V. Anatomy and Physiology

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V. ANAT OMY & PHYSIOLOGY PHYS IOLOGY ANATOMY

The Bone Marrow The Bone marrow marrow is the soft, soft, flexible, flexible, vascular tissue tissue found  found in the hollow interior  cavities cavi ties and cancellou cancellous s bon bone e spac spaces es in the center center of many bones bones   and which is the source of erythrocytes (red blood cells) and leukocytes leukocytes (white  (white blood cells). There are two main types of bone marrow. Red bone marrow  is   is the center of production of all blood cells except one type of lymphocyte lymphocyte,, which matures in the thymus thymus.. Yellow  bone marrow  stores  stores fats fats..  As the source of blood cells, the bone marrow is critical to the health of people people.. The disruption of the intricate harmony, such as the production of too many, too few, or  abnormal blood cells, results in diseases, such as leukemia, that can be life-threa life-threatenin. tenin. !edical procedures have been developed to examine the bone marrow (bone marrow aspiration and biopsy) of patients and also to transfer normal stem cells from a donor  into a recipient (bone marrow transplantation). "T#$%T$#& #ed marrow consists primarily of a loose, soft network of blood vessels and protein fibers fibe rs inte interspe rspersed rsed with deve develop lopin in bloo blood d cell cells. s. The blood vessels are term termed ed the vascular component, and the protein fibers and developin blood cells collectively are referred to as the stroma, or the extravascular component. The protein fibers crisscross the marrow, formin a meshwork that supports the developin blood cells clustered in the spaces between the fibers. #ed marrow contains a rich blood supply. Arteries transport blood containin oxyen and nutrients into the marrow, and veins remove blood containin carbon dioxide and other  wastes. The arteries and veins are connected by capillaries, blood vessels that branch throuhout the marrow. 'n various places, the capillaries balloon out, formin numerous thin, blood-filled cavities. These cavities are called sinusoids, and they assist in bloodcell production.

 

ellow marrow is so named because it is composed of yellow fat cells interspersed in a rich mesh of connectiv connective e tissue that also supports many blood vessels. hile not usually actively involved in blood formation, in an emerency yellow marrow is replaced by blood-formin red marrow when the body needs more blood.

Gray's Anatomy illstration o! "ells in #one marrow. $%rom New orl (n"y"lo)eia* *$+%T'+" #ed marrow produces all of the bodys blood cellsred blood cells, white blood cells, and platelets. #ed blood cells in the circulatory system transport system transport oxyen to body tissues and carbon dioxide away from tissues. hite blood cells are critical for fihtin bacteria and other forein invaders of the body. /latelets are essential for the formation of blood clots to heal wounds. ithin red bone marrow, all blood cells oriinate from a sinle type of cell, called a hematopoietic stem cell. "timulated by hormones and rowth factors, these stem cells divide to produce immature, or proenitor blood cells. !ost of these proenitor cells

 

remain in the stroma and rapidly undero a series of cell divisions, producin either red blood cells or white blood cells. At any one time, the stroma consists larely of proenitor  cells in various staes of development. At the appropriate developmental stae, the fresh, new cells s0uee1e throuh the walls of the capillaries. *rom there, the cells leave the bone and enter the bodys circulatory system. "ome proenitor cells mirate to the sinusoids, where they produce platelets, which also travel to the circulatory system via the capillaries.  Althouh stem cells are relatively rareabout rareabout 2 in every 23,333 marrow cells is a stem cellthe cell they y typ typical ically ly pro produce duce the fore forerunn runners ers of an est estimate imated d 4 milli million on red cells per  second and 4 billion platelets per day. 5owever, if sinificant amounts of blood are lost or other conditions reduce the supply of oxyen to tissues, the kidneys secrete the hormone erythropoietin. This hormone stimulates stem cells to produce more red blood cells. cell s. To fiht fiht off infe infectio ction, n, horm hormone ones s coll collecti ectively vely termed colo colony ny stim stimulat ulating ing grow growth th factors are released by the immune system. These hormones stimulate the stem cells to produ pro duce ce mor more e inf infec ectio tion-f n-fih ihtin tin  wh white ite blo blood od ce cells lls.. An And d in sev severe ere ca cases ses,, th the e bo body dy converts yellow marrow into red marrow to help produce needed blood cells.

TH( H(MATOPOI(TI+ SYST(M

5ematoloy is the science of blood and blood formin tissues. 't includes both cellular and non-cellular blood components. 5ematoloic activities occur in many orans of th the e bo body dy an and d ha have ve the potenti potential al fo forr mul multip tiple le for forms ms of pa path tholo oloy y.. Bl Bloo ood d its itself elf is composed of two elements 6 the li0uid component, plasma, and the solid components, which whic h are main mainly ly ery erythro throcyte cytes, s, leu leukocy kocytes, tes, and thro thromboc mbocyte ytes. s. The These se elem elements ents are formed by hematopoiesis.

5ematopoiesis is the continuous, reulated formation of blood cells. There are three primary functions of hematopoiesis. 2. xyen delivery 4. 5emostasis 7. 5ost defense

 

Note e th that at so some me com comple plexit xity y is om omitt itted ed fro from m th the e di diag agram ram.. Lymphocytes Lymphocytes   com come e from Not "Lymphoid" "Lymph oid" line, whereas granulocytes granulocytes,, monocytes monocytes,,  megakaryocytes  megakaryocytes,, and erythrocytes come from "Myeloid" "Myeloid" line line.. m mong ong myeloid myeloid cell cells, s, granulocytes granulocytes   and and monocytes monocytes   ha!e a common precursor, "#$%&M".

