HAEMOPOIESIS Means formation of the blood cells which include RBC, WBC (Granulocytes and Agranulocytes) and platelets

Blood is a special type of fluid connecti!e tissue "t is an opa#ue fluid and it is red in colour due to presence of haemoglobin Physical Properties : Colour $ Arterial blood is scarlet red and !enous blood is purple %olume $ !olume of blood is a normal adult is & litres Reaction and p' $ "t is slightly al(aline and its p' is ) * +pecific Gra!ity $ +pecific gra!ity of total blood is , -&. / , -0, +pecific gra!ity of blood cells +pecific gra!ity of plasma and plasma proteins Composition of Blood 2lasma 2roteins (&&3) 6rganic +ubstances "norganic +ubstances Blood Cells (4ormed 5lements) (*&) RBC 7ymphocytes 8 9eutrophils 8 Basophils 8 5osinophils Plasma : "t has around 1,3 8 1.3 of '.6 and : / 13 of solid organic substances ,) 2roteins (albumin), Globulin and 4ibrinogen), .) Carbohydrates (Glucose), ;) 4acts, *) 9o protein nitrogenous substances (9' ; amino acids, creatine, uric acid etc), &) "nternal secretions (hormones), 0) 5n<ymes and )) Antibodies , WBC 2latelets $ , -1. to , ,-, $ , -.. to , -.0

%iscosity $ Blood is & times more !iscous than water "t is mainly due to RBC

Agranulocytes 8 7ymphocytes 8 +mall 8 7arge 8 Monocytes

Inorganic Substances : ,) Calcium .) +odium ;) 2otassium *) Magnesium &) Chloride Functions of Blood : ,) 9utrient function $ "t helps in absorption of nutriti!e substances li(e glucose, A A , lipids and !itamins from G"= and carried to different parts of body .) Respiratory function $ =ransport of respiratory gases is done by blood 6. and C6. are transported through blood ;) 5>cretory function $ Waste products due to !arious metastasis are remo!ed and carried to the e>cretory organs through this medium *) =ransport of 'ormones $ 'ormones and few en<ymes are carried by blood to different parts of body &) Regulation of '.6 balance $ '.6 content of blood is freely interchangeable with interstitial fluid which helps in regulation of water content of body 0) Acid base balance $ 2lasma proteins and 'b acts as buffers and helps in regulation of A8base balance )) Regulation of body temperature $ ?ue to high specific heat of blood, helps in maintaining thermoregulatory mechanism :) +torage function $ ser!es as a ready source of substance li(e water, glucose, 9a and @ which are ta(en from blood during star!ation and fluid loss etc 1) ?efense functions $ ?ue to !arious cells present in it Blood cells are basically di!ided into ; categories A 8 Red blood cells 0) "odide )) "ron :) 2hosphates 1) Copper

8 8

White blood cells 2latelets

ed Blood !ells $ =hey are circular, biconca!e cell without a nucleus be considered as a (ind of a li!ing bag containing 'b, RBC Mainly carry o>ygen from lungs to the tissues White Blood Cells $ =hey are basically di!ided into A i) Granulocytes o 9eutrophils o 5osinophils o Basophils ii) Agranulocytes o Monocyte o 7ymphocyte i +mall ii 7arge =hey are basically di!ided based on the presence or absence of granules in the cells =hey all are nucleated cells with granules or of granular =hey are mainly in!ol!ed in the bodyBs defence mechanism against !arious bacteria and e!en some foreign material Platelets : =hey are small colourless, non8nucleated and moderately refracti!e bodies =hese formed elements of blood are considered to be the fragments of cytoplasm =hey are spherical C o!al shaped and become o!al shaped when inacti!ated 2lates play (ey role in the reaction of hemostasis All the blood cells including lymphocytes, originate from a single class of primiti!e cells, the pluripotent stem cell But howe!er lymphocytes differ from other blood cells, which arise normally arise after fetal life only within the

bone marrow and referred to as marrow cells

7ymphocytes although

originating from the marrow precursor cells, mature and proliferate outside of the marrow in the thymus and peripheral lymphoid tissue 5rythrocytes, neutrophils, eisinophils, monocytes and platelets ha!e finite life span and therefore fraction of these cells must be replaced daily Appro>imate concentration and ?aily 2roduction in 2eripheral Blood Cells $ Mean concentration C Microitre & * > ,-0 * : > ,-0 *,&-;-*,&.&-. & > ,-0 ?aily 2roduction Rate C @g Body Wt ; : > ,-0 , 0 > ,-1 , ) > ,-: 8 %ariable 8 . : > ,-1

5rythrocytes / Males 8 4emales WBC 8 9eutrophils 8 Monocytes 8 Basophils 8 5osinophils 8 7ymphocytes 2latelets

"n addition to this bone marrow must respond intermittently to increased demands for specific cells li(e 5g Granulocyte to tight bacterial infection or for erythrocytes after acute blood loss HAEMOPOIE"I! O #A$S: ?uring embryogenesis (?e!elopment of fetus),the site of haeamopoiesis changes for se!eral times =he first blood cells which is formed i e the nucleated erythrocyte appear in the blood islands in Dol( sac and Ethese yol( sacF heamopoiesis is produced during early de!elopment i e ; rd wee( / ;*d month gestation period ("G7) =he embryonic erythrocytes (yol( sac deri!ed) do not loose their nuclei during maturation and they contain heamoglobin molecules of H and I family which are different from those founding later fetal C adult erythrocytes As the fetus de!elops, the organic formation ta(es place =his stage that is during the mid8gestation period the main organ for heamopoiesis is fetal li!er 5!en the spleen also participates in the formation ?uring this period I8 *

