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Blood tissue1. Blood as a tissue
2. Functions and composition of blood
3. Plasma. Antibodies
4. Formed elements of blood:� erythrocytes
� leukocytes
� platelets
5. Bone marrow
6. Stages and sites of hemopoiesis
7. Hematopoiesis:� erythropoiesis
� granulopoiesis
� megakaryocytopoiesis
8. Regulation of hematopoiesis
Prof. Dr. Nikolai Lazarov 2
Blood as a tissue
�specialized (trophic-defensive) fluid form of connective tissue
� liquid intercellular substance: plasma
� formed elements of blood(blood cells):�erythrocytes (red blood cells) – 96%
� leukocytes (white blood cells) – 3%
�thrombocytes (blood platelets) – 1%
� Blood tissue – A. Hadjiolov, 1930
Prof. Dr. Nikolai Lazarov 3
Functions of the blood
� transport – nutrients, gases (О2, СО2),
hormones, waste products of metabolism
� removes toxins from the body
� maintains body temperature
� buffer – рН control, homeostasis
� defense – leukocytes, antibodies
� blood clotting –
prevention of hemorrhage
Prof. Dr. Nikolai Lazarov 4
Composition of blood
�amount: 4-6 liters in a man, ~7-8% of its body weight�arteries – 1 liter
�veins – 3 liters
�heart
�blood depots
�plasma: 55%
�blood cells: 45%
�hematocrit: 0.32-0.53
�0.40–0.50 in men
�0.35-0.45 in women
Prof. Dr. Nikolai Lazarov 5
Blood plasma
� Composition:
� 92% water, 7-8% proteins, 1-2% electrolytes, nutrients (glucose, amino acids, fatty acids), vitamins, gases, metabolites
� osmotic pressure: 0.85% NaCl
� pH: 7.35-7.45
� serum = plasma – fibrinogen
� plasma proteins:
� albumins (Lat. albus, white): 60% –maintaining the osmotic pressure
� globulins: α, β, γ (immunoglobulins) – 20%
� fibrinogen: blood clotting
� lipoproteins – HDL, LDL
� complement proteins
Gr. plasma, something molded or created
~55% of whole blood
Prof. Dr. Nikolai Lazarov 6
Formed elements of blood
Giemsa-stained blood smear – acid and basic dyes:methylene blue, eosin, azure, methyl violet
Prof. Dr. Nikolai Lazarov 7
Erythrocytes
� size: 7.5±0.5 µm� > 9 µm: macrocytes
� > 12 µm: megalocytes
� < 6 µm: microcytes
� anisocytosis, Gr. aniso, uneven
� diameter: 0.8 µm in the center2.6 µm at the rim
� shape: flexible biconcave disks – spectrin
� total surface: 140 µm2 (3500 m2)
�Red Blood Cells (RBCs)
� total number: 25х1012/blood~ 4-6 million/mm3
� ↑ erythrocytosis (polycythemia)� ↓ anemia
♂ – 4.1-6.0 x 1012/l♀ – 3.9-5.5 x 1012/l
Gr. erythros, red
Jan Swammerdam (1637-1680)
1658 – Jan Swammerdam1674 – Anton van Leeuwenhoek
Prof. Dr. Nikolai Lazarov 8
Erythrocytes
� hemoglobin types:
� HbА1 (2α+2β): 96-97%
� HbA2 (2α+2δ): 2%
� HbF (2α+2γ): 1-2% in adults, 80% in newborns
• increased level in thalassemia
� HbS – sickle cell disease
� lack a cell nucleus and most organelles
� hemoglobin > 90% of dry content:
120-180 g/l
� heme+globin
Prof. Dr. Nikolai Lazarov 9
Erythrocytes
� glycophorins A, B, C –transmembrane, single-pass glycoproteins that carry the MNS blood groups antigens
� protein Rh-antigen
� Plastic plasmalemma[40% lipids (incl. phospholipids, glycolipids, cholesterol), 50% proteins, 10% carbohydrates]:
�Main function: transport of oxygen�O2 – oxyhemoglobin
�CO – carboxyhemoglobin
�CO2 – carbaminohemoglobin
�Lifespan in the bloodstream: 120 days
♂ ~140 days; ♀ ~109 days
