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ISRAEL JOURNAL OF VETERINARY MEDICINE
H M N I T A E O S I M N G O U I (VG U A N R V N U M U O L B LN I I ) THERAPY I VETERINARY M DCN - A R VE N EIIE EIW
Kol,A. DVM ..
American Medical Center, Herzlia, Israel.
s se is not fully understood, although there is eviden yt m I T O U TO NR D CI N support several hypotheses (2,12-14). Intravenous immunoglobulin (IVIG) is a therapeutic n biological product containing highly purified polyspecific IgG IVIG modulates both humoral a d cell immunity in obtained from pooled plasma on a large scale ( 0 0 to 1 m0y locations, different cell types, different receptors a 30 0 ,a0 00n different effector molecules (4, 1-3). IVIG preparations c healthy blood donors) (1-3). Donors are screened for antibodies r for h m n immunodeficiency virus (HIV), hepatitis B a dactivate/block Fc receptors. IgG Fc receptors (FcyRs) ae ua n C ters e ba e glycoproteins of macrophages, neutrophils r nm m r n a a d h m n T cell lymphotrophic retroviruses (HTLV). Oth n ua at m a ue such a treatment with solvents a d detergents, eosinophils, platelets, m s cells, natural killer cells and esrs s n lymphocytes (1). Binding of IgG molecule at its Fc region trypsin, pasteurization, nano-filtration, a d low pH are used n modi a y to minimize the possibility of transmitting infectious disease fy m n functions, depending on the type of the e cell. Such e h n e functions are phagocytosis, degranula nacd agents. antibody-dependent cell-mediated toxicity, cytokine releas T e final product should contain m r then 9 % IgG (all h oe 0 aa ny subclasses) a d only traces of IgM a d IgA. Osmolality m d regulation of antibody production. n n r n e from physiological values (280-296 m s / ) to greater is accepted that the main m c a i m of action of IV ag O m1 It e h ns then 10 0 m s / a d m s of the products h v a pHthe ueatment of ITP and other i m n mediated cytopen , 0 O m1 n o t ae valtre m ue of 6-7. mediated through the blockade of m co h g s FcyRs, lea ar p a e to a IVIG treatment w s introduced in the 1950's a a replacement slower removal rate of antibody coated platelets (1, a s cani a en hw o o ye therapy for congenital humoral immunodeficiency syndromes, ne in vitro model, it h s b e s o n that m n c t s n e h ns a d since then IVIG h s proved to h v i m n modulIVIG through the Fc receptor a d that this m c a i m of n a ae m u e ating leads properties a d successful in treating inflammatory, immune- to a slower removal rate of antibody coated erythro n hs n mediated a d a t i m n diseases. C m o clinical t e e authors also found that IVIG binds to B, CD4 a n uo u e m o mn m ue indications include different immunodeficiencies such a lymphocytes (4). Other i m n modulation properties inc s di o p et e hypogammaglobulinemia, pediatric HIV infection a d B cellfferent antigen binding, attenuation of c m l m n media n n chronic lymphocytic leukemia. IVIG treatment h s also b ea a e neutralization of pathologic auto-antibodies a d a ed m g , n found beneficial in different immune-mediated diseases suchduction of anti-inflammatory cytokines. IVIG can bind in a idiopathic thrombocytopenia purpura (ITP), a t i m ndifferent antigens including natural antibodies, which are s uo u e m hemolytic a e i (AIH), a t i m n neutropenia, pure red result of an i m n response a d are present even n ma uo u e m the m ue n cell aplasia, Kawasaki s n r m (severe childhood vasculitis), by a d gnotobiotic animals. T e e natural antibodies y do e e ro n m hs prevention of graft-versus-host disease in b n m ro a part of the innate i m n system but they can also b o e ar w m ue e recipients, chronic