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 oxyen 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 throuhout 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 emerency yellow marrow is replaced by blood-formin red marrow when the body needs more blood.
Gray's Anatomy illstration o! "ells in #one marrow. $%rom New orl (n"y"lo)eia* *$+%T'+" #ed marrow produces all of the bodys blood cellsred blood cells, white blood cells, and platelets. #ed blood cells in the circulatory system transport system transport oxyen to body tissues and carbon dioxide away from tissues. hite blood cells are critical for fihtin bacteria and other forein invaders of the body. /latelets are essential for the formation of blood clots to heal wounds. ithin red bone marrow, all blood cells oriinate from a sinle type of cell, called a hematopoietic stem cell. "timulated by hormones and rowth factors, these stem cells divide to produce immature, or proenitor blood cells. !ost of these proenitor cells
remain in the stroma and rapidly undero a series of cell divisions, producin either red blood cells or white blood cells. At any one time, the stroma consists larely of proenitor cells in various staes of development. At the appropriate developmental stae, the fresh, new cells s0uee1e throuh the walls of the capillaries. *rom there, the cells leave the bone and enter the bodys circulatory system. "ome proenitor cells mirate to the sinusoids, where they produce platelets, which also travel to the circulatory system via the capillaries. Althouh stem cells are relatively rareabout rareabout 2 in every 23,333 marrow cells is a stem cellthe 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 sinificant amounts of blood are lost or other conditions reduce the supply of oxyen to tissues, the kidneys secrete the hormone erythropoietin. This hormone stimulates stem cells to produce more red blood cells. cell s. To fiht fiht 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-fih ihtin 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
5ematoloy is the science of blood and blood formin tissues. 't includes both cellular and non-cellular blood components. 5ematoloic activities occur in many orans 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 oloy 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, reulated formation of blood cells. There are three primary functions of hematopoiesis. 2. xyen 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 deree and location of bone marrow activity varies dependin on the ae 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 oriinator of all blood cells. 't has the ability to self-renew and create proenitor 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 aent 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 frame 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 throuh throuh the body of : oxyen oxyen 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 aainst infections and other forein materials. All the B%s participate in these defenses. Red Blood Cells (erythrocytes)
The most numerous type in the blood. omen averae about ?.@ million of these cells per cubic millimeter (mm7 which is the same as a microliter ClD) of blood. !en averae about E.? x 23 F per Cl. These values can vary over 0uite a rane 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 macrophae. They manufacture hemolobin until it accounts for some G3H of the dry weiht of the cell. The nucleus is s0uee1ed out of the cell and is inested by the macrophae. +o-loner-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 inested by phaocytic cells in the liver and spleen.
!ost of the iron in their hemolobin is reclaimed for reuse. The remainder of the heme portion of the molecule is deraded into bile piments and excreted by the liver. "ome 7 million #B%s die and are scavened by the liver each second. #ed blood cells are responsible for the transport of oxyen and carbon dioxide. Hemoglobin 5emolobin is a protein that is carried by red cells. 't picks up oxyen in the luns and delivers it to the peripheral tissues to maintain the viability of cells. 5emolobin is made from two similar proteins that Istick toetherI. Both proteins must be present for the hemolobin to pick up and release oxyen normally. normally. ne of the component component proteins is called alpha, the other is beta. Before birth, the beta protein is not expressed. A hemolobin protein found only durin fetal development, called amma, substitutes up until birth. 'n adult humans humans the hemolobin hemolobin (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 oxyen can bind to each heme. ;ike all proteins, the IblueprintI for hemolobin 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 toether for the life of the red cell. 5emolobin synthesis re0uires the coordinated production of heme and lobin. 5eme is the prosthetic roup that mediates mediates reversible bindin of oxyen by hemolob hemolobin. in. Mlobin
is
the
protein
that
surr rro ounds
and
protects
the
(rythro"ytes an ,elate Va Vales les ,e Bloo +ell $,B+* Normal ,an-e /.010.2 34506mm2 $males* /.7 18./ 34506mm2 $!emales*
heme
molecule.
&rythrocytes, or red blood cells, oriinate 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 damaed, the liver, spleen, and bone marrow cleanse them from the blood. ,eti"lo"yte +ont Normal ,an-e 5.817.89 o! ,B+s hen released from the bone marrow red blood cells are slihtly immature and are known as reticulocytes. #eticulocytes mature into red blood cells within a few days.
Hemo-lo#in Normal ,an-e 4/14: -6L $males* 47140 -6l $!emales* 5emolob 5emo lobin in is a pro protein tein-iron -iron compound compound in red blood cell that carr carries ies oxyen. oxyen. This laboratory value is used to evaluate the oxyen-carryin capacity of the blood. #ed blood blo od cel cells ls an and d he hemo molo 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 hemolobin value. *or example: 'f your patients hemolobin is O.3 Pdl, and you ive him one unit of packed red blood cells, your patients hemolobin should come up to @.3 Pdl.
