Robbins Essential Pathology PDF Hematopoietic and Lymphoid Systems

CHAPTER 9 Hematopoietic and Lymphoid Systems 142.e1 Supplemental eFig. 9.1 Hemolysis in G6PD deficiency. Peripheral blood smear. As the splenic ma...

CHAPTER 9 Hematopoietic and Lymphoid Systems 142.e1 Supplemental eFig. 9.1 Hemolysis in G6PD deficiency. Peripheral blood smear. As the splenic macrophages pluck out these inclusions, “bite cells” like the one in this smear are produced. Inset, Red cells with precipitates of denatured globin (Heinz bodies) revealed by supra- vital staining. (Courtesy Dr. Robert W. McKenna, Department of Pathol- ogy, University of Texas Southwestern Medical School, Dallas.)  CHAPTER 9 Hematopoietic and Lymphoid Systems 143 Ine c  on o re d ce s w   P. facpar um nduces sur ace k nobs con anng p aras e- enco de d proe ns  a b nd o ad es  on moe c u es on ac  vae d end o eum,  r app ng  ne c e d re d ce s n p osc ap   ar y venu es. In s ome p a  ens, man y c   d re n ,   s pro- cess nvoves cerebr a  vess es , w   c b e c ome e ngorge d and o c cud e d by  e en rapp e d re d ce s. Clncal Features. Cnca eaures commony seen n acparum maara ncude emoyc anema, spenomegay, and epsodc sakng, cs, and ever, wc occur durng e reease o organsms rom ysed red ces. Inraeryrocyc ropozoes seen n perpera bood smears are dag- nosc. Cerebra maara, seen n P. facparum necon, may ead o coma and dea and s a eadng ker o cdren n some pars o Arca. Underproduction Anemias Lke emoyc anemas, anemas semmng rom decreased red ce Fig. 9.5 Microangiopathic hemolytic anemia: peripheral blood smear. producon ave dverse eooges, ncudng nered and acqured This specimen from a patient with hemolytic uremic syndrome contains causes, and are commony seen. hey range n severy rom aboraor y several fragmented red cells. (Courtesy of Dr. Robert W. McKenna, abnormaes o mnor cnca sgncance o le-reaenng dsor- Department of Pathology, University of Texas Southwestern Medical ders a requre rapd dagnoss and reamen. We wll sar our ds- School, Dallas.) cusson w underproducon anemas relaed o nlammaon, and en move o nuronal decences, e mos mporan o wc are decences o ron, olae, and vamn B (cobalamn). 12 Anemia of Chronic Inflammation Sporozoite Anemia associated with chronic inammation is the most common form of anemia in hospitalized patients. Mosquito hs ype o anema occurs n a varey o dsorders assocaed w Circumsporozoite stages Thrombospondin protein susaned nlammaon, ncudng: receptor    Cronc bactera nfectons, suc as oseomyes, bacera endo- cards, dssemnaed ubercuoss, and ung abscess    Cronc mmune dsorders, suc as poory conroed reumaod arrs and nlammaor y bowe dsease Hepatocytes    Cancer, parcuary wen dssemnaed Gametocytes Pathogeness. he anema o cronc nlammaon s caused n arge par by ncreases n crcuang eves o epcdn, a crca reguaor o ron meabosm. Hepcdn s a sma proen made by epaocyes. I nbs Sialic acid e acvy o erroporn, an ron ransporer a s expressed on duode- binding protein na epea ces and on macropages. Hepcdn producon by e ver s normay nversey reaed o ron eves. In ron decency (dscussed Glycophorin laer), epcdn levels all, erroporn acvy rses, and ron upake rom e gu and ron moblzaon rom macropage sores ncreases (Fg. 9.7). RBC However, epcdn expresson s also ncreased by nlammaory medaors “Ring” suc as nereukn-6 (IL-6), ndependen o e ron saus o e paen. Merozoites trophozoites hus, nlammaon decreases ron upake and aso prevens reease o ron rom macropages, “sarvng” deveopng red bood ces o ron. Cronc Endothelial cells nlammaon aso buns eryropoen syness by e kdney roug dferen mecansms, urer lowerng marrow red cell oupu. Knobs Clncal Features. As n anema o ron decency, serum ron levels usually