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Blood Physiology: Castillo, Calderon, Aquino Blood functions: 1. Primary function: Homeostatic function (constancy of internal environment) 2.

Respiratory function: Transport of O2 from lung to tissues and elimination of CO2 from lungs 3. Nutritive function: Transport of nutritive materials from intestines to all other body parts 4. Excretory function: Transport of tissue aste produ!ts to the "idneys for elimination #. Transport of internal secretions from se!retory effe!tor !ells $. Maintain acid- ase alance: %ia buffers and proteins in blood &. Maintenance of !ater-electrolyte alance: 'egulation of !olloid and total osmoti! pressure. (. "mmunity ). T#ermore$ulation: *istribution of heat from the mus!les Normal Blood volume: %ei$#t Normal #ealt#y adult male Healt#y adult female &+ "g. 11111 Total lood volume #, 4.# , &omposition 3.+ - 3.2 , plasma .$+/0 1.( - 2.+ , formed elements .4+/ 1 4#/0

July 20,2009

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2estimation of blood volume may be based on about &( ml3"g body eight or 3,3m2 body surfa!e area.

Relations#ip of Blood 'olume to (at

Blood 'olume )etermination *+ )ye Met#od Known amount of number of marked plasma blood cells are injected into the circulation and their proportion is compared 4n5e!tion of a "no n amount of harmless dye Evans Blue: T11(24 6lood volume !an be !al!ulated using the formula7 Plasma 'olume 8 9mount of *ye 4n5e!ted Con!entration of *ye after :;uilibrium T,T-. Blood 'olume / Plasma %olume 1++ 1 <emato!rit <emato!rit: Per!entage of the volume of a blood sample o!!upied by !ells. Radiotracer Met#od Known amount of number of marked plasma blood cells are injected into the circulation and their proportion is compared 'adio iodinated plasma proteins are in5e!ted Mar2ed Red Blood &ell Met#ods Measurement of marked blood volume '6C are tagged ith radioa!tive substan!e =e##7 =e#)7 p32!#1 and >92 :?tent of dilution is measured to dedu!e the total blood volume -s# y4s tec#ni5ue Measurement of marked blood volume 9 different but !ompatible '6C group is in5e!ted Proportion is determined by their agglutination Electrical "mpedence Met#ods

0+

1+

3+

6+

Blood Physiology: Castillo, Calderon, Aquino

July 20,2009

:stimation of blood volume from alterations in !ondu!tivity of the blood brought by the in5e!tion of hypertoni! solutions *egree of dilution of the in5e!ted material is determine 9dvantage: @easures !hanges in hole blood7 so errors brought by the hemato!rit values are eliminated 7+ Based on Hei$#t Page | 2 'e;uirement: 4ndividual must be healthy Total Blood volume 8 #&2+ A $+ B<eight .!m0 - 1&4C Re$ulation of lood volume Plasma 'olume is the result of the dynami! e;uilibrium of &apillary Hydrostatic Pressure =or!e that pushes plasma out of the !apillaries ,ncotic8,smotic Pressure

=or!e that retains fluids inside !apillaries 9ttra!ts fluids from tissue spa!e =un!tion of proteins7 e.g. 9lbumin (ormed8&ellular Elements BD6C7 '6C7 PlateletsC depends on the dynami! e;uilibrium of Rate of Production of the bone marro Rate of )estruction (actors in normal lood volume maintenance: 1. %as!ular !apa!ity 2. Capillary fluid shift me!hanism 3. 'enal me!hanism of ater and ele!trolyte retention and elimination 4. 6one marro a!tivity #. Plasma protein 9enesis of Blood &ells: Pluropotential #ematopoietic stem cells &ommitted cells )ifferent lood cell types o Pluripotential Hemapoietic stem cell Parent !ell of 6lood !ells Eumbers diminish by age &ommited stem cells: !ommitted to a parti!ular line of !ells o Colony forming unit - erythro!yte BC=F1:C: :rythro!ytes o Colony forming unit - Granulo!yte7 @a!rophages: Granulo!yte and @ono!yte 9ro!t# "nducers o Proteins that !ontrol gro th and reprodu!tion of the different stem !ells o @a5or Gro th 4ndu!ers "nterleu2in-1: Committed stem !ells )ifferentiation inducers: promote differentiation of !ells Bstem !ell mature !ellC &omposition of Blood *+ (ormed Elements 9. Red Blood &ells8 Eryt#rocytes -nucleated Biconcave dis!s: 2m1thi!"7 &.#1(.+ in diameter7 1m1!enter Bthinnest partC )eforma le Prostaglandin BPG:C increases '6C deformability PG:2 decreases '6C deformability Hemo$lo in Carrier 1 liter of blood !arries only 3m, dissolved O2

Blood Physiology: Castillo, Calderon, Aquino <emoglobin !an !arry &+? su!h amount Normal 'alues of RB& RB& &ount (:" ;nits) Hemo$lo in Hematocrit (Hct+) --relative red cell content of lood Red &ell Production Men #.+1$.+ ? 1+12 3, blood 14+11&+ g3, +.4+1+.#+ %omen 4.+1#.+ ? 1+12 3, blood 12+11#+ g3, +.3(1+.4(

July 20,2009

"nfants $.# ? 1+12 3, blood Page | 3

22:ven for membranous bones7 '6C produ!tion de!lines ith age BChart 1C 222:?!ept for pro?imal portions of humeri and tibiae7 marro s of long bones be!ome fatty and do not produ!e '6C beyond 2+ years of age. BChart 1C

Eryt#ropoeisis: Hteps in :rythropoiesis 1. 9!!umulation of hemoglobin Bup of Basop#il eryt#ro last: very little hemoglobin 2. Condensation and e?trusion of the 3. 'eabsorption of endoplasmi! reti!ulum Reticulocyte <ave remnants of the mito!hondria7 reti!ulum other organelles Ioungest erythro!yte !ir!ulate o )iapedesis: s;ueeJing through the pore of the !apillary membrane *uration: 11 2 days B3 days based on our <istology !lassC RB& (eed ac2 control: 4nhibited by the rise of '6C to supernormal values Htimulated by Hypoxia (.o! ,0) o <igh altitude ,o O27 <igh '6C Produ!tion 'ate o 4n!rease Eryt#ropoietin at "idney7 and 4n!rease 9lo ulin produ!tion at liver 4n!rease in '6C results to: o 4n!rease in hemato!rit o 4n!rease in Total blood volume o 4n!rease O?ygen o 4n!rease <emoglobin Produ!tion

34/C !ontain nu!leus Golgi7 and to

Blood Physiology: Castillo, Calderon, Aquino Re$ulation of RB& Total mass of '6C regulation: 1. 9de;uate amount for suffi!ient transport of O2 from the lungs to the tissues 2. Eot numerous7 that they impede blood flo )estruction of RB& ,ifespan: 12+ days =un!tion of '6C Cytoplasmi! enJymes o @aintain pliability of !ell membrane o @aintain membrane transport ions o >eep the =e of the !ells hemoglobin is =errous form rather than ferri! form o Prevents O?idation of the proteins in the '6C Hpleen: '6C self1destru!tion site =ragile !ell membrane rupture during diapedesis

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Eryt#ropoietin Cir!ulating hormone7 principal stimulus for RB& production during hypo?ia :timulates proeryt#ro last from hematopoieti! stem !ells in the bone marro 4n!rease speed of maturation of '6Cs 4n its absen!e7 hypo?ia have little or no effe!t in blood produ!tion Eegative feedba!": @any '6Cs or @any O2 ,ri$in: 1. <idney .)+/0 'enal tubular epithelium se!rete erythropoietin There is a possibility of having a non renal sensor 2. .iver .1+/0 Eoepinephrine and :pinephrine7 and several of the protaglandins stimulate erythropoietin produ!tion 4n the absen!e of erythropoietin: fe '6Cs are formed 4n the abundan!e of erythropoietin Plenty of =e and other re;uired nutrient 1+? faster '6C produ!tion