Prof. Dr. Nikolai Lazarov 10
Reticulocytes
� young erythrocytes = polychromatophilicerythrocytes (0.1-1.5% of the total number of RBCs)
Lat. rete, network
� morphological characteristics:
� reticular (mesh-like) network
of rRNA (polyribosomes) –
substantia reticularis
� basophilic nuclear fragments
of DNA – Howell-Jolly bodies
� mitotic spindle (microtubule)
remnants – Cabot rings
� pathological conditions:
� reticulocytosis – elevation in the number of reticulocytes (after acutehaemorrhage, ascent to high altitude, chronic haemolytic anaemia)
� loss of reticulocytes in the peripheral blood: unsufficient erythropoiesis
Prof. Dr. Nikolai Lazarov 11
Leukocytes
� total number: 4-10x109/l blood
� ↑ leukocytosis
� ↓ leukopenia (Gr. λευκό, white +
πενία, deficiency)
� two groups and five types leukocytes:� granulocytes
(polymorphonuclear leukocytes)• neutrophilic granulocytes
• eosinophilic granulocytes
• basophilic granulocytes
� agranulocytes(mononuclear leukocytes)
• lymphocytes
• monocytes
Gr. λευκό, leukos, white�White Blood Cells (WBCs)
Prof. Dr. Nikolai Lazarov 12
Percentage of leukocytes
� differential count (frequency) of blood leukocytes:
� granular leukocytes (granulocytes):(Lat. granulum, granule + Gr. kytos)
� neutrophils 60 - 70%
� eosinophils 2 - 4%
� basophils 0.5 - 1%
� band cells 2 - 3%(immature neutrophils)
� agranular leukocytes (agranulocytes):
� lymphocytes 20 - 30%
�monocytes 3 - 8%
Prof. Dr. Nikolai Lazarov 13
Polymorphonuclear leukocytes
� Neutrophils:� 60-70% of all leukocytes
� size (in diameter):
• 10-12 µm
� segmented nucleus
� 2-5 (usually 3) lobes> 5 lobes � hypersegmented
� Granules: total number 50-200
� specific (В-granules): 80%
�small-sized – 0.1-0.2 µm
�lysozyme, lactoferrin, collagenase, several nonenzymatic antibacterial basic proteins, alkaline phosphatase
� azurophilic (А-granules): 15%
�lysosomes – 0.4-0.5 µm
�acid hydrolases, peroxidase etc.
Prof. Dr. Nikolai Lazarov 14
Functions of neutrophils
� Life span: 12-14 h in the bloodstream, 1-4 days in the connective tissue
�diapedesis
through the blood vessel walls
�phagocytosis (microphages):
�specific granules + membrane of the
phagosome � bactericide substances
�azurophilic granules – fusion with the
phagosome � lysis of target cell
�exudative phase of
inflammation – pus (dead neutrophils, bacteria
and semi-digested material)
Prof. Dr. Nikolai Lazarov 15
� Eosinophils:
�2-4% of leukocytes
�size (in diameter):• 12-17 µm
�bilobed nucleus� specific granules:
about 200/cell, 0.5-1.5 µm/0.3-1 µm
� LM: acidophilic (eosinophilic)
�acid phosphatase, arylsulfatase,peroxidase, histaminase, protein cations (MBP, ECP, EPO, EDN)
� ЕМ: ultrastructure
�unit membrane, crystalline core(major basic protein), parallel to the long axis of the granule
� azurophilic granules:� lysosomal enzymes
Eosinophilic granulocytes
Prof. Dr. Nikolai Lazarov 16
Functions of eosinophils
� Life span: �6-16 h in the blood
�8-12 daysin the connective tissue
�motile cells: chemotaxis
(ECF-A) – mast cells
�expression of receptors for IgE: �destruction of parasites
(helminthic infections)
�allergic processes
�anaphylaxis – inactivation of leukotrienes (SRS-A) and histamine produced by other cells
Prof. Dr. Nikolai Lazarov 17
�Basophils:� less than 1% of leukocytes