are low and red cells may be slgly ypocromc and mcro- Schizont Platelets cyc. Unlke ron decency anema, owever, sorage ron n e marrow s ncreased, e serum errn concenraon s elevaed, and e oal ron-bndng capacy s normal or reduced Admnsraon |CAM-1 CD36 o er yropoen and ron can mprove e anema, bu only efecve Fig. 9.6 Life cycle of Plasmodium falciparum. Entry of sporozoites into reamen o e underlyng condon s curave. hepatocyes is mediated through binding to the thrombospondin recep- tor, whereas merozoites recognize and gain entry into red cells by bind- Iron Deficiency Anemia ing glycophorin. Arrest of infected red cells in capillaries is mediated Deciency of iron is the most common nutritional deciency in the by interactions with CD36 and ICAM-1 expressed on endothelial cells. ICAM-1, intercellular adhesion molecule-1; RBC, red blood cell. (Drawn world. by Dr. Jeffrey Joseph, Department of Pathology, Beth Israel Deaconess Abou 10% o people lvng n ger ncome counres and 25% o Hospital, Boston.) 50% o ose n lower ncome counres are anemc, and n bo sengs 144 CHAPTER 9 Hematopoietic and Lymphoid Systems NORMAL FOOD IRON Heme Nonheme iron iron 2+ Fe 3+ Fe Heme transpor ter Duodenal DMT1 LOW PLASMA IRON cytochrome B HIGH PLASMA IRON OR INEFFECTIVE ERYTHROPOIESIS Iron loss by SYSTEMIC INFLAMMATION HEMOCHROMATOSIS shedding of FOOD IRON epithelial cells FOOD IRON Heme Heme 2+ Nonheme iron Fe Nonheme iron iron iron 2+ 2+ Fe Fe 3+ 3+ Fe Fe Ferropor tin Hephaestin 2+ Fe 3+ Fe Decreased Increased Plasma loss by loss by hepcidin shedding shedding Por tal blood Plasma 2+ 2+ Fe Fe transferrin Increased Mucosal absor ption Er ythroid ferritin Liver marrow Destruction of ferropor tin 2+ Fe 3+ Fe Low plasma High plasma hepcidin hepcidin Por tal blood Plasma transferrin Er ythroid Liver marrow Liver Fig. 9.7 Regulation of iron absorption. Duodenal epithelial cell uptake of heme and nonheme iron discussed in the text is depicted. When the storage sites of the body are replete with iron and erythropoietic activity is normal, plasma hepcidin balances iron uptake and loss to maintain iron hemostasis by downregulating ferroportin and limiting iron uptake (middle panel). Hepcidin rise in the setting of systemic inflammation or when iron levels are high, decreasing iron uptake and increasing iron loss by shedding of duodenocytes (right panel), and fall in the setting of low plasma iron or primary hemochromatosis, resulting in increased iron uptake. DMT1, divalent metal transporter-1. e mos requen cause s ron decenc y, oug e eolog y dfers Morphology. Perperal smears reveal small (mcrocyc) red cells he norma Wesern de s rc n eme  rom mea and pour y and w ncreased cenral pallor (Fg. 9.8). Oblong, cylndrcal red conans suicen ron o baance day osses, wc oa abou 2 cells (penc ces) are commonly seen and are caracersc o ron mg/day. hus, n e Wes, ron decenc y s mosly due o excessve decency. bleedng (e.g., menorraga, occul gasronesnal malgnanc y) or ncreased pysologc requremens (e.g., pregnanc y). In conras, n oer pars o e world e dear y supply o ron s margnal a bes Clncal Features. Iron decency anema s usually mld and asymp- and dear y ron decenc y s more common and more severe. omac; weakness, lslessness, and pallor are presen n severe cases. W long-sandng ron decency anema, paens may demonsrae Pathogeness. Iron s requred or emoglobn syness; ron decency pca, a drve o consume non–oodsufs suc as dr or clay. Laboraor y mpars red cell mauraon and dmnses red cell producon. Accord- sudes reveal mcrocyc anema, low serum errn and low serum ngly, ron decency produces a mcrocyc ypocromc anema. ron levels, and elevaed ranserrn levels. Wen e cause o ron  CHAPTER 9 Hematopoietic