Hematologic Manifestations of Liver Disease Peter W. Marks ‘The Teer plas a hey cole i both protein biogas an Ipal mctbolion, Asa mt hepatic grahec Assfunaion can have advene effec om bosh adler and siuble componeens of Mowad, Ane ny ousur duc 1 the hemolysis of auanulieyies (ur eel), whidh fy uldinately dur oy abwormal lipid Comnpusiies of the rad Mad coll menhewe, Thioenbagtopenia say eeuik Gen sever lier mechunisens. Cytopenias abo may be a enrsequence of hypesplenivn. The Tver isthe primary sie foe da proses, The caagulipuily of iver diese i herelore sytubesis none procul ad ania ceenplee. Fiely is the coune of ver diseawe dhrombocytopania and = coaplopathy asocieed wih prohreenbioic sete are nine anaimnenn, where wily tore seks diver paneyigsenis se coupnlopatiy asodaed with hemorhre bewome snanilet. Fra [nen lina axl adhanas 1 Temas nay be wel ws tempor measures in bleedin: panna. Flmeren, definitive manages of rman ol dhe defen dae cw fulminsen hepatic Gilure requires ver tnewpdvetion, Sernin ems he Boer ic a key se lie poms hingrthesis and Fpl metabors Knesset of the sre of the phsiclae seule fanctons pesfornea lyr the Then well is anutnnic rlaanshipy ao dhe splee, Gales appreciaien «the nealyy hemeaeleyge aire males that ocaur in socision witliver dea (Figure 0 ‘Wihthe nouble exceptions of fiaoes VIM ad X01, all iswor M1, V, VT, ND) ed the simiaural pron Ulsinoyge (laesor Dare syruhesise primarily in hepstceyes aiviaogpulaie proeins such as proc Cy prneia Sy atl of de other sumnbered dot Ts ation, several ssuidumnedsin are don rade dee. The subs proce i the Tver invokes nine inky de eneation af palbpepie ‘Guns sud yrveosplaion but also other appropriate pose tansions! woicaions. Faaors 1, VT TX, and X proein Canad prone S all napute sunmnarcarhoesfason itomin Kolepenclene pes i ie sett Fibseyge is a plyeopmmtein dha: normally contin she seid resis. aur sic ack adel by innsuure hepaoges proce i Tie disease amy be snwceisted wiih sbsionra prowin Fhnexion (lyldinenerema “The lise & al 2 ste bir the srathess of 3 nuenber of ‘oer proses important co de hematopeeie sytetn, Ty Mt, Adminitasion. H101 Rockville Tike, : *, (0037-1 96805 - sce Fowt mae! Pasha hy Blow HAVE. Roce MD a6 ‘150-216-221. Pabslshed by Flevier Tn 10%. ie primary sie for die syuhiess of ihroenbopoiginy, 2 crag f paicle meee? Caneel of siklees co Ting proxhiction of erhmopoietin abou the tymotl Eaton it lata ease fret trough bap He ayrubanis a opie fn Fespcthe to infection, ilammation, oF raplete ir stores irealy aes the eryihrqpoietic reponse.’ The Bver aly happens wo be die primary ste Gorinon worse, canning, an anon anon the bey sere othe erin (yererlly abet 1 yin ev ad.” Finally, becease the liver has a cenrd synch atl ia Tipid meubolismy the Ther b responsible for the ropuiiie tendane coenpenddons ol Hiptck and cholesterol needed lor xin red blood cell delormabiiy The aromy of dhe ver hs a elect on the beanie ppoiecagster as wl Mach othe Move llowinys co the Theat ees the abun passes ro he pret eters, incluling that form the spletic vein AL any yven cere an 1 quiner 10 shind of Keuhocytes and plates, as wall sari proportion oF enrages ane enenally Seiesierel uring their passe chrouyth ie spleen.