inflammatory demyelination polyneuropathyreactive auto-antibodies, promoting autoimmunity (1). (CIDP), Guilain-Barre s n r m (acute, a t i m n y do e uo u e IVIG contains antibodies to super-antigens that m y acce m a polyradiculoneuropathy) a d in other conditions (1-3). n viral or bacterial induced a t i m n manifestations; it uom u e conta n At a r c m e d d d s of lg/kg a d a production cost of ins antibodies against CD4 a d MHC class 1 wh eo m n e oe n U $ 0 per ga ( 0 US$/10kg dog), the high cost m y hinder the function of CD4 positive lymphocytes and C S5 rm 50 a block lymphocytes, respectively. Moreover natural antibodies aga its routine u e for therapy in veterinary medicine. Moreover, s div on until now, its cost a d the uncertainty of its usefulness h fferent pro-inflammatory cytokines are d w regulated n ae IVIG. hindered controlled randomized clinical trails in veterinary medicine. Another m c a i m involves the attenuation of c m l m e h ns o pe a ae 3 n n No canine or feline origin intravenous immunoglobulin mediated d m g by activated C b a d C4b, a d thus e ba e product is currently available on the m r e d e to its highprevents the C5b-9 m m r n attack complex (1). This m ak t u cost acti of production for a potentialy small market. Moreover, n on is very importance in the treatment of dermatomy o y do e n serious adverse effects h v b e detected following the u e ofain-Barre s n r m a d myasthenia gravis. IVIG is ae e n sGuil n h m n immunoglobulin in d g or cats. For pet o n r w o are d pathogenic auto-antibodies a d to induce the produ ua os w es hto bin willing to pay the high price, this novel therapy m y m kofthe -inflammatory cytokines by T helper I & II such a ae anti interleukin-1 receptor antagonist (1-3). difference b t e n life a d death. ew e n I m n m d t d t r m o yo e i (IMT) m u e e i e ho b c t p na a I m n m d l to : M c a i m o a to m u e o uai n e h n s f ci n n T e exact m c a i m by which IVIG modulates the i m n ne i m n mediated thrombocytopenia refers to a h e h ns m u Cani m u e e VOLUME 6 (1) 2 0 3 08
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thrombocytopenia that results from immunological destructionatelets count of6,000 cell/uL immediately after the treatm pl of platelets, usually by m a s of phagocytosis of antibody coated 2 hours later platelets count rose to 58,000 cells/uL. en but 4 platelets by the m n n ce r phagocytic s se (5). IMT canne d g did not respond immediately a d vincristine the o o ul a yt m ob o e n primary (i.e. a t i m n ) or secondary to a primary conditw s initiated. N n of the d g relapsed over the follow uom u e ion a oe os such a neoplasia, infectious agents, systemic a t i m nperiod ( months). s uo u e m 6 disease a d drug or toxin exposure. n I m n m d t d h m l tc a e i m u e e i e e oyi n m a a Idiopathic thrombocytopenia purpura (ITP) w s the firstCanine m u e mediated hemolytic a e i (IMHA) is a i mn n ma i m n mediated disease to b successfully treated by IVIGtively a c m o life threatening, hematological disor m ue e rela o mn in h m n medicine. I b c et al. ( 9 1 s o e that highpathogenesis comprises auto-antibody formation agains ua m ah 18) hwd Its d s s of IVIG could reduce the destruction of platelets inaue erythrocytes or erythrocytes precursors, c m l m oe m ar t o p e child suffering from ITP. Since then IVIG therapy h s bactivation a d hemolysis (8). a en e n reconfirmed in m n clinical trails, a d ITP is o e of the best ysis m y b intravascular a a result of the form ay n n Hemol a e s established clinical indications.. of m m r n attack complexes, a d a a consequence, os e ba e n s Since IVIG is very expensive, a d