Structure and Function of the Hematologic System Chapter 19 All body’s tissues and organs require oxygen and nutrients to survive. Red blood cells provide the oxygen, and the fluid portion of the blood carries the nutrients.

Components of the Hematologic System Composition of blood 90% water and 10% solutes 6 quarts (5.5 L) Plasma 55% to 60% of the blood volume Organic and inorganic elements Blood consists of various cells that circulate in the cardiovascular system suspended in a solution of protein and inorganic materials (plasma). Blood is 90% water and 10% solutes. The blood volume amounts to 6 quarts (5.5 L). Plasma is 55% to 60% of the blood volume.

Components of the Hematologic System Chief function Delivery of substances needed for cellular metabolism Removal of wastes Defense against microorganisms and injury Maintenance of acid-base balance The continuous movement of blood guarantees that critical components are available to all parts of the body to carry out their chief functions: (1) Delivery of substances needed for cellular metabolism (2) Removal of wastes (3) Defense against microorganisms and injury (4) Maintenance of acid-base balance

Components of the Hematologic System Composition of blood Plasma proteins Albumins Function as carriers and control the plasma oncotic pressure Globulins Carrier proteins and immunoglobulins (antibodies) Clotting factors Mainly fibrinogen Plasma is a liquid containing a variety of organic and inorganic elements. The concentration depends on diet, metabolic demand, hormones and vitamins. Plasma contains a large number of proteins which are classified into two major groups: (1) Albumins: Function as carriers (drugs, blood components) and control the plasma oncotic pressure (2) Globulins: Carrier proteins and immunoglobulins (antibodies) Plasma proteins can be classified by function: Clotting (clotting factors promote coagulation and stop bleeding) Defense Transport Regulation

Components of the Hematologic System Composition of blood Cellular components Erythrocytes Most abundant cell in the body Responsible for tissue oxygenation Biconcavity and reversible deformity 120-day life cycle The cellular elements of the blood are broadly classified as red blood cells (i.e. erythrocytes), white blood cells (i.e. leukocytes) and platelets. Erythrocytes are the most abundant cell in the body. They are mainly responsible for tissue oxygenation, The erythrocyte contains hemoglobin (Hb). It has a limited life span of 120 days and is removed from circulation. It has biconcavity (shape) and reversible deformity provides a surface area/volume ratio that is optimal for gas diffusion into and out of the cell. Reversible deformity enables the erythrocyte to form a torpedo shape and squeeze through microcirculation.

Composition of Blood Cellular components Leukocytes (white blood cells) Defend the body against infection and remove debris Granulocytes Membrane-bound granules in their cytoplasm The granules contain enzymes capable of destroying microorganisms Inflammatory and immune functions Capable of ameboid movement (diapedesis) Leukocytes (white blood cells) defend the body against infection and remove debris. They are primarily in the tissues but are transported in the circulation. Leukocytes are classified by structure as either granulocytes or agranulocytes and according to function as either phagocytes or immunocytes. Granulocytes have many membrane-bound granules in their cytoplasm. The granules contain enzymes capable of destroying microorganisms. The granules also contain powerful biochemical mediators with inflammatory and immune functions. Granulocytes are capable of ameboid movement by which they migrate through vessel walls (diapedesis) and then to sites where their action is needed.

Composition of Blood Granulocytes Neutrophils Eosinophils Polymorphonuclear neutrophil (PMN) Phagocytes in early inflammation Eosinophils Eosinophils ingest antigen-antibody complexes Induced by IgE hypersensitivity Increase in parasitic infections The neutrophil (polymorphonuclear neutrophil [PMN]) is the most numerous and best understood of the granulocytes. They constitute about 55% of the total leukocyte count in adults. Neutrophils are the chief phagocytes in early inflammation. Eosinophils which have large course granules constitute only 1% to 4% of the normal leukocyte count. They have ameboid movement and phagocytosis an ingest antigen-antibody complexes. Eosinophils are induced by IgE hypersensitivity reactions and attack parasites (Chapter 5). The granules contain a variety of enzymes including histaminase.