Hemo$lo in (ormation (unction: Combine and 'elease O?ygen &oordination ond: =e atom A O?ygen mole!ule Be$ins in the proerythroblasts and ends into the reti!ulo!yte stage :teps: 2 su!!inyl1CO9 A 2 gly!ine pyrrole 4 pyrrole protoporphyrin 4K Protophyrin 4K A =e2A hemoglobin !hain B L or MC 2 L !hains A 2 M !hains hemoglobin 9 BThis step variesC 4 different types of !hains 9lpha !hains 6eta !hains *elta !hains Gamma !hains <emoglobin 9 @ost !ommon typeform of hemoglobin

Blood Physiology: Castillo, Calderon, Aquino

July 20,2009

2 alpha !hains A 2 beta !hains Prostheti! group: <eme !ontains =e :a!h <ema !an bind ith 1 O?ygen mole!ule B2 O?ygen atomC )estruction <emoglobin is released during phago!ytosis by ma!rophages Bmost espe!ially the >upffer !ells of the liverC

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"ron Meta olism :ssential element7 important for the formation of hemoglobin 9bsorption Hite: Hmall 4ntestine .slo pro!ess0 'egulatted by: 'ate of =e 9bsorption BHlo s do n and Hpeeds up depending on =e !on!entrationC Htorage: ,iver hepato!yte and reti!uloendothial !ells of the bone marro Transferrin o 9potransferrin .beta globulin0 A =e 9potransferrin is se!reted by the liver7 into the bile o ,o!ation: Plasma o 6inds strongly ith re!eptor !ells in membranes of the erythroblast (erritin o 9poferritin .Protein0 A =e o Htorage =e o ,o!ation: Cell !ytoplasm Hemosiderin o Hmaller insoluble storage form o Present7 hen apoferritin is unable a!!omodate =e <emoglobin is released from !ells ingested mono!yte1ma!rophages o Transported to the bone marro Bprodu!tion of ne '6CC or to the liver3other tissues for storage o Porp#yrin portion of hemoglobin !onverts to the bile pigment7 iliru in by the ma!rophages :?!retes +.$ mg =e in fe!es
"ron - sorption

the !ell

to by the

,iver se!retes apotransferrin into bile Bbile du!tC *uodenum


B9potransferrin binds ith =eA .myoglobin from meat0 and hemoglobin to form transferrinC

6inds ith intestinal epithelial !ell membrane Pino!ytosi s 'eleased into blood !apillaries as P,9H@9 T'9EH=:''4E Eote: =e absorption at intestines is e?tremely slo

Blood Physiology: Castillo, Calderon, Aquino

July 20,2009

-nemias N'6C or N <emoglobin :ffe!ts of anemia on fun!tion of !ir!ulatory system o O !ardia! output7 O pumping or"load of heart and due to N vis!osity P N resistan!e to blood flo P O venous return -cute cardiac failure: hen person ith anemia e?er!ises be!ause blood3 !ardia! output !anQt Page |$ supply o?ygen Bdue to lo <gbC to hypo?i! tissues Vitamin B12 and Folic Acid Me$alo lastic -nemia o '6C !annot proliferate rapidly enough to 4mportant for the final maturation of '6C form normal numbers of '6C :ssential for *E9 synthesis o @egaloblast3@a!ro!ytes: ,arge oval 'e;uired for thymidine triphosphate Bbuilding shaped '6C ith flimsy membrane blo!" of *E9C formation o Pernicious -nemia )eficiency Results to: *ue to atrophi! gastri! mu!osa 9bnormal and diminished *E9 abnormality =ailure to se!rete =ailure of nu!lear maturation and !ellular normal gastri! se!retion division Parietal !ells of gastri! glands fail to produce intrinsic factor7 hi!h binds to %it. 612 for absorption by gut Hteps: 1. 6inding of intrinsi! fa!tors to %it. 612 !oating of %it. 612 Bprote!tion from digestionC 2. 6inding to brush borders of ileum 3. %it. 612 transported to blood via pino!ytosis 4. Htored in liver7 then released to marro as needed @in. 9mount of 612 to maintain normal '6C: 113 Rg 314 years of defi!ien!y is needed before it !an !ause perni!ious anemia o :prue =ailure to absorb 612 and foli! a!id in the small intestine =oli! 9!id: found in green vegetables7 fruits and meat Bespe!ially liverC -plastic -nemia8Bone marro! -plasia o ,a!" of fun!tioning bone marro o Caused by: Gamma ray radiation :?!essive ?1ray treatment Certain industrial !hemi!als Hemolytic -nemia o =ragile !ells that rupture ;ui!"ly :#orter .ifespan of '6C o Hereditary :p#erocytosis Hpheri!al '6C rather than bi!on!ave dis!s Cannot ithstand !ompression for!es o :ic2le &ell -nemia Cells have Hemo$lo in : %aline is substituted for Glutami! a!id at one point in ea!h of the t o beta !hain 4f e?posed to N!on!entration of O2

Blood Physiology: Castillo, Calderon, Aquino

July 20,2009

<emoglobin pre!ipitates into a !rystal !hain Therefore7 NO2 tension !auses si!"ling Eryt#ro lastosis (etalis 'h1positive blood !ells of fetus are atta!"ed by 'h1negative blood !ells of mother 'h1positive blood !ells are fragile Blood .oass -nemia Page | & 1st hemorrhage7 '6C repla!ement duration: 113 days 2nd hemorrhage 7 '6C repla!ement duration: 31$ ee"s &#ronic lood loss: fre;uently !annot absorb enough =e from intestines to form hemoglobin Microcytic8Hypoc#romic -nemia o N <emoglobin o Hmall '6C

Polycyt#emia o :?!essive '6C produ!tion B!ounterpart of ,eu"emia in D6CC o %ery O blood vis!osity and O total blood volume *+ :econdary Polycyt#emia hypo?ia1indu!ed $1& million3 mm3 B3+/ above normalC :?. P#ysiolo$ic Polycyt#emia: for those ho live at high altitudes Ba physiologi! adaptation to poor o?ygen supply in the atmosphereC 0+ Polycyt#emia vera8 Eryt#remia Caused by geneti! aberration in hemo!ytoblasti! !ells Eo negative feedba!" for '6C7 hemato!rit7 D6C and platelet produ!tion o :ffe!ts of Poly!ythemia *ue to O blood vis!osity7 blood flo is sluggish BNvenous return from vis!ous blood !an!els out ith Ovenous return from elevated blood volumeC Eo mar"ed effe!t on !ardia! output Generally7 normal arterial pressure .pressure: regulating me!hanisms offset in!reased blood velo!ity0 Cyanoti! s"in due to large volumes of blood7 most of hi!h are deo?ygenated

Blood Physiology: Castillo, Calderon, Aquino B+ %#ite Blood &ells (%B&) 1 (unction: Prevention of diseases by 1. Phago!ytosis3 a!tual destru!tion of invaders 2. 9ntibodies and sensitiJed lympho!ytes 1 .eu2ocytes: mobile units of immunity o Granulo!ytes7 mono!ytes7 and lympho!ytes Bfe C 6one marro o

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1 1 1 1 1

1 1

,ympho!ytes and plasma !ells and granulo!ytes Bbaso17 neutro17 eosino1C lymphogenous tissues .lymph glands7 spleen7 thymus7 tonsils7 PayerQs pat!hes Bunderneath epithelium of gut allC0 9ranulocytes: Spolys7T multinu!leated7 polymorphonu!lear Granulo!ytes A mono!ytes 8 phago!ytoti! ,ympho!ytes A plasma !ells 8 related to immune system Platelets: blood1!lotting me!hanism Bfragments of !ellsC Con!entrations of D6C in blood: o 9dult human: &7+++ D6C3 R, o Eeutrophils: largest number in population 6asophils: smallest number in population o 'e!all: # million '6C 3++7+++ platelets 9enesis of %B&

C=F16 BC=F1blastC

C=F1: BC=F1erythro!yteC

:rythro!yt e Granulo!yte B6aso17 Eeutro17 :osino1C @ono!yte

Pluripotential <ematopoieti! Htem Cell BP<HCC

Colony =orming Fnit BC=FC in spleen

C=F1G@ BGranulo!yte7 @ono!yteC

P<HC

,ymphoid Htem Cell B,HCC T1,ympho!yte 61 ,ympho!yte

Blood Physiology: Castillo, Calderon, Aquino 1 ma=or linea$es of %B&: 1. Committed stem !ell that also produ!es the '6C 2. @yelo!yti! 3. ,ympho!yti! 2 $1day supply of bone marro produ!es D6C: mostly stored in marro o ,ifespan