Hemato"rit Normal ,an-e /71879 $males* 2;18;9 $!emales* 5ematocrit is an expression of the total percentae 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"-6L As mentioned mentioned earlier, earlier, iron is necessary necessary for for the formation formation of hemolobin hemolobin,, 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 hemolobin.
Total Iron Binin- +a)a"ity Normal ,an-e 7851/45 m"-6l The amount of iron that can still bind with transferrin (to be transported to bone marrow to make hemolobin) 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 +ont $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 nonran ranuloc ulocyte ytes s (als (also o know known n as ara aranulo 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 seme mente nted, d, so the they y may als also o be cal called led se semen mented ted neutr ne utrop ophil hils s or Ise Ises. s.II
The Th e no non nran 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 ranes 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 fihtt infe fih infectio ction n thro throuh uh a proc process ess know known n as pha phaocy ocytosi tosis. s. Luri Lurin n pha phaocy ocytosis tosis,, the leukocytes surround and destroy forein oranisms. 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 (althouh 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 macrophaes and neutrophils to the site of infection or other tissue damae. %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. Althouh Althou h bone marrow is the ultimate source of lymphocy lymphocytes, tes, the lymphocy lymphocytes tes that will become T cells mirate 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 antiens 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 macrophaes. !acrophaes are lare, phaocytic cells that enulf forein material (antiens) that enter the body dead and dyin dy in ce cell lls s of th the e bo body dy.. Th They ey in ine 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 dys s a arba rbae 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 8arbae9 or cellular debris and take it away.
Netro)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 rorap raph h sh show ows s a sin sinle le neutrophil surrounded by red blood cells. +eutrophils s0uee1e throuh the capillary walls and into infected tissue where they kill the invaders (e.., bacteria) and then enulf the remnants by phaocytosis. This is a never-endin task, even in healthy people: ur throat, nasal passaes, 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 bein in to proliferate. The resultin opportunistic infection can be life-threate life-threatenin. nin. ;eukocyte types are counted and expressed as a percentae. +eutrophils are the predominant type of ranulocytes. +eutrophils are special soldiers in your bodys immunity army. Their main responsi resp onsibilit bility y is to kill bac bacteria teria,, dest destroy roy bact bacteria erias s abil ability ity to repr reprodu oduce, ce, and destroy bacterias ability to produce endotoxins.
Bans Normal ,an-e 51:9 +eutrophils 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 diaram of the hematopoietic
system was read from left to riht, not top to bottom as it does today. Thus, if you had an increase in a cell type, movin left to the proenitor 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 fih fihtin tin parasites parasites,, and are increased increased in alleric or autoimmune disorders. *or example, eosinophils increase when a patient has hives due to alleric 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 dischare 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, prostalandina 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 eric ic res respo pons nses es suc such h as ha hay y fev fever er an and d an anaphylactic response to insect stins. 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 proressive. 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 sinificantly 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 sin 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 interity, placin them at risk for an infection that they do not have enouh white blood cells to fiht. *or example, leukopenic patients should not have intramuscular in<ections, rectal temperatures or enemas. Le=o"ytes "riti"al low an hi-h ?ales 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 framents framents produced produced from mea meakary 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 (neativ ative-fe e-feedb edback) ack) mech mechanis anism. m. 'f this valu value e should drop much below E3,333PCl, there is a daner of uncontrolled bleedin because
of the essential role that platelets have in blood clottin. "ome causes: certain drus and herbal remedies autoimmunity.
hen blood vessels are cut or damaed damaed,, 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 coaulation 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 damaed vessels to decrease blood loss, 4) formin blockaes in in<ured vessels to decrease blood loss, and 7) with plasma providin the correct inredients needed to accelerate blood coaulation.
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 damae, platelets are one of the first responders. They stick to the damaed vessel and recruit more platelets to the site. This areation of platelets forms a temporary plu that safeuards 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 throuh the action of plasmin. /lasmin is a protein that is responsible for diestin 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
chanes ("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 suars amino acids other oranic 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) exchane orans like the intestine and depots of materials like the liver to places (IsinksI) where they will be removed from the blood, every cell and exchane orans like the kidney, and skin.