the fact the canine destruction of erythrocytes, b t m r frequently it occurs n IMT u oe usually responds well to c m o immunosuppressive a dan extravascular location (mainly in the spleen or liver) o mn n immuno-modulating drugs such a glucocorticoids, vincristine,e n of phagocytosis of antibody coated erythrocytes by s mas azathioprine, cyclosporine, danazole, cyclophosphamide a d o o u l a phagocytic system. T e efficacy of IVIG treatm nm n n ce r h leflunomide, only a f w c s studies w r published with canine ne primary IMHA w s evaluated (9-11, 6, 12), m e ae ee in cani a IMT but n controlled randomized clinical trials. Another major studies w r published m r than ten years ago, a d o the ee oe n fault connected with its high cost is that only severe, refractory on is available. informati cases h v b e treated with IVIG, which c m r ms s the the only prospective clinical trial, 1 d g that w r ae e n o po i e In 0 os e ability to evaluate its clinical relevance. refractive to conventional immunosuppressive drugs w r ee Only two case studies h v b e published in the veterinary with IVIG (6). T e authors concluded that IVIG th ae e n treated h literature regarding IVIG therapy in canine IMT. In a h d a short term effect, a d hematocrit, hemoglobin a n a n n early study o e d g with a pe u e diagnosis of primaryulocytes counts improved significantly over a short pe n o rsmd retic IMT w s reported (6). T e d g w s treated with 2 mg/kgme b t did n t last for the long term, a d only 3 d a h o a of ti of u o n o prednisone every 1 hours for 1 d y without improvement. o e year after thefirstclinical presentation. Neverthe 2 1 as alive n Prior to IVIG therapy the platelet count w s 5 0 cells/uL. should bear in mind that only the cases that w r re a 00 oe n ee IVIG w s administrated at a d s of 1 g/kg over a period m o drug therapy w r treated, i.e., cases that had a oe to c of n om ee 1 hours. During this period a d thereafter, prednisone therapy s at the outset. 2 n prognosi w s continued. Six hours after IVIG w s infused t e platelet another retrospective study (6), 1 d g with prim a a h In 3 os count rose to 70,000 cells/uL; 2 hour later platelet count IMHA that w r responding to immunosuppressive therap 4 ws a ee 1 50 0 cell/uL, a d 4 d y later it w s 240,000 cells/uL.wh 4,0 n as a Te ee IVIG. u 1 dg 1 wr 3 o 0 ee d g relapsed on d y 2 post treatment with a platelet countroftreated with cient i Ortvof the in theirshematocrit.a o a 3 discharge after suffi m oe e t p mn 5 , 0 cells/uL. T e authors of this study did not d c m nOn of these 1 d g 8 w r still alive after a median 70 0 h ou e t a t y s e signalment, medical history, physical examination or clinicalus (a g 1 0- , o5 days). eh authors suggested that dm r n e 2 10 a y 0 7 pathological data such a CBC, blood s e r examination, s therapy should b consideredT e m r severe cases of c s ma eu r in oe chemistry a d b n m ro analysis of the dog. In the IMHA despite itse gh cost which should b interpreted in n o e ar w sm ae hi e study it w s noted that 4 d g that w r diagnosed with i ofue shorter time of hospitalization a d the potential d c a os ee m the mn n e mediated hemolytic a e i (IMHA) a d w r treated with IVIG e u e of blood product transfusions. n ma n ee in th s had concurrent thrombocytopenia. In all 4 d g platelets count os returned to the reference r n e within 1 to 1 days; h w More prospective, large scale clinical trials with longer fo ag 6 o ee 3 vr u peri p edd eo m n i g s d g relapsed with thrombocytopenia. In a m r recent study 5 ods are n e e before r c m e dn the u e of IV os oe d g that w r refractory to conventional therapy w r treatedtreatment