�size (in diameter):�10-12 µm
� large nucleus�irregular lobes
�U- or S-shaped
� specific granules: 0.5 µm
� metachromasia – similar to mast cells
�histamine, (serotonin), heparin,
prostaglandins
� ultrastructure
�dense-cored granules
�azurophilic granules:�lysosomes � hydrolytic enzymes
Basophilic granulocytes
Prof. Dr. Nikolai Lazarov 18
Functions of basophils
� Life span: 10-12h in the blodstream
�motile cells:
chemotaxis
�expression of
receptors for IgE:
• allergic processes
�cutaneous basophil
hypersensitivity
Prof. Dr. Nikolai Lazarov 19
Agranulocytes
�Lymphocytes:�size (in diameter):
� small – 6-8 µm
� medium – 8-12 µm
� large – 12-18 µm
�nucleus:� large, hyperchromatic,
eccentrically located
�cytoplasm:�scanty, thin rim
around the nucleus
�basophilic with manyfree polyribosomes
� B-lymphocytes� Т-lymphocytes� NK cells (NKC)
Prof. Dr. Nikolai Lazarov 20
Functions of lymphocytes
� humoral immune response� B-lymphocyte � plasma cells � antibodies
� cell-mediated immune response� Т-lymphocyte � lymphokines � cell-bound antibodies
TH1
TH2
TS
TK (NKC)
TA
TM
Prof. Dr. Nikolai Lazarov 21
Agranulocytes
� Monocytes:� size (in diameter):
� 13-20 µm
� nucleus: �eccentrically placed,
oval, horseshoe- or kidney-shaped with 1-2 nucleoli
� pinocytotic vesicles and many microvilli
� cytoplasm – basophilic (bluish-gray color)
� Granules:
� very fine azurophilic (lysosomes)
�peroxidase-positive(acid phosphatase)
�peroxidase-negative(nonspecific esterase)
Prof. Dr. Nikolai Lazarov 22
Functions of monocytes
� Life span:
� 1-8 h in the bloodstream
� do not complete their differentiation
� no functions in the blood vessels
� after crossing capillary wall
they enter connective tissue:
months-to-years life
� phagocytosis � macrophages
� antigen-presenting cells – play
an essential role in recognition
and interaction of antigen and
immunocompetent cells
Prof. Dr. Nikolai Lazarov 23
Prof. Dr. Nikolai Lazarov 24
Platelets
� fragmentations from giant polyploid megakaryocytes:
� number: 20-40х109/l
� ellipsoid or discoid in shape
� size: 1.5-5 µm
� central zone – granulomere(chromomere) containingpurple granules
� peripheral light-blue-stained transparent zone – hyalomere (microtubules and actin filaments)
Prof. Dr. Nikolai Lazarov 25
Ultrastructure of platelets
� membrane with prominent glycocalyx:� cell adhesion molecules – platelet
adhesion to the capillary wall
� cytoplasm:� open canalicular system (channels)
� actin-containing microfilaments
� granules:� alpha granules (0.2-0.5 µm) –
platelet-derived growth factor (PDGF), platelet factor IV, other clotting proteins (thrombospondin and fibronectin, and von Willebrand factor)
� delta (beta) granules (0.25-0.3 µm) –dense bodies � Ca2+, pyrophosphate, ADP, ATP, serotonin, histamine
� lambda granules (0.175-0.250 µm) –lysosomes � hydrolytic enzymes
� peroxisomes – peroxidase and probablycatalase activity
Prof. Dr. Nikolai Lazarov 26
Platelet functions
� Life span: 9-12 days in blood
� Functions – hemorrhage control:
� hemostatic mechanism:
�platelet adhesion
�platelet aggregation �
platelet plug
�blood coagulation �
fibrin formation �
blood clot (thrombus)
�clot retraction
�clot removal plasmin
Prof. Dr. Nikolai Lazarov 27
Hematopoiesis