July 20,2009

Granulo!ytes: 41 hours lifespan after release from bone marro to blood @ono!yte: 1+12+ hours in blood On!e in tissue7 mono!ytes tissue ma!rophages7 hi!h !an live for months

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,ympho!ytes: diapedesis Bs;ueeJing throughC - goes in and out of !apillary pores Platelets: repla!ed every 1+ days =un!tions

Eeutrophils: destroy invading ba!teria7 viruses and other agents even in !ir!ulating blood @ono!ytes: have little immunity signifi!an!e until it transformation to ma!rophage Eote: Eeutrophils and mono!ytes !an diapedesis too7 and !an also move via amoeboid motion &#emotaxis o @ovement or migration of !ells in response to !hemi!alsU !an either be attra!tion Bpositive !hemota?isC or repulsion Bnegative !hemota?isC o Transport of or attra!tion of neutrophils and ma!rophages to inflamed areas o Can be !aused by: 1. 6a!terial3 viral to?ins 2. *egenerative produ!ts of inflamed tissues 3. 'ea!tion produ!tion of !omplement !omple? 4. 'ea!tion produ!tion of plasma !lotting o Chemota?is depends on !on!entration gradient of !hemota!ti! substan!e :ffe!tive up to 1++ Rm a ay from inflamed tissue 1 precedents of neutrop#ilic8macrop#a$ic p#a$ocy: 1. 'ough surfa!e of substan!e .be!ause normal tissues are smooth0 2. Hubstan!es ithout prote!tive !oats dead3infe!tious 3. ,psonisation: antibody !ombines ith C3 produ!t of !omplement !as!ade7 atta!hes self to ba!terial membraneU C3 atta!hes to re!eptors of phago!yte membrane to initiate phago!ytosis Neutrop#ilic p#a$ocytosis B3 to 2+ ba!teria at a timeC o 9moeboid pseudopodia o Chamber invagination o Creation of phagosome3 phago!yti! vesi!les o *ies ith ba!teria Macrop#a$ic p#a$ocytosis B1++ ba!teria at a timeC o :?trude parti!les bigger than ba!teria and outlives them P#a$osome Bphago!yti! vesi!lesC o *igestive vesi!les on!e inside7 ith enJymes to digest phago!ytosed substan!e @a!rophages and neutrophils have many lysosomes ith proleolyti! enJymesU neutrophils have lipases for thi!" ba!terial membranes Bi.e. tuber!ulosis ba!illusC 6oth have acterial a$ents o O?idiJing agents from enJymes of membrane and pero?isome O217 <2O7 O<1 o <ypo!hlorite from <2O2 and Cl !atalyJed by myelope!tinase Ba lysosomal enJymeC @ono!yte1ma!rophage !ell system reti!uloendothelial system o @a!rophages atta!hed to tissue Reticulocytes: mono!ytes A mobile ma!rophages A fi?ed tissue ma!rophage A spe!ialiJed endothelial !ells of marro 7 spleen7 and lymph nodes

1 1 1 1

1 1

Blood Physiology: Castillo, Calderon, Aquino

July 20,2009

Eote: @ono!yte1ma!rophage !ell system and reti!ulo!ytes have the same origin Bmono!yti! stem !ellC . see ,ymph nodes at p. 433 of Guyton0 1 "nflammation o S alling offT to prevent spread of ba!teria to other areas o Chara!teriJed by: 1. %asodilation in!reased lo!al blood flo Page | 1+ 2. 4n!reased permeability of !apillaries to allo lea"age of fluid into interstitial area 3. *ue to e?!ess fibrinogen7 !lotting of fluid in tissue interstitial area 4. Chemota?is of granulo!ytes and mono!ytes #. H elling BedemaC o Causes: histamines7 brady"inin7 serotonin7 prostaglandin7 rea!tion produ!ts of !omplement system rea!tion7 rea!tion proliferation of blood !lotting system and lympho"ines o ,ines of defen!e: 1st line: @a!rophage 2nd line: Eeutrophils 3rd line: He!ond ma!rophage invasion of inflamed tissue antibody formation affe!ted by ma!rophage 4th line: 4n!reased produ!tion of granulo!ytes and mono!ytes by bone marro from stimulation of granulo!yti! and mono!yti! progenitor !ells of the marro B!an !ontinue for months and even yearsC o 'ea!tions !aused by inflammation: 1. 9lter endothelial tissue neutrophil aderes to it B!apillary allsC marginaliJation 2. *iapedesis from blood to tissue spa!es !aused by loosening of endothelial all of !apillaries and smalle venules 3. Chemota?is !aused by other produ!ts of inflammation o Neutrop#ilia

4n!rease of neutrophils in blood due to inflammation Caused by produ!ts of inflammation that enter blood stream and transported to bone marro =eedba!" !ontrol of ma!rophage and neutrophil responses Bfrom a!tivated ma!rophage !ells in inflamed tissueC 1. Tumor ne!rosis fa!tor BTE=C 2. 4nterleu"in14 B4,14C 3. Granulo!yte1mono!yte !olony1stimulating fa!tor BGm1 CH=C 4. Granulo!yte !olony H= BG1CH=C #. @ono!yte CH= B@1CH=C G@1CH= stimulate granulo!yte and mono!yte produ!tion TE= and 4,14 A CH=s po erful feedba!" me!hanisms that help remove !ause of inflammation 1 Pus o *ead ne!roti! tissue7 ma!rophages and tissue fluid o 9utolyJe over a period of days o :nd produ!ts are eventually absorbed into surrounding tissue and lymph 1 Eosinop#ils

Blood Physiology: Castillo, Calderon, Aquino o o o o

July 20,2009

2/ of blood leu"o!ytes Dea" phago!ytes :?hibit !hemota?is but are !onsiderably ea"er3 less effe!tive than neutrophils Parasite defense BveriformsC :?. :c#istosomiasis - eosinophils atta!h themselves to 5uvenile forms of these parasites via 1. 'elease of hydrolyti! enJymes from their granules7 hi!h are modified lysosomes Page | 11 2. 'elease of highly rea!tive forms of o?ygen lethal to parasites 3. 'elease of ma5or basi! protein highly larva!idal polypeptide B"ills larvaeC o Eosinop#ilia !aused by: 1. Tri!hinosis by Tri!hinella parasite BSpor" ormTC 2. @ast !ells and basophils release eosinophil !hemota!ti! fa!tor Proliferate at areas of allergies 6elieved to deto?ify some of inflammation1indu!ing substan!es released by mast !ells and basophils and destroy allergen1antibody !omple?es Prevent spread of lo!al inflammatory pro!ess 6asophils7 li"e mast !ells: heparin Banti!oagulantCU histaminesU brady"inin7 serotonin o 9llergi! rea!tion o 4mmunoglobin : B4g:C propensity to atta!h to basophils and mast !ells 'upture basophil and mast !ells hen they lyse Bdue to antigen1antibody atta!hmentC Contents are poured out7 !ausing lo!al vas!ular and tissue rea!tions .eu2openia o 6one marro produ!es very fe D6C o ,ess prote!ted o *ue to radiation of gamma rays or ?1rays7 drugs and !hemi!als ith benJene and arthra!ene nu!lei aplasia Bdefe!tive development due to absen!e of all or part of an organC of bone marro o *rugs that indu!e leu"openia Chlorampheni!ol Bantibioti!C Thioura!il Btreats thyroto?i!osisC 6arbiturate Bhypnoti!sC