and Lymphoid Systems 145 Fig. 9.8 Iron deficiency anemia: peripheral blood smear. Note the increased central pallor of most of the red cells. Scattered, fully hemo- globinized cells, from a recent blood transfusion, stand out in contrast. Fig. 9.9 Megaloblastic anemia. A peripheral blood smear shows (Courtesy of Dr. Robert W. McKenna, Department of Pathology, Univer- a hypersegmented neutrophil with a six-lobed nucleus. (Courtesy of sity of Texas Southwestern Medical School, Dallas.) Dr. Robert W. McKenna, Department of Pathology, University of Texas Southwestern Medical School, Dallas.) decency s no obvous, a oroug clncal evaluaon s warraned o exclude an occul gasronesnal malgnancy or oer sources o precursors also demonsrae nuclear-cyoplasmc asyncrony, bleedng. yeldng gan meamyelocyes and megakaryocyes w large, bzarre mullobed nucle. Caracerscally, e perperal blood conans hypersegmented Folate and Vitamin B Deficiency Anemias (Megaloblastic 12 neutrophs (Fig. 9.9). Normal neuropls ave ree or our nuclear Anemias) lobes, bu n megaloblasc anemas ey oten ave ve or more. Red Deciencies of folate and vitamin B result in anemias caused 12 cells may appear as large, egg-saped macroovaocytes, and e MCV s by metabolic defects in the biosynthesis of thymidine, one of the markedly elevaed (macrocytoss). Megaloblasc morpologc canges essential building blocks of DNA. are also seen n oer rapdly growng cells, parcularly cells o e he ne efecs o e olae and vamn B decences on emaopoe- 12 gasronesnal epelum. ss are dencal, bu er causes and consequences dfer n mporan ways. We wll rs revew commonales and en ouc on dsncve eaures. We now urn o specc eaures o olae and B decences. 12 Pathogeness. he uncons o oae and vamn B w respec o Fol ate D e f  c  e nc y Ane m a. Fol ae s pres en n ne arly all o o ds 12 ymdne syness are nerwned. Foae exss n severa orms a bu s des roye d by 10 o 15 m  nues o c o ok  ng; as a re su l, ol ae ac as donors or accepors o one-carbon uns. For oae o parc- sores are marg na l n many e a l y p e rs ons. Te r sk o d e c  enc y pae n e syness o deoxyymdne monopospae (dTMP), an s g es n  os e w   a p o or d  e ( e p o or,  nd  gen, and el d erly) essena budng bock or DNA,  needs o be convered rom dy- or w   ncre as e d me ab olc ne e ds (pre g nan women and  os e w   drooae o eraydrooae. I nraceuar sores o eraydrooae cronc emoly c anem a). D e  c e nc y a ls o may resu l  rom d ee c  s a due o oae decency, nsuicen dTMP s syneszed and DNA n ol ae abs or p on or me ab olsm. Fo o d ol ae s are pre d om  nan ly repcaon s bocked. Vamn B s requred or e recycng o oae n p olyg lu amae or m and mus be spl  no monog lu amaes or 12 o eraydrooae; us s decency also leads o nadequae syne- abs or p on, a pro cess  a s  n be d by ac d c o o ds and subs anc es ss o dTMP. ound n b e ans and o er le g ume s. S ome d r ugs a ls o ner e re w   hymdne decency afecs all rapdly dvdng cells, bu e ol ae abs or p on, and o ers , su c as me o re x ae, n  b ol ae emaopoec marrow s mos severely afeced. he syness o RNA me ab olsm. Ma l ab s or p ve d s ord ers , suc as cel ac ds e as e,  a and cyopasmc eemens proceeds normay and oupaces a o e a e c   e upp er  rd o  e s ma l l  nes  ne w ere ol ae s ab s orb e d, nuceus (nucear-cytopasmc asyncrony). he deec n DNA syness a ls o may mp ar ol ae up a ke. conrbues o anema n wo ways: (1) ncompee repcaon o DNA acvaes ce cyce ceckpons and nduces apoposs o marrow pro- Clncal Features. he ons e o e anema o oae decenc y s genors (neectve hematopoess) and (2) ces a maure do so ater nsdous, b eng ass o caed w nonsp ecc sympoms suc as weak- ewer ce dvsons, dmnsng marrow oupu. Red ce precursors ness and easy agably. he cnca