5ematopoiesis occurs in the bone marrow. The deree and location of bone marrow activity varies dependin on the ae and health status of your patient. ithin the bone marrow there is a pluripotent stem cell. This stem cell is the 8!other %ell9 or the oriinator of all blood cells. 't has the ability to self-renew and create proenitor stem cell lines. They are naturally limited in number. By reviewin the chart above, you can see that all cells come from the stem cell. An attack on the stem cell can theoretically affect all of them similarly. A disease or aent that impacts erythroblasts could impact all the cell type in that 8line,9 but not those in a different 8line.9

The Blood 

 

Blood is a li0uid tissue. "uspended in the watery plasma are seven types of cells and an d cel celll fra frame ments nts..

The Th e #e #ed d Blo Blood od %ells %ells (#B% (#B%s) s) or ery erythr throc ocyte ytes s , /l /late atele lets ts or 

thrombocytes, and five kinds of white blood cells (B%s) or leukocytes. Three kinds of  ran r anul uloc ocyt ytes es ar are e as fo foll llow ows: s: +e +eut utro roph phil ils, s, &o &osi sino noph phil ils, s, Ba Baso soph phil ils. s. Tw Two o ki kind nds s of  leukocytes without ranules in their cytoplasm are: ;ymphocytes and !onocytes,

%n"tions o! the Bloo Blood performs performs two ma<or functions: functions: transport throuh throuh the body of : oxyen oxyen and carbon carb on diox dioxide, ide, food mole molecule cules s (lu (lucose cose,, lipi lipids, ds, amin amino o acid acids), s), ion ions s (e. (e.., ., +a=, %a4=, 5%7>), wastes (e.., urea), hormones, heat and defense of the body aainst infections and other forein materials. All the B%s participate in these defenses. Red Blood Cells (erythrocytes)

The most numerous type in the blood. omen averae about ?.@ million of these cells per cubic millimeter (mm7 which is the same as a microliter ClD) of blood. !en averae about E.? x 23 F per Cl. These values can vary over 0uite a rane dependin on such factors as health and altitude. (/eruvians livin at 2@,333 feet may have as many as @.7 x 23F #B%s per Cl.) #B% precursors mature in the bone marrow closely attached to a macrophae. They manufacture hemolobin until it accounts for some G3H of the dry weiht of the cell. The nucleus is s0uee1ed out of the cell and is inested by the macrophae. +o-loner-needed proteins are expelled from the cell in vesicles called exosomes. Thus #B%s are terminally differentiated that is, they can never divide. They live about 243 days and then are inested by phaocytic cells in the liver and spleen.

 

!ost of the iron in their hemolobin is reclaimed for reuse. The remainder of the heme portion of the molecule is deraded into bile piments and excreted by the liver. "ome 7 million #B%s die and are scavened by the liver each second. #ed blood cells are responsible for the transport of oxyen and carbon dioxide. Hemoglobin 5emolobin is a protein that is carried by red cells. 't picks up oxyen in the luns and delivers it to the peripheral tissues to maintain the viability of cells. 5emolobin is made from two similar proteins that Istick toetherI. Both proteins must be present for  the hemolobin to pick up and release oxyen normally. normally. ne of the component component proteins is called alpha, the other is beta. Before birth, the beta protein is not expressed. A hemolobin protein found only durin fetal development, called amma, substitutes up until birth. 'n adult humans humans the hemolobin hemolobin (5b) molecule molecule consists of four polypeptides: polypeptides: two alpha (J) chains of 2?2 amino acids and two beta (K) chains of 2?F amino acid. &ach of  these is attached the prosthetic roup heme. There is one atom of iron at the center of  each heme. ne molecule of oxyen can bind to each heme. ;ike all proteins, the IblueprintI for hemolobin exists in L+A (the material that makes up enes). +ormally, an individual has four enes that code for the alpha protein, or alpha chain. Two other enes code for the beta chain. (Two additional enes code for  the amma chain in the fetus). The alpha chain and the beta chain are made in precisely e0ua e0 uall amo amoun unts, ts, de desp spite ite the di diffe fferin rin  nu numbe mberr of e ene nes. s. Th The e pro protei tein n cha chain ins s <o <oin in in developin red blood cells, and remain toether for the life of the red cell. 5emolobin synthesis re0uires the coordinated production of heme and lobin. 5eme is the prosthetic roup that mediates mediates reversible bindin of oxyen by hemolob hemolobin. in. Mlobin

is

the

protein

that

surr rro ounds

and

protects

the

(rythro"ytes an ,elate Va Vales les ,e Bloo +ell $,B+* Normal ,an-e /.010.2 34506mm2 $males* /.7 18./ 34506mm2 $!emales*

heme

molecule.

 

&rythrocytes, or red blood cells, oriinate from a stem cell. Nitamin B24, folic acid, iron, and copper are essential in the formation of erythrocytes. &rythropoietin is released by kidneys in response to hypoxemia which stimulates the bone marrow to produce red blood cells. Typically, red blood cells live approximately 243 days. hen the red blood cells become old and damaed, the liver, spleen, and bone marrow cleanse them from the blood. ,eti"lo"yte +ont Normal ,an-e 5.817.89 o! ,B+s hen released from the bone marrow red blood cells are slihtly immature and are known as reticulocytes. #eticulocytes mature into red blood cells within a few days.