Composition of Blood Granulocytes Mast cells Basophils Central cell in inflammation Found in vascularized connective tissue Basophils Structurally and functionally similar to mast cells A mast cell (or mastocyte) is a resident cell of several types of tissues and contains many granules rich in histamine and heparin. Although best known for their role in allergy and anaphylaxis, mast cells play an important protective role as well, being intimately involved in wound healing and defense against pathogens. Mast cells play a key role in the inflammatory process. When activated, a mast cell rapidly releases its characteristic granules and various hormonal mediators into the interstitium. Mast cells can be stimulated to degranulate by direct injury (e.g. physical or chemical [such as opioids, alcohols, and certain antibiotics ], cross-linking of Immunoglobulin E (IgE) receptors, or by activated complement proteins. Basophils are structurally and functionally similar to mast cells. They make up less than 1% of leukocytes.

Composition of Blood Agranulocytes Monocytes and macrophages make up the mononuclear phagocyte system (MPS) Monocytes Macrophages Lymphocytes Natural killer (NK) cells Agranulocytes contain relatively fewer granule than granulocytes. Monocytes and macrophages make up the mononuclear phagocyte system (MPS). Monocytes are immature macrophages. As they mature, monocytes migrate into a variety of tissues (e.g. liver, spleen, lymph nodes, GI tract) and fully mature into tissue macrophages. Both monocytes and macrophages participate in the immune and inflammatory response, being powerful phagocytes. Lymphocytes constitute approximately 36% of the total leukocyte count and are the primary cells of the immune response. Most lymphocytes transiently circulate in the blood and eventually reside in lymphoid tissues as mature T cells, B cells, or plasma cells. Natural killer (NK) cells, which resemble lymphocytes, kill some types of tumor cells (in vitro) and some virus-infected cells without prior exposure.

Composition of Blood Platelets Disk-shaped cytoplasmic fragments Essential for blood coagulation and control of bleeding Thrombopoietin Main regulator of platelets Platelets (thrombocytes) are not true cells but disk-shaped cytoplasmic fragments that are essential for blood coagulation and control of bleeding. They lack a nucleus, have no DNA, and are incapable of mitotic division. One third of the body’s available platelets are reserved in the spleen. A platelet circulates for approximately 10 days, ages, and is removed by macrophages of the MPS, mostly in the spleen. Thrombopoietin (TPO) is the main regulator of platelets.

Lymphoid Organs Spleen Largest secondary lymphoid organ Splenic pulp Masses of lymphoid tissue containing macrophages and lymphoid tissue Venous sinuses Phagocytosis of old, damaged, and dead blood cells Blood storage Spleen is the second largest secondary lymphoid organ. The spleen contains splenic pulp which are masses of lymphoid tissue containing macrophages and lymphoid tissue. There are highly distensible storage areas called venous sinuses. In this area, there is phagocytosis of old, damaged, and dead blood cells and blood storage. The spleen is not necessary for life or for adequate hematologic function. Its absence, however, has several effects that indicate its function. High levels of circulating leukocytes often occurs after a splenectomy, so the spleen must exert some control over the rate of proliferation of leukocyte cells. After a splenectomy iron levels in the circulation are decreased, immune function is diminished, and the blood contains more structurally defective blood cells than normal.

Lymphoid Organs Lymph nodes Part of the immune and hematologic systems Facilitates maturation of lymphocytes Transports lymphatic fluid back to the circulation Cleanses the lymphatic fluid of microorganisms and foreign particles Lymph nodes are part of the lymphatic system. Lymph nodes: (1) Facilitates maturation of lymphocytes (2) Transports lymphatic fluid back to the circulation (3) Cleanses the lymphatic fluid of microorganisms and foreign particles

Lymphoid Organs Cross Section of the lymph Node Several afferent valved lymphatics bring lymph to node. A single efferent lymphatic leaves the node at the hilus. (note that the artery and vein also enter and leave the hilus). The arrows show the direction of lymph flow.

Mononuclear Phagocyte System (MPS) The MPS consists of a line of cells that originate in the bone marrow, are transported into the bloodstream, differentiate into monocytes, and settle in the tissues as mature macrophages Cells of the MPS ingest and destroy microorganisms and foreign material The MPS is mostly the liver and spleen The MPS consists of a line of cells that originate in the bone marrow, are transported into the bloodstream, differentiate into monocytes, and settle in the tissues as mature macrophages. The cells of the MPS ingest and destroy microorganisms and foreign material. The MPS is mostly the liver and spleen.

