ANEMIA EMOLITICA AUTOIMMUNE
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1 Convegno interregionale SIE Delegazione Triveneto Citopenie autoimmuni Udine, 8 maggio 2009 ANEMIA EMOLITICA AUTOIMMUNE A. Zanella Ematologia 2, IRCSS Fondazione Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milano
2 12 Incidence per AIHA caldi Warm freddi Cold misti Mixed Atypical warm IgM AIHA DAT neg AIHA Age (years) Sokol et al., J Clin Pathol 1992; 45:1047
3 FACTORS THAT INFLUENCE AUTO-Ab PATHOGENICITY-1 Characteristics of antibody Class Subclass Thermal amplitude Specificity Affinity Complement activating efficiency Quantity of cell-bound IgG/complement Type of cell-bound complement Characteristics of target antigen Activity of reticuloendothelial system Erythroblastic response
4 Autoimmune hemolytic anemia with reticulocytopenia. A medical emergency. Conley CL, Lippman SM, Ness P. (JAMA 244: , 1980)
5 Clinical data of patients with AIHA & reticulocytopenia Case Age/Sex Hct Retics Duration Tx Results (%) reticulocytopenia (N. RBC units) (Days) 1 52/F CR 2 78/F CR 3 53/F PR 4 35/M PR 5 49/F PR
6 SEVERE AND LETHAL AIHA CAUSED BY WARM IgM AUTOANTIBODIES...AIHAs associated with IgM warm auto Abs are often severe with more fatalities than other types of AIHA. (Garratty et al, Vox Sang. 1997,72:124-30). McCann EL et al. IgM autoagglutinins in warm AIHA: a poor prognostic feature. Acta Hematol 1992;82: Garratty G et al. Severe AIHA associated with IgM warm autoantibodies directed against determinants on or associated with glycophorin A. Vox Sang 1997;72: Friedman AM et al. Fatal AIHA in a child due to warm-reactive immunoglobulin M antibody. J Pediatr Hematol Oncol 1998;20: Nowak-Wegrzyn A et al. Fatal warm AIHA resulting from IgM autoagglutinins. J Pediatr Hematol Oncol 2001;23:250-2.
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8 SEVERE AND LETHAL AIHA CAUSED BY WARM IgM AUTOANTIBODIES (Garratty et al, Vox Sang. 1997,72:124-30) Spontaneous RBCs agglutination due to crosslinking of IgM autoabs Can appear to have only C3 on RBCs by routine DAT IgG may be present also Can appear to be DAT by routine DAT
9 Authors DAT-negative AIHA n cases/ total AIHA % Worlledge S.M. (1972) 10/333 3 Gilliland B.C. (1976) 4/37 10 Chaplin K. (1977) 4/103 4 Petz L.D. (1988) 27/347 8 Heuft H.G. (1993) 15/89 17 Vaglio S. (2007) 21/100 21
10 Incidence of DAT-Negative AIHA in 378 patients (Petz and Garratty, 2004) Warm AIHA Patients % n DAT DAT * *8% of total AIHAs
11 TAD lav. A 4 C TAD lav. A 4 C +++ Giorni
12 False positive AIHA DAT + AIHA DAT- DAT tube DAT card DAT solid phase DAT IFA DAT ELISA No one test was found to be optimal; a battery of tests seems to be the most efficient approach to the diagnosis of DAT-negative AIHA. Garratty & Arndt, Transfusion, 35, , 1995
13 Does a negative DAT exclude warm AIHA? A prospective Study of 504 cases. Sachs et al. Br J Haemat 132, 655, 2006 Even with improved, monospecifric DAT using the gel technique, DAT expected to be negative in up to 3% of AIHA
14 Mitogen-stimulated DAT (MS-DAT) functional test Mytogenic and/or cytokine stimulation quantitative test ng/ml OD mean OD 1 OD 2 OD 3 ng/ml log OD log , , , , , , , , , , , , , , OD cytokines anti-igg ng/ml coated RBC 3,1 3 Auto-Ab in culture Binding of Auto-Ab to autologous RBC log OD 2,9 2,8 2,7 2,6 2,5 y = -0,1284x + 3,248 R 2 = 0, ,5 2 2,5 3 3,5 log anti-igg ng/ml coated RBC