of refractive canine IMHA patients. os ee ee the with IVIG (7). All the d g u d r e t a thorough clinicalMdl fbo i o s n ew n ay oi r ss ne laboratory investigation including physical examination, CBC Myelofibrosis is characterized b deposits offibroustissue y a d blood s e r examination, s r m biochemistry profile, e extracellular matrix of the b n m ro by reactive m n ma eu th o e ar w a coagulation panel (including PT/aPTT/FDPs a d fibrinogen), n fibroblasts, hindering normal hematopoiesis (13). Tran serological tests for tick borne disease a d b n m ro core h factor p (TGF- P), platelet derived growth factor (P n o e ar w growt biopsy a d cytology. n a d epidermal growth factor (EGF) arefibrogeniccytokin n s All d g w r extremely thrombocytopenic ( 30 0 celthat are implicated a important modulators of prolifera o s ee < , 0 ls/ n8 ar w n uL) before IVIG infusion. IVIG w s infused in a d s of a.d¬synthesis in m ro fibroblastsa d endothelial ce a o e 02 Myelofibrosis is a reactive process associated with vario 07 g/kg over a six hours period. No adverse reactions w r .6 ee e noted during a d after treatment in a y of the dogs. Three diseases a d can b resolved by the correction of the p n n of the n condi d g had dramatically improved thrombocyte counts (12,000 - tion. os 68,000 cells/uL) immediately after the treatment. O e d g h d a the cat the m s c m o underling c u e for myelof n o a In ot o m n as 2 4
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is myelodysplasia a d acute myeloid leukemia while in theinvolvement. n dg o it is mostly associated with m u e mediated, non-regenerative a c s study of d g with myelofibrosis a d a sus i mn In o n anemia. Affected d g are a e i a d reticulocytopenic despite u e a e ated underlyisg disease w r treated with I os n mc n m n medi im n ee significant, but ineffective, erythroid hyperplasia. MyelofibrosiDoses, s a d post- IVIG n also occurs in d g with hemolytic a e i d e to pyruvate onpre-response a d o t ohematocrit,oreticulocyte co os n ma u durati of n u e are s w n kinase deficiency. Other underlying c u e include infectious the original paper) (6).c marly, mhh m in table 1 ass from Cle u oe informa c r diseases, radiation, drugs a d cancer, with or without m roe e before r c m e dn IVIG therapy in myelofibrosi n anw d re d eo m n i g
T be 1 D s , r s o s a d o to e o I I te t e t o fv d g wt n ne e eai e a e i a d m eo a l . o e e p n e n u m f VG r am n f i e o s ih o r g n r tv n m n y l c a Cs ae 1 2 3 4 5 D s of oe IVIG (g/kg) 15 . 1 . 5 15 . 1 1 Pre-IVIG Hematocrit ( ) % 91 . 66 . 77 . 1 6 1 0 Post-IVIG hematocrit (peak) 2 (day 1 ) 8 0 1 (day 27) 7 1 (day 24) 8 3 (day 1 ) 1 1 2 ( a 47) 4 dy Pre-IVIG retic- Post-IVIG ulocyte count reticulocyte (/uL) count (/uL) 42,000 22,000 21,000 22,000 35,000 378,000 306,000 1 90 0 9,0 550,000 474,000 Duration of r s o s ep ne (days) 22 6 3 7 49 3 7 19 5 O to e uc m Euthanized (PCV= 2 % 6 ) Retreated Retreated Euthanized (PCV= 2 % 7 ) Relapsed ( C =2 ) P V1%
from hospitalization but with remission of clinical signs 2 P m h u f la e s e p i s oi c u g P m hg s foliaceus (PF) is the m s c m o i m n w e s eter ianother d sthe immunosuppressiveatherapy. T e piu o t o m n m u e after thla intiation of e of IVIG (0.5 g/kg) w s given. F e o mediated skin disease of the dog. Its pathogenesis includesremained in remission for 9 w e s post hospitalization thek ek formation ofauto-antibodies against desmogelin 1, akeratinocytee disease relapsed with n w skin lesions, fever a d wea thof e n d s oo e c m o e t (14-16). T e d s oo e are the site h d g received an additional 2 d s s of IVIG (0.5 g/k em s m o p n n h em s m s Te o oe