.eu2emia o 4n!reased number of abnormal or dysfun!tional D6C ,yphati!: !an!erous produ!ts of lymphoid !ell usually beginning at lymph nodes @yelogenous: !an!erous produ!ts of myelogenous !ells in bone marro then spreads around the body7 espe!ially in spleen7 liver7 and lymph nodes. Eeutrophili!7 eosinphili! leu"emia7 basophili! or mono!yti! leu"emia produ!tion of partially differentiated !ells7 but most of the time7 undifferentiated and not identi!al to any normal D6C. o O !hroni!: more differentiated o O a!ute: undifferentiated o :ffe!ts of leu"emia on the body @etastati! gro th of leu"emi! !ells in abnormal areas of the body Can !ause pain to surrounding tissues as to bones from marro 9lmost all leu"emias affe!t spleen7 liver7 and lymph nodes regardless of origin Common effe!ts Bresult from displa!ement of normal bone marro and lymphoid !ells by non1 fun!tional leu"o!yti! !ellsC: Hevere anemia Thrombo!ytopenia Bla!" of plateletsC - indu!ed bleeding 4nfe!tions

Blood Physiology: Castillo, Calderon, Aquino :?!essive use of metaboli! substrate by gro ing !an!erous !ells o

July 20,2009

*epletion of energy7 fast utiliJation of amino a!ids rapid deterioration of normal protein tissues of ody Chroni! metaboli! starvation leads to death 4mmunity and 9llergy

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o o o o o o o o o o o o o o o o "mmunity - ability to resist almost all types of organisms o 2 types of immunity: 9. "nnate immunity BGeneral pro!essC 1. Phago!ytosis by tissue ma!rophage system 2. *estru!tion of s allo ed organism by gastri! and intestinal se!retions 3. 'esistan!e of s"in to invaders 4. ,ysoJyme: mu!olyti! polysa!!haride that atta!"s ba!teria 6asi! polypeptides: rea!t ith !ertain gram BAC ba!teria Complement Comple?: system of 2+ proteins for destru!tion of ba!teria Eatural "iller lympho!ytes: destroy foreign !ells7 tumors7 and infe!ted !ells 6. -c5uired "mmunity B9daptive 4mmunityC :?tremely po erful spe!ifi! immunity against individual invading agents Caused by spe!ial immune system that forms antibodies and3or a!tivated lympho!ytes that atta!" and destroy spe!ifi! invading organisms or to?ins 1 4mmuniJation 9!;uired immunity 9. 9ntibodies B<umoral3 61!ell immunityC Globulin mole!ule in blood plasma !apable of atta!"ing invading agent 61lympho!ytes produ!e them 6. Cell1mediated3 T1!ell immunity 9!tivated by T1lympho!ytes o 6oth types of a!;uired immunity are initiated by antigens -nti$ens: proteins3 large polysa!!harides that initiate a!;uired immunity : must have (7+++ mole!ular eight or more antigeni!ity7 depends on epitopes .regularly o!!urring mole!ular groups0 of large mole!ules

Blood Physiology: Castillo, Calderon, Aquino Proteins and large polysa!!harides are almost al ays antigeni! 9!;uired immunity are produ!ed by your lympho!ytes *estru!tion of lympho!ytes Bat lymph nodesC 8 no immunity 9reas and other lymphoid organs: spleen7 submu!osa7 G4T7 thymus and bone marro

July 20,2009

P<H C T1 ,ympho!yte 9!tivated T1 lympho!ytes

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6ursa of =abri!us of birds

61 ,ympho!yte Liver (at mid fetal life) + bone marrow (late fetal to after birth 9ntibodies

.ymp#ocyte: !ommitted stem !ell of embryo o T1lymp#ocytes: bone marro thymus to here: 1. Hpe!ifi! rea!tivity to one antigen is developed 2. *ivision into many !opies thousands ith differential sensitivities3 rea!tivities 3. ,eave thymus Bprepro!essed T1lymphC and spread via blood and lodge in lymphoid tissue every here 4. Dhere T1lympho!ytes that do not auto1atta!" are formed @ainly responsible for re5e!tion of transplanted organs @ost of prepro!essing o!!urs shortly before birth and a fe months after 'emoval of thymus diminishes but not eliminate !ell1mediated immunity o ,iver and bone marro prepro!ess 61lympho!ytes V liver 8 midfetal V bone marro 8 late fetal and after birth o T1lympho!yte hole !ell is rea!tive o 61lympho!yte only se!retions BantibodiesC are rea!tive more3 greater diversity have more antibodies o !lone of lympho!ytes only one "ind Bspe!ifi!ityCthat repli!ates Origin of many !lones of lympho!ytes o Only gene segments are present in the original stem !ellsU they mi? and mat!h :?plains ho millions of T and 6 lympho!ytes !an be !oded from only a fe thousand gene !odes @e!hanism for a!tivating a !lone of lympho!ytes: o T1lympho!ytes: you have T1!ell mar"ers3 T1surfa!e re!eptor proteins at the membrane o 61lympho!ytes: T1!ell mar"ers have a 61lympho!yte !ounterpart7 hi!h is the antibody at membrane o On!e a!tivated7 T or 6 lympho!ytes reprodu!e ildly @a!rophages are also present at lymph nodes and other lymphoid tissues. They phago!ytose antigens first7 then they pass the partially digested substan!e !ell1to1!ell to Bdire!tly toC lympho!ytes7 a!tivating !loning.

Blood Physiology: Castillo, Calderon, Aquino

July 20,2009

o @a!rophages also se!rete 4nterleu!in147 hi!h promotes further gro th and reprodu!tion of spe!ifi! lympho!ytes o T1!ells .the helper1T !ell in parti!ular0 se!rete lympho"ines that a!tivate 61lympho!ytes 1 Dithout the helper !ells7 the 61lympho!ytes produ!ed ill be very fe <umoral 4mmunity B61lympho!yte systemC

9ntigen 9tta!"

Page | 14

Triggers T1lympho!yte7 helper T1!ell ill further enhan!e 61 lympho!yte produ!tion

@a!rophage ill phago!ytose7 then present antigen to 61lympho!ytes

61lympho!yte enlarges .,ymphoblast0 Differentiate into Plasmablasts pre!ursor

@emory !ells

Plasma !ell Plasm a produce

9ntibodies are se!reted into lymph and !arried to !ir!ulatory blood

Gamma globulin antibodies .3++ mole!ules3se!3plasma !ell0

Eote: 4t

ta"es several ee"s or months before pro!ess stops .until e?haustion or death of plasma !ells0 o Memory cells !ir!ulate around the body and populate all lymphoid tissue Primary Response :lo! onset Transient anti ody Not so potent attac2 'emain dormant until the ne?t atta!"7 but more vi!ious the 2 nd time immuniJation :econdary Response =ast onset :ffe!ts of antibodies last long Potent atta!" 1 Eature of antibodies o "mmuno$lo ulins B4gC 9ntibodies3 W Globulins @ole!ular eight: 1$7+++ - )&+7+++ Comprise 2+/ of plasma proteins Combination of light and heavy polypeptide !hains 211+ pairs of light and heavy !hains parallel to ea!h other

Blood Physiology: Castillo, Calderon, Aquino

July 20,2009

Htru!ture of antibodies: o &onstant portion: determines diffusability7 adheren!e of antibody to Page | 1# different stru!tures7 !ondu!tan!e of membranes to antibody7 and atta!hment to !omplement !omple? o 'aria le portion: different for ea!h spe!ifi!ity of antibodyU is the atta!hment point for antigens Hpe!ifi!ity of antibodies: o Caused by uni;ue amino a!id stru!tures at the variable portion o 6onds that hold antibody1antigen !oupling: <ydrophobi! bonding <ydrogen bonding 4oni! bonding %ander Daals for!es >a Baffinity !onstantC 8 Con!entration of bound antibody1antigen .!on!. of antibody0.!on!. of antigen0 -ffinity constant: measure of ho tightly bound th 9n19b are :?: bivalent Bhas 2 varibale binding sitesC # general !lasses of antibodies 4mmunoglobulins B4gC: 1. "$9: &#/ of antibodiesU bivalent 2. "$E: fe BrelativelyC but potent in allergies 3. "$M: 1+ binding sitesU fe but potent against invadersU primary response 3+"$6+"$) @e!hanisms for antibody a!tion 1.*ire!t atta!" of invader 2.9!tivation of !omplement system -+ )irect action of anti odies on invaders Bnot as potent as !omplement systemC 1. -$$lutination: !lumping of multiple large parti!les ith antigen 2. Precipitation: mole!ular !omple? of soluble antigens Be?. Tetanus to?inC and antibody be!omes large and insoluble pre!ipitates Bthey !anQt travel and are depositedC 3. Neutrali>ation: antibodies !over to?i! sites of antigeni! agent 4. .ysis: rupture of agent by dire!t atta!" on membrane B+ &omplement system for anti ody action o Hystem of 2+ proteins7 most of hi!h are enJyme pre!ursors o Fsually present in plasma proteins and proteins that lea" from !apillary to tissue spa!e o &lassic Pat#!ay 9!tivated by antigen1antibody rea!tion Bvariable portionC !onstant portion binds ith C1 mole!ule of !omplement system C1 mole!ules a!tivates !as!ade of enJyme produ!tion