Hemo-lo#in Normal ,an-e 4/14: -6L $males* 47140 -6l $!emales* 5emolob 5emo lobin in is a pro protein tein-iron -iron compound compound in red blood cell that carr carries ies oxyen. oxyen. This laboratory value is used to evaluate the oxyen-carryin capacity of the blood. #ed blood blo od cel cells ls an and d he hemo molo lobin bin o ha hand nd in ha hand nd.. n ne e un unit it of pa packe cked d red blood blood cel cells ls enerally e0uals one whole number increase in your hemolobin value. *or example: 'f your patients hemolobin is O.3 Pdl, and you ive him one unit of packed red blood cells, your patients hemolobin should come up to @.3 Pdl.

Hemato"rit Normal ,an-e /71879 $males* 2;18;9 $!emales* 5ematocrit is an expression of the total percentae of blood volume that is composed of  red blood cells. 't is also known as the packed cell volume of your blood ("herwood, 2GGO).

Iron Normal ,an-e 851485 m"-6L  As mentioned mentioned earlier, earlier, iron is necessary necessary for for the formation formation of hemolobin hemolobin,, an essential essential part of the red blood cell. 'ron is absorbed from the small intestine into the blood and binds

 

with transferrin. Transferrin transports iron tothe bone marrow where it is used to make hemolobin.

Total Iron Binin- +a)a"ity Normal ,an-e 7851/45 m"-6l The amount of iron that can still bind with transferrin (to be transported to bone marrow to make hemolobin) is known as the total iron bindin capacity or T'B%. Think of your  T'B% as the total amount of people that can et on a bus. The iron is the people and the bus is transferrin. hen your serum iron levels increase, your T'B% decreases. hen you serum iron levels decrease, then your T'B% increases.

%erritin Normal ,an-e 75 1 255 n-6mL $males* 75 1 475 n-6mL $!emales* *erritin is a protein that binds to iron. !ost of the iron stored in the body is attached to ferritin. *erritin is found in the liver, spleen, and bone marrow. nly a small amount is found in the blood. ;ike the T'B%, the amount of ferritin in the blood may help indicate the amount of iron stored in your body. hite Bloo +ell +ont $B+* an <i!!erential

hit h ite e bl bloo ood d ce cell lls, s, or le leuk ukoc ocy yte tes, s, ar are e cl clas assi sifi fied ed in into to tw two o ma main in r rou oups ps:: ranulo ran ulocyte cytes s and non nonran ranuloc ulocyte ytes s (als (also o know known n as ara aranulo nulocyte cytes). s). The ran ranuloc ulocytes ytes,, which wh ich inc includ lude e ne neutr utrop ophil hils, s, eo eosin sinop ophil hils, s, an and d ba basop sophi hils, ls, ha have ve ra ranu nules les in th their eir cel celll cytoplasm.. +eutroph cytoplasm +eutrophils, ils, eosinophils, and basophils also have a multilobed nucleus. nucleus. As a

 

resu result lt they are also called poly polymorp morphon honucle uclear ar leuk leukocyt ocytes es or Ipol Ipolys.I ys.I The nucl nuclei ei of  neutr ne utrop ophil hils s als also o ap appe pear ar to be se seme mente nted, d, so the they y may als also o be cal called led se semen mented ted neutr ne utrop ophil hils s or Ise Ises. s.II

The Th e no non nran ranul uloct octye ye wh white ite blo blood od cel cells, ls, ly lymph mphoc ocyte ytes s an and d

monocyte mono cytes, s, do not have ran ranules ules and hav have e non nonlob lobular ular nucl nuclei. ei. The They y are some sometime times s referred to as mononuclear leukocytes. The lifespan of white blood cells ranes from 27 to 43 days, after which time they are destroyed in the lymphatic system. hen immature B%s are first released from the bone marrow into the peripheral blood, they are called IbandsI or Istabs.I ;eukocytes fihtt infe fih infectio ction n thro throuh uh a proc process ess know known n as pha phaocy ocytosi tosis. s. Luri Lurin n pha phaocy ocytosis tosis,, the leukocytes surround and destroy forein oranisms. hite blood cells also produce, transport, and distribute antibodies as part of the bodyQs immune response. Le=o"ytes Total B+ Normal ,an-e 8>555 145>5556mi"roliter  ;eukocytes, or white blood cells, protect the body from bacteria and infection. The white blood cell count is expressedas the number of leukocytes per microliter of  blood. The total B% count increases in response to infection or trauma.

Lym)ho"ytes Normal ,an-e 401/09 There are several kinds of lymphocytes (althouh they all look alike under the microscop micro scope), e), eac each h with different different functions functions to perf perform orm . The most comm common on typ types es of  lymphocy lymph ocyte tes s are B ;y ;ymph mphocy ocyte tes s (IB cel cellsI lsI). ). Th These ese are res respo pons nsibl ible e fo forr mak makin in  antibodies. T lymphocytes (IT cellsI). There are several subsets of these: 'nflammatory T-cells that recruit macrophaes and neutrophils to the site of infection or other tissue damae. %ytotoxic T-;ymphocytes (%T;s) that kill virus-infected and, perhaps, tumor  cells. 5elper T-cells that enhance the production of antibodies by B cells.  Althouh  Althou h bone marrow is the ultimate source of lymphocy lymphocytes, tes, the lymphocy lymphocytes tes that will become T cells mirate from the bone marrow to the thymus  thymus where they mature. Both B cells and T cells also take up residence in lymph nodes, the spleen and other  tissues where they encoun encounter ter antiens continue continue to divide by mitosis mature into fully functional cells. ;ymphocytes mature in the lymph nodes. They live approximately 233733 73 3 da days ys.. Th The e to total tal ly lymph mphoc ocyte yte cou count nt rep repres resen ents ts to total tal T an and d B ly lymph mphocy ocytes tes.. T