® Ponal hypertension due 10 Fver diese can substarially incense the laaion of cals prevent iv the spleet stl herd may be weociated with gtcpenia iv any or all of the ol ney (CELLULAR ABNORMALITIES. Anemia, thrombocytopenia, ard Teukoperis are asso Gated with Tiver dhease iwel but may abo rel Tr agp jncluaiegs antivied appr or Bor we of alesbe Asks anernés unasnckned wh any olde keowey sa cuss may lellow the presentation of hepatitis. Aluhoui this hepuitis ssoxiatedd wich sulsexpicm severe plastic Seminars in Hematology, Vol $0, No 3, July 2013, pp 216-221Hematologic manitesations of er discos 27 Liver Hepeidin Hematopoietic growth factors ropa 108) Coagulation factors Figure 1. Schematic diagram ilustrating select tuncions ‘ofthe iver relavant to me hematologic mantestations ot liver diease. Eoth the anatomic Deation and the physio logic tuncton of the iver nave major stects on the hematopoietic system. mmonty occurs in young males and is geneally of mild ro moderate severity, fulminane heparie ilu requiring liver eansplanerion sometimes occu.” Addionally, immune-mediated thromhosyropania, may ‘occir in liver disease in asosiation vith vital inficrion sch as with epatrs C."" Tocnsing. on the eyrapenine amihured to lvoe diene incelt the incidence of these abnormalities reported in the lirsrnare varies widely fom ahour 59% a 759%, leh reflecting varchlity in the patient populations observed In one eohore af 213 patints with compensated cirrhosis and portal hypertension without scophageal varices fle lowed over rime hy the Poral Ihperension Collaborating Group, isola thmmbacyropeniz was mas caramen and vas present in 46% of individuals ar baseline, with an additional 32% having thromboermpenia in enmhination swith anemia, etkopania, oF hom abnormal.” Over the nurse of a madian followup of approxima ont, addirinnal eyrapanias derelopd in many individ tals By the ead of the study 92% af those enrolled had ‘hromhogympenia. In the major of the individuals this ras zezompanied hy cither a bigrmpenia ot pancytopenia, the presence of thrombocytopenia and loukopenia. at baseline was aso find ro correlere with morality. Anemia "The etiology of ansina in liner disease cane onal ‘Bcmndal# Ancmia may simply rose fom acurs or chronic blood loss die m varices! or onher gasmoinrstinal Hes. Akcnatiely. as liver diease pregyssses, abnormalities in lipopronsin metabolism may lad to cholestrol loading, of thy Inially, this is acoinad with the laboratory Findings ofan inereacd mean corpusailr vokunne and rrpst all forma rion.” Howaret with the pmgresion oliver dea, inter choleasrol loading is asocated with reduced daformabling of the ed Hood all membrane dis m stare hindrance of raé blond ll membrane, inerasing its sanfice ae, the mization ofnneyal membrane peering This leads to the davlopment of aythmarrss that appear spiculated on psipheal lond smeit (spar ails, acanthosis) As Somplisrion of adeancal dicho ic the development of Spur cal amin. Onkya Faron of individu with xe liar disease devlop this complision, and the Ben asocned with i deloyenent in given inviual kaye sorhsun fly alsidarad. Wham ir dese oar. hs hamolss con he quite soars and itis csentaly unreponsie m onverrinnal thesis adminired for hemabtis disass Hovanse, rer ransplanmton is aunt” Anevical thotpy adminisared for hapatiis © can be ascocived with grmponis in any of the lineages. bur nema may bs oer prominant. Lah of the apenre sad in corsin approved eomination rjmens exn eons to anamias peplaned iorerfsonalpha may cause mylon