chains of heam are present which are different from the adult I8globin chains of heamoglobin ?uring, about .-th embryonic wee(, heamopoiesis begins in bone marrow "t is fully acti!e in RBM by )8: th month of fetal life As fetus matures heamopoiesis increases in the RBM and decreases in the li!er and spleen At birth practically whole of bony s(eleton contains acti!e marrow After birth all blood cells e>cept lymphocytes are generally made in RBM Bone marrow is supplied by nutrient arteries which widely branch into capillaries which in turn enter sinuses and sinusoids Between the sinuses and sinusoids the stem cells and precursors cells which by process of multiplication and differentiation form the erythrocytes, granulocytes and platelets walls Sites : "n young children, acti!e heamopoietic marrow is found throughout both the a>ial s(eleton (cranium ribs, !ertebra and pel!is) and the bone of e>tremities But in adults heamopoietic marrow is confirmed to a>ial s(eleton and pro>imal end of femur and humors "n an adult heamopoietic marrow, it normally consist of islands of cellular acti!e marrow separated and supported by fat "n old age, proportion of acti!e marrow decreases and thereby fat increases "n some pathological conditions li(e heamolytic anaemias, 6nly once they are matured they enter the circulation through the apertures in sinus

thalassaemias, the marrow cellular acti!ity increases at the e>pense of fat and sometimes cellular changes also ta(es place e>tramedullary sites li(e spleen and li!er "n certain rare pathological conditions li(e myeloidmetaplasia, the heamopoietic acti!ity runs bac( to

&

# O%"H FA!"O S : =hese are cyto(ines which control growth, differentiation and function of blood cells +e!eral different growth factors e>ist each capable of supporting a particular spectrum of hemopoietic cell types 2hysiochemically they are acid glycoproteins which define these ability to alter growth and function of progenitor cells and differentiated cells =hese heamopoietic growth factor are present in tissue fluids and blood in concentration of ,- 8,- to ,-8,, they effect the target cells through binding to specific cell surface receptors Growth factors has . types of actions $ ,) "nduction of cell growth and differentiation in immature cells .) Modulation of effector functions in mature cells +ome growth factors act synergistically and multiple growth factor act simultaneously upon the precursor cells Macrophage play a central role in controlling heamopoiesis through secretion of cyto(ine, "78, "78, stimulation growth of =8lymphocytes with ele!ates "7 ; , and stem fibroblasts, endothelial cells to secrete GM8C+4 and G8C+4 "7 ; and GMC+4 inturn stem, early cell di!ision of progenitors of most, if not all the myeloid cell lineages "7,8 also acts upon mature blood cells, stimulation of release of neutrophils from RBM "7; acts upon myeloid cell progenitors along with GM8C+4 subse#uent e>posure to GM8C+4 GM8C+4 ,st record to its ability to stimulate growth of gran, macrocytes and eosinophils =hey also stimulate early di!ision of erythrocyte progenitor and mega(aryocytic progenitors "t also acts on mature granulocytes and macrophages including enhancement of granulocyte responses to chemotactic stimuli and ability of macrophages to (ill intracellularly 0 "t acts

particularly on earlier progenitor cell subset e>panding and preparing for

4or full de!elopment such factors ("7 ; and GMC+4) are not enough, but also simultaneous C se#uential presence of . nd growth factor acting specifically on more differentiated precursors 4or neutrophilic gram it is Ci8C+4 5rythrocytes 5rythropoietin "n addition to growth factor a !ariety of humoral agents ha!e been identified that inhibit myeloid cell growth =hey include =G4 (transforming growth factor), granulocytic protein lactoferrin, acidic isoferritius (certain intracellular iron storage proteins) and 5sthetics prostaglandins #ro&th Stages ,) 4actors that act on multilineage progenitors .) Granulocyte and macrophage growth factor ;) ?ifferentiation of neutrophils, monocytes and eosinophils *) Mega(aryocyte growth factor &) I / 7ymhocytes 0) 5rythroid cells Heamopoietic Stem !ells : =hey can be said as Estem cells represent a cell type which, in adult organic can maintain its non numbers in spite of physiological C artificial remo!al of cells from the population Means Emaintaining its own numberF =hey possess found props i) ii) 8 An ability by cell di!ision to gi!e rise to new stem cell (self renewal) An ability to different mature speciali<ed blood cells 4re#uency of in bone marrow established $ ,8. C,--- nucleic stem cells and small number also circulate in blood #ro&th Factors GM8C+4, G8C+4, C+48,, "78;, *,0,,,,,. GM8C+4 (monocytes and granulocytes) G8C+4, C+48,, "78& C4G8M@, "78;, "780 C4G82re B, "78) B4G8B, C4G85, "G48,, "78;

+pecific supporting tissues li(e bone marrow (man) permit growth and differentiation of stem cells and they are referred as Eheamopoetic microen!ironmentF

When multitude of cells arises from a single cell, or when a single stem cell gi!es rise to a spleen colony that multitude of cells is called a C7695

8 8

"n normal heamopoesis, mature blood cells originate from multiple stem cells, so normal heamophoisis is polyclonal "n hematological malignancies, the progency of single abnormal stem cell may o!ergrow and suppress normal stem cells and here heamopoiesis is monoclonal

As the stem cells differentiations, it losses its ability to gi!e rise to all blood cells and becomes committed to production of one C more cell lines ?ifferent mechanism ha!e been postulated to regenerate commitment a) 2robability of differentiation increases with each di!ision of a stem cells b) 5>tra cellular inducti!e factor perhaps the heamopoetic growth factor C cell surface molecules in the heamopoietic microen!ironment determine the changes within a stem cell that leads to commitment c) 6thers says, due to some series of un(nown factors influence the probabilities for self renewal C commitment

"t is said that, functionally ; different stem cells a) 2luriopotent stem cell b) Myeloid stem cell (which gi!es rise to erythrocytes, granulocytes of all types, monocytes and plateletsc) 7ymphocytes stem cells

As commitment progress, the capability of the stem cells for self renewal diminishes and when it is mar(edly limited C lost, the cell is no longer called a stem cell but called as 2R6G59"=6R C577

8 8

=his progenitor cell are recogni<ed by their ability to gi!e rise to clonal aggregates colonies) of differentiated cells on cultures 2rogenitor cells are more numerous than stem cells and li(e stem cells present in both bone marrow and circulating blood