Blood Physiology: Castillo, Calderon, Aquino

July 20,2009

:ffe!ts: 1. ,psoni>ation and p#a$ocytosis: C3b a!tivates phago!y by both neutrophil and ma!rophagesU enhan!es ba!teria engulfment3destru!tion by a hundredfold 2. .ysis: lyti! !omple? !ombination of multiple !omplement a!tors and designted C#b7$7&7(7) Bruptures membranes of invadersC 3. -$$lutination: !ause !omplement produ!ts to adhere to one another Page | 1$ 4. Neutrali>ation of viruses #. &#emotaxis: fragment of C#a initiates neutrophil and ma!rophage !hemota?is $. Mast cell and asop#il activation: C3a7 C4a7 an C#aU histamine7 heparin7 e!t. release to lo!al fluids Histamine in!reases blood flo and lea"age of fluid and plasma protein into tissue to hep immobiliJe antigeni! agentU ma5or role in inflammation ?+ "nflammatory effects: in!reased blood flo in!reased !apillary lea"age of protein !oagulation of interstitial fluids in tissue spa!es o Hpe!ial attributes of T1lympho!yte system a!tivated T8!ells and Cell1mediated immunity Hame me!hanism as ith 61lympho!yte system - only differen!e is instead of se!retions BantibodiesC7 it is the entire T1lympho!yte is released into !ir!ulation o 'e!all that antigen1antibody rea!tion !auses proliferation of !lones7 some of hi!h ill remain plasmoblasts7 hi!h ill be your T1lympho!yte memory !ells. o T1lympho!ytes only respond to antigens bound to MH& proteins on surfa!e of antigen1presenting !ells in lymphoid tissues 3 types of anti$en-presentin$ cells Bonly fun!tion is to presentC 1. @a!rophage 2. 61lympho!ytes 3. *endriti! !ells - most potent &ell-ad#esion proteins: allo T1!ells to bind to antigen1presenting !ells long enough to be!ome a!tivated o MH& proteins: en!oded by Major Histocompatibilit !omple" (MH!) o There !an be 1++7+++ re!eptors on a single T1lympho!yte o Types: 1. MH& " Proteins - present antigen to c toto"ic T#cells 2. MH& "" Proteins - present antigens to T#helper cells o 9ntigens on their surfa!es bind ith re!eptor mole!ules of T1lympho!ytes B hi!h also have a variable portion7 but stem is bound to T1lympho!yte membraneC T-&ells <elper T1!ells Cytoto?i! T1!ells Huppressor T1!ells *+ Helper T-cells The most numerous BX334 of all T1!ellsC @a5or regulator of all immune fun!tions through lymp#o2ines7 hi!h are protein mediators that a!t on other !ells of immune system and bone marro !ells 4mportant lympho"ines: 4nterleu"in12 B4,12C7 4,137 4,147 4,1#7 4,1$7 Granulo!yte1mono!yte !olony stimulating fa!tors7 4nterferon1W Eote: 94*H destro or deactivate lympho"ines o =un!tions:

Blood Physiology: Castillo, Calderon, Aquino

July 20,2009

Htimulation of gro th and proliferation of !ytoto?i! T1!ells and suppressor T1!ells Bby 4nterleu"in1 2C Htimulation of 61!ell gro th and differentiation to form plasma !ells and antibodies B4,147 4,1#7 and 4,1$ are espe!ially involved !ell1stimulating3 61!ell gro th fa!torsC 9!tivation of @a!rophage Hystem Page | 1& 9!tivate ma!rophage more phago!ytosis

Hlo 3stop migration of ma!rophagi! !ells after !hemota?is a!!umulation of ma!rophages =eedba!" stimulatory effe!t on the helper !ells themselves B4,12C amplif in$ effect &ytotoxic T-cells >iller !ell be!ause it dire!tly atta!"s organisms sometimes7 even o n !ells of the body He!rete perforins Bhole1forming proteinsC after binding to antigen Holes: here interstitial fluids flood in7 in addition to !ytoto?i! se!retions H ollen antigen that ill eventually dissolve They ithdra from atta!"ed !ell after perforin and !ytoto?i! se!retions and move on to "ill othersY BDin"y: Sfor more mer!enary tenden!iesT 'o?: 2,O,2C o :spe!ially potent to: %iral atta!"s Bentrapped in tissue membranesC Can!er !ells <eart transplant !ells =oreign !ells :uppressor T-cells o ,i"e helper T1!ell7 is a re$ulator T#cell be!ause it regulates !ytoto?i! T1!ell a!tivity o 9lso suppresses <elper1T1!ell "mmune tolerance o 9s in 96O blood typing7 you develop antigens for your o n tissues so the antibodies ill atta!" everything else instead o @ost toleran!e results from !lone sele!tion during pro!essing o =ailure of toleran!e me!hanism !auses auto1immune diseases :?. R#eumatic fever :?posure to spe!ifi! strepto!o!!al to?in ith epitope in mole!ular stru!ture similar to bodyQs o n antigens immuniJation against tissues of 5oints and heart 9lomerulonep#ritis 4mmunity against o n bastment membrane of glomeruli Myast#enia $ravis 9gainst 9!h re!eptor of E@Z paralysis .upus eryt#ematosus 9gainst many different body tissues at the same time rapid death or e?tensive damage 4mmuniJation by in5e!tion of 9ntigens B9!tiveC o %njection of dead or$anisms ith some of their antigens still inta!t7 as in typhoid fever7 hooping !ough7 diaptheria7 and other ba!terial diseases o To"ins whose to"icit had been destro ed as in tetanus7 botulism7 and other to?i! diseases o &ttenuated live or$anisms B!ultured so they onQt be disease1!ausingC as in poliomyelitis7 yello fever Beffe!t on liver !aused by mos;uitos .the ve!tor0C7 measles7 small po7 and other viral diseases -ctive immunity: body develops its o n immunity to su!h substan!es Passive immunity: infusion of antibodies7 a!tivated T1!ells7 or both from someone else that had been a!tively immuniJed

Blood Physiology: Castillo, Calderon, Aquino

July 20,2009

o 9ntibodies last for 213 ee"s Bin re!ipientQs bodyC7 a!tivated T1!ells for 1 ee" Bif from another person7 but only a fe hours to fe days if transfused from an animalC 9llergy and <ypersensitivity o Hide1effe!t of immunity o )elayed-reaction aller$y: !aused by a!tivated T1!ells Be?. Poison ivy infe!tionC Poison3 to?in of person ivy itself is not harmful7 but T1!ell mediated immunity !auses release of Page | 1( harmful to?ins and ma!rophage !ro ding at tissues tissue damage after repeated e?posure o -tropic aller$ies: !aused by non1ordinary immune system response : inheritable : in!reases amounts of 4g: antibodies in blood o "$E : reagins3 sensitiJing antibodiesU has strong propensity to atta!h to basophils and mast !ells o -ller$en: antigen that rea!ts spe!ifi!ally ith spe!ifi! 4g: regain antibody o Dhen allergens bind to antibodies7 4g: already atta!hed to mast !ells or basophils the antigen1antibody !omple? membranes !ontort and ruptures mast !ells and basophils7 leading to the release of: 1. <istamine22 2. Protease22 3. Hlo 1rea!ting substan!e of anaphyla?is Bmi?ture of to?i! leu"otrienesC22 4. :osinophil !hemota!ti! substan!e22 #. Eeutrophil !hemota!ti! substan!e22 $. <eparin22 &. Platelet a!tivating fa!tors 22 !ause blood vessel dilation7 attra!tion of eosino and neutrophil7 in!reased permeability of !apillaries and loss of fluid into tissues7 !ontra!tion of lo!al and smooth mus!les :?amples: 9naphyla?is: 4f allergen is in5e!ted dire!tly into !ir!ulationU if basophils and mast !ells ere sensitiJed by binding to 4g: idespread allergi! rea!tion in vas!ular system and asso!iated tissues <istamine is released into !ir!ulation !ause vasodilation and in!reased !apillary permeability and loss o plasma 9 person may die ithin minutes of !ir!ulatory sho!" if not treated ith epinephrine 9lso7 death by suffo!ation due to slo rea!ting substan!es of anaphyla?is hi!h !auses bron!hiole smooth mus!le spasms Basthma1li"e effe!tC Frti!aria 9ntigen enter spe!ial s"in areas lo!aliJed anaphyla!ti!toid rea!tions <istamine Blo!alC !auses 1. %asodilation: red flare 2. H elling due to in!reased permeability of !apillaries BhivesC prevented by antihistamine before e?posure <ay =ever 9t nose <istamine !auses lo!al intranasal vas!ular dilation in!reased !apillary pressure and permeability 'apid fluid lea"age Bs ollen nasal liningsC