Suppraston, nhavnn can he asociatad wth the deslop= rnant of a rlativly seve hamolyme anciia, and the protease inhiirorsrlapravir and hosaprivie indicated for hepars C vinus genorype 1) alo sppeat co be associ swith anemia.” Nafuarion in dose. parvcularl of havin andlor use of aythropaiatin oF other emthropoisie ‘slimlting apanes ara the mainstay af management.” Thrombocytopenia As norsd. stows, thiomshosympenia is remarkably common in hepatie cinta, The Fv isthe primary ie forthe syahess of thrombopoiatin. which iss hematorie ne ghowth Rene with parcular nfcnes ove pls bumsher. The plasler binding of chiomhopoisrin is involved in the raglaron of platelet mass” In the ease fof lier dias, dacrexed thrombopotati levels ae porsneally responsible fora compenant of fe thromfno= [Sropsnia thar is commorly absense, although these ae soll some apace of the rglrion of planer numb har remain unclear or comromasal* Splenic sequasrarion of parla dus m hypsrplensoy nay raul in Ruther reduction of the platter number or thar caused by other machanisms. To try 9 raduce she sed fr plalarransfision and to daease complains opens plralr eoune 30,000 pl). shrmbopeisin analogass have hain examined for tsi abil oneness the plea ome prior ro inves procadar randomized coneolled trl ase of he agonstelromno= pag, vas asiociaed sith a signifsane plawler spon tnd reduerion in the sed for plarder mansfusion”” Tower. is tie was aso ascoied with postal sin thrombosis, and it ae nor damonimated ro radace Blesding, Somplicaions in comparison with planter in individuals with cerhosis and mote so218 PW. Marks Table 1. Changes in Liver Disease Predisposing Toward Hemorthage and Thrombosis Predisposing to Hemorrhage Predisposing to Thrombosis Thiombocytopenia Reduced levels of factors I, V, MII, IX, X, XI Dysfibrinogenemia Reduced alpha-2-antiplasmin Increased fector VII and von Willebrand factor Reduced protein Cand protein § Reducad entithrambin Decreased plasminogen tearolision. Ta Tver disease, moderate dhronboeysopeia (elaider grant 30,000-100,0000411) is areal well lolersed However, ity be wc) with mone severe Deen Gun snight otherwise be expectad when cone conriuant dysirinogeiemis ce eaher angpiluin abuwr nul ae preset, Fhevers dis fy highly aepenalene est the mature of the accompaniny deo or dein Leukopenia Tecthoyenis i ppncnlly late develgrment in airs wih ciehosi Tex mone commonly obenved ir conjurtc= See with aher cropeniin Geis, dvrabeeytopent, oe portal 2b punial spleecerny nud complete splenectomy fuse been pistons) and nay be altributable «ose hypenerion lealive co npenslenisns Tho explored ap therapeutic iuerentieny dey are asocte wih SGoaly high soda and ray only be ol feomnient bene?! Cretligae celonnestimabaing tor (G-CSF) seid yranuloesiesmacrogtiye colony, facie (GAECSF) cant be used eleva wo bicrese che Igratth,C. Howarer, i iv unnlesethat their wwe pices say red benef in weme of stained veloc repame wher compated io dose rection strates = Thergoy wih ayers use for the reaert of hepatitis Cray cause leukopenia, Those wiih mild wo reer neuropenia do nn upper w experience an exenve snumber of infeaious aomppbetions.” Tr adliony anti= eal eTiacy olin preevel wth dove redtion Sirseies to state this connphatioes Leukopena, sor with olher cstopenias, yenerlly resolves lowing Tver iransplination. Foweser, iv she postininyplin seine ao) shoud