adhesions b t e n keratinocytes. Binding of antibodies result the next 2 d y a d azathioprine therapy w s discon ew e in a n a in breakdown of adhesions b t e n keratinocyes, acantholysiAnother single d ss (0.5 g/kg) of IVIG w s given on w ew e s, oe a e subcorneal blister formation a d pustules.Conventional therapy n 22,26 a d 31. T e d g remained in remission for 1 year n h o includes immunosuppressive d s s of corticosteroids a d other diagnosis a d 4.5 m nh after the last IVIG therap oe n n ots cytotoxic a d immunosuppressive drugs such a azathioprininitial n s e, cyclophosphamide, cyclosporine, chlorambucil a d gold In a resent review study of 9 d g with PF by Mul n 1 os therapy. (2006), the m a a ea e time to remission w s 93 en v r g a . (a g 13 m nh (15). It w s noted that d g treated r n e -6 o t s a os In a case report by Rahily et al (2006) a single d g with combinati o severe of prednisone n azathiopri had lo d PF w s treated with IVIG (16). IVIG therapy w s initiatedssionon therapym ae to theao s treated neh predn a a remi periods c p r d o dg before other immunosuppressive drugs w r given. After alone ( 1 m nh vs. 7 months), though there wits n d ee w o a the initial d s of 0.5 g/kg there w s a m r e i po ebe t e1 the o t s regarding the initial response to the oe a ak d m r v mtne n ew groups of clinical signs, skin lesions b c m drier, erythema b g n an earlier review study by G m z et al (2004) the ea e ea oe to resolve a d n n w skin lesion w r noted at 1 d yound a case fatality rate of 60.5% (14). In the survival g n o e ee 2 aIn post fs d IVIG therapy, m r o e the d g b c m stronger a d s oduration of treatment ranged from 6-63 m nh w ee 1 oe v r o ea e n hw e ots a interest in food. T e initial d s w s then repeated threee 1 survivors continued to receive treatment.h r the n h oe a of th 7 m r times in the next 4 d y (total d s of 2 g/kg) following by 9 % had a survival time of less than 1 Of h oe as oe 2 mont immunosuppressive therapy (prednisone 2.2 mg/kg PO q 4 vors 2 2survi h a d azathioprine 2 mg/kg PO q24h). T e d g w s discharged n h o a VOLUME 6 (1) 2 0 3 08
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Te t e t o a v r e c t n o s du r a to s r am n f d es ua e u r g e ci n Side effects Adverse reaction during, a d after, IVIG infusion ae n r Severe, adverse c t n o s drug reactions are rare in the ua e u u c m o v ns no ua n d g a d the cat a d m y include erythema multiforma (EM), m n e e t in h m n patients a d rare in vete o n n a o mn ua Steven-Johnson s n r m (SJS), toxic epidermal necrolysis apatients. C m o mild side effects reported in h m n me y do e n d Stevens-Johnson epidermal necrolysis overlap syndrome. are fever, headache, chills, back pain, nausea, vomiting, tachycardia, shortness of breath, a d chest n M T e basis ofthese s n r m s is the d t c m n ofthe epidermis reactions m y include an anaphylactictightness. to h y do e ea h e t severe a reaction from the dermis, probably d e to m u e mediated processes, u i mn in hemol u blood g a d the formation of erythematous macular dermatitis with IgA-deficient patients,nation, ytic anemia d etito acute re n antibodies, viral contami aseptic meningi s, focal to widespread m c c t n o s vesicles a d ulceration. lure d e to osmoti nephrosi n u o ua e u n fai u Patients m r severely affected are usually pyrexic, depressederly patients treatedcfor ITP. s a d thrombotic episode oe eld and prone to secondary infections. Prognosis is grave in severe cases but can b good in the m r localized a d non-systemic m j r side effects h v b e noted in veterinary e oe n No ao ae e n affected animals. Te t e t usually comprises of withholding