Hematopoiesis Hematopoiesis is the process of blood cell production Two stages Mitosis Mitosis stops before the cell enters the peripheral blood Maturation and differentiation Hematopoiesis: The production of all types of blood cells generated by a remarkable self-regulated system that is responsive to the demands put upon it. The levels of the different types of the white blood cells in the granulocyte series (the neutrophils, eosinophils, and basophils) are normally maintained within preset normal ranges and prompt adjustments are made in response to demands such as infections, allergic reactions, etc. All types of blood cells are derived from primitive cells (stem cells) in the bone marrow. The production of blood cells is largely controlled by feedback. When the demand for production of cells of a particular type of cells increases or the levels of the cells fall in blood, stimulatory substances called cytokines are released. And the cytokines stimulate the stem cells to generate new mature blood cells. This occurs in the few days required for blood cell maturation. The production of lymphocytes is an exception. Many more lymphocytes are generated daily than are needed in the blood. Most lymphocytes are destroyed during development. Thus, lymphopoiesis (the production of lymphocytes) is inefficient compared to all other hematopoiesis.

Hematopoiesis Stem cell system Bone marrow Pluripotent stem cells Colony-stimulating factors Bone marrow Also called myeloid tissue Red and yellow bone marrow Adult active bone marrow Pelvic bones, vertebrae, cranium and mandible, sternum and ribs, humerus, and femur Stem cells have the r potential to develop into many different cell types in the body during early life and growth. In addition, in many tissues they serve as a sort of internal repair system, dividing essentially without limit to replenish other cells as long as the person is still alive. When a stem cell divides, each new cell has the potential either to remain a stem cell or become another type of cell with a more specialized function, such as a muscle cell, a red blood cell, or a brain cell. Stem cells are distinguished from other cell types by two important characteristics. First, they are unspecialized cells capable of renewing themselves through cell division, sometimes after long periods of inactivity. Second, under certain physiologic or experimental conditions, they can be induced to become tissue- or organ-specific cells with special functions. In some organs, such as the gut and bone marrow, stem cells regularly divide to repair and replace worn out or damaged tissues. In other organs, however, such as the pancreas and the heart, stem cells only divide under special conditions. Pluripotency is the ability of the human embryonic stem cell to differentiate or become almost any cell in the body. Colony-stimulating factors (CSFs) are secreted glycoproteins which bind to receptor proteins on the surfaces of hemopoietic stem cells and thereby activate intracellular signaling pathways which can cause the cells to proliferate and differentiate into a specific kind of blood cell (usually white blood cells, for red blood cell formation see erythropoietin). Bone marrow contains a population of hematopoietic stem cells that have partially differentiated. They have the capacity to differentiate into any of the hematologic cells but can no longer differentiate into other cell types like nerve or muscle cells. Red marrow is also active (hematopoietic) marrow. Yellow marrow is inactive and contains large amounts of fat. Adult active bone marrow is found primarily in flat bones (pelvis, ribs, sternum, etc)

Erythropoiesis Erythrocytes are derived from erythroblasts (normoblasts) Maturation is stimulated by erythropoietin Erythropoiesis is the process by which red blood cells (erythrocytes) are produced. It is stimulated by decreased O2 delivery to the kidneys which then secrete the hormone erythropoietin. This activates increased erythropoiesis in the hemopoietic tissues. This this usually occurs within the red bone marrow. A feedback loop involving erythropoietin helps regulate the process of erythropoiesis so that, in non-disease states, the production of red blood cells is equal to the destruction of red blood cells and the red blood cell number is sufficient to sustain adequate tissue oxygen levels but not so high as to cause sludging, thrombosis, or stroke. Erythropoietin is produced in the kidney and liver in response to low oxygen levels. In addition, erythropoietin is bound by circulating red blood cells; low circulating numbers lead to a relatively high level of unbound erythropoietin, which stimulates production in the bone marrow.

Erythropoiesis Sequence Uncommitted pluripotent stem cell, committed proerythroblast, normoblast, basophilic normoblast, polychromatophilic normoblast, orthochromic normoblast, reticulocyte (nucleus is lost), erythrocyte In each step the quantity of hemoglobin increases and the nucleus decreases in size In the process of red blood cell maturation, a cell undergoes a series of differentiations. The following stages 1-7 of development all occur within the bone marrow: hemocytoblast a pluripotent hematopoietic stem cell Common Myloid Progenitor multipotent stem cell unipotent stem cell pronormoblast also commonly called proerythroblast or rubriblast. basophilic normoblast/early normoblast also commonly called erythroblast polychromatophilic normoblast/intermediate normoblast orthochromatic normoblast/late normoblast - Nucleus is Expelled before becoming a reticulocyte reticulocyte The cell is released from the bone marrow after stage 7, and so of circulating red blood cells there are ~1% reticulocytes. After 1-2 days these ultimately become "erythrocytes

Erythropoiesis Erythrocyte differentiation Erythocyte differentiation from large nucleated stem cell to small, nonnucleated erythrocyte.