ger fave foe pocential drvgyrelced or info ius caine COAGULATION ABNORMALITIES Since the liver i the primary sie sjruhesis of mest of the asagulation Facices i follows lagtally da liver dese shuld be somiated with disrden of uypdationy and that as Tier diwine prygresey the cnapaion amoral iain shawl geeoray Lestnne nies pros. lena, because of the fleet of hepatic iepulement beat on. proteins wily procmaqzuint ancl andeonalant atv, ye or thromiunis may be olnervel Table 1). Thrombosis weds w be aseeiated wih les ciiher Desnreh sshasnoud hejuic fire Ta dhs cave, che sib Tndance owaed the davdopiment of hyperuaguldle crmplcatons resis tn combination of Fciors inching reese level of vor Willebrand factor atkl factor VIM (synthe. ddntefuen and wher sized ie pan outstle de Hiver ith cel), dewesel Evel of proicin Cy praca Sand geullhoombiny ieresval levels of che ph Stor, and decreased level plasninys onal sin dinimisoss fee ellcinreniel comple ort ol fser diese. Th addiion, sinus Highly dependent upon the pepulaton of patients wih Tver dea salad (ioerdirharic P Get) dhe ish of venous dander ben cornpanel ca earl bnpalzed population beads fowl? Ths indacls fo seep pumoray ebolion, Lae in the Gune of Giese is fidmsinar heyaic Gilure dewdops, the tendency towanl ecg, des inlead prediniuae in this ppation in chev ard Diagnostic Testing Flevations it dhe prothrombin ime (PT Viwernaiond ponmalized rao (INR) and parts] dheombeplasin, vine (PTT) are rest cnanaterel fs Tver dea. Home exer ic his become incresing’y apparent dat dno Fig fn sack sanded cecaglation tous, quaniculady the PTIINR, dso cerca well wit the rk of eng The Gsconlarce between the PTR value std the risk ol bleeding muy be puniculrly rue whe iis only lly sneaky exvated (NR appeosinatly in dhe sang of T5-25). Asumptions ane surname Ly prac anon that rulvihaols with slevaued TNT ales ae Sauuosenianaguliied” However, such sssunplions ae ot juvilied wldy on the bass of the PT/INK, since reaucsion ine Tevel of factor VTT, which has rdlaively shor hfe 48 binary ws below 25-30% of eer Gin be somiswed wih an inzuwel PTVINR, whens ofthe much lonypeived fase Tad X Tee to levels lone out 259% 1 normal are acti social witt therapeutic aruicoagulaion.”” The lia dat dle FTMNR dees st chacly celle. eng sik should rio be ll dha erpesingy nee as Gevdoped aed ther optimioed: for dhe mmasuremenn of Ie discon bance fwadiniy, Hse Deoweet the PTTNR. value and bleeding ssh i Tiver disease hus only beer faly apprectued more recently. 1. Teas beet sugested shat calibrations starndand, sivilar 4 the TSR [or antulatiory be developed for pattene,Lematoloai: mantestations of ver disease 219 with Tver disene®* The unvertsning that 3 only oo madera elevated TNT is nox itary ssseciated sith ingeaed Heading esk duriug procedures Ins Ted, ard ‘onus wo lea, uo diane in Civica praaice a various Freduatior®” First ol al fresh oem plans (FFP) 0 loeige routindy being administerad proplylaaielly wo pts with Her dnese and an elevated PTINR who Se tot hlealing © Senta ry canoe pcedines snd etural yeti catheter plement are bey, suey perioral without dhe comple coreaint of ihe TTY TNRO! Though there are no alot idenes, nd wit the event ht the PTIINR is por rlletin of bleed, INI valaey inthe range of 222.5, Dental ination slo com be subly perfvrmed in pazients with cichosis, mode ‘erue thanrboesoneniay axl TNR