ents. O e normal d g vomited during IVIG infusion. r am n pati n o the offending drug a d giving aggressive supportive care; thrombocytopenia w s recorded in three normal d g a n a os standard immunosuppressive drugs such a glucocorticoids a d infusion, another 3 d g treated for IMHA that w s n IVIG os e azathioprine are not of value in these cases. thrombocytopenic prior to therapy b c m thrombocytopenic ea e to 6 a l y a nadir of32,000 to 8 , 0 There h v b e three c s reports in the veterinary literature ddsbater withthat thrombocytopenia1s90 0 cells/uL, ae e n ae it shoul e noted a well o m c concerning the treatment of 3 d g a d o e cat with severe ication of canine IMHA. No adversei reactions dau os n n compl hv e adverse c t n o s drug reaction with IVIG. T e first creported in m r recent case reports. ua e u h ae s oe reported by Byrne et al ( 0 2 w s of a 5 m nh old cat that 20) a ots developed extensive crusts a d a single ulcerated fissure with mr n S m ay u purulent exudates (17). T e cat w s febrile, lethargic a d thin. is a novel promising therapy for a wide verity of i h a n IVIG m A tentative diagnosis of EM w s established u o history, ated diseases with the potential of long-term remissio a pn medi clinical signs, clinical pathology a d histopathology. Becausem n medicine only a few indications are approved by the n h u of the extent a d severity of clinical signs, the lack of responsea n after controlled randomized clinical trails h v s o n effica ae h w to supportive care a d the progressive nature of EM, treatment n with IVIG w s initiated. IVIG w s infused at lgr/kg d s overs indications are: a a oe T ee h a 4-hour period b.i.d. for two days. Eight d y later the cat w s as a • o e ar w reevaluated a d w s bright, alert, afebrile a d m s of the skin Allogenic b n m ro transplant n a n ot lesion had progressively improved with > 0 resolution of 9% • the crusts. Fifty-seven d y later the cat returned for routine Chronic B lymphocytic leukemia as • ovariohysterectomy. T e cat s o e n remarkable findings on Idiopathic thrombocytopenia purpura h hwd o physical examination a d h d gained 1 kg ( 0 % rise in body Pediatric HIV n a . 4 10 weight), CBC, s r m biochemistry a d urinalysis results w r• eu n ee • Primary immunodeficiencies all within the reference range. T e second case reported w s of a 2 year old d g that•h d Kawasaki diseases. h a o a developed severe m c c t n o s ulceration, consistent with• u o ua e u Host vs. graft disease SJS, after trimethoprim-potentiated sulphadiazine therapy. But a y oe Systemic signs included severe hepatopathy, dyspnea, pyrexia m n m r off-label indications are used today. cachexia, a d keratoconjunctivitis sicca (KCS) w s also In veterinary medicine only a f w i m n mediated dise n a e m ue noted. Aggressive supportive care did not improve the dog's evaluated for their response to IVIG therapy but the wr ee condition, moreover, glucocorticoid therapy probably lead n approved indications. Nevertheless, its u e m y b ind to o s a e Pseudomonas aeruginosa infection of the nasopharynx. D ein a wide variety of severe unresponsive m u e media u to i mn the deterioration a d the unresponsive state of the dog, a single n dithe seases. infusion of 05 g/kg IVIG w s initiated. Te t e t after .1 a r am n IVIG infusion consisted of antimicrobial therapy a d topical n liquid paraffin ointment. All clinical sign resolved a d the d g n o did n t relapse. o T o cases w r reported b Trotman et al (2006) w r of d g w ee y ee o s suffering from severe adverse c t n o s drug reactions (18). ua e u Both w r refractory to aggressive supportive therapy, a d w r ee n ee treated with 2 d s s of lgr/kg IVIG in two consecutive days. In oe both cases all clinical signs resolved a d n relapse w s noted n o a in the follow-up period of m r than 3 years. oe 2 6