Blast !ells : 8 =he immediate offsprings of progenitor cells are the blast cells 4or the erythroid series, there are blast cells li(e the pronormoblasts, early, intermediate and late normoblasts 8 8 "n case of granulocytic series, they are the myeloblasts and similarly there are lymphoblasts, monoblasts and mega(aryoblasts Blast cells are immature cells

Stages of 'e(elopment : 5>cept for ,st ; months of fetal life, all erythroid de!elopment are e>tra!ascular When erythroids cells is almost mature, it enter the sinusoids from the e>tra!ascular space =he most primiti!e cell is called the pluripotent stem cell =his cell di!ides and differentiates, whereas the pluripotent stem cell can gi!e rise to erythrocytes, granulocyte, monocyte, lymphocyte, platelet, that is why it is called pluripotent stem cell (2luripotent / Capable of producing many C different cells) 8 8 But the daughter cells are not capable of producing all the types of cells they can produce either A Myeloid series 5rythroid series More they ad!ance in lineage, more they become plurality of the patency restricted in the

=he pluripotent stem cells di!ides and differentiated to gi!e rise to committed stem cell 'ere there are two types, one type of committed stem cells gi!es rise to myeloid series (Gram, no, RBC, platelets) but not lymphocytes Whereas other type of committed stem cell gi!es rise to lymphocyte (= and B) Cells committed to produce myeloid series now di!ide and differentiate to produce the daughter cells called E2rogenitor cellsB +e!eral type of progenitor cells de!elop 6ne type of 2C gi!es rise to cells of erythroid series, another granulocyte Monotype and other mega(aryocyte, and last eosinophil 2rogenitor cells are usually called EColony GnitsF (C4G) and designated as C4G85, C4G, C4G856, C4G8Mega RBC $ =here are . 2 C a) B4G85 b) C4G85 9ucleus is 4rom 4rom C4G8- $ 2ronomoblast cell (,st cell in the which is morphologically recogni<able cell in erythro series) de!elops strongly basophilic which !ery scanty cytoplasm and no 'b found

pronormoblast early neuroblast / also called change basophilic neuroblast intermediate C chromatophilic normoblast late normoblast ortho chromatic normoblast 'b appears in intermediate normoblast and so but poly chromatophilic and nucleus becomes smaller "n late neuroblast plenty of cytoplasm which is eosinophilic with fair amount of 'b, nucleus !ery small and deep py(notic 7ate 9ormoblast $ Reticulocyte (matures for J in RBM and then enters peripheral blood, where it not a still a fully matured RBC =hen it matures from mature RBC 9ucleus becomes smaller as cell matures from pronormo to late normoblast and here the py(notic nucleus is e>tend to form reticulocyte

,-

As cell mature s8 more and abundant cytoplasm 'b8appears in intermediate normoblast and de!elops Cell is capable of di!ision to intermediate normoblastic After this stage only maturation no di!ision P O')!"IO$ OF M*E+OI' !E++ +I$ES : E *"H OPOIESIS : 5rythroid 2rogenitor Cells (52C) $ =he 52C are of . types A Burst forming Gnits / 5rythrocyte (B4G85) Colony forming units / 5rythrocyte (C4G85) 8 8 8 B4G85 are large, multilobulated colonies whereas the C4G85 are much smaller colonies Actually the B4G85 ga!e rise to C4G85 through continuum of intermediate forms and it is a most differentiated erythroid progenitors Growth of B4G85 re#uires presence of one C more growth factors which are collecti!ely refer to as Burst 2romoting Acti!ity (B2A) which is general present in "78; and GM8C+4 8 "n contrast C4G85 is independent of B2A but re#uire hormone erythropoietin for proliferation and maturation to heamoglobin containing erythrocytes 8 9either B4G85 nor C4G85 ha!e morphological features permitting their distinction from each other or their recognition as members of erythroid series MA") A"IO$ OF $O MOB+AS"S : 8 8 =he earliest morphologically recogni<able member of erythroid series is the 2ronormoblast C erythroblast =his appears as cell of moderate / large si<e with a round nucleus occupying most of the cell and containing fine punctuate chromatin and blue nucleoli and with a rim of cytoplasm which is deeply basophilic =he deep blue colour of the immature cells is due to the presence of ,,

large amounts of R9A and which is associated with acti!e protein synthesis 8 +ubse#uently as the cell matures the nuclei become smaller and denser, losing their nucleoli and then cell is then called normoblast and subse#uently the si<e of normoblast diminishes progressi!ely, the nucleus shrin(s into a purple blac( py(notic mass that is finally e>tended Any remaining nuclear material is !ery effecti!ely remo!ed by a process of pitting during passage through the splenic sinus walls and e!entually the nuclei become py(notic and structureless before being e>truded from the cell after which they are phagocytosed 8 =he cytoplasm also matures, the dense blue colour gradually changes through intermediate shade to orange pin( as increasing amount of hemoglobin are synthesi<ed 8 8 8 8 =he successi!e cytoplasmic change from blue to orange pin(, !arious adKecti!es are gi!en as / Basophilic, 2olychromatic, 6rthochromatic ;8& cell di!isions ta(esplace during pronormoblast8 normoblast maturation 6thers are pronormoblast gi!es rise to form :8;. RBC cell di!ision stops at the late normoblast stage =he normal time re#uired for an erythroid cell to mature from a pronormoblast to a newly released circulating RBC is generally &8) days 8 'eamoglobin synthesis has ; re#uisites a) Ade#uate amounts of mR9A for polypeptide chains of globin b) Cell must synthesi<e normal amounts of tetrpyrole porphyrin c) "ron must be a!ailable for incorporation into protoporphyrin to form '5M5 2lasma transferring brings the iron to the de!eloping erythroid cells 8 When lac( of body iron pre!ents transferring from bringing sufficient iron to de!eloping RBCBs for heamoglobin synthesis erythropoiesis is impaired leading anaemiabesis

,.