� еrythropoiesis = formation of erythrocytes
� granulopoiesis = formation of granulocytes
� mono-/lymphocytopoiesis =formation of agranulocytes
� megakaryocytopoiesis = formation of platelets
� Hemopoiesis, Gr. haima, blood + poiesis, a making(origin and maturation of new blood cells)
� Hemopoietic tissues – blood-forming tissue, consisting of reticular fibers and similarly specialized connective tissue cellsof mesenchymal origin that give rise to new blood cells
� myeloid tissue, Gr. µυєλός, myelos, marrow (red bone marrow) = formation of most of the blood cells: erythrocytes, granulocytes and thrombocytes (platelets)
� lymphoid tissue (thymus, spleen) = formation of T-lymphocytes, proliferation of B-lymphocytes, immune defense (lymph nodes andassociated lymphoid tissue, MALT, GALT, BALT)
Prof. Dr. Nikolai Lazarov 28
Periods of hematopoiesis
� prenatal hematopoiesis(intraembryonic):� mesoblastic
(megaloblastic) phase –14 days (2nd gestational week)
� yolk sac mesoderm �
hemocytoblasts
� hepatolienal phase –5th to 6th gestational week
� liver � erythrocytes
� spleen � Er+granulocytes, lymphocytes (after 5th month)
� thymus � Т-lymphocytes
� medullary (myeloid) phase –since 4th month
� bone marrow
� liver and spleen
� postnatal hematopoiesis:� myeloid phase –
in red bone marrow(textus myeloides)
�red (hematogenous)
�yellow bone marrow
Prof. Dr. Nikolai Lazarov 29
Mesoblastic phase
� Megaerythroblastic hematopoiesis:� erythrocytopoiesis, incl. normoblast
� absent granulo, mono- and lymphocytopoiesis
� initial blood cell – hemocytoblast =pluripotential stem cell:
� large, spherical, basophilic
� synthesize hemoglobin
� form primitive erythrocytes
(located in groups or islets
“blood islands”,
retain their nuclei)
Prof. Dr. Nikolai Lazarov 30
Hepatolienal phase
� hematopoietic organs:
� liver
�spleen
� thymus
NB!NB!NB!NB! from 2nd-3rd month until birth
� normal precursor cells and erythrocytes, no megakaryoblasts
� erythroblasts (from lymphoid organs)
� begin of leukopoiesis
� lymphocyte appearance
Prof. Dr. Nikolai Lazarov 31
Medullary phase
� begin in clavicle – 2nd month
� in the 5th fetal month –
the major blood-forming
organ is the red bone marrow
� all cell lines of hematopoiesis
� lymphoid organs –
only lymphoblasts
Prof. Dr. Nikolai Lazarov 32
Unitary (monophyletic) theory
� Common undifferentiated
stem cell (hemocytoblast):
� one of 1000 nuclear cells
in the bone marrow
� origin: mesenchyme of
the embryonic sac (3rd week)
� functionally distinct but
morphologically indistinct
� has the potential to give rise
to any type of blood cells
�Alexander А. Maximow, 1901
Pluripotent stem cell
functionalblood cell
Progenitor cell (CFU, CFC)
(uni- and bipotent)
Precursor(blast) cell
Prof. Dr. Nikolai Lazarov 33
Stem cells� CFU – erythrocyte (CFU-E)� CFU – granulo-monocyte (CFU-GM) � CFU – lymphocyte (CFU-L) � CFU – megakaryocyte (CFU-Me)
(colony-forming units)
� Two types ofpluripotent stem cells:
�type І – 10%in permanent mitosis
�type ІІ – 90%in G0 phase
Prof. Dr. Nikolai Lazarov 34
Erythrocytopoiesis
�Basic principles in maturationof red blood cells:� decrease in cell size and volume
� loss of nuclear material and disappearing of cellular organelles:- increase of condensed chromatin
- decrease in the number of nucleoli