Hemoglobin Synthesis Oxygen-carrying protein of the erythrocyte A single erythrocyte contains as many as 300 hemoglobin molecules Two pairs of polypeptide chains Globins Hemoglobin (Hb), the oxygen-carrying protein of the erythrocyte, constitutes approximately 90% of the cell’s dry weight. Hemoglobin-packed blood cells take up oxygen in the lungs and exchange it for carbon dioxide in the tissues. A single erythrocyte contains as many as 300 hemoglobin molecules. Each hemoglobin molecule is composed of two pairs of polypeptide chains (the globins)

Hemoglobin Synthesis Four colorful iron-protoporphyrin complexes Adult hemoglobin Two alpha chains and two beta chains Each hemoglobin molecule is also composed of four colorful complexes of iron plus protoporphyrin (the hemes). Hemoglobin is responsible for blood’s ruby red color. There are several variants of hemoglobin, but they differ only slightly in primary structure. Based on the use of polypeptide chains. The most common adult hemoglobin is composed of two alpha chains and two beta chains.

Hemoglobin Synthesis Molecular structure of hemoglobin

Hemoglobin Synthesis Nutritional requirements Building blocks Proteins Amino acids Vitamins Vitamins B12, B6, B2, E, and C; folic acid; pantothenic acid; and niacin Minerals Iron and copper Folate Normal development of erythrocytes and synthesis of hemoglobin depend on an optimal biochemical state and adequate supplies of the necessary building blocks, including protein, vitamins, and minerals. If these components are lacking for a prolonged time, erythrocyte production slows and anemia (insufficient number of erythrocytes) may result.

Hemoglobin Synthesis Iron cycle Total body iron is bound to heme or stored bound to ferritin or hemosiderin mononuclear phagocytes and hepatic parenchymal cells Less than 1 mg per day is lost in the urine, sweat, epithelial cells, or from the gut Transferrin Apotransferrin Approximately 67% of total body iron is bound to heme in erythocytes (hemoglobin) and muscle cells (myoglobin) and approximately 30% is stored in mononuclear phagocytes 9i.e. macrophages) and hepatic parenchymal cells as either ferritin or hemosiderin. Less than 1 mg per day (3%) is lost in the urine, sweat, epithelial cells, or from the gut. Transferrin is a blood plasma protein for iron ion delivery. Transferrin is a glycoprotein that binds iron very tightly but reversibly. When not bound to iron, it is known as "apo-transferrin

Iron Cycle Iron (Fe) released from gastrointestinal epithelial cells circulates in the bloodstream associated with its plasma carrier, transferrin. It is delivered to erythroblasts in bone marrow, where most of it is incorporated into hemoglobin. Mature erythrocytes circulate for approximately 120 days, after which they become senescent and are removed by mononuclear phagocyte system (MPS). Macrophages of MPS (mostly in spleen) break down ingested erythrocytes and return iron to the bloodstream directly or after storing it as ferritin or hemosiderin.

Regulation of Erythropoiesis Numbers of circulating red cells in healthy individuals remain constant The peritubular cells of the kidney produce erythropoietin Hypoxia stimulates the production and release of erythropoietin Most steps of this process are primarily under the control of erythropoietin. Numbers of circulating red cells in healthy individuals remain constant. Hypoxia stimulates the production and release of erythropoietin by the kidneys.

Regulation of Erythropoiesis Erythropoietin causes an increase in red cell production and release from bone marrow The release of erythropoietin causes a compensatory increase in erythrocyte production if the oxygen content of blood decreases because of anemia, high altitude, or pulmonary disease.

Regulation of Erythropoiesis Role of erythropoietin in regulation of erythropiesis. Decreased arterial oxygen levels stimulates production of erythropoietin, which in turn stimulates red cell production and expansion of the erythron. The increase in red cells frequently corrects the problem of low oxygen levels (hypoxia). This restoration to normal oxygen levels alerts the kidneys to stop producing erythropoietin (negative feedback). Further erythrocyte production is not needed.