MA") A"IO$ OF E"I!)+O!*"E : When first formed by e>trusion of nucleus of the late normoblast, a non nucleated RBC which is larger than the mature RBC and does not yet ha!e its full complement of heamoglobin but still possess some cytoplasmic R9A, mitochondria and surface transferring receptors i e the synthetic machinery re#uired to continue to ma(e heamoglobin =his newly differentiated immature RBC is called as reticulocytes, which is named because the staining procedures show the cells residual R9A, gi!ing rise to beads and strands of dar( blue material that form reticulin networ( within cytoplasm Reticulocyte normally matures for ,8. days before entering the circulation, during which time heamoglobin synthesis continues and the cells si<e decreases egulation and Assessment of Erythropoiesis : Although the growth factors with B2A may help in the earliest stage of erythropoiesis, the 5RD='R626"5="9 functions as a maKor regulate of erythropoiesis E *"H OPOIE"I$ : =his is produced by the cells of the (idney that sense tissue hypo>ia =his tissue hypo>ia may result from any of the ; cases i) ii) iii) 8 ?ecreased blood hemoglobin content (Anaemia) 4ailure to o>ygenate 'b ade#uately in the lungs (lung disease, certain congenital heart diseases, high attitude) "mpaired release of 6. from 'b at a normal tissue 6. tension (as occurs when blood C 6 le!el is ele!ated) 9ormal erythropoiesis re#uires a basal le!el of stimulation of erythroid progenitor cells by erythropoietin

,;

Factors Influencing Erythropoiesis : ,) 5rythropoietin .) B2A / 4or proliferation of B4G85 ;) %itamins / B,., folic acids important other li(e %itamin B0 and C *) "ron / Re#uired for 'b synthesis &) Miscellaneous +ife Span and 'estruction : =otal life span is ,.- days As age ad!ances, the en<ymes which protect the erythrocyte from damaging effects of 6. begin to loose their efficiency =herefore o>idati!e damages begin to appear and RBC, becomes rather rigid, spheroidal and fragile ?uring circulation, RBC pass through spleen whose diameters are !ery narrow and when such fragile RBC pass through these, they are ruptured But young and healthy RBC with sufficient degree of biconca!ity can sur!i!e 9ormally spleen is the important slaughter house for RBCs, but when erythemia are diseased, fragility increases, they brea( down when passing through other structures also particularly li!er Functions of B! : ,) RBC mainly help in carrying of the o>ygen from the lungs to the peripheries .) "t also helps in carrying C6. from the peripheries to the lungs About ;-3 of C6. is transported in this form ;) 'b in RBC also function as a good buffer by this action, it regulates the ' L ion concentration and thereby ta(es part in the maintenance of the acid8 base balance =he haemoglobin in the RBC combines which C6. and form carbheamoglobin

,*

*) RBC

carry

the

blood

group

antigens

li(e

A agglutinogenous,

B agglutinogen and Rh factor which helps in determination of blood group 8 "n end stage (idney disease C after bilateral nephrectomy, the basal secretion of erythropoietin is eliminated, patients become se!erely anaemic unless they are infused with e>ogenous recombinant erythropoietin "n chronic steady state anemiaBs, the plasma 'b concentration rises in in!erse proportion to degree of reduction of blood haemoglobin concentration 8 8 When erythropoietin secretion is increased, C4G85 and their more mature progency increase in number =otal marrow cellularity and relati!e proportion of erythroid precursors to granulocytic forms are augmented Reticulocytes are released without first maturing in the marrow 8 =he reticulocyte count will be ele!ated, reflecting both an ele!ated rate of RBC production and persistence for a longer period n the circulating blood of reticulocytes released early from the marrow Erythropoiesis !ount : 8 8 =otal erythropotsis / estimated from the number of nucleated RBC in bone marrow 5ffecti!e erythropoiesis / erythropoiesis producing RBCBs that circulate which can be estimated from the absolute reticulocyte count correlated for the early release of marrow reticulocytes 8 "n effecti!e erythropoiesis / erythropoiesis which gi!es rise to defecti!e cells that do not circulate but are phagocytosed by macrophages within the marrow counts =his can be e!aluated by comparing the number of nucleated RBCs seen in marrow with the corrected, absolute reticulocyte

,&

"n healthy persons only negligible fraction of erythropoiesis is ineffecti!e, but in certain disorders of erythorpoiesis, li(e pernicious anaemia, in effecti!e erythropoiesis may predominate

When erythropoiesis is stem by erythropoesis and large amounts of iron for 'b synthesis are readily a!ailable from the brea(down of RBCBs, s occurs in most heamolytic disorders, effecti!e erythropoiesis may increase 08: fold

Whereas erythropoiesis stem by erythropoiesis, but only limited amounts of iron are readily a!ailable from normal body stores li(e in acute blood loss, effecti!e erythropoesis increases only about .8; fold

+E),OPOIESIS : 8 8 "t is defined as de!elopment and maturation of leu(ocytes =he leu(ocytes are of . main !arieties based on their presence of granules i) =hose with granules / Granulocytes / . types a) 6ne with multi lobed nuclei 8 2olymorphonuclear leu(ocytes 15osonophils, Basophils, 9eutrophils) b) 6ther has a single sound C lobulated nucleic monocytes ii) =he non granular leu(ocytes / lymphocytes

Formation - +eu.opoiesis : =he bone marrow and blood contains progenitor cells that gi!e rise to colonies of granulocytes macrophages or both =he progenitor cells cannot be distinguished morphologically from other undifferentiated marrow and blood cells =he earliest morphologically identifiable member of granulocyte series is he myeloblast "t has a large sound nucues containing fine stippled chromatin and from ,8& nucleoli, cytoplasm bulue and of any granules