- basophilia is replaced by acidophilia
� synthesis and accumulation of hemoglobin
= decrease in the processes of dividing
= decrease in the synthetic processes
= loss in the proliferative capabilities
Prof. Dr. Nikolai Lazarov 35
Erythrocytopoiesis� duration – approximately 7 days� the division stops at normoblast level� stimulated by erythropoietin, folic acid,
iron, vitamin B12Cell Size Nucleus Cytoplasm
Proerythroblast 20-30 µm large, prominent nucleolus
basophilic
Basophilic еrythroblast 15-20 µm condensed, no visible nucleolus
basophilic
Polychromatophilic еrythroblast
12-15 µm reduced under 50% basophilic to acidophilic
Orthochromatophilic erythroblast (Normoblast)
8-10 µm small, condensed no basophiliais evident
Polychromatophilicerythrocyte (Reticulocyte)
8-10 µm no nucleus acidophilic
Prof. Dr. Nikolai Lazarov 36
Granulocytopoiesis
� Basic principlesin granulocyte formation:
� moderate decrease in the cell volume
� increase in the nuclear density and
segmentation
� accumulation of specific granules
� diferentiation and maturation– about 11-14 days
Prof. Dr. Nikolai Lazarov 37
Granulocytopoiesis
Cell Size Nucleus Cytoplasm
Myeloblast 15-21 µm large with finely dispersed chromatin
light blue, without visible granules
Promyelocyte 18-30 µm oval with condensed chromatin
basophilic with azurophilic granules (blue)
Myelocyte 12-15 µm small oval specific granules (pink)
Metamyelocyte 12-15 µm kidney-shaped filled with granules
� the myelocyte is the last cell to divide
Prof. Dr. Nikolai Lazarov 38
Lymphocytopoiesis
� in lymphoid tissue:� thymus� lymph nodes� spleen
� maturation principles:� condensation of chromatin� decrease in cellular volume� dedifferentiation ability
� no evident morphological changes in differentiation:� pluripotent stem cell� unipotent progenitor cell� В- and Т-cell stem cell � lymphoblast (15-20 µm)� prolymphocytes� В- and Т-lymphocytes
Lymphoblast
Prolymphocytes
Prof. Dr. Nikolai Lazarov 39
Monocytopoiesis
� maturation (55 h):� decrease in cell size
� appearance of small number of fine azurophilic granules
� monocytes arise from a pluripotent stem cell in the bone marrow:� multipotent progenitor cell
� bipotent progenitor cell(commited for neutrophils and monocytes)
� monoblast
� promonocyte
� monocyte
Prof. Dr. Nikolai Lazarov 40
Thrombocytopoiesis
� megakaryocyte(Gr. megas, big, + karyon, nucleus, + kytos, cell),
giant cell (35-150 µm) in the red bone marrow
� maturation stages:
� megakaryoblast
� promegakaryocyte
� megakaryocyte – 500-5000 platelets
Prof. Dr. Nikolai Lazarov 41
Thrombocytopoiesis
Cell Size Nucleus Cytoplasm
megakaryoblast 15-60 µm large ovoid or kidney-shaped, numerous nucleoli, peripherally dense heterochromatin
homogenous and intensely basophilic
promegakaryocyte 30-70 µm large and highly lobulated lightly-stained with centrally locatedazurophilic granules
megakaryocyte 35-150 µm irregularly lobulated, highly polyploid (4N-64N),coarse chromatin and no visible nucleoli
spotted basophilicwith azurophilic granules
Prof. Dr. Nikolai Lazarov 42
Regulation of hematopoiesis
� hematopoietic growth factors
� colony-stimulating factors (CSF)
� hematopoietins (poietins)
Prof. Dr. Nikolai Lazarov 43
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