 

lymphocytes are killer cells. They tell B lymphocytes to make antibodies. ;ymphocytes increase incre ase in viral illnesses, illnesses, such as meas measles, les, mumps, chic chicken ken pox, infl influen uen1a, 1a, vira virall hepatitis, mononucleosis, and in acute transplant re<ection.

Mono"ytes Normal ,an-e 51479 !onocytes leave the blood and become macrophaes. !acrophaes are lare, phaocytic cells that enulf forein material (antiens) that enter the body dead and dyin dy in  ce cell lls s of th the e bo body dy.. Th They ey in ine est st ce cell llul ular ar de debr bris is at th the e ar area ea of in infe fect ctio ion n or  inflammation. They increase after several days of active infection or inflammation. They are like yo your ur bo body dys s a arba rbae e tru truck: ck: they are a lit little tle slow, slow, bu butt the they y pic pick k up al alll th the e 8arbae9 or cellular debris and take it away.

Netro)hils Normal ,an-e /51;59 The mo most st ab abun unda dant nt of th the e B% B%s. s. Th This is ph photo otomic micro rorap raph h sh show ows s a sin sinle le neutrophil surrounded by red blood cells. +eutrophils s0uee1e throuh the capillary walls and into infected tissue where they kill the invaders (e.., bacteria) and then enulf the remnants by phaocytosis. This is a never-endin task, even in healthy people: ur  throat, nasal passaes, and colon harbor vast numbers of bacteria. !ost of these are commensals, and do us no harm. But that is because neutrophils keep them in check. 5owever, heavy doses of radiation, chemotherapy, and many other forms of stress can reduc red uce e the nu numbe mbers rs of ne neutr utrop ophil hils s so tha thatt for forme merly rly ha harml rmless ess ba bacte cteria ria be bein in to proliferate. The resultin opportunistic infection can be life-threate life-threatenin. nin. ;eukocyte types are counted and expressed as a percentae. +eutrophils are the predominant type of  ranulocytes. +eutrophils are special soldiers in your bodys immunity army. Their main responsi resp onsibilit bility y is to kill bac bacteria teria,, dest destroy roy bact bacteria erias s abil ability ity to repr reprodu oduce, ce, and destroy bacterias ability to produce endotoxins.

Bans Normal ,an-e 51:9 +eutrophils primal cell type is bands. Bands are adolescent neutrophils. 't is abnormal to have elevated bands in your blood stream. hen the percent of bands is increased you have a 8shift to the left.9 5istorically, the diaram of the hematopoietic

 

system was read from left to riht, not top to bottom as it does today. Thus, if you had an increase in a cell type, movin left to the proenitor cell 6 you would have a shift to the left.

(osino)hils Normal ,an-e 51;9 The nu numbe mberr of eo eosin sinop ophil hils s in th the e blo blood od is no norma rmally lly 0u 0uite ite low (36 (36?E ?E3PC 3PCl). l). 5owever, their numbers increase sharply in certain diseases, especially infections by parasitic worms. &osinophils are cytotoxic, releasin the contents of their ranules on the invader. invader. &osi &osinop nophils hils are resp responsi onsible ble for fih fihtin tin parasites parasites,, and are increased increased in alleric or autoimmune disorders. *or example, eosinophils increase when a patient has hives due to alleric reaction.

Baso)hils Normal ,an-e 5149 The number of basophils also increases durin infection. Basophils leave the blood and accumulate at the site of infection or other inflammation. There they dischare the con content tents s of the their ir ran ranules ules,, rele releasin asin  a vari variety ety of medi mediato ators rs such as: hist histamin amine, e, serotonin, prostalandina and leukotrienes which increase the blood flow to the area and in other ways add to the inflammatory process. The mediators released by basophils also als o pla play y an imp import ortan antt pa part rt in som some e all aller eric ic res respo pons nses es suc such h as ha hay y fev fever er an and d an anaphylactic response to insect stins. 5istamine and heparin and increase only in the healin process. ;eukocytosis, a B% above 23,333, is usually due to an increase in one of the five types of white blood cells and is iven the name of the cell that shows the primary increa inc rease se..

+eutr +e utrop ophil hilic ic

leuko le ukocy cytos tosis is

R

neut ne utrop rophi hilia lia,,

;ymph ;y mphoc ocyti ytic c

leukoc leu kocyto ytosis sis R

lymphocy lymp hocytosi tosis, s, &osi &osinop nophilic hilic leuk leukocy ocytosi tosis s R eos eosinop inophilia hilia,, !on !onocy ocytic tic leu leukocy kocytosis tosis R monocytosis, Basophilic leukocytosis R basophilia.