Normal Destruction of Senescent Erythrocytes Aged red cells are sequestered and destroyed by macrophages of the MPS, primarily in the spleen The liver takes over if the spleen is absent Globin chains are broken down into amino acids Aged red cells are sequestered and destroyed by macrophages of the MPS, primarily in the spleen The liver takes over if the spleen is absent by macrophages (Kupffer cells). Globin chains are broken down into amino acids

Normal Destruction of Senescent Erythrocytes Porphyrin is reduced to bilirubin, transported to the liver, and secreted in the bile Porphyrin is reduced to bilirubin, transported to the liver, and secreted in the bile. Conditions causing accelerated erythrocyte destruction increase the load of bilirubin for hepatic clearance, leading to increased serum levels of unconjugated bilirubin and increased secretion of urobilinogen.

Development of Leukocytes Leukocytes arise from stem cells in the bone marrow Granulocytes mature in the bone marrow Agranulocytes and monocytes are released into the bloodstream before they fully mature Leukocytes arise from stem cells in the bone marrow. Granulocytes mature in the bone marrow Agranulocytes and monocytes are released into the bloodstream before they fully mature

Development of Leukocytes Growth factors and colony-simulating factors encourage production and maturation of leukocytes Further maturation is under the control of several hematopoietic growth factors, including interleukins, granulocyte-macrophage colony-stimulating factor (GM-CSF), and granulocyte colony-stimulating factor (G-CSF). Leukocyte production increases in response to infection, to the presence of steroids, and to the reduction or depletion of reserves in the marrow.

Development of Platelets Endomitosis The megakaryocyte undergoes the nuclear phase of cell division but fails to undergo cytokinesis The megakaryocyte expands due to the doubling of the DNA and breaks up into fragments Platelets (thrombocytes) are derived from stem cells and progenitor cells that differentiate into megakaryocytes. During thrombopoiesis, the megakaryocyte progenitor is programmed to undergo an endomitotic cell cycle (endomitosis) during which DNA replication occurs, but anaphase and cytokinesis are blocked (Chapter 1). The megakaryocyte expands due to the doubling of the DNA and breaks up into fragments.

Development of Platelets Platelet levels are maintained by thrombopoietin and IL-11 Platelets circulate for 10 days before losing their functional capacity An optimal number of platelets and committed platelet precursors (megakaryoblasts) in the bone marrow is maintained by primarily by thrombopoietin with other factors. Platelets circulate for 10 days before losing their functional capacity. Senescent platelets are sequestered and destroyed in the spleen by mononuclear cell phagocytosis.

Hemostasis Hemostasis means arrest of bleeding Requirements Platelets Clotting factors Blood flow and shear forces Endothelial cells Fibrinolysis Hemostasis means arrest of bleeding. As a result of hemostasis, damaged blood vessels may maintain a relatively steady state of blood volume, pressure, and flow. Three equally important components of the control of hemostasis are platelets, clotting factors, and the vasculature (endothelial cells and subendothelial matrix).

Hemostasis Platelet aggregation, review page 497

Hemostasis Platelet plug formation Activation Adhesion Aggregation von Willebrand factor (vWF) Aggregation Secretion Platelets normally circulate freely, suspended in plasma, in an unactivated state. The state of platelet activation is primarily under the control of endothelial cells lining the vessels. Endothelial products, such as nitric oxide (NO) and the prostaglandin derivative prostacyclin I2 (PGI2) maintain platelets in an inactive state. When a vessel is damaged, platelet activation may be initiated. Activation proceeds through a process of increasing platelet adhesion, aggregation, and activation. Initially, platelets adhere weakly to the vessel wall, followed by increased strength of adherence to the vessels, adherence between platelets (aggregation), and finally the development of an immobilization meshwork of platelets and fibrin. During vessel damage, the damaged endothelial layer may expose the matrix containing collagen. The matrix also contains von Willebrand factor (vWF).