9sthma 9t bron!hioles Hlo 1rea!ting substan!es of anaphyla?is 9nti1histamines are not very effe!tive

Blood Physiology: Castillo, Calderon, Aquino

July 20,2009

Blood types: Transfusion@ Tissue and ,r$an transplantation 6lood Type O and 9 are most fre;uent Titer of agglutinins at different ages: Pea"s at (11+ years of age7 de!lines gradually thereafter 9gglutinins BantibodiesC are from plasma as all other antibodies @ost are 4g@ and 4gG Dhy agglutinins are for agglutinogens not present in the body e?plained via a!;uired immunity 9gglutinin formation o!!urs after birth -$$lutination process in transfusion reactions Possible be!ause agglutinins B4gG and 4g@C have t o binding sites Clumping plugs small blood vessels throughout the !ir!ulatory system Hemolysis of RB&: hen membranes of agglutinated !ells release haemoglobin into plasma Bdestru!tion due to D6C or distortion of membraneC -cute #emolysis: hen thereQs a mismat!h bet een re!ipients and donorsQ bloods : 9ntibodies lyse '6C by a!tivating !omplementary system7 hi!h releases the lyti! !omple? : ,ess fre;uent than delayed hemolysis follo ing agglutination be!ause large titer BvolumeC of antibodies are needed Bespe!ially 4g@7 hi!h is hemolysinC Blood typin$8matc#in$: hatever rea!ts ith agglutinin !orresponds to the blood type R# lood types 96O blood system: plasma agglutinins responsible !ausing transfusion rea!tion develop spontaneously 'h: needs massive e?posure to agglutinogens first before delayed transfusion rea!tion happens B'hA or 'h1C 'h fa!tors: C7*7:7 ! 7d7 e 'h A: has antigen * 'h 1: <as no *1antigen R# immune response *elayedU ta"es about 2 to 4 months later for transfusion rea!tions to o!!ur !haracteristics of 'h Transfusion delayed transfusion rea!tions =irst !onta!t: mild rea!tions only7 but the transfusion rea!tions get progressively e?posure

Page | 1)

orse

ith subse;uent

Eryt#ro lastosis fetalis (Hemolytic )isease of t#e ne! orn) 9gglutination and phago!ytosis of fetusQ '6C @ostly7 mother is 'h1 and father is '<A and baby is 'hAU mother7 due to e?posure to fetusQ 'h antigen7 develop 'h agglutinin 9gglutinin from the other diffuse through pla!enta into fetus and !ause '6C agglutinogens

Blood Physiology: Castillo, Calderon, Aquino

July 20,2009

"ncidence of diseases subse;uent pregnan!ies have higher3 more potent agglutination Effects of mot#er4s anti odies on fetus 9nti1'h from mother diffuse through pla!enta 9gglutination of fetusQ blood <emolysis 'elease of haemoglobin into blood @a!rophage of fetus !onverts haemoglobin to bilirubin s"in be!omes yello B5aundi!edC 2antibodies !an also atta!" and damage other !ells in body

Page | 2+

&linical picture of Eryt#ro lastosis 1. Zaundi!e 2. 9naemi! anti1'h agglutinin !ir!ulates in blood for one to t o months after birth. Therefore7 thereQs more blood destru!tion 3. Eu!leated blasti! forms of '6C pass from babyQs bone marro into !ir!ulatory system Bthus7 the nameC 4. Permanent mental impairment3 damage to motor areas of the brain be!ause of bilirubin pre!ipitation in neuronal !ells "erni!terus Treatment of eryt#ro lastotic neonate: repla!e blood ith 'h1negative blood 4++ m, of 'h1negative blood infused over a period of 1.# or more hours hile neonateQs o n 'hA blood is being removed To "eep bilirubin level lo prevention of "erni!terus 6y the time the transfused 'h1 !ells are repla!ed ith infantsQ o n 'hA7 B$ or more ee"sC the anti1'h ould have been destroyed Prevention of Eryt#ro lastosis fetalis *uring 1)&+Qs: 'h immunoglobulin globin7 an antibody administered to mother starting 2(13+ ee"s of gestation 9lso for 'h1 omen ho deliver 'hA babies to prevent sensitiJation Bheightened rea!tionC of mothers to *1 antigen Transfusion reactions resultin$ from mismatc#ed lood types Hmall amount of infused blood does not signifi!antly dilute the agglutinins in the re!ipientQs plasma Therefore7 the re!ipientQs agglutinins !an still agglutinate the mismat!hed donor !ells 25ust remember that your donorQs blood Band its propertiesC is insignifi!ant7 by virtue of its titer7 in transfusions

Transfusion reactions cause 1. <emolysis7 due to hemolysin B!an be a!ute or other iseC 2. Zaundi!e

Blood Physiology: Castillo, Calderon, Aquino 'elease of haemoglobin bilirubin e?!reted in bile by liver 5aundi!e -cute 2idney s#utdo!n after transfusion reactions >idney failure: one of most lethal effe!ts of transfusion

July 20,2009

Three !auses: Page | 21 1.C renal vaso!onstri!tion due to to?i! substan!es released indu!ed by antigen1antibody rea!tion 2.C loss of !ir!ulating red !ells in re!ipient7 produ!tion of to?i! substan!es from hemolyJed !ells and from immune rea!tions7 hi!h !auses !ir!ulatory sho!" arterial blood pressure8de!reased renal blood and urine output !ir!ulatory sho!" 3.C if the free haemoglobinX haptaglobin Bplasma protein that binds small amounts of haemoglobinC e?!ess lea"s though glomerulus membranes into "idney tubules ':E9, TF6F,9' 6,OC>9G: 2all three !ause a!ute renal shutdo n: !an !ause death ithin a ee" to 12 days if unresolved7 unless treated ith an artifi!ial "idney Transplantation of tissues and or$ans 9utograft: transplant of a tissue3 hole organ from one part of same animal to another part 4sograft: from one identi!al t in to another 9llograft: one human to another3 any animal to another animal of same spe!ies Kenograft: lo er animal to human one spe!ies to a different spe!ies Transplantation of cellular tissues 9utograft and 4sograft: sin!e almost same antigens7 normal Kenograft: immune rea!tion almost al ays o!!urs7 !ausing death of !ells in graft in a day to five ee"s after transplantation 9llograft: e?. H"in7 "idney7 heart7 liver7 glandular tissue bet een persons -ttempts to overcome tissue reactions in transplanted tissue *+ tissue1 typing: <,9 !omple? of antigens 2. Prevention of graft re5e!tion by suppressing immune system7 espe!ially T1lypho!ytes :?amples of therapeuti! agents: a. glu!o!orti!oid hormones from adrenal !orte? glands suppress gro th of all lymphoid tissue. Thus7 de!reased antibody and T1!ell formation b. %arious drugs that have to?i! effe!ts on lymphoid system e?. 9Jathioprine !. !y!losporine: has spe!ifi! inhibitory effe!t on helper1T !ell formation Thus7 blo!"ing T1!ell re5e!tion rea!tion 2One of most valuable of all drugs be!ause it does not depress some other portions of immune system Hemostasis (prevention of lood loss) and lood coa$ulation @e!hanisms: 1. %as!ular !onstri!tion 2. Platelet plug 3. 6lood !lot due to blood !oagulation 4. :ventual gro th of fibrous tissue into blood !lot to !lose the hole in vessel permanently 'ascular constriction Contra!tion of vessel all smooth mus!les results from 1. ,o!al myogeni! spasmdue to dire!t damage to vessel all and a!tion of t#rom oxane -@ a vaso!onstri!tor Bsevere damage spasmC 2. ,o!al auto!oid fa!tors from automiJed tissue and blood platelets 3. Eervous refle?es due to pain re!eptors