,0

As the cell matures is nucleus undergoes condensation and finally regeneration "t cytoplasm ac#uires ; types of granules / large a<urophilic primary granules (appropriate), =wo types of granules called specifies tertiary granules $E)" OPHI+ : =hey are generally found in peripheral blood, bone marrow and e!en in tissues +o it is said that neutrophils are present in ; pools a) Bone marrow pool c) =issue pool )3 Formation : =he red bone marrow pool 8 8 Mitotic 2ool and 2ost8mitotic pool 8 "n mitotic pool / neutrophil are di!iding as well as maturing (;8& days) and it consists of myeloblasts, promylocytes and myelocytes mitotic pool / cells no longer di!ided but only mature 8 =he committed stem cells in the myeloid series are the main cells which di!ide and differentiate to form different colony forming units which later gi!e rise to different blood cells 8 8 8 8 8 =he progenitor cells for neutrophils being the C4G8GM which gi!es rise to both granulocytes or neutrophil and monocyte =he C4G GM undergoes gradual change to form myeloblast which is the precursor of neutrophil Myeloblast di!ides and matures to promyelocyte and this and di!ides and matures to form myelocyte =ill here the di!ision ta(es place in the mitotic pol 4rom myeloblast myelocyte it ta(es 8; / * days =he myelocyte enters the post mitotic pool where only matures but not di!ides and is con!erted to the neutrophil =his ta(es about 0 days in post mitotic pool 8 "n short Kourney of neutrophil from birth to gra!e "n post 1-3 of neutrali<ation b) 2ool of peripheral blood ;3 8 Actual circulation and Marginal pool

,)

Myeloblast Myelocyte 9eutrophil entry into intra !ascular pool (08) hours) 5migration into tissue pool (,8* days) ?eath

=otal life span from the stage of myeloblast which is a recogni<able state is ,.8,* days

8 8

=he most primiti!e cell as the C4G8GM $ it is a common ancestor for both neutrophil and monocyte But it is not recogni<able C4G8GM di!ides and differentiates to myeloblast which is the first cell (precursor) of neutrophil which can be identified by the microscope 9ucleus is large, contains many nuclei and cytoplasm ta(es the bluish stain and contains no granules

Myeloblast matures further and become promyelocyte where there is only one nucleolus in nuclei and the cytoplasm contain primary granules (a<urophilicgram)

2romyelocyte de!elops to myelocyte which has radish nucleus with some indentation and abundant cytoplasm and cytoplasm contains pin( staining granules (here primary granules no longer !isible) no nucleolus

8 8 8

9e>t stage of de!elopment is metamyelocyte where the nucleus shows indentation and cytoplasm contains large number of secondary granules Metamyelocytes matures to form band cell where the indentation in nucleus further deeps and ac#uires almost a horse shoe shape 4inally the nucleus is segmented and becomes lobed Gptill this stage it was in bone marrow now it is released into circulation by forming young neutrophil

Factors Influencing : i) ii) Colony stimulating factor $ Re#uired for growth of C4G8GM 2roduced by mononuclear cells 2rostaglandin85 $ "nhibits C4G8GM (inhibit chec( mechanism (feed bac( much) by which e>cess C+4 acti!ity is pre!ented

,:

iii) i!) 8

Acidic lactoferrin $ 2roduced by monocytes

"nhibits the normal

C4G GM columns in both marrow but not the leu(emic ones 7acrtoferrin $ 2roduced by granules of neutrophils in whites C4G GM =he life span is shortened e>ample, in acute infections the immature forms (i e e!en metamyelocytes) are released into blood to meet demands of e>cessi!e needs of neutrophils 8 =he normal bone marrow reser!e for neutrophil is ; days and for children it is more less Most neutrophil which are destured to die enter G"= where they die and are e>creted out EOSI$OPHI+ : 8 =hese are also present in different pools li(e neutrophils i e i) ii) Bone marrow pool / & & days "ntra!ascular pool $ :8,. hours Circulatory Marginal iii) 8 =issue pool / ?eath

5osin are born and matured in RBM where their total stay is about & & days =hen they enter the circulation i e the intra !ascular pool and stay for about :8,. hours +i<es in the marginal and the actual circulatory pool is they are almost e#ual 4rom the circulatory pool they migrate to the tissues where they die

Formation : 8 8 8 6rigin and de!elopment of eosinophil is similar to that of the neutrophil =he most primiti!e cell for eosin is C4G856 which cannot be identified by microscopic method forms myeloblast =he myeloblast (more specific eosinophilic myeloblast) matures to form eosinophilic myelocyte

,1

8 8

=his further matures to form the meta myelocyte and then finally the mature eosinophil =his is released into the peripheral blood

Factors effecting the Origin -'e(elopment - elease : i) ii) iii) i!) C+4 Re#uired for growth of C4G85 5osinopoitin $ "ncreases the eosinophil count in the peripheral blood 5specially when there is eosinopenia 2arasitic in!asions and allergic conditions causes rise of eosiniophil count Cortisol $ Causes eosinopenia (fall of eosinophil count)

Eosinophil /Matureform0 : 8 8 =he mature eosinophil contains bilobed nucleus and distincti!e large granules which stains orange red Material called MaKor Basic 2rotein (MB2) and ma(e sup &-3 of large granule has a (ey role to play in the eosinophils ability to damage the lar!a tissue stage 8 &-3 of large granule has a (ey role to play in the eosinophilBs ability to damage the lar!a issue stage of heliminthic parasite and is e>tremely potent tissue to>in 8 A potent bactericidal and tissue to>in called (a) 5osinophilic cationic protein (5C2), (b) a neuroto>ic protein and (c) 5osinophilic pero>idase are also present in large granules 8 Along with these it also contain Aryl +ulphatase en<yme which hydrolyses the +86 ester lin(ages and which can inacti!e the sulfur containing leu(otrienes that tissue mast cells liberate in immediate hypersensiti!ity 8 4or these reasons the blood eosinophils, increased count rise in helminthic infestations and in allergic states 5!en when blood eosinophil counts are normal eosinophils are usually increase din