Hemostasis Function of clotting factors Intrinsic pathway Activated when factor XII contacts subendothelial substances exposed by vascular injury Extrinsic pathway Activated when tissue factor (TF) (tissue thromboplastin) is released by damaged endothelial cells A blood clot is a meshwork of protein strands that stabilizes the platelet plug and traps other cells such as erythrocytes, phagocytes, and microorganisms. The strands are made up of fibrin which is produced by the clotting (coagulation) system. This was reviewed in Chapter 5. There are two pathways: Intrinsic and extrinsic, that join in a common pathway.

Coagulation Cascade Page 499 Blood clotting mechanisms. The clotting mechanism involves release of platelet factors at the injury site, formation of thrombin, and trapping of red blood cells (RBCs) in fibrin to form a clot. An electron micrograph showing entrapped RBCs in a fibrin clot

Control of Hemostatic Mechanisms Clot retraction Fibrin strands shorten; become denser and stronger to approximate the edges of the injured vessel and site of injury Facilitated by large numbers of platelets within the clot and actin-like contractile proteins in the platelets After a clot is formed, it retracts or “solidifies”. Fibrin strands shorten, becoming denser and stronger, which approximates the edges of the injured vessel wall and seals the site of injury. Retraction is facilitated by large numbers of platelets within the fibrin meshwork. Contraction expels protein-free serum from the fibrin meshwork. This process usually begins within a few minutes after a clot has formed, and most of the serum is expressed within 20 to 60 minutes.

Control of Hemostatic Mechanisms Lysis of blood clots Fibrinolytic system Plasminogen and plasmin Fibrin degradation products D-dimers Lysis (breakdown) of blood clots is carried out by the fibrinolytic system. Another plasma protein, plasminogen, is converted to plasmin by several products of coagulation and inflammation. Plasmin is an enzyme that dissolves clots (fibrinolysis) by degrading fibrin and fibrinogen into fibrin degradation products (FDPs). The fibrinolytic system removes clotted blood from tissues and dissolves small clots (thrombi) in blood vessels. A balance between the amounts of thrombin and plasmin in the circulation maintains normal coagulation and lysis. D-dimer is a fibrin degradation product, a small protein fragment present in the blood after a blood clot is degraded by fibrinolysis. It is so named because it contains two crosslinked D fragments of the fibrinogen protein. D-dimer concentration may be determined by a blood test to help diagnose thrombosis. Since its introduction in the 1990s, it has become an important test performed in patients suspected of thrombotic disorders. While a negative result practically rules out thrombosis, particularly in young and healthy patients, a positive result can indicate thrombosis but does not rule out other potential causes. Its main use, therefore, is to exclude thromboembolic disease where the probability is low. In addition, it is used in the diagnosis of the blood disorder disseminated intravascular coagulation.

Fibrinolytic System The fibrinolytic system The central reaction is the conversion of plasminogen to the enzyme plasmin. Activity of plasminogen is achieved by the extrinsic pathway (blue) initiated by the release of tissue-type plasminogen activator t-PAI (also called T-PA) released from the endothelial cells and by the intrinsic pathway (gold) fram factor XIIa and urokinase. Plasmin splits fibrin in the clot into fibrin degradation products.

Evaluation of the Hematologic System Tests of bone marrow function Bone marrow aspiration Bone marrow biopsy Measurement of bone marrow iron stores Differential cell count Blood tests Large variety of tests Tests of bone marrow function Bone marrow aspiration Bone marrow biopsy Measurement of bone marrow iron stores Differential cell count Blood tests Large variety of tests pg 501-503

Pediatrics and the Hematologic System Blood cell counts increase above adult levels at birth Trauma of birth and cutting the umbilical cord The hypoxic intrauterine environment stimulates erythropoietin production Results in polycythemia Blood cell counts increase above adult levels at birth T-rauma of birth and cutting the umbilical cord The hypoxic intrauterine environment stimulates erythropoietin production -Results in polycythemia

Pediatrics and the Hematologic System Children tend to have more atypical lymphocytes as a result of frequent viral infections Children tend to have more atypical lymphocytes as a result of frequent viral infections

Aging and the Hematologic System Erythrocyte life span is normal but erythrocytes are replaced more slowly Possible causes Iron depletion Decreased total serum iron, iron-binding capacity, and intestinal iron absorption Lymphocyte function decreases with age The humoral immune system is less responsive Erythrocyte life span is normal but erythrocytes are replaced more slowly -Possible causes 1. Iron depletion 2. Decreased total serum iron, iron-binding capacity, and intestinal iron absorption Lymphocyte function decreases with age The humoral immune system is less responsive