Physiolo-y 'n response to an acute infection, trauma, or inflammation, white blood cells release a substance called colony-stimulatin factor (%"*). %"* stimulates the bone marrow to increase white blood cell production. 'n a person with normally functionin bone marrow, the numbers of white blood cells can double within hours if needed. An

 

increase in the number of circulatin leukocytes is rarely due to an increase in all five type ty pes s of le leuk ukoc ocyt ytes es.. h hen en th this is oc occu curs rs,, it is mo most st of ofte ten n du due e to de dehy hydr drat atio ion n an and d hemoconc hemo concentr entratio ation. n. 'n some diseases, diseases, such as meas measles, les, per pertuss tussis is and sepsis, the increa inc rease se in wh white ite blo blood od ce cells lls is so dr drama amatic tic th that at the pi pictu cture re res resem emble bles s leu leukem kemia. ia. ;eukemo ;eu kemoid id reac reaction tion,, leu leukocy kocytosi tosis s of a temp temporary orary nature, must be dif differe ferentia ntiated ted from leukemia, where the leukocytosis is both permanent and proressive. Therapy with steroids modifies the leukocytosis response. hen corticosteroids are iven to healthy persons, the B% count rises. 5owever, when corticosteroids are iven to a person with a severe infection, the infection can spread sinificantly without prod pr oduc ucin in  an ex expe pect cted ed B B% % ri rise se.. An im impo port rtan antt co conc ncep eptt to re reme memb mber er is th that at,, leukocytosis as a sin of infection can be masked in a patient takin corticosteroids. ;euk ;e ukop open enia ia oc occu curs rs wh when en th the e B B% % fa fall lls s be belo low w ?, ?,33 333. 3. Ni Nira rall in infe fect ctio ions ns,, overwhelmin overwhelmi n bacterial infections, and bone marrow disorders can all cause leukopenia. leukopenia. /atients with severe leukopenia should be protected from anythin that interrupts skin interity, placin them at risk for an infection that they do not have enouh white blood cells to fiht. *or example, leukopenic patients should not have intramuscular in<ections, rectal temperatures or enemas. Le=o"ytes "riti"al low an hi-h ?ales  A B%  B% of less than E33 places the patient at risk for a fatal infection. A B% over 73,333 indicates massive infection or a serious disease such as leukemia. hen a patie pa tient nt is rec recei eivin vin  che chemot mothe herap rapy y th that at su supp ppres resses ses bo bone ne ma marro rrow w pro produ ducti ction on of  leukocytes, the point at which the count is lowest is referred to as the nadir.

Bloo +lottinPlatelets Normal ,an-e 485>555 @ /55>5556mi"roliter  /latele /la telets ts are cell framents framents produced produced from mea meakary karyocy ocytes. tes.

Blood Bloo d norm normally ally

contains 2E3,33367E3,333 per microliter (Cl) or cubic millimeter (mm 7). This number is normally norm ally main maintain tained ed by a hom homeost eostatic atic (ne (neativ ative-fe e-feedb edback) ack) mech mechanis anism. m. 'f this valu value e should drop much below E3,333PCl, there is a daner of uncontrolled bleedin because

 

of the essential role that platelets have in blood clottin. "ome causes: certain drus and herbal remedies autoimmunity.

hen blood vessels are cut or damaed damaed,, the loss of blood from the system must be stopped before shock and possible death occur. This is accomplished by solidification of the blood, a process called coaulation or clottin. A blood clot consists of a plu of  platelet plat elets s enm enmeshe eshed d in a netw network ork of inso insolubl luble e fibri fibrin n mole molecule cules. s. /la /latele telets ts are small, colorless cells that have a lifespan of seven to ten days. They perform three ma<or roles: 2) decreasin the luminal si1e of damaed vessels to decrease blood loss, 4) formin blockaes in in<ured vessels to decrease blood loss, and 7) with plasma providin the correct inredients needed to accelerate blood coaulation.

TH( +LOTTING +AS+A<( The end result of the clottin cascade is fibrin clots, fibrin, and thrombin. hen the clottin cascade is activated, usually due to vessel in<ury or damae, platelets are one of the first responders. They stick to the damaed vessel and recruit more platelets to the site. This areation of platelets forms a temporary plu that safeuards the vessel wall from further bleedin. "imultaneously, additional proteins from the clottin cascade are activated in a specific order that lead to the formation of fibrin. *ibrin is a very sticky substance and acts as lue at the site, securin the platelet plu. *inally, *inally, the clot must be dissolved in order for normal blood flow to resume followin tissue repair. The dissolution of the clot occurs throuh the action of plasmin. /lasmin is a protein that is responsible for diestin fibrin. &ventually, scar tissue forms completin the healin of  the in<ured vessel ("herwood, 2GGO). Plasma /lasma is a straw-colored, clear li0uid that is ninety percent water. 't is essential for the tra trans nspo port rt of ou ourr blo blood od com compo pone nent nts. s. Be Besid sides es wa wate ter, r, pl plasm asma a als also o con contai tains ns dissolve diss olved d elec electroly trolytes tes resp responsi onsible ble for memb membrane rane exc excitab itability ility,, pla plasma sma prot proteins eins tha thatt mainta mai ntain in th the e osm osmoti otic c di distr stribu ibutio tion n of flu fluid id an and d sub substa stanc nces es ca capa pable ble of bu buff fferi erin n p5

 

chanes ("herwood, 2GGO). /lasma transports materials needed by cells and materials that must be removed from cells: various ions (+a =, %a4=, 5%7>, etc. lucose and traces of other suars amino acids other oranic acids cholesterol and other lipids hormones urea and other wastes. !ost of these materials are in transit from a place where they are added to the blood (a IsourceI) exchane orans like the intestine and depots of materials like the liver to places (IsinksI) where they will be removed from the blood, every cell and exchane orans like the kidney, and skin.