pcure may be compcaed by are mos severey afeced, bu granulocyes and plaele precursors also e co exsence o oer vamn decences, esp ecally n alcool- sow efecs. cs. Sympoms reerable o e almenar y rac , suc as s ore ongue, als o are common. he dagnoss s bas ed on e recognon o e pres ence o megaobasc anema and e measuremen o s er um or red ce oae e ves. he anema resp onds rapdy (n 3 o 5 days) o Morphology. In all orms o megaloblasc anema, e marrow reamen w oae. s ypercellular and conans numerous megaloblasc eryrod progenors. Megaloblass are larger an normal eryrod progenors Vtamn B (Cobalamn) Deicency Anema. Vamn B s (normoblass) and ave delcae, ne nuclear croman. As 12 12 wdey presen n oods, s ressan o cookng and bong, and s even megaloblass dferenae and acqure emoglobn, e nucleus reans syneszed by gu lora. hus, unke oae, vamn B decency s s nely dsrbued croman and als o undergo e croman 12 no caused by nadequae nake excep n vegearans wo scrupulously clumpng ypcal o normoblass. Granulocye and megakaryocye avod mlk and eggs. Insead, decences ypcally arse rom an 146 CHAPTER 9 Hematopoietic and Lymphoid Systems abnormay o vamn B absorpon. Normay, vamn B mus bnd (dscussed aer), conssen w e dea a e marrow progenors 12 12 o e ntrnsc factor secreed by gasrc parea ces or absorpon; ave genomc damage. Hemaopoec sem ce ranspanaon oten e B –nrnsc acor compex en bnds o a recepor or nrnsc s curave, parcuary n younger paens. 12 acor n e dsa eum and eners ea epea ces. Vamn B s 12 Anemia due to Marrow Infiltration sored n e ver and epac reserves are usuay suicen o suppor body needs or 5 o 20 years. Because o ese arge ver sores, cnca Anemia due to marrow inltration is caused by replacement of the manesaons usuay oow years o unrecognzed maabsorpon. marrow by tumors or other lesions. Anema due o marrow nlraon s mos commonly assocaed Pathogenes s. he mos requen cause o vamn B decency s 12 w measac breas, lung, or prosae cancer, bu can also be seen n perncous anema, due o an auommune aack on e gasrc mucosa advanced uberculoss and lpd sorage dsorders. Mssapen red cells, assocaed w e loss o pareal cells and nrnsc acor producon. some resemblng eardrops, are seen n e perperal blood. Immaure he serum o mos afeced paens conans several ypes o auoan- granulocyc and er yrocyc precursors also may be presen (euko- bodes agans nrnsc acor, bu  s oug a an auoreacve T-cell erytrobastoss), along w mld leukocyoss. he prncpa manes- response naes gasrc mucosal njury and rggers e ormaon o aons ncude anema and rombocyopena; e we ce seres s auoanbodes. Oer causes o vamn B malabsorpon nclude gas- 12 ess afeced. Treamen s dreced a e underlyng condon. recomy, leal resecon, and dsorders a dsrup e uncon o e dsal leum (suc as Cron dsease). In addon, gasrc aropy and aclorydra may nerere w e producon o acd and pepsn, WHITE BLOOD CELL DISORDERS wc elp release vamn B rom s bound orm n ood. 12 Dsorders o we cells nclude decences (leukopenas) and prol- eraons, wc may be reacve or neoplasc. Reacve proleraon Clncal Features. he emaopoec manesaons o vamn B 12 n response o a prmar y, oten necous, dsease s common. Neo- decency are dencal o ose seen w olae decency. Unque o pasc dsorders, aoug ess common, are more omnous. ey vamn B decency are neurologc sympoms, wc may be presen 12 cause approxmaey 9% o cancer deas n adus and 40% n cdren even wen anema s absen, and nclude psycarc dsorders (suc as younger an 15 years o age. depresson) and demyelnaon o e laeral racs o e spnal cord. Sp- Presened nex are descrpons o some nonneopasc condons, nal cord dsease begns w symmerc numbness, nglng, and burn- oowed by more deaed consderaons o neopasc proeraons ng n e ee or ands, ollowed by aaxa and loss o poson