sidies ap 10 23." Given dhe fnbsdlance between prownagdaen sand aie ‘esgulent Guin, wosennent othe staal Heese Tnndvidush with liver dkene neque a sysienatic syproach that incorporates ealaaton of the clini seus, complete blood cal cnant bringer, PTUINR, PTT, stl potentially other more specialized coagulation: ests such, 8 dhromboeksioyrephy (TEG). Assessment indide ul dean: fctor Eves is only accsionlly Belptid, and {Tin is wally the et tins ohich a diainusion between Tissue or due to seme ober cause is ena, sich as isolated stain K delicency or prwibly dsserrintel inwrosscular ccaulaton (DIC). Fxcepx i dtinant ‘ees fibrinogen level in fer deine are senerally noma for desta. Hinveven dc dhe evans vidi ai hat is pews fs abou coon third of individ with varying, Agpee of Fepatie Glare, the abst of heaoyen uo pljmerize pmpety amiy be spilicarhy ieapsima Because the enbakice in procoayulzu and anticoarulant foras in liver diseive can be asextated with hyperibr hols the ually oF tess of elo Tyss such as de ceudobalis vs dine las bees explored.” Ualimuanatcy, {his tens non standandiend and Tacks wllicealy seo ocraliton so be of use inv prediany: Deady, Other tests with preter digmate 2cauraey or leal= ings ns it Ther disease hase been under nwesigatin Although TEG require wire bxerpretations sce i sa imeygative vet of buh procaggiann aud sauhagulane suite, fv imiy be of benelt in prekuing Heed pricy fn conan seta such ay Hoar iansplante Foon. ? Theaigh tow simen, evidence sagpets ste se “TEC durin ver rvopitnation omy be ssaciste wih screised red blood sell (ratlision require ‘Thrombotic Complications Somme amtroveny surrounds the ansgeenent of three Irae cnplcaions i Her diease. Due to the perarnedl risk of heroes, dhoeboproptykacs ray be withheld From patients with er disase in che setinys of rid Uhrombueyupenia ve uel elevaied baseline PTTNR ils. However is notad hoe, the sk of sens Urner rg actually be hiher i hese ould tude chit in he erin) population of hoxpiuival packs Tha, individu asesment stud aiideran St appmpsite prophyliiie modilsies i warartedl Civ the seluialy high incase ol hiseline dhnenbooycopends fev dhs pepulaion, awe of crayy such oy loreapeet, Which sre sowie ths aninisl risk of heptn-inelacel imanlogupenia, may be jusilied Alveiaively, pee matic anmpresscet bors can be cornered i the bleedin, hk & fel to he exconive with phemacrdae apn Fairer uldelbies now euoenmend ancenailon le beth porta van dhewmdooss and Bude-Chiae agree fn patients whey sks rit fuse an mccoy high elk of Mealy, due 0 varices or odier concomitant andl ions. Use of worl int these Stuationsy as wells foe dhe munnapinenit of deep vei dross id pulnom ruary emboli, ini be complicated by devs Inseline sales of the PTVINR ana ley Uataations in his pare fn mapomme to adjuntment of dhe dove of warfarin (One potential solution this peabean iso obkain bor TT sead X levels alone ish dhe PTITNR invicilly and correlate the PTITNT. with the factor Kes, skier a PTMINR issoxiated with Giaor TT and X leveb of abou 20%%-25%6, slihouggy the appropriae ware ewe vale, fo we are Laboratory ckperdent. Altesaiive strateyies dude the ane olan ol the lowornlecularsvnighn evans of londspurinux However, pian) acceptin fof parenteral herapies can be chidlewpeyy send thew Uherapies do swt shire the relative ease of reveriliy with wwalirin, The rule of dhe newer