose gammaglobulin, steroid therapy, and platelet transfusions 1031 Lymphopoiesis The bone marrow and thymus are the primary lymphoid organs, the site of lymphocyte production The secondary lymphoid organs, to which the B and T cells migrate, include the spleen, lymph nodes, and gut-associated lymphoid tissue (tonsils, appendix, and Peyer patches of the small intestine) The following discussion will be limited to the spleen, which is a frequent organ of interest in the PICU Spleen The spleen is enclosed in a thick, fibromuscular capsule Numerous trabeculae spring from the capsule to divide the interior pulp into lobules, within which is a scaffolding of reticular cells and fibers Unlike the thymus, the spleen has a hilum through which the splenic artery and its branches enter and then branch further to course along the trabeculae Collaterals from the gastric artery enter through the splenic capsule so that splenic artery ligation does not result in infarction The branches of the splenic artery pass into the parenchyma to form central arteries that are surrounded for much of their length by a dense sheath of T lymphocytes and macrophages Lymphoid follicles, some with germinal centers containing B cells from the bone narrow (as noted previously), are also present in the periarterial lymphatic sheath Together, the B-cell– and T-cell–dependent areas compose the white pulp of the spleen The rest of the splenic parenchyma is the red pulp It contains radial branches of the central arteries that carry hemoconcentrated blood (plasma is skimmed off and runs in other arterial branches), well-defined endothelial-lined venous sinuses that ultimately drain into the splenic vein, and an anatomically separate reticulin network, the splenic vein, which functions as endothelial-lined blood vessels Most of the circulation runs from the arterial system into the cords and then into the venous system, probably by squeezing through gaps in the endothelium After the neonatal period, a marginal zone of the red pulp that abuts the white pulp becomes more prominent It contains antigen-processing macrophages that are needed for B-cell function It is believed to be the initial site of interactions between antigen and lymphocytes Small numbers of efferent lymphatic vessels lie at the proximal end of the central arteries and leave the spleen through the trabeculae Normally, the spleen is found in the upper-left quadrant of the abdomen Its weight increases linearly with body weight until puberty, after which it shrinks somewhat A spleen tip is palpable in 10% of normal children On the basis of data from splenectomy cases, small accessory spleens occur in almost 20% of individuals Generally, they are located near the hilum of the main spleen, with which they share their vascular supply The spleen has many functions The red pulp filters damaged and old RBCs from the systemic circulation by several mechanisms: (1) The cells are distorted and disrupt as they pass through the small lumens of the arterial capillaries or between the endothelial cells of the sinuses In particular, cells with HbS undergo increased sickling, and cells with abnormalities of glycolytic metabolism or senescent cells become increasingly fragile in the face of decreased O2 tension with lactic acidosis and decreased adenosine triphosphate production (2) Cells are entrapped in the viscous blood within the fine mesh reticulin (3) Cells undergo antibodymediated (especially immunoglobulin G) hemolysis or phagocytosis, as seen in some autoimmune hemolytic anemias Damaged cells or their debris produced by any of these mechanisms are 1032 S E C T I O N I X Pediatric Critical Care: Hematology and Oncology removed by macrophages of the red pulp or may escape back into the circulation Rigid inclusions, such as Howell-Jolly bodies, may be pitted without destroying the parent RBC on passage through the sinus endothelium Therefore, the presence of even small numbers of Howell-Jolly bodies is a subtle indicator of impaired splenic function except in the term neonate and especially in the premature neonate, where they also are seen and thought to be a normal developmental stage As mentioned earlier, the spleen also is a temporary reservoir for platelets and to a small extent for WBCs Thus, after splenectomy, there is usually a transient thrombocytosis that resolves within to months In children, it does not appear to carry a predisposition to thrombosis even with platelet counts as high as 109/mL In the presence of antiplatelet or anti-WBC antibody (some synthesized by the spleen) and in hypersplenism without antibody, the spleen may also function as a filter and result in thrombopenia and neutropenia, which may be reversible by surgical or pharmacologic (steroids, high-dose gamma globulin) splenectomy (see the Megakaryocyte and Platelet Production section) The spleen, predominantly the white pulp and marginal zone, also plays a number of roles in host defense Splenectomy has been associated with an increased incidence of serious infections with encapsulated bacteria, intraerythrocytic parasites, and possibly leukemia in patients who have splenectomy as part of the management of Hodgkin disease Most clinicians recommend use of Haemophilus influenzae type B, meningococcal, and pneumococcal vaccines to weeks before splenectomy (in previously unimmunized individuals or in individuals who were immunized more than years before), with boosters against pneumococcal disease every to 10 years, and prophylactic antibiotics for variable times but at least through adolescence Although it is not a site of hematopoiesis beyond fetal life under normal conditions, in certain disease states the spleen can reactivate its hematopoietic potential These states include some congenital hemolytic anemias and acquired diseases, such as myeloid metaplasia All are associated with splenomegaly and usually with hepatomegaly, signifying a more general expansion of hematopoiesis The liver can fulfill some of these functions so that in functionally or literally asplenic patients RBC life span, for example, is not increased However, the liver is less effective at other functions, including pitting and host defense Key References Fiorito BA, Mirza F, Doran TM, et al Intraosseous access in the setting of pediatric critical care transport Pediatr Crit Care Med 2005;6: 50-53 Morrison SJ, Scadden DT The bone marrow niche for haematopoietic stem cells Nature 2014;505:327-334 Orkin SH, Zon LI Hematopoiesis: an evolving paradigm for stem cell biology Cell 2008;132:631-644 Orlowski JP, Julius CJ, Petras RE, Porembka DT, Gallagher JM The safety of intraosseous infusions: risks of fat and bone marrow emboli to the lungs Ann Emerg Med 1989;18:1062-1067 Ramaswamy K, Hsieh L, Leven E, Thompson MV, Nugent D, Bussel JB Thrombopoietic agents for the treatment of persistent and chronic immune thrombocytopenia in children J Pediatr 2014;165:600-605 Rodriguez S, Chora A, Goumnerov B, et al Dysfunctional expansion of hematopoietic stem cells and block of myeloid differentiation in lethal sepsis Blood 2009;114:4064-4076 The full reference list for this chapter is available at ExpertConsult.com ... reticuloendothelial system Although this is primarily a function of the spleen (see the following section), asplenic patients with normal RBCs accomplish this process in the liver and other sites... before the RBC 2,3-DPG increases to normal During this time, there is a shift to the left in both the in vivo and in vitro O2 dissociation curves This phenomenon may compromise tissue oxygenation... PICU Spleen The spleen is enclosed in a thick, fibromuscular capsule Numerous trabeculae spring from the capsule to divide the interior pulp into lobules, within which is a scaffolding of reticular