Blood Physiology: Castillo, Calderon, Aquino

July 20,2009

(ormation of platelet plu$ 4f !ut in blood vessel is very small7 platelet plug instead of blood !lot (h sical and chemical characteristic of platelets) #thrombo!ytosis 1platelets are minute dis!s B114 mi!rometer in diameterC Page | 22 1formed from mega"aryo!ytes Be?tremely large !ells of hematopoieti! series in marro C in bone marro 1#++++ to 3+++++3mi!roliter 9nu!lei! and unable to reprodu!e =ound at the !ytoplasm are 9!tin and myosin mole!ules Thrombostenin 'esidues of :' and golgi apparatus that synthesiJe various enJymes and store large ;uantities of !al!ium ions @ito!hondria and enJyme systems that form 9TP and 9*P :nJyme systems that synthesiJe prosta$landin lo!al hormones that !ause many vas!ular and other lo!al tissue rea!tions =ibrin1stabiliJing fa!tor Gro th fa!tor: !ellular gro th due to vas!ular endothelial7 vas!ular7 smooth mus!le !ells and fibroblasts to multiply and gro Platelet cell mem rane --has gly!oprotein that repulse adheren!e to normal endothelium o Platelets sti!" to in5ured areas of vessel all only7 espe!ially to e?posed !ollagen from deep ithin vessel all o <as phospholipids that a!tivate multiple stages in blood !lotting o Thus7 platelet is an a!tive stru!ture o <as a half1life of (112 days o :liminated via ma!rophage system Mec#anism in platelet plu$ Platelets s ell up !onta!t ith damaged vas!ular all 9ssume several forms ith numerous irradiating pseudopods Contra!tion of !ontra!tile proteins !ause granules that !ontain a!tive fa!tors to be released They be!ome sti!"y Bto all and to von Dille brand fa!tor7 a protein that lea"s into traumatiJed tissue and se!rete 9*P and their enJymes form thrombo?ane 9C 9*PA thrombo?ane 9 a!tivate other nearby platelet !ells =ibrin threads form and atta!h to platelets Bblood !oagulation later onC "mportance of platelet mec#anism for closin$ vascular #oles =or minute ruptures in very small blood vessels that happen thousands of times everyday Blood coa$ulation in ruptured vessel after trauma: 1#12+ se!onds if severeU 112 minutes if not !oagulation triggers: 11a!tivator substan!es from severed vessel 11platelet 11blood proteins adhering to traumatiJed vas!ular all 31$ minutes after rupture: hole vesselQs filled ith !lot

Blood Physiology: Castillo, Calderon, Aquino 9fter 2+ minutes to one hour: retra!tion of !lot7 hi!h !loses the vessel further

July 20,2009

(i rous or$ani>ation or dissolution of lood clot 2 fates of !lot: 1. *issolution 2. @ore !ommon: be!ome invaded by fibroblasts7 hi!h form !onne!tive tissue all over the !lot Bpromoted by gro th fa!torsC organiJation of !lot into fibrous tissue in about 1 or 2 ee"s Mec#anism of lood coa$ulation: 6lood !oagulation tenden!ies are a fa!tor of the balan!e bet een pro!oagulants and anti1!oagulants present in the blood 4n !ir!ulation7 anti!oagulants dominate Thus7 not mu!h !lotting in !ir!ulation 4n damaged vessels7 pro!oagulants dominate !lotting 9eneral mec#anisms of clottin$: 3 steps: 1. Prothrombin a!tivator is produ!ed by !as!ade of !hemi!al rea!tions involving blood !oagulation fa!tors 2. Prothrombin7 ith help of Prothrombin a!tivator7 be!omes thrombin 3. Thrombin helps the !onversion of fibrinogen to fibrin fibers =ibrin fibers enmesh platelets7 blood !ells and plasma to form !lot

Page | 23

Blood Physiology: Castillo, Calderon, Aquino &onversion of Prot#rom in to t#rom in: 'ate1limiting fa!tor of !oagulation is the formation of Prothrombin a!tivator %:HH:, *9@9G:

July 20,2009

Hynthesis of Prothrombin a!tivator

Page | 24

Dith suffi!ient CaAA7 Prothrombin is !onverted to thrombin

Thrombin !auses polymeriJation of fibrinogen mole!ule to fibrin fibers Platelets --mu!h of Prothrombin first atta!hes to Prothrombin re!eptors on platelets already bound to damaged tissue Prot#rom in: plasma proteinU 1# mg3d, : 9lpha121globulin ith mole!ular eight of $(&++ : Fnstable7 thus7 splits into fragments Be?. Thrombin is almost e?a!tly one half of ProthrombinC : formed !ontinually by liver and used by hole body for !lotting : %it. > is re;uired by the liver for normal Prothrombin and for other fa!torsQ formation AAbleeding tenden!ies !an arise from %it. > defi!ien!y or liver problem &onversion of fi rino$en to fi rin formation of t#e clot =ibrinogen: <igh mole!ular eight B34++++C in plasma : produ!ed by the liver : CanQt easily lea" out into interstitial fluids. Therefore7 thereQs not mu!h !lotting of interstitial fluids unless thereQs a pathologi!al in!rease in !apillariesQ membranesQ permeability -ction of t#rom in on (i rino$en to form (i rin Thrombin: protein enJyme ith ea" proteolyti! !apabilities : 9!ts on fibrinogen by removing four lo 1mole!ular eight peptides from ea!h mole!ule of fibrinogen !reation of a fibrin monomer7 hi!h has automati! ability to polymeriJe ith other fibrin monomer mole!ules to form fibrin fibers7 hi!h ma"e up the reti!ulum of blood !lot : The same thrombin also a!tivates the fi rin-sta ili>in$ factor7 hi!h !onverts the former non1!ovalent <1 bond among fibrin fibers into !ovalent bonds7 hi!h are stronger Blood clot @esh or" of fibrin fibers that entrap blood !ells7 platelets and plasma =ibrin fibers also adhere to blood vessel damages

Blood retraction Herum: fluid e?pressed3e?tra!ted from !lot 2+1$+ minutes after a !lot : !anQt !lot : =ibrinogen and most of the !lotting fa!tors are removed : Platelets determine !lot retra!tion 9tta!h to fibrin fibers7 binding different fibers together :ntrapped in !lot7 but still releasing pro!oagulants espe!ially fibrin1stabiliJing fa!tor 9lso !ontribute to !lot !ontra!tion by a!tivating platelet Thrombostenin7 9!tin and myosin mole!ules7 hose !ontra!tion helps !ompress fibrin mesh or" into smaller mass

Blood Physiology: Castillo, Calderon, Aquino

July 20,2009

The !ontra!tion is a!tivated and a!!elerated by thrombin and !al!ium ions Bfrom mito!hondria. :' and Golgi apparatus of plateletsC 22as !lot retra!ts7 edges of bro"en blood vessels are pulled together for hemostasis &lot formation cycle Clot is a positive feedba!" for more !lotting due to e?tensive rea!h of thrombinQs proteolyti! a!tion B!an intera!t ith Page | 2# other !lot fa!tors hile a!ting on fibrinogenC

Prot#rom in activator formation Triggers of Prothrombin a!tivator formation: 1. Trauma to vas!ular all3 ad5a!ent stru!tures 2. Trauma to blood 3. Conta!t of blood ith damaged endothelial !ells or ith !ollagen and other tissue elements outside the blood vessel Extrinsic pat#!ay for initiatin$ clottin$: "ntrinsic Pat#!ay Triggers 1 and 3 Trigger 2 2:?trinsi! path ay is very e?plosive: on!e initiated7 the only limiting fa!tor ill be the amount of !lot fa!tors7 espe!ially 1+7& and #.