.-

number at tissue sites of allergic reactions, whereby degrading mast cells thereby decreasing the clinical mean of allergic responses 8 Administration of adrenal lucocorticoids causes blood eosinophil le!els to fall within about . hours, presumably because of marignation and se#uestration of the circulating cells Continued administration leads to eosinopenia and impaired release of eosinophils from bone marrow Functions : 8 8 8 =hey ha!e antibacterial function due to M26 granules "t has anti parasitic roles / act against the lar!a of the parasites =his is due to presence of MB2 "t also helps in allergic reaction

BASOPHI+ : 8 8 8 8 =hey constitute around ,3 of total WBCBs =he basophiles of blood de!elop in the ed bone marrow =he basophils ha!e a !ery closed relation to the mast cells, but it is e>actly not (nown Basophils are produced by RBM and present within the blood but whereas the must cells are present outside the circulation C blood within the tissue, that are produced in the RBM 8 =he functions of both being some due to same constitution and same morphology "he 'e(elopment : =he de!elopment stages of basophil are basically same as that of he other granulocytes 8 8 8 8 =he first cell which can be secondary is the blast cell =his differentiate and di!ides to form promyelocyte =his again di!ides and differentiates from myelocyte =his myelocyte differentiates to form the metamyelocyte =he granules being to appear in the myelocyte stage

.,

8 8 8 8

=he meta myelocytes mature to form into a band cell =his band cell matures fully to form a basophil =his basophil is released into the blood where they stay for couple of hours and then migrate into the tissues After this what happens is un(nown

Mature Basophil : ?iameter !aries from ,-8,. 9ucleus is irregular and often M+B shaped Cytoplasmic granules are coarse and basophil and often so present or the nuclear <one that the nucleus appears partly co!ered by the granules =he granules of basophil (its counterpart in the tissue mast cell) contain ,) 'istamine, .) 'eparin, ;) Acid peptides, *) Acid hydrolases, &) 9eutral proteolytic en<yme 4unctions $ , "t reacts in the allergic conditions . "t has an antibacterial effect ; "t also helps in phagocytosing of the foreign cells, i e it acts as a defence mechanism in !arious conditions MO$O!*"ES : 8 =hey constitute around .3 8 :3 of total WBC and the target of the WBCBs (,.8.- ) 8 li(e other WBCs it is also distributed into different pols of the body i) ii) iii) 8 Marrow pool "ntra!ascular pool / :8), hours =issue pool / R5+

=here is a contro!ersy regarding the marginal pool whether it is present Cnot +ome say its si<e is o!er ; times of the circulatory pool and some say it is totally absent

?e!elopment

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8 8

=he most primary cell being the C4G8GM as said earlier and cannot be identified by the staining procedure =his differentiates to form promonocyte which can be identified and which has nucleus roundedC slightly indented and cyto deeply basophilic and contains !ery few granules

8 8 8

=his promonocyte differentiates to form the monocyte Gptil here the de!elopment occur sin RBM Monocyte is released into blood circulation where it stays for some time (e>actly not (nown) "t enters the tissue and becomes tissue macrophage and member of R5+ 'ere it undergoes further differentiation in tissues to gi!e rise to cells of the mononuclear phagocyte system =issue macrophage

7ife span of it is un(nown

Mature Monocyte - macrophage : 8 8 9ucleus not lobed, commonly o!oid and !ery often indented, the indentation is so deep than it ac#uires a horse shoe shaped appearance Although it is categori<ed as anon granulocyte the cytoplasm yet contains !ery fine granules Functions : i) 4ormation of tissue macrophage $ main function is to remo!e !arious undesirable substances by phagocytosis in !arious tissues li(e li!er, spleen, lungs and so forth ii) Role in acute and chronic infection$ "n any site of infection, neutrophils emigrate and phagocytose them, therefore in first .* hours bacterial in!asion neutrophils preponderate, whereas after that monocytes emigrate and attac( them but no granules are present in them, but digest by production of '.6. 9eutrophils / ,st line of defence Monocyte s8 .nd line of defence

.;

"n chronic infection, macrophage engulf the bacteria but does not (ill them C digest which is seen typically in incubation period of typhoid fe!er iii) Role in lymphocyte mediated immunity $ "n this macrophages produces mono(ines which causes death of in!ading antigen and well as innocent host cells i!) Monocytes produce / C+2, prostaglandin and acid lactoferrin to control production of neutrophils +*MPHO!*"ES : 8 =his constitutes around .&8;-3 of the WBC, the lymphocytes play an important role in immunity 4unctionally these lymphocytes are =8 classified into . types / = lymphocytes and B lymphocytes for humoral immunity 'e(elopment : 8 8 8 =he de!elopment starts in the bone marrow directly from the stem cells =he pluripotent stem cell gi!es origin to the C4G and lymphoid +=5M C577+ (7+C) "n the RBC the most primiti!e cells is the pluripotent stem cell, which gi!es rise to committed tem cells 6ne type of C+C gi!e rise to cells of myeloid series (erythrocytes, granulocytes, monocytes and platelets) and other type gi!es rise to lymphocytes (either BC= lymphocytes) 2luripotent stem cells Committed stem cells Myeloid series and 7ymphoid series Formation of "1lymphocytes : 8 4rom the RBM the committed stem cells of lymphocyte migrate to corte> of the thymus where they greatly proliferate in number by mitotic di!ision 8 4rom corte> of thymus these newly formed cells go to the medulla of thymus where no further di!isions ta(e place .*

lymphocytes respecti!e for cellular immunity B lymphocytes / respect

"n medulla of corte> they undergo further processing and after such processing they become immunologically competent = cells and now they are released into circulation