&nvironmental &xposures (hih doses of radiation, chemicals like ben1ene, tobacco "moke) /rior &xposure To %hemotherapeutic Aents *or *or Another Another !alinancy !alinancy
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
!eakaryoid %ommitted %ells
!eakaryoblast
!yeloid %ommitted %ells
!onoblasts
!yeloblasts
;ymphoid %ommitted %ells
;ymphoblasts
/roliferation of immature lymphocytes /roliferation of immature phaocytes
/roliferation of immature meakaryocytes
/roliferation of immature monocytes
/roliferation of immature myelocytes
Bleedin Tendencies
Lecreased production of
/etechiae &cchymosis Minival bleedin
'nability to protect body aainst invasion
Affectations Affectations in B% cells components
epistaxis Anemia
t. loss
pallor
+eutrophils Basophils &osinophils
!alaise
&asy fatiability fatiability
#isk for infection
Affectations of Affectations B lymphocytes Tlymphocytes
a. "+T5&"'" * T5& L'"&A"& G(N(,AL <(S+,IPTION The underlyin pathophysioloy consists of a maturational arrest of bone marrow cells in the earliest staes of developm development. ent. The mechanism of this arrest is under study, study, but in many cases, it involves the activation of abnormal enes throuh 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 dere 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 undero prorammed 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 ae. The median ae of onset is FE years. 5owever, this disease affects all ae 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 $nknown own etio etioloy loy tha thatt occu occurs rs most often in older patients and manifests as proressive cytopenias that occur over months
to years. ther that predispose patients to A!; include aplastic anemia, myelofibrosis, paroxysmal nocturnal hemolobinuria, and polycythemia vera. %+M&+'TA; L'"#L&#" - "ome conenital disorders that predispose patients to A!; include Bloom syndrome, Lown syndrome syndrome,, conen conenital ital neutrop neutropenia, enia, *anconi anemia, and neurofibromatosis. !ore subtle enetic disorders, includin polymorphisms of en1ymes that metaboli1e carcinoens, also predispose patients to A!;. &+N'#+!&+TA &+N'#+!& +TA; ; &U/"$#&" -"everal studies demonstra demonstrate te a relations relationship hip betwee between n radiation exposure and leukemia. &arly radiolo radioloists 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 sinificantt (odds sinifican ( odds ratio, 2.E) increased risk of developin A!;. A!;. 'n several studies, the risk of A!; was slihtly 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 morpholoy. /#' /# '# #
&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 malinan malinancy 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 aents. /atients with a prior exposure to alkylatin aents, 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 aen 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> Netro)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 fatiue ue.. /ati /atient ents s ofte often n retr retrospe ospectiv ctively ely not note e a decreased enery level over past weeks. ther symptoms of anemia include dyspnea upon exertion, di11iness, and, in patients with coronary artery disease, aninal 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 findins 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-fihtin 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 hihest 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 Bleein- ( Bleein- ( noseble nosebleeds, eds, inival 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, hemorrhaic rashes that are not palpable. Areas of dermal bleedin or bruises (ie, ecchymoses) that are lare or present in several areas may indicate a coexistent coaulation disorder such as L'%. /urpura /urpura is cha charact racteri1e eri1ed d by flat brui bruises ses that are larer tha than n pet petechi echiae ae but smaller than ecchymoses. /otentially life-threatenin life-threatenin sites of bleedin include the luns, 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 hepatosplenomealy and, to a lesser deree, lymphadenopathy /atients with splenomealy 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 hih 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 emerency that re0uires immediate intervention.
B. PATHOPHYSIOLOGY PATHOPHYSIOLOGY $+LI(NT1+(NT(,(<* /recipitatin *actors: /redisposin *actors:
&nvironmental &xposures - %iarette "moke - &xposure to certain chemicals (carbonated drinks even before
Mender (!ale) Ae (7 years years old)
reachin of aeP foul-smellin envt 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
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
Minival bleedinZ
'nability to protect body aainst invasion
+eutrophils
&pistaxis (upon admission) Y
Y
5ematomaZ -/eriorbital -in the sole of left foot
AnemiaZ
10-/7/8/14-19-08
Lyspnea (
'+*&%T'+ "ins of infection n off *ever (23-7P24P27P2OP 2@P2GP4E- 3@)
##,
Y
ran '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 pathophysioloy consists of a maturational arrest of bone marrow cells cell s in the earliest earliest sta staes 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 dere 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 undero prorammed 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 ae. The median ae of onset is FE years. 5owever, AG( this disease affects all ae 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 slihtly increased in people who smoked compared with those who did not smoke.
%. "'M+" A+L "!/T!" 'T5 'T5 #AT'+A;& #AT'+A;& 2. Anemia> Netro)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 fatiue.
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 infectionfihtin capacity. ?. A#normal Bleein- ( nosebleeds, eds, inival bleedin, purpura, ecchymosis, petechiae Bleein- ( 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 hepatosplenomealy and, to a lesser deree, lymphadenopathy. F. Bone Pain Pain - /atients with a hih 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 emerency that re0uires immediate intervention.