onal ance sah a dabippicant send elvanoaban in dhe mienyement of prsients with chrombotic complications fas noie be skqusidly invewiigtal. Thougth some of thexe buy may appear prenisiny: for use in patients with Tver diez clue to their meduanisn of acters and routes of metabo Testy dei lack of emy revenibiay in dhe everu of Healing, ‘oa Han thei gypbubiy.” Hemorrhagic Complications The mariagenen of active blealing in patents with Tver disease requires 2 thouzhlil approach Whenever posible snawnie canes of blealing, such as dat fu ophigl wascen are bev addrsvel with lool interven Gon suds as endospy and banding More lila Ihereediape may he alebescel wih prvahiet brine sor aking ince scanunt he seiable hemwodeyte parr ler, the degree of hepatic drlunsion, sed dhe location soul sever othe bles. is imporutn oo consider tlliive or pacntally serge eBeus of dhombeyior pevia, dhelibsnoypania, and coapulaion lauoe deli Gency vat sag be meen in balivubuse widh Boer liven Thonagh its clinical ebicacy i sadly rot well docu mented i the muragenent of dhe eandepathy of liver diese, dhe aliiuturaion of FFP is resunble i de220 PW Marks praien cet wheute she volume loa! Thos of 15 HO Ey, nay Le mare elective da he 24 us chat bee rely saiivbaared ie vical prac!” Sinoe FEP foal ay hase rine TNR of upto aban 130, eerste io the mortal mayge Heer shney exiutal nor teewurily eauired:Tdssirinyetei is Acamented or wrongly snpecedadbniairaion of 10= 20 unis of erynprexipiite may be eesvmadle Other aljuncis to hernoveats inckude Bier comune seates anal aniline. Use of provkeurabin annplen coments can replace sore or all of the vitarin ‘Kudeendent Gaon, depending ont he specie product wed"? Haweves, uae the cave with warn fi sil ‘cagglation, Goeth blesding is Ther disese iy alse ser the dimple esl of dai toy in he sarin Keeper factors, tad there i soe thrombotic rick ncaa with use of dee product. The dhmbotic rik potently sssociatel with ise of the activated prohurnbin coruplex ‘ener even peat. Recombinant factor Vilx (°VTla) fy bee evaluated far the marayement of bleeding in paeras wich Ever diese inchulinygthose underpins liver earnplamatinn The adiinisirabon of dose of ever: 2030 ype is lier awociaied with correaion of the PINT.” Howe fever this es snot accewirly corre wis ay bnprone™ tment in other hemantatc parameters or a reduaion: ewdnyy Tacit, dere nore tan just 3 Deoretical risk ol complicadons Aldhouath some rik in bled? patients with iver disease (vance! bleeding) or in Bee transplantations hive shown « redaction ithe esquire tmnt or red bload cell cattlasiony « review of several clinical cals Gonchuded dha there i so cletr dined Theres tr fs ane nv eis setting ad cite wae aye ssweinied with harm in «he form ol hnvmipobe cemplications Oiher hernentatic agent, inducing the anifsiaalic sypnt isansenamie ac, lees exalusted i she seins of vaiced Dlenlin and Boer iarsplantaton. The alain Frain of teinesievde ac tmay) reduce Moved lens in sored bledny, but a clear elle ont mani has rt been demonstrated.” The almiivration of trtexaric sd w individuals underpin Bver oranypkancation abs Th been shower to) rede Iobood Tow ard canine requirements wihout an exces of dirombeaie anmnphce fions'” Evidence (rant snl diniesd al sires tt eqsionsmincespmic seid cary be effective int reducing: Dlesinyg eesuling from hyperibsinclyss in the seuiy of Ter deine