Hematopoyesis

• Producción diaria de células hemáticas:– GR 200.000 millones– GB 70.000 millones

• Sin embargo es inefeciente sólo un 5% alcanzan el estadío final de maduración

• Vida Media de las células hemáticas:– GR 120 días– Granulocito6-8 horas– Plaqueta 7-10 días

Índices

• Hematocrito (Ht)– 47 5 %– 42 5 %

• Hemoglobina (Hb)– 13-15,5 g/dL– 12,5-14 g/dL

• Velocidad de Sedimentación Globular (VSG)

– 2-8 mm/h– 2-10 mm/h

•Hemoglobina Corpuscular Media (HCM)HCM = Hb(g/L)/nº de eritrocitos (cel/L)HCM = 150 g/L/5 x 10 12 cel./L =30 x 10- 12 g/cel

•Concentración Media de Hemoglobina Corpuscular (CMHC)CMHC = Hb(g/L)/HtCMHC = 150 g/L/0,45 = 333 g/L, 33 %.

•Volumen Corpuscular Medio (VCM)VCM = Ht/nº de eirtrocitos VCM = 0,45 / 5 x 10 12 cel./L = 90 fL

Un eritrocito tiene un diametro aprox. 7,5 , un volumen de 90 fL y contiene 30 pg de Hb que ocupan el 33 % del volumen celular

Normal Hematopoiesis

Modified from Dick: ASH Education Program Book, 2001

CD34+, CD38-

( ) SCID-Repopulating Cell

c-kit+, Thy1+, CD71+, HLA-DR+, IL3R-

( ) Hematopoietic Stem Cell

Disminución del tamaño celularDisminución del número de organelas

Condensación nuclearAumento del contenido de Hb

ProeritroblastoCélulas grandes (20-25 mm)Citoplasma pequeñoAbundante mRNA

Eritroblasto basófiloCélulas grandes (16-18 mm)Aumento relación citoplasma/núcleosíntesis de Hb

Eritroblasto policromatófiloCélulas pequeñas (8-12 mm)Citoplasma grandeAbundante Hb Eritroblasto ortocromático

Células pequeñas (10 mm)Citoplasma grandeAbundante HbAl perder el núcleo se transformaen reticulocito (restos de organelas)

ERITROPOYESIS

Figure 19-01

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Figure 19-02

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Table 19-02

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Figure 19-03

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Figure 19-04

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FACTOR TARGET CELLS PRODUCING CELLS RECEPTORS

Erythropoietin CFC-E kidney cells cytokine family

Interleukin 3 (IL-3) multipotent stem cell, most progenitor cells, many terminally differentiated cells

T lymphocytes, epidermal cells

cytokine family

Granulocyte/ macrophage CSF (GM-CSF)

GM progenitor cells T lymphocytes, endothelial cells, fibroblasts

cytokine family

Granulocyte CSF (G-CSF)

GM progenitor cells and neutrophils macrophages, fibroblasts cytokine family

Macrophage CSF (M-CSF)

GM progenitor cells and macrophages fibroblasts, macrophages, endothelial cells

receptor tyrosine kinase family

Steel factor (stem cell factor)

hemopoietic stem cells stromal cells in bone marrow and many other cells

receptor tyrosine kinase family

Total Blood Total Body Pool

Circulating Pool

Half-Life in Circulation

Percentage of Volume Replaced Daily in Healthy Adult

Red blood cell (× 1010/kg)

33 33 50 65 days 0.8

Neutrophil (× 107/kg)

70 (14 160) 31 (11 46) 6.7 (4 10) hour

Lymphocyte (× 107/kg)

133 266 8 12 1 hour 1,500 days

230.0

Platelet (× 1010/kg)

2.8 (2.1 3.8)

2.1 (1.6 2.9)

4 5 days 10.0

Type Characteristics Receptor Examples

Type 1 cytokine receptor

Does not possess intrinsic kinase acivity. IL-1, -2, -3, -4, -5, -6, -7, -9, -13, -18, - 21;GM-CSF; G-CSF; EPO; TPO; leukemia inhibitory factor; interferon and IL-10; fms (M-CSF receptor); flt3; c-kit (SCF receptor); PDGFR

Receptor acts as docking site for adaptor molecules, which leads to phosphorylation of cellular substrates.