 

'N. T5& /AT'&+T A+L 5'" ';;+&""  A./AT5/  A./A T5/5"';M 5"';M  (BS (BS %&+T&#&L) %&+T&#&L) /recipitatin *actors:  Antecedent  Anteced ent 5ematoloicLiso 5ematoloicLisorders rders %onenital Lisorder 

/redisposin *actors: #ace ( hite race ) Mender (!ale)  Ae (increases (increases with ae) 5eredityP*amilial Tendency

&nvironmental &xposures (hih doses of radiation, chemicals like ben1ene, tobacco "moke) /rior &xposure To %hemotherapeutic  Aents *or *or Another Another !alinancy !alinancy

Lisruption of pluripotent stem cells  

Lisruption of specific enes

!utant leukemia cells proliferate and fill the bone marrow

 

 Affectations  Affect ations in different different committed cells

Bone /ain

 

 Affectations  Affecta tions in different different committed cells cells

;eukoblast &rythroid %ommitted %ells

&rythroblasts

!eakaryoid %ommitted %ells

!eakaryoblast

!yeloid %ommitted %ells

!onoblasts

!yeloblasts

;ymphoid %ommitted %ells

;ymphoblasts

/roliferation of  immature lymphocytes /roliferation of  immature phaocytes

/roliferation of  immature meakaryocytes

/roliferation of  immature monocytes

/roliferation of  immature myelocytes

Bleedin Tendencies

Lecreased production of   

/etechiae &cchymosis Minival bleedin

'nability to protect body aainst invasion

 Affectations  Affectations in B% cells components

epistaxis    Anemia

t. loss  

  pallor 

+eutrophils Basophils &osinophils

!alaise

&asy fatiability fatiability

#isk for infection

 Affectations of   Affectations B lymphocytes  Tlymphocytes

 

a. "+T5&"'" * T5& L'"&A"&  G(N(,AL <(S+,IPTION The underlyin pathophysioloy consists of a maturational arrest of bone marrow cells in the earliest staes of developm development. ent. The mechanism of this arrest is under study, study, but in many cases, it involves the activation of abnormal enes throuh chromosomal translocations and other enetic abnormalities. This developmental arrest results in 4 disease dise ase proc processe esses. s. *irst *irst,, the prod producti uction on of nor normal mal bloo blood d cell cells s mark markedly edly dec decreas reases, es, which wh ich res resul ults ts in var varyi yin n de dere rees es of an anemi emia, a, th throm rombo bocyt cytop openi enia, a, an and d ne neut utrop ropen enia. ia. "econd, the rapid proliferation of these cells, alon with a reduction in their ability to undero prorammed cell death (apoptosis), results in their accumulation in the bone marrow, blood, and, fre0uently, the spleen and liver. b. #'"S *A%T#"

P,(1<ISPOSING %A+TO,S: %A+TO,S: ,A+( - A!; is more common in whites than in other populations. S(3

- A!; is more common in men tha than n in women. women. The differen difference ce is even more apparent in older patients. "ome have proposed that the increased prevalence of   A!; in men may be related to occupational occupational exposures. exposures.

AG(

- /revalence increases with ae. The median ae of onset is FE years. 5owever, this disease affects all ae roups.

*A!';'A; T&+L&+% - Merm-line mutations mutations in the ene ML' ene  ML' (  (R$N(', R$N(', )# )#*  * ) occur  in the fami familial lial pla platele telett diso disorder rder with pred predispo ispositio sition n for A! A!;, ;, an aut autoso osomal-d mal-domin ominant ant disorder characteri1ed by moderate thrombocytopenia, thrombocytopenia, a defect in platelet function, and propensity to develop A!;. "ome hereditary cancer syndromes, such as ;i-*raumeni syndrome, can manifest as leukemia.

P,(+IPITA P,(+IP ITATING TING %A %A+TO,S +TO,S :  A+T&%&L&+T  A+T&%&L& +T 5&!A 5&!AT; T;M'% M'% L'"#L&# L'"#L&#" "  - $nkn $nknown own etio etioloy loy tha thatt occu occurs rs most often in older patients and manifests as proressive cytopenias that occur over months

 

to years. ther that predispose patients to A!; include aplastic anemia, myelofibrosis, paroxysmal nocturnal hemolobinuria, and polycythemia vera. %+M&+'TA; L'"#L&#" - "ome conenital disorders that predispose patients to  A!; include Bloom syndrome, Lown syndrome syndrome,, conen conenital ital neutrop neutropenia, enia, *anconi anemia, and neurofibromatosis. !ore subtle enetic disorders, includin polymorphisms of en1ymes that metaboli1e carcinoens, also predispose patients to A!;. &+N'#+!&+TA &+N'#+!& +TA; ; &U/"$#&" -"everal studies demonstra demonstrate te a relations relationship hip betwee between n radiation exposure and leukemia. &arly radiolo radioloists ists (prior to appropriate shieldin) were found fou nd to ha have ve an in incre crease ased d lik likeli eliho hood od of de devel velop opin in leu leukem kemia. ia. /a /atie tient nts s rec recei eivin vin  therape ther apeutic utic irrad irradiati iation on for anky ankylosin losin  spo spondy ndylitis litis we were re at incre increase ased d risk of leu leukemi kemia. a. "urvivors of the atomic bomb explosions in Vapan were at a markedly increased risk for  the de deve velop lopmen mentt of leu leukem kemia. ia. /e /erso rsons ns wh who o smo smoke ke ha have ve a sma smallll bu butt sta statis tistic tical ally ly sinificantt (odds sinifican ( odds ratio, 2.E) increased risk of developin A!;. A!;. 'n several studies, the risk of A!; was slihtly increased in people who smoked compared with those who did not smoke. &xposure to ben1ene is associated with aplastic anemia and pancytopenia. These patients often develop A!;. !any of these patients demonstrate !F morpholoy. /#' /# '# #