Fsually responds to severe trauma Bonly 1# se!ondsC intrinsi! path ay is mu!h slo er B1 to $ minutesC 22Cal!ium is needed in promotion of all blood !lotting rea!tions7 e?!ept for first t o steps of intrinsi! path ay7 so mu!h so that defi!ien!y3absen!e of it ill impede both path ay a!tions 222 it is very seldom that !al!ium a!tually falls belo threshold for !lotting7 unless you remove blood and deioniJe the !al!ium via !itrate ion or by pre!ipitating it ith o?alate ion

Blood Physiology: Castillo, Calderon, Aquino

July 20,2009

"ntravascular anti-coa$ulants 4. :ndothelial surfa!e fa!tors 1. Hmoothness of endothelial !ell surfa!e 2. Gly!o!aly? layer on endothelium[repels !lotting fa!tors and platelets 3. Thrombomodulin[a protein bound ith endothelial membraneU binds ith thrombin 2thrombomodulin1thrombin !omple? a!tivates protein & that ina!tivates =a!tors # ad & Page | 2$ 22 Dhen endothelial all gets damaged7 it loses 1 and 27 hi!h a!tivate =a!tors 12 and platelets 4ntrinsi! Path ay 222 @ore po erful a!tivation if =a!tor 12 and platelets !ome in !onta!t ith subendothelial !ollagen 44. 9ntithrombin 444 and fibrin 'emove thrombin in the blood: 1.=ibrin fibers absorb almost (#1)+/ thrombin during formation 2.9ntithrombin 4443 9ntithrombin1heparin !ofa!tor 22remaining thrombin Bnot used up by fibrinC binds ith 9ntithrombin 4447 fibrinogen and dea!tivates thrombin in 1212+ minutes thereafter 444. <eparin <as a lo !on!entration in blood =or prevention of intravas!ular !lotting <ighly negatively1!harged !on5ugated polysa!!haride that a!ts as anti!oagulant by enhan!ing the effe!ts of 9ntithrombin 444 Dith heparin7 removal of free thrombin from !ir!ulating blood by 9ntithrombin iii is almost instantaneous 9lso removes =a!tors 1271171+ and ) Produ!ed by basophils and mast !ells Bprolifi! at tissues surrounding !apillaries of lungs and to a lesser e?tent7 liver7 be!ause there are many emboli! !lots thereC

hi!h blo!"s effe!ts of thrombin on

.ysis of lood clots Plasminogen3profibrinolysinfibrinolysin Plasmin: proteolyti! Bbrea"s do n protein by hydrolysis of peptide !hainsC : digests fibrin fibers and fibrinogen7 =a!tors #7 (. 12 and Prothrombin 22may !ause hypo!oagulation Tissue plasminogen a!tivator Bt1P9C: !onverts plasminogen to plasmin7 hi!h removes unne!essary blood !lot a fe days after 22important in removing minute !lots from millions of tiny peripheral vessels that ould other ise be!ome o!!luded &onditions t#at cause excessive leedin$ in #umans: 4. %itamin > defi!ien!y 44. <emophilia 444. Thrombo!ytopenia BPlatelet defi!ien!yC 2Eote that the liver produ!es almost all of the blood !lotting fa!tors 222<epatitis7 !irrhosis and a!ute yello atrophy may !ause depression of !lotting system %itamin > is responsible for formation of Prothrombin7 =a!tor &7 )7 1+ and protein C Produ!ed by ba!teria at the intestinal tra!t %it > defi!ien!y often results from poor absorption of fats from G4T Bfailure of liver to se!rete bile into G4TC or liver diseases

Blood Physiology: Castillo, Calderon, Aquino %it. > is fat soluble and absorbed into blood along ith fats

July 20,2009

<emophiliao!!urs e?!lusively in males7 omen are 5ust !arriers Classi! haemophilia3 <emophila 9 Bmore !ommonC is !aused by =a!tor ( Bspe!ifi!ally of the smaller !omponent of fa!tor (C defi!ien!y %on Dillebran!"Qs disease: bleeding disease !aused by =a!tor ( Bsmaller !omponent7 hi!h is | 2& Page important in intrinsi! path ayC 2almost same ith !lassi! haemophilia B\C Treatment for prolonged bleeding !lassi! haemophilia is therapy3in5e!tion of =a!tor ( Bvery e?pensiveC Thrombo!ytopenia bleeding from small venules and !apillaries and not from larger vessels as ith hemophili!s Hmall pun!tuate hemorrhage8small purplish blot!hes (t#rom ocytopenic purpura)

'e!all: Platelets are for repair of minute brea"s in !apillaries and other small vessels Platelet levels ] #+7+++ bleeding 6elo 1+7+++ per mi!roliter death Higns of defi!ien!y: inability to retra!t !lot 22idiopathi! thrombo!ytopenia: platelets are destroyed by o n antibodiesU un"no n !ause Treatments: fresh hole blood transfusion Brelief for one to four daysC or splene!tomy Bas spleen removes a lot of platelets from bloodC Thrombus: 9bnormal !lot in blood vessel :mboli: =ree floating !lot :mboli from large arteries Bleft side of the heartC !an flo peripherally and plug arteries3arterioles in "idney7 brain7 et!. :mboli from venous system Bright side of the heartC flo into lungs pulmonary arterial embolism Causes of thromboemboli! !onditions: 1. 'oughened endothelial surfa!e of vessels Binitiates !lottingC 2. %ery slo flo of blood through vessels here thrombin and pro!oagulants are formed Tissue plasminogen a!tivator Bt1P9C: effe!tive in a!tivating plasminogen !onversion to plasmin7 hi!h dissolves intravas!ular !lot Bbut only for relatively fresh !lotC @assive pulmonary embolism starts ith femoral venous thrombosis B here emboli are formed from leg veinsU !aused by stasis for hoursCU goes ith venous flo Bright side of the heartC and !auses blo!"age of pulmonary arteries Can !ause immediate death if pulmonary arteries are both blo!"ed Treatment: t1P9 *isseminate intravas!ular !oagulation: idespread !oagulation Bsmall but plentyC due to dying or traumatiJed tissues that release !lotting fa!tors 4n patients ith septi!aemia7 here edoto?ins Bba!terial to?insC a!tivate !lotting ,eads to lo o?ygen and nutrient supply7 hi!h may lead to !ir!ulatory sho!" Patient bleeds o!!asionally be!ause so many fa!tors are removed due to idespread !lotting Bfe pro!oagulants are leftC -nticoa$ulants for clinical use: 4. <eparin: <eparinase BenJyme that brea"s it do nC : prolongs !lotting time Bfrom $ 3+ mins. or longerC by slo ing thromboemboli! !onditions 44. Coumarin Be?. DarfarinC : has depressant effe!t on liver !ompounds BProthrombin7 =a!tors (7 ) and 1+C

Blood Physiology: Castillo, Calderon, Aquino

July 20,2009

: !ompetes ith %it. > for rea!tive sites in enJymati! pro!ess for Prothrombin and other !lotting fa!torsQ formation Prevention of coa$ulation outside t#e ody: 4. Hili!on !ontainer prevents !onta!t a!tivation of platelets and =a!tor 12 44. <eparin: Fsed in surgi!al pro!edure here blood passes through heart1lung ma!hine or through "idney ma!hine and ba!" to the person Page | 2( 444. O?alate: de!reases ioni! !al!ium 4%. Citrate ion: !an be in5e!ted intravenously be!ause it !an be removed by the liver and turned into glu!ose 22!an !ause tetany or !onvulsive death if liverQs damaged Blood coa$ulation tests: 4. 6leeding time: pier!ing of lobe or finger Bnormal: 11$ minutesC 44. Clotting time: !olle!t blood in !hemi!ally !lean test tube and ro!" ba!" and forth every 3+ minutes until !lotting happens : no longer used : normal: $ to 1+ minutes 444. Prothrombin time: @easure of thrombin !on!entration in blood