sense. o we ces. he dagnoss s based on e recognon o megaobasc anema and/ or caracersc neuroogc ndngs and e measuremen o serum vamn B levels. Treamen usually consss o pareneral vamn B 12 12 NONNEOPLASTIC DISORDERS OF WHITE CELLS because e underlyng deec n absorpon (regardless o cause) s lkely o perss. Aloug e anema resolves rapdly ollowng vamn B 12 Leukopenia erapy, e neurologc manesaons oten a o respond. Leukopena usuay relecs a decrease n granuocyes, e mos numer- ous crcuang we ces. Lympopena s muc ess common;  s Aplastic Anemia assocaed w rare congena mmunodecency dseases, advanced Aplastic anemia is a disorder caused by suppression of multipotent uman mmunodecency vrus (HIV) necon, and reamen w hematopoietic stem cells, leading to bone marrow hypocellularity g doses o corcoserods. Only e more common leukopenas o and pancytopenia. granulocyes are dscussed ere. Pathogeness. e marrow n apasc anema s oten devod o recog- Pathogeness. A reducon n e number o neuropls n blood s nzabe emaopoec eemens (Suppemena eFg. 9.2). ere are wo known as neutropena or, wen severe, agranuocytoss. he meca- major eooges: an exrnsc, mmune-medaed suppresson o marrow nsms underyng neuropena can be dvded no wo broad caegores: progenors and an nrnsc abnormay o sem ces. In e ormer,     D ecreased granuocyte producton. Causes ncude marrow ypo- s oug a sem ces are angencay aered by exposure o drugs, pasa (durng cancer cemoerapy or due o apasc anema), necous agens, or oer nsus, provokng a ceuar mmune response exensve marrow repacemen by umor (e.g., eukema), and do- n wc acvaed T ces produce cyoknes a suppress and k ema- syncrac reacons o ceran drugs. opoec progenors. T-ce mmunosuppressve erapy resores ema-    Increased granuocyte destructon. Causes ncude mmune-med- opoess n 60% o 70% o paens. Aernavey, a roe or an nrnsc aed njur y and over wemng necons due o ncreased perp- sem ce abnormay s suppored by observaons sowng a 5% o era uzaon. Spenomegay aso can ead o e sequesraon and 10% o paens w apasc anema ave nered deecs n eomer- acceeraed remova o neurops. ase, wc s needed or e manenance and saby o cromosomes. e deec n eomerase may ead o premaure senescence o emao- Clncal Features. Neuropenc paens are suscepbe o severe, poec sem ces and marrow aure. ese wo mecansms are no poenay aa bacera and unga necons. he rsk o necon muuay excusve, because genecay aered sem ces (e.g., ose w rses as e neurop coun as beow 500 ces/μL. Inecon oten abnorma eomeres) aso mg express “neoangens” a coud serve begns a a supercal se (e.g., oropar ynx) wou sgns and symp- as arges or a T-ce aack. oms because o e nadequae nnae mmune response. Because o e danger o sepss, neuropenc paens are reaed w broad-spec- Clncal Features. Apasc anema afecs persons o all ages and bo rum anbocs a e rs sgn o necon. sexes. he sowy progressve anema causes e nsdous deveopmen Reactive Leukocytosis o weakness, paor, and dyspnea. hrombocyopena oten man- ess w peecae and eccymoses, and neuropena may resu n he ndng o ncreased numbers o we cells n e blood s com- serous necons. e prognoss s unpredcabe. Wdrawa o an mon n a varey o nlammaor y saes. Leukocyoses are reavey ncng drug ony rarey eads o remsson. Immunosuppresson can nonspecc and are classed accordng o e we cell seres a s resore emaopoess, bu many paens deveop a myeod neopasm afeced (Table 9.5). In some cases, reacve leukocyoss may be severe  CHAPTER 9 Hematopoietic and Lymphoid Systems 146.e1 A B Supplemental eFig. 9.2 Aplastic anemia (bone marrow biopsy). Markedly hypocellular marrow contains mainly fat cells. (A) Low power. (B) High power. (Courtesy Dr. Steven Kroft, Department of Pathology, Univer- sity of Texas Southwestern Medical School, Dallas.)