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REFERENCES 1 Boros, R, Gondolesi, G. and Bromberg, J.S.: High d s15. . oe intravenous immunoglobulin treatment: m c a i m of eh n s s action. Liver Transpl. 11:1469-1480,2005. 2. Lemieux, R., Bazin, R. a d Neron, S.: Therapeutic16. n intravenous immunoglobulins. Mol Immunol. 42:839-848, 2005. 3. Nimmerjahn, F. and Ravetch, J.V.: The antiinflammatory activity of IgG: the intravenous IgG paradox. J Exp Med. 17. 204:11-15,2007. 4. Reagan, W.J., Scott-Moncrieff, C, Christian, J., Snyder, R, Kelly, K. and Glickman, L.: Effects of h m n intravenous ua 18. immunoglobulin on canine m n c t s and lymphocytes. o o ye Am J Vet Res. 59:1568-1574, 1998. 5. Scott, M.A., Immune-Mediated Thrombocytopenia, in Schalms Veterinary Hematology, B.F. Feldman, J.G. Zinkl, ' and N.C. Jain, Editors. 2000, Lippincot Wiliams a d n Wilkins: Philadelphia, p. 4 8 4 7 7=8. 6. Scott-Moncrieff, J.C., Reagan, W.J., Snyder, P.W. a d n Glickman, L.T.: Intravenous administration of h m n ua i m n globulin in d g with immune-mediated hemolytic m ue os anemia. J Am Vet Med Assoc. 210:1623-1627,1997. 7. Bianco, D., Armstrong, P.J. and Washabau, R.J.: Te t e t r am n of severe immune-mediated thrombocytopenia with h m n ua IV immunoglobulin in 5 dogs. J Vet Intern Med. 2 : 9 ¬ 16 4 699, 2007. 8. Day, M.J., Immune-Mediated Hemolytic Anemia, in Schalm's Veterinary Hematology, B.F. Feldman, J.G. Zinkl, and N.C. Jain, Editors. 2000, Lippincott Wiliams a d n Wilkins: Philadelphia, p. 799-807. 9. Scott-Moncrieff, J.C., Reagan, W.J., Glickman, L.T., DeNicola, D.B. a d Harrington, D.: Te t e t of n r am n nonregenerative anemia with h m n gamma-globulin in ua dogs. J Am Vet Med Assoc. 206:1895-1900, 1995. 10. Kellerman, D.L. and Bruyette, D.S.: Intravenous h m n ua immunoglobulin for the treatment of immune-mediated hemolytic anemia in 13 dogs. J Vet Intern Med. 1 : 2 - 3 , 13 73 2 1997. 11. Scott-Moncrieff, J.C. and Reagan, W.J.: H m n intravenous ua immunoglobulin therapy. Semin Vet Med Surg (Small Anim). 12:178-185,1997. 12. Grundy, S.A. and Barton, C: Influence of drug treatment on survival of d g with immune-mediated hemolytic anemia: os 88 cases (1989-1999). J Am Vet Med Assoc. 218:543-546, 2001. 13. Blue, J.T., Myelodysplastic Syndromes and Myelofibrosis, in Schalm's Veterinary Hematology, B.F. Feldman, J.G. Zinkl, and N.C. Jain, Editors. 2000, Lippincott Wiliams and Wilkins: Philadelphia, p. 682-689. 14. Gomez, S.M., Morris, D.O., Rosenbaum, M.R. a d n Goldschmidt, M.H.: O t o e and complications associated uc m with treatment of p m hg s foliaceus in dogs: 43 cases e piu (1994-2000). J Am Vet Med Assoc. 224:1312-1316,2004. VOLUME 63 (1) 2 0 08
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Mueller, R.S., Krebs, I., Power, H.T. and Fieseler, K.V P m hg s foliaceus in 91 dogs. J Am Anim Hosp Ass e piu 42:189-196,2006. Rahily, L.J., Keating, J.H. and O'Toole, T.E.: The use o intravenous h m n immunoglobulin in treatment of seve ua p m hg s foliaceus in a dog. J Vet Intern Med. 2 : 4 3 e piu 01 8 ¬ 1486,2006. Byrne, K.P. and Giger, U.: Use of h m n immunoglobu ua for treatment of severe erythema multiforme in a cat. J Vet Med Assoc. 220:197-201,183-194,2002. Trotman, T.K., Phillips, H., Fordyce, H., King, L.G., Morris D.O. and Giger, U.: Te t e t of severe adverse c t n o r am n ua e drug reactions with h m n intravenous immunoglobulin ua two dogs. J Am Anim Hosp Assoc. 42:312-320, 2006.
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