&U/ U/" "$# $#& &

T

%5&! %5 &!T T5& 5&#A #A/& /&$T $T'% '%

AM& M&+T +T" "

*# * #

A+ +T5 T5&# &#

!A;'M+A !A; 'M+A+% +% - As more patients patients with cancer survive survive their primary malinan malinancy cy and more patients receive intensive chemotherapy (includin bone marrow transplantation B!T B !TD) D),, th the e nu numb mber er of pa pati tien ents ts wi with th A!; in incr crea ease ses s be beca caus use e of ex expo posu sure re to chemotherapeutic aents. /atients with a prior exposure to alkylatin aents, with or  without radiation, often have a myelodysplastic phase prior to the development of A!;. The typical latency period between dru exposure and acute leukemia is approximately 7-E 7E ye year ars s fo forr al alky kyla lati tin n a aen ents tsPr Prad adia iati tion on ex expo posu sure re bu butt on only ly GG-24 24 mo mont nths hs fo for  r  topoisomerase inhibitors.

%. "'M+" A+L "!/T!" 'T5  'T5 #AT'+A;& #AT'+A;& 2. Anemia> Netro)enia> an Throm#o"yto)enia 6 Throm#o"yto)enia 6 These are due to bone marrow failure. 't results from the fact that as leukemic clone of cells rows, it tends to displace development of normal blood cells in the bone marrow. There is also decreased neutrophil levels despite an increased total B% count.

 

4. Physi"al  Physi"al si-ns o! anemia, anemia, includin pallor and a cardiac flow murmur, are fre0uently fre0uently 4. present 6 These are due to the increased number of white blood cells displacin or  otherwise interferin with the production of normal blood cells in the bone marrow. The most common symptom of ane anemia mia is fati fatiue ue.. /ati /atient ents s ofte often n retr retrospe ospectiv ctively ely not note e a decreased enery level over past weeks. ther symptoms of anemia include dyspnea upon exertion, di11iness, and, in patients with coronary artery disease, aninal chest pain. !yocardial infarction may be the first presentin symptom of acute leukemia in an older patient. 7.%e?er 7. %e?er an other si-ns o! in!e"tion can in!e"tion can occur, includin lun findins of pneumonia 6 These are due to the lack of normal white blood cell production that makes the patient susceptible to infections, while the leukemic cells are derived from white blood cell precursors, they have no infection-fihtin capacity. /atients present with fever, which may occur with or without specific documentation of an infection. /atients with the lowest absolute neutrophil counts (ie, WE33 cellsPC; and especially W233 cellsPC;) have the hihest risk of infection. /atients also often have a history of upper respiratory infection symptoms that have not improved despite empiric treatment with oral antibiotics. ?. A#normal Bleein- ( Bleein- ( noseble nosebleeds, eds, inival bleedin, purpura, ecchymosis, petechiae  6These are due to thrombocy thrombocytopenia. topenia. /atients usually demonstra demonstrate te petechia petechiae, e, particularly on the lower extremities. /etechiae are small, often punctate, hemorrhaic rashes that are not palpable. Areas of dermal bleedin or bruises (ie, ecchymoses) that are lare or present in several areas may indicate a coexistent coaulation disorder such as L'%. /urpura /urpura is cha charact racteri1e eri1ed d by flat brui bruises ses that are larer tha than n pet petechi echiae ae but smaller than ecchymoses. /otentially life-threatenin life-threatenin sites of bleedin include the luns, astrointestinal tract, and the central nervous system . E. Si-ns relatin- to or-an in!iltration with le=emi" "ells  6 The most most common sites of infiltration include the spleen, liver, and ums. These include hepatosplenomealy and, to a lesser deree, lymphadenopathy /atients with splenomealy note fullness in the left upper 0uadrant and early satiety. . ccasionally, patients have skin rashes due to infiltration of the skin with leukemic cells (leukemia cutis). %hloromata are extramedullary deposits of leukemia. #arely, a bony or soft-tissue chloroma (solid leukenic mass or tumor outside of the bone marrow) may precede the development of marrow infiltration by A!; (ranulocytic sarcoma).

 

Pain - /atients with a hih leukemic cell burden may present this symptom F. Bone Pain which is caused by increased pressure in the bone marrow. O. Si-n Si-ns s rela relatintin- to le= le=osta ostasis sis   - /a /atie tients nts wi with th ma marke rkedly dly ele elevat vated ed B% cou counts nts (X233,333 cellsPC;) can present with symptoms of leukostasis (ie, respiratory distress and altered mental status). ;eukostasis is a medical emerency that re0uires immediate intervention.