widhout a exces of dhombeaic annphcae iors! Dewoprenin (HAVE) hss beers repoetal ie homers the proleenged Ileeding, dive: br patients with ccichuss However in one stall eal ivesigaiyy its use the wait a GAVE uo oxher therapy was tot fut 10 ppovide Fs bevel” ier dhe relatively provenval Seer Willebrand level and dhe endese thrombocvoperie that fies accotnsany derhoais this ral i perhaps ra all that surprising CONCLUSIONS “Heemtologic abmormalites se cooranonly encountered in Tver diene. These indule dcrrbocytepenia, sate, Teukopesiss sil wenbinations deseo ay well sy castihee ppathies, Reduction ir anangyalaw procs as ppmersadaey Gaston, say meal i pabroenbraie tse despite almonnalives in staruunl cnjulation texts such 3s the TINE chat might sus otherwise. Optimal smanageene i Gaclated by the uewlersuanding, das ic sale perkins a varity of intervenes proueurey wih TNR values fn the singe of 2-25. Tr blewiay patenns with liver diese FED remains asnadentay doe che replace iment of soluble couulation Gaciors chou salient sdlumne needs 0 be alminisered for optimal elicie. REFERENCES |. Brumma:iesins K, Mann Nt. Molecular has of lone! naguerion, In: tleBay Ry Renz Ui} Ir. Sihorrin. U1 Stal odin. Temarcicay aie prnsiles nd price (4 6, Pdi. Sanders Vea, 20 51824 2. Nesthsle | Barsoley % Bagot Zot al Vase Xille rgulorion fet swith makiple plsearie anc clllar functions. Physial Re. 201138193 23. Tine Fave RC. Moleclar hase of ean Kedependen pimmacanhonpation. hed 9973 735.62 44. Marriner, MacDonald KA, Taiasek Jf. The role of Sake seid fn the dpBhrinogenemia asncad with liner disa dlrintion of ale se on the comeinas chains. Heed 198321966202, 5. Kar Dl Belgyend chemise in Uhamral 2010472438 (6. Andrars NC. Forging.» fl the golden ae ono obey lend. 2008511291920. Andras NC. Micador afimn marsolicm. NW Uingh J Med 1999134 1198-95, 8. Sicin of thmmbopeictic agave Llarker LA. Kinetic and Binet seis of ed plcmingen in pvisnm wh hepate errhosc | a Clin Mad, 19829:2 17-90. 9. Touff 8, khacs ML, Shah SA et a. leptin svocined plete smn a easaw Vied 2010887 (0, Sai R Wilkie F. Shannon MIS, GondomeSmith UC Ini rinus cuss ofchrisc immune hiombegrpeni,fmaral Ose Gn Nowh Avs 2008123112758 1. Gymir 4A. Gee ND. Gmirmann i) et a Ineines, ppovalencs, aml elie! sigsifeance of shoormal heman= legis indice in snmpancaral cinhass, Ch Castes] spare. 20087689-95, 2. GommaleicCaxs Rone TA, Morente R. Spear of novia sondisd with chronic Iror dens World J Carrnentrl. 2008 3463558 2. Morse EL. Mechanism af harms in lr sens. Ann (in Labi, 1990,206169.74, 44. Chtale #8, Seting RK, Post AD. oral, Reston of spar IV ania with lier eansplantren! 4 ease report abd sw ofthe rere. Trarsplian. 199 (5:993 lspanee then apdars Cr pin 5 Ger iC he Wr Castner, 20122818 Sallewsk MS, Poordad F, Manes MP, ox Anam dann rarmere wih perineicon alb-2bibavirin areHematologic martesavons of ter dase 221 hegre Anais form the pine? i Hpardegr. 35. Wing, SU. Shih J Ching, KY, oe a. Thrombo OLS 797 champanrgeided mantis decease rape 17, Tele PY Gurney AL Stich Fab Repaion of Blood anisen dng orhoroic fn tans stromhopinn late by emplanainal Bid fo pon candowined sie wid. Tranplne Pye” 20102 te Blood. 9687213501 von 18, Mario TG 3k Sombsy RA, My, YCieraThvumbapisn 36, Sanmlo’ M. Soe MY Laman Shall we ive lack poon wth hn bead ar ooh er thembopraphlns so pacans with lr cha std renpiavanon. Ant en Mt e97H ZT pepe IPR (One). 