15 Mitogen-stimulated DAT: a new method for the diagnosis of AIHA W.Barcellini, A.Zaninoni, F.Imperiali, A.Zanella. Blood Transf 2003; 2: Table II - Clinical and laboratory characteristics of DAT-negative, MS-DAT positive AIHA patients atient N Gender Hb g/dl Total bilirubin (unconjugated) µ mol/l Reticulocytes % Haptoglobin mg/l LDH U/l Steroid therapy DAT * MS-DAT IgG ng/ml 1 F (5) yes neg F (12) yes neg F (7) no neg M (9) no neg M (8) yes neg M (8) no neg M (22) no neg F (22) no neg M (18) no neg F (19) no neg M 8.8 n.d yes neg M (27) no neg F (8) no neg 314 ormal ange female male (0-12) <2% * DAT was performed with standard tube test, in solid phase and with enhancing solutions. In the last 6 years we collected 10 cases of DAT (tube, microcoumn and solid phase)- negative AIHA in which the diagnosis was made on the basis of a positive MS-DAT. These cases represent roughly 3% of the 304 DAT-tube positive cases observed in the same period.
16 TAD NEGATIVE TAD standard (polyspecific sera) POSITIVE YES STOP NEGATIVE Cause of hemolysis identified? Other (MS-DAT) NEGATIVE NO - Monospecific sera - Alternative DAT - Microcolumn - Solid phase - Cold wash 4 C - LISS - IFA POSITIVE Serum/Eluate: - Abs screening - Abs identific. POSITIVE
17 IMMUNE HEMOLYTIC ANEMIAS - PECULIAR ASPECTS ASSOCIATION OF AIHA WITH BLOOD TRANSFUSION ASSOCIATION OF IMMUNE HEMOLYSIS WITH ALLO_ GENEIC HEMOPOIETIC STEM CELL TRANSPLANTATION ASSOCIATION OF AIHA WITH THERAPY WITH PURINE NUCLEOSIDE ANALOGUES THROMBOEMBOLISM AND AIHA
18 ASSOCIATION OF AIHA WITH BLOOD TRANSFUSION (1) Alloantibody formation is a well-recognized complication of blood transfusion A small percentage (1-2%) of transfused pts develope autoantibodies as well, close in time to alloimmunization (Young et al, Transfusion 2004, 44:67-72) Several reports of both alloantibody and autoantibody production in multiply transfused pediatric pts with sickle cell disease and thalassemia -among 184 children with SCD, 7.6% had IgG autoabs, after median 24 units transfusion (Castellino et al, Br J Haematol 1999, 104: ) -among 64 pts with thalassemia, 25% developed positive DAT, but infrequent hemolysis (Singer et al, Blood 2000, 96: )
19 ASSOCIATION OF AIHA WITH BLOOD TRANSFUSION (2) Analysis of blood bank records for a 2 yrs period: 38 pts with warm type autoabs occurring after blood transfusion (27 had also alloabs); clinically significant AIHA rare but at times life-threatening (Sigler et al Transfusion 2009, April 3, Epub) Possible mechanism not known. Postulated hypothesis include: -persistence of immune cells of donor origin in recipient causing antibody production against recipient RBCs? -alloantibody induced conformational change in the antigenic epitope that stimulate autoantibody production? (Garratty G., Transfusion 2004,44:5-9)