 

B. PATHOPHYSIOLOGY PATHOPHYSIOLOGY $+LI(NT1+(NT(,(<* /recipitatin *actors: /redisposin *actors:

&nvironmental &xposures - %iarette "moke - &xposure to certain chemicals (carbonated drinks even before

Mender (!ale)  Ae (7 years years old)

reachin of aeP foul-smellin envt cause by 2-yr nearby poultry)

Lisruption of pluripotent stem cells  

Lisruption of specific enes

!utant leukemia cells proliferate and fill the bone marrow

 

 Affectations  Affect ations in different different committed cells

 

 Affectations  Affecta tions in different different committed cells cells

!yeloid %ommitted %ells !eakaryoid %ommitted %ells

&rythroid %ommitted %ells

!eakaryoblast

&rythroblasts

/roliferation of  immature phaocytes

/roliferation of  immature meakaryocytes

!onoblasts

!yeloblasts

/roliferation of  immature monocytes

/roliferation immature of  myelocytes

  10-7/8/12/14-19-08

Bleedin Tendencies

Y

Lecreased production of  normal #B% 10- 3/7/8/ 12/14/15/17/   18/19-08

/etechiaeZ (both palms of the hand)

Y

 &cchymosisZ

Y

 Minival bleedinZ

'nability to protect body aainst invasion

+eutrophils

 &pistaxis (upon admission) Y

Y

 

 5ematomaZ -/eriorbital -in the sole of left foot

 AnemiaZ

  10-/7/8/14-19-08

Lyspnea (

'+*&%T'+ "ins of infection  n  off  *ever  (23-7P24P27P2OP 2@P2GP4E- 3@)

##,

Y

 

 

ran 'nfiltration (distended abdomen) Y

 ; euko"tasis

Y

 A ltered !ental "tatus

Y

 #

  ;ymphocytes

Y

  /allorZ

 Affectations in  Affectations B% cells components

10-7/8/12/14-19-08

/resence of  Blast %ells 10-7/8/12/14-19-08

 

a. "+T5&"'" T5& L'"&A"& (%;'&+T BA"&L) Malaise/* Fatigue*

  L&AT5

M&+&#A; L&"%#'/T'+ The underlyin pathophysioloy consists of a maturational arrest of bone marrow cells cell s in the earliest earliest sta staes es of deve developm lopment. ent. This developmen developmental tal arre arrest st resu results lts in 4 disease dise ase proc processe esses. s. *irst *irst,, the prod producti uction on of nor normal mal bloo blood d cell cells s mark markedly edly dec decreas reases, es, which wh ich res resul ults ts in var varyi yin n de dere rees es of an anemi emia, a, th throm rombo bocyt cytop openi enia, a, an and d ne neut utrop ropen enia. ia. "econd, the rapid proliferation of these cells, alon with a reduction in their ability to undero prorammed cell death (apoptosis), results in their accumulation in the bone marrow, blood, and, fre0uently, the spleen and liver. 'n A!;, the bone b. #'"S *A%T#"

P,(1<ISPOSING %A+TO,S: %A+TO,S: S(3

- A!; is more common in men tha than n in women. women. The differen difference ce is even more apparent in older patients.

AG(-- /revalence increases with ae. The median ae of onset is FE years. 5owever, AG( this disease affects all ae roups.

P,(+IPITA P,(+IP ITATING TING %A %A+TO,S +TO,S : &+N'#+ &+N '#+!&+T !&+TA; A; &U/"$#& &U/"$#&" " - 'n seve several ral stu studies dies,, the risk of A!; was slihtly increased in people who smoked compared with those who did not smoke.

%. "'M+" A+L "!/T!" 'T5  'T5 #AT'+A;& #AT'+A;& 2. Anemia> Netro)enia> an Throm#o"yto)enia 6 Throm#o"yto)enia 6 These are due to bone marrow failure. 't results from the fact that as leukemic clone of cells rows, it tends to displace development of normal blood cells in the bone marrow. There is also decreased neutrophil levels despite an increased total B% count.

 

4.   Physi"al si-ns o! anemia1  anemia1   includin pallor and dyspnea upon exertion.These are 4. due to the increased number of white blood cells displacin or otherwise interferin interferin with the production of normal blood cells in the bone marrow. marrow. The most common symptom of  anemia is fatiue.

7. %e?er an other si-ns o! in!e"tion /atients in!e"tion  /atients present with fever, which may occur with or without specific documentation of an infection. These are due to the lack of normal white blood cell production that makes the patient susceptible to infections, while the leukemic cells are derived from white blood cell precursors, they have no infectionfihtin capacity. ?. A#normal Bleein- ( nosebleeds, eds, inival bleedin, purpura, ecchymosis, petechiae Bleein- ( noseble  6These are due to thrombocy thrombocytopenia. topenia. E. Si-ns relatin- to or-an in!iltration with le=emi" "ells 6 "ells  6 The most common sites of infiltration include the spleen, liver, and ums. These include hepatosplenomealy and, to a lesser deree, lymphadenopathy. F. Bone Pain Pain - /atients with a hih leukemic cell burden may present this symptom which is caused by increased pressure in the bone marrow. O. Si-n Si-ns s rela relatintin- to le= le=osta ostasis sis   - /a /atie tients nts wi with th ma marke rkedly dly ele elevat vated ed B% cou counts nts (X233,333 cellsPC;) can present with symptoms of leukostasis (ie, respiratory distress and altered mental status). ;eukostasis is a medical emerency that re0uires immediate intervention.

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