FO MA"IO$ OF 23+*MPHO!*"ES : 8 =he committed stem cells (committed to produce I8lymphocytes) migrate to bursa of fabricus (in humans the homologous organ for this being lymphoid tissues of gut 5g =onsils, 2ayers patches of intestine and appendi> and they are collecti!ely (nown as gut associated lymphoid tissue (GA7=) and nowadays they say that homologous to it is the RBM) where they are further processed and after rule processing the mature I8lymphocytes are released into the circulation 8 8 =hymus and Bursa 4abricus (GA7= and RBM) are termed the central lymphoid tissue 4rom the central lymphoid tissue, the immunologically competent =8 cells and B cells come out and enter the peripheral blood, stay for couple of hours in the blood and later enter the peripheral lymphoid tissue 8 "n primary lymph tissue they stay for couple of hour sand come and again come bac( to the peripheral blood and from where it again goes bac( to peripheral lymphoid tissue thereby ma(ing, bac( and forth shutting between blood and peripheral lymphoid tissue 8 8 =he life span of lymphocytes is !ariable, some ha!e unusually long life span (yes together) While these lymphnodes are staining lymphnode, if the person is suddenly challenged by antigen, the lymphocytes become lymphoblast and multiply !igorously with the lymphnodes 8 =hymus regresses in adult life and in old age it regresses remar(ably 'owe!er =8lymph continue to multiply within lymph nodes (2eripheral

.&

lymphoid tissue) and = lymphocytes can increase e!e in old age when necessity arises 8 "n case of RBC, de!elopment occurs only in RBM in the post natal life Btu for lymphocytes, these reside in the lymph nodes and help in de!elopment 7ymphocytes belong to different clones when an in!asion occurs by specific antigen, members of specific clone undergo blast transformation and proliferation 8 =i is in this way, the lymphocyte supply to the peripheral blood is maintained =herefore the deepening of bone marrow in adult life, the absolute count of lymphocytes count in peripheral blood should not fall, although that of WBCBs belonging to myeloid series should fall 8 "t also e>plains that although thymus regresses and becomes atrophied in adult life, the supply of lymphocytes to the peripheral blood is not hampered 8 But if thymus de!elopment is poor in the et al stage, the = lymphocytes do not de!elop and child dies early Functions : 8 8 =hey helping the specific immunity of the body, remo!es the !arious antigen li(e bacteria C !irus C tumor cells =issues when transplanted to our body from foreign persons are usually reKected and this phenomenon is called as tissue reKection tissue 8 9@ and @ cells (ill cancer cells =his mechanism specifically plays a !ital role in tissue reKection of the cancer

P+A"E+E" - "H OMO!*"E : =here are three types of formed elements of which thrombocytes are the one which assists in hemostasis (pre!ention of blood loss) by !arious processes including the helping in the coagulation 9ormal platelet count is between ,&-,--- / *--,---Ccmm When the count goes below ,,--,--- / thrombocytopenia is diagnosed and when it goes

.0

below *-,--- hemorrhagic manifestations occurs =hus *-,--- platelet count is called the critical count 'e(elopment : 8 2latelets are deri!ed from the giant cells in RBM i e mega(aryocytes, whose diameter is usually around ,-- m 8 A single mega(aryocyte can gi!e rise to about ,--- platelets platelet production as usual is the pluripotent stem cells 8 8 8 8 8 =his stem cell di!ides and differentiates to C4G mega(aryocyte, which gi!es rise to promega(aryoblast (small si<ed cell) =he promega(arblast matures to form a mega(aryobalst which inturns matures to from mega (eraocyte =hey are readily recogni<able by heir large si<e, multi lobulated nucleus, abundant cytoplasm 9ormal marrow contains about , mega(alC&-- nucleated red blood cells Analysis of ?9A content of mega(aryoblasts suggest that they contain e!en number of multipliers of the normal human ?9A content (2olyploidy) Nn, Gn, :n etc 8 =his results from nuclear duplication of cell di!ision, a process called entoreduplication =he pseudopods of mega(aryocyte are thrown inside of the sinusoids of bone marrow and then the tip of the pseudopoid is detachedA this detached part of pseudopoid which does not contain any nucleus become a platelet 8 A single mega(aryocyte can gi!e rise to about ,--- platelets and after this, the remnant of mega(aryocytic is attached by the macrophages of the bone marrow, engulfed and digested 8 9ormally bone marrow contains only about one days reser!e of platelets =herefore human begins are susceptible to de!elop more #uic(ly than granulocytopeniaC thrombocytopenia erythrocytopenia =he platelets are produced in the RBM =he most primiti!e cell in line of

.)

Morphology : 8 8 2latelets are !ery small borders consisting of cytoplasm encased within a membrane =hey are non nucleated structures When inacti!e state i e circulating in blood they ha!e disc li(e structure but when there is an inKuryC bleeding they become acti!ated and ha!e a spherical structure 8 2latelets contain mitochondria and golgi apparatus and apart from these some special structures li(e granules, tubules, filamentous structures made of actinomycin and !arious chemicals li(e adrenalin, serotonin, A?2 and thrombospondin =he platelet does not contain ?9A C R9A Factors Influencing "hrombopoisis : i) ii) =hrombopoietin $ +ubstances which stimulates thrombopoiesis =G4I $ Released from H granules of platelets and cause deepening of platelet count by suppressing (8!e feed bac( mechanism) Functions of Platelets : 8 When here is any inKury to blood !essels, these platelets adhere (to inKured site), to aggregate (large number adhere to one another) and release many chemicals and pulp in hemostatic plug formation 8 8 8 8 8 2latelets and release adrenaline and serotonin, thus helping in the !asoconstriction (which is necessary for hemostasis) =hey also release some chemicals which help the blood to coagulate and they are called or coagulants =hey contain actinomyosin which helps in contraction and retraction of the platelet plug =hey also help in fi>ation of fibrin and platelets so that ultimately clot formation occur sonly where there is platelet plug =hey also release some substances which oppose the hemostasis and blood coagulation +ife Span :

.:

8 8

9ormal life span is about )8,. days Most of platelets are destroyed in spleen About ,C; rd of platelet reside in spleen =herefore spleenectomy causes a rise in blood platelet count