Type II cytokine receptor

Contains extracellular fibronectin III type domain

Receptors with tyrosine kinase domains (type) III

Large extracellular immunoglobulin-like domain, single transmembrane spinning region, and a cytoplasmic tyrosine kinase domain(s)

Chemokine receptor Seven transmembrane-spanning G protein-linke regions

IL-8

Tumor necrosis factor family

Cysteine-rich repeats in the extracellular domain, and cytoplasmic 80-amino acid "death domain"

Tumor necrosis factor and Fas

EPO = erythropoietin; G-CSF = granulocyte colony-stimulating factor; GM-CSF = granulocyte-macrophage colony-stimulating factor; IL = interleukin; M-CSF = macrophage colony-stimulating factor; SCF = stem cell factor; TPO = thrombopoietin.

Some Cytokines Using Subunit Receptor Subunit Shared

IL-3, IL-5, and GM-CSF subunit

IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 IL-2 receptor c chain

IL-2 and IL-15 chain of IL-2 receptor

IL-4 and IL-13 IL-4R and IL-13R1

IL-6, oncostatin M, leukemia inhibitory factor, and IL-11 gp130

IL10, IL-22 IL-10R

IL-19, IL-20, IL-24 IL-20R, IL-20R

IL-20, IL-22, IL-24 IL-22R

IL-12, IL-23 IL-12R1

GM-CSF = granulocyte macrophage colony-stimulating factor; IL = interleukin.

Characteristic27 38 Stem Cell Factor Comment

Chromosomal localization

12q22 12q24

Natural forms of SCF

Transmembrane and soluble Both forms are biologically active

Major sites of production

Marrow stroma IL-1 and TNF increase stromal SCF reproduction

Hematopoietic cells

Gut epithelial cells

Central nervous system, thymus

Skin keratinocytes

Selected biologic activities

Promotes hematopoiesis at multiple levels; migration during embryonic life; Influences primordial germ cell and melanocyte

Affects immunoregulatory cells (B and T cells, mast cells, NK cells, dendritic cells);

Influences hematopoietic cell adhesive properties

Receptor c-kit Also known as CD117: encoded on 4q11 q13 (piebald locus)

Natural antagonists

Soluble c-kit receptor Kit is mutated in gastrointestinal stromal tumors

Major clinical trials Peripheral blood progenitor mobilization (SCF + G-CSF better than SCF alone);

Aplastic anemia (trilineage responses seen after SCF) STI571 (Gleevec) targets the activated Kit kinase activity and produces striking responses in gastrointestinal stromal tumors with Kit mutations

Causes of Anemia, Thrombocytopenia, and Leukopenia in Cancer

Bone marrow replacement by primary tumor (eg, leukemia)

Bone marrow involvement by metastatic tumor (eg, breast, prostate)

Derangement of normal physiology

  Nutritional (eg, folate, iron, negative nitrogen balance)

  Abnormal feedback (eg, stimulation/inhibition of hematopoiesis)

  Bone marrow reaction (eg, fibrosis)

  Peripheral destruction (eg, immune hemolysis, diffuse intravascular coagulation, splenomegaly)

  Blood loss

Myelosuppression by chemotherapy or radiotherapy

Summary

The many types of blood cells, including erythrocytes, lymphocytes, granulocytes, and macrophages, all derive from a common multipotent stem cell. In the adult, hemopoietic

stem cells are found mainly in bone marrow, and they depend on contact-mediated signals from the marrow stromal (connective-tissue) cells to maintain their stem-cell

character. The stem cells normally divide infrequently to produce more stem cells (self-renewal) and various committed progenitor cells (transit amplifying cells), each able to

give rise to only one or a few types of blood cells. The committed progenitor cells divide extensively under the influence of various protein signal molecules (colony-stimulating

factors, or CSFs) and then terminally differentiate into mature blood cells, which usually die after several days or weeks.

Studies of hemopoiesis have been greatly aided by in vitro assays in which stem cells or committed progenitor cells form clonal colonies when cultured in a semisolid matrix. The

progeny of stem cells seem to make their choices between alternative developmental pathways in a partly random manner. Cell death by apoptosis, controlled by the

availability of CSFs, also plays a central part in regulating the numbers of mature differentiated blood cells.