2081 45968, 19, Aided NIE, Gismini EG, Tapp G. eal Elomsbopsg, 37, TIuard i, ladeae I. Manajemene of anicapalaton befre pmeedre in pater wk circ: and shombo foe portal vin somos inva with cin enn 3 geoperiaN [gl | Ned 201286771628 sgetmaris aw Ine} Hapatl. 2012 Fp 2012 an 29, Pun & Gus Kear NM. Ceagulepthy in Ive ot oss Ade Med Se. 2010553162 28. Mavchls OMS, Has Tp. An pan 21, Sots, Nose ll, Paetumapalt otal Teamene ‘he dngun and management of Bodin one rida oe rpenpli i Ter earplane nines pce hee oman Heed, 01731 ‘ie rere hepa C World | Gusacnel 2008: 39, Gea D Lihhy Ey Crovths MAL ‘The ney era ante 503 oop Hen. 201041151520 22, Tandon P, Donzat K,fshowder K, etal Gramalgyte gp, Smears] Brun 8} Up CJ, oa ef ron colonrstnslang Bet Br hearse € shop acon Sree uae ee A es tenes aanrepcnns gcmic wer and come crfein Sel emda iB J Taal 2008 16139-5, a, LR DRE 201 ISAS 41, Vout WL Siar F, Datathy Saal Role of sh Shahan Vs Nein A, Warss Saute neta fy fear pla ifaien in corecion of conioarly gargs eth comic eas Ca hoieneneion rowel dss: adal phase smd. Arm] acre Baus 2886-100 senses 24, Papo 8. Monmuss ML the coagleptiy of choose 49. apna 8, Prthmin comple cansonns fi cre ror dn N Fl | Med 2011-365:14736 stein Ann Pharmacare. 201859905. 25. Wipe A Ansee QM Sopserd KK. a al Mypssoartl= 43, Kl JC, Mando Il, cana, CS, Mera J Cla ahi im ibe cases and ennsecres, | Three bcc of rcneninan aoe Vl in parm wit er 2, po 9 Cala SI oan Meta Rave as fers wedi ies peers An Pharos Fae ie is dase Alma Pharmeal Teer gare, York V. ashy CN. Logan AC, ota. Sptematis revi mes Bens and harms ofiehoopal we oF eewnbnamfer 2, Bil Goo Kk P Nolin aoa ifr ofa lets. Aon sim Ml 201:58 herr noma sartlzad reo and fam : “ Kcdgendar aplatendets! pam inermalnaity 4 owed TA Pret MT oe de ed ol ace ea pes Th | eee eros 28, Pome, Liman , Tepodt A cea The ineenaton lend 11 Kinganbrg SI. Uanghal F. Ticamie aid armani INR) in he MELD sore preload for arp geri bling, Cochrane Daas Sat tleriane Are} Tappan 01030: 39.38 ee a Sollee AN @ at 4 28, Seal Th, Deke WI, Tiansiion Niaficinettemonsis 47 Reyfsn J Alc JR. Sandor AN, cr a Poms ok (Gln Tins Nework Phuc of sade appre hat reduces Hen less. rsisan rites and ena ahooralcoplnion wit reals qrecis bloating in the tion fier ase primary onthe lier anos corny of ane dagrosne roedatoe an ends Anethsle 199685 083-8 sore, Tantus, S053 125 48. Ganaman B-Rusgon 1. The eBay and ayo plone 30. OShayfreay DE Amery CBee Mage Po amineepeie ad earn i peRene wh eho 2 (Gaudin fer eho we of Fatnhone pra, emesis hypetbrindyss. Aimee Pharmac “Tha. 200625; and eyesupaarane. FJ Hasna 20532628 115.28 3H. Mawar I Willa V, Tearfonsn Mt al Conmal 48. Camanen N. Tenant PM, Alres |, al. Sakexmanes vou enor lasiment pers wrk dcrdcm of desmopees DDANP shares the ploned bls heroes Aen [Sg 20011805034 fie in peione ith lier bax ‘Theom Hamat 52 Perigo Alsida PC, Roch, Fotos toons blccdng scr dem ceracton_ in lirer_pransplnt 50. denis, Arizona PC, Carnell eral Random parisnte| Oral Manila Surg, 20127017784 ied corr al of desmapreinlas tein ws 238, Rotors IN, Papl REC Ars R Tasstae and sro ‘lipin inc fr fe eamene of are wea! heme in Ine ssa Be} soma. 20101685072 shape fh etnhriepupsnne = maiteeres. deuse-sind “8, Ctr A Chaleaps mee borannyanayes. oF hese, Sry. Now dan Lndacepe Clue epg 129308 Aiorder, Thromb Re 20121306 1103-7.