ORIGIN AND DIFFERENTIATION OF HEMATOPOIETIC CELLS

The formed elements of blood—red cells, granulocytes, monocytes, platelets, and lymphocytes—have a common origin from pluripotent hematopoietic stem cells sitting at the apex of a

complex hierarchy of progenitors ( Fig. 13-1 ). Most of the work supporting this scheme comes from studies conducted in mice, but it is believed hematopoiesis in man proceeds in a highly

analogous fashion. The pluripotent stem cell gives rise to two types of multipotent progenitors, the common lymphoid and the common myeloid stem cell. The common lymphoid stem cell

in turn gives rise to precursors of T cells (pro-T cells), B cells (pro-B cells), and natural killer cells.[2] The details of lymphoid differentiation are not discussed here, but it is worth pointing

out that morphologic distinctions among lymphoid cells at various stages of differentiation are subtle at best. As a result, monoclonal antibodies recognizing differentiation-stage-specific

antigens are used widely to define normal lymphocyte subsets ( Chapter 14 ). From the common myeloid stem cell arise at least three types of committed stem cells capable of

differentiating along the erythroid/megakaryocytic, eosinophilic, and granulocyte-macrophage pathways.[3] In functional assays the committed stem cells are called colony-forming units

(CFU), because each can give rise to colonies of differentiated progeny in vitro (see Fig. 13-1 ). From the various committed stem cells are derived intermediate stages and ultimately the

morphologically recognizable precursors of the differentiated cells, such as proerythroblasts, myeloblasts, megakaryoblasts, monoblasts, and eosinophiloblasts, which in turn give rise to

mature progeny.

The specific characteristics of rare cells lying high up in the hierarchy shown in Figure 13-1 are still debated. What are agreed upon are certain overarching themes that apply to

hematopoiesis. Since mature blood elements are terminally differentiated cells with finite life spans, their numbers must be replenished constantly. It follows that stem cells must not only

differentiate, but also self-renew, a critical property of stem cells. Pluripotent stem cells have the greatest capacity for self-renewal, but normally most are not in cell cycle. As commitment

to particular lines of differentiation proceeds, self-renewal becomes limited, but a greater fraction of committed cells divide actively. For example, few common myeloid stem cells are

normally in cell cycle, but up to 50% of CFU-GM

Figure 13-1Differentiation of hematopoietic cells. SCF, stem cell factor; Flt3L, Flt3 ligand; GM-CSF, granulocyte-macrophage colonys-timulating factor; M-CSF, macrophage colonystimulating

factor; G-CSF, granulocyte colony-stimulating factor. (Modified from Wyngaarden JB, et al [eds]: Cecil Textbook of Medicine, 19th ed. Philadelphia, WB Saunders, 1992, p.

820.)

TABLE 13-1-- Classification of Anemia According to Underlying Mechanism

Blood Loss

Acute: trauma

Chronic: lesions of gastrointestinal tract, gynecologic disturbances

Increased Rate of Destruction (Hemolytic Anemias)

Intrinsic (intracorpuscular) abnormalities of red cells

••Hereditary

••Red cell membrane disorders

••••Disorders of membrane cytoskeleton: spherocytosis, elliptocytosis

••••Disorders of lipid synthesis: selective increase in membrane lecithin

••Red cell enzyme deficiencies

••••Glycolytic enzymes: pyruvate kinase deficiency, hexokinase deficiency

••••Enzymes of hexose monophosphate shunt: G6PD, glutathione synthetase

••Disorders of hemoglobin synthesis

••••Deficient globin synthesis: thalassemia syndromes

••••Structurally abnormal globin synthesis (hemoglobinopathies): sickle cell anemia, unstable hemoglobins

••Acquired

••Membrane defect: paroxysmal nocturnal hemoglobinuria

Extrinsic (extracorpuscular) abnormalities

••Antibody mediated

••••Isohemagglutinins: transfusion reactions, erythroblastosis fetalis

••••Autoantibodies: idiopathic (primary), drug-associated, systemic lupus erythematosus, malignant neoplasms, mycoplasmal infection

••Mechanical trauma to red cells

••••Microangiopathic hemolytic anemias: thrombotic thrombocytopenic purpura, disseminated intravascular coagulation

••••Cardiac traumatic hemolytic anemia

••Infections: malaria, hookworm

••Chemical injury: lead poisoning

••Sequestration in mononuclear phagocyte system: hypersplenism

Date: 2016-04-22; view: 685