Applied Physiology: 8 8 =hrombocytopenia / condition where platelet count is low which leads to purpura but not coagulation defect After surgical operation and child birth number of platelets increase this produces ris( of intra!ascular clotting and to pre!ent this early ambulation is ad!ocated !+I$I!A+ !O$SI'E A"IO$S : Anaemias $ means deficiency of RBCs which can be caused A ,) =oo rapid blood loss .) =oo slow production of RBCs =ypes $ a) Blood loss anaemia =o rapid loss of blood / Acute and Chronic b) A plastic anemaia $ 7ac( of bone marrow functioning, which may be due to 8 8 8 8 Gamma ray radiation 5>cessi!e >8ray e>posure Certain industrial chemicals ?rugs <inc and intrinsic factor d) 'emolytic anaemias $ ?ue to early destruction C e>cessi!e destruction of RBCs anaemia occurs 8 'ereditary spherocytosis Cells are small and spherical, so they canBt compress themsel!es when they pass through spleen, so easily rupture .1

c) Megaloblastic anaemia $ 7oss of any of these i e !itamin B ,., folic acid,

e) +ic(le cell anaemia $ ?ue to abnormal shape of 'b, cells becomes elongated and thereby fragile and rupture easily =halassaemias / %ery little hb is present (which is due to deficiency) cells are abnormal in shape and fragile 5rythroblasts fetalis / Rh (L)!e antibodies of fetus are attached by Rh(8)!e mother and leads to destruction of RBCBs and se!ere anaemia Effect of 4iscosity : 9ormally the !iscosity of blood is ; times that of water, due to anaemia, it falls around , & times that of '.6 +o this decreases the resistance to blood flow in peripheral !essels, so that greater #uantities of blood return to heart Moreo!er hypo>ia due to diminished transport of 6 . by blood causes the tissue !essels to dilate, allowing further increase in return of blood to heart +o one of the maKor effects of anaemia is greatly increased wor( load on heart PO+*!*"HEMIA : When tissues become hypo>ic due to little 6 . in atmosphere (high altitudes, etc) the blood forming organs produce large #uantities of RBCBs =his is physiological polycythemia 'ere increases upto 08: milCcm; Polycythemia 4era $ RBC as high as )8: milCm; and hematocrit increases as high as 0-8)-3 8 8 8 "t is a tumours condition of organs that produce blood cells Also causes e>cess production of WBCs and platelets 'ere total blood !olume increases by . times which results in entire !ascular system engorged and many capillaries become plugged by !iscous blood, because the !iscosity increases by ,- times to that of '. 6 'E$"A+ MA$A#EME$" : "n patients with G8082? deficiency where there is hemolysis due to alteration of cell membrane and thereby fragile and leading to rupture of cells

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Bloc(age of 'e>ose monophosphate shunt path way in indi!iduals with G808 2? deficiency allows accumulation of o>idans in RBCs =hese substances which generally produce wet hb and denatured 'b forms 'ein< bodies which attach to cell membranes thereby altering the cell membranes which leads to hemolysis of cells +uch patients ha!e increased incidence of drug sensiti!ity with sulfonamides, aspirin and chloremphenicol, penicillin, streptomycin and isonia<id etc ?rugs containing phenacetin is a!oided in these patients Sic.le !ell anaemias : 8 8 8 8 Arrange short appointments A!oid long and complicated procedures Maintain good dental repair "nstitute aggressi!e pre!enti!e dental care a) 6ral hygiene instruction b) ?iet control c) =ooth brushing and flossing d) 4luoride gel application 8 8 8 8 8 8 A!oid oral infectionA treatment aggressi!ely when present Gse 7 A (a!oid G A ) C epinephrine for routine dental care and for surgical procedures use ,$,,--,--- epinephrine in 7A A!oid Barbiturates and strong narcoticsA sedation with ?ia<epam can be used Gse prophylactic antibiotics for surgical procedures A!oid liberal use of salicylates 2ain control with acetaminophen and codeine Gse 9.6 / 6. with great care

%B! : ,) Agranulocytosis $ Where bone marrow stops producing WBCBs lea!ing body unprotected agonist bacteria and other agents which in!ade body ;,

General human body li!es in symbosis with many bacteria and all mucous membranes of body are constantly e>posed to large number of bacterial, i e mouth, G"=, eyes, urethra and !agina =herefore any decrease in number of WBC imm Allows in!asion +o within . days after RBM stops producing WBCs, ulcers appear in mouth and colon and de!elops respiratory infection Bacteria from these enter surrounding tissues and in!ade the body and blood =reatment death often ensues ;80 days after acute agranulocytosis begins ?ue to irradiation of O8raysCe>posure to drugs and chemical (ben<ene C anthracene) cause aplasia of RBM +o after irradiation inKury where all stem cells and other cells are destroyed in RBM, sufficient time should be gi!en for the regeneration to occur before doing any dental treatment 'E$"A+ MA$A#EME$" OF +E),EMI! PA"IE$" : 9ew dental patients under medical treatment for leu(emias, lymphoma and multiple myeloma must be identified by their health history and current status established by consultation with the physician 2atient who is in a state of remission can recei!e mot indicated dental treatment 2atient with acute signs and symptoms of disease should recei!e only cons 5mergency dental care until infection has been recei!ed and patient has returned to normal state 2atient with ad!anced disease and when prognosis is limited as in many cases of acute leu(emia and multiple myeloma, should recei!e only emergency care, comple> restorati!e procedure and e>tensi!e dental restorations are usually not indicated "f any procedure is to be done a platelet count C bleeding time should be obtained and if abnormal platelet replacement is indicated 4or recently diagnosed leu(emic patient dentist should be in!ol!ed early on during the treatment planning stages of cancer therapy 4or e>ample, in

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addition to pro!iding oral prophyla>is and hygiene instrument he may recommend RC= Ce>tension of teeth susceptible to acute e>acerbations !O$!+)SIO$ : As good as the saying Eif it werenBt for the roc(s in its bed the stream would ha!e no songB +o li(ewise if no heamopoiesis, there is no formation of blood, as blood is the medium of life

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