20 ASSOCIATION OF IMMUNE HEMOLYSIS WITH ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION (1) ALLOIMMUNE HEMOLYSIS - Passenger lymphocyte syndrome, due to the antibody production by passively-transferred lymphocytes included in the stem cell product, in case of minor ABO incompatibility (often donor O and recipient A) - Bystander hemolysis, mechanism unknown: C-mediated lysis? absorption of A or B ag onto group O rbcs, thereby allowing them to be lysed by anti-a or anti-b? Lack of specificity of alloantibodies? AUTOIMMUNE HEMOLYSIS AIHA in 3-4.4% up to 6% in pediatric HSCT pts., often severe and abrupt (Drobyski et al, B. Marrow Transplant 1996, 17: ; Chen et al, B. Marrow Transplant 1997,19:491-5; Sanz, B. Marrow Transplant 2007,39:555-61)
21 ASSOCIATION OF IMMUNE HEMOLYSIS WITH ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION (2) Additional reports have included several cases following cord blood transplants ( Mullen et al, Bone Marrow Transplant. 2000, 25:1093-7; Sevilla et al, Bone Marrow Transplant. 2001, 28:89-92; Urban et al, Eur J Haematol 2004; 72: 444-7) Median onset of warm AIHA 6-18 mo after transplant, vs. 2-8 mo for CHD (Chen et al, Bone Marrow Transplant 1997, 19:491-5) Antibody production by donor immune system against antigens on donor rbcs - hence AIHA. No evidence of residual recipient cells,
22 ASSOCIATION OF AIHA WITH THERAPY WITH PURINE NUCLEOSIDE ANALOGUES (1) Report of 12 cases of AIHA occurring in 52 pts (23%) treated with Fluda for CLL. 9 /12 had no prior history of AIHA (Myint et al, Br J Haematol. 1995, 91:341-4) 8 pts later retreated with Fluda and 6 recurred with severe AIHA Other studies reported 15/19 pts, and 7/8 pts respectively, retreated with Fluda had recurrent AIHA (Diehl & Ketchum, Semin Oncol. 1998, 25:80-97; Weiss et al, J Clin Oncol. 1998, 16: ) In a randomized trial of Fluda vs CTX/ADR/PRED for CLL, 5% of pts on Fluda had autoimmune events (AIHA, ITP, PCRA) vs none in the C/A/P arm (Johnson et al, Lancet. 1996, 347: )
23 ASSOCIATION OF AIHA WITH THERAPY WITH PURINE NUCLEOSIDE ANALOGUES (2) The UK CLL4 trial demonstrated that AIHA is more frequent in pts receiving chlorambucil or fluda alone compared with the combination of fluda and cyclophosphamide, and showed that a positive DAT and occurrence of AIHA were poor prognostic markers (Dearden, 2008) Cases of AIHA have also been reported with cladribine and pentostatin (Fleischman & Croy, Am J Hematol. 1995,48:293 ; Aslan et al, Transfusion. 2006, 46:90-4) Many of the cases of AIHA associated with purine nucleoside therapy have been severe or fatal Mechanism of induction of hemolysis is not known (proposed mechanisms have included a disturbance of immunoregulatory T cells leading to antibodies to a native RBC antigen)
24 AIHA & THROMBOEMBOLISM (1) In 1967 review of 47 pts: commonest cause of death (n. 4) was Pulmonary Embolism Recent review of 30 pts reported 8 (27%) with VTE (Pullarkat et al, Br J Haematol. 2002, 118:1166-9): -Overall, LA detected in 9, anti-cardiolipin abs in 17 -Among the 8 with thrombosis, 5 had LA and 4 anti-cardiol. -Mechanisms suggested to be exposure of PS on disrupted RBC membranes -Thrombosis also occurred in 15% of patients who did not have LA (other factors must contribute)
25 AIHA & THROMBOEMBOLISM (2) In a review of AIHA pts with Lupus, risk of thrombosis increased, especially with IgG anti-cardiolipin antibody present ( Kokori et al, Am J Med. 2000, 108: ) Among 23 pts with warm-antibody AIHA and 5 with CHD, VTE was noted in 6 (fatal in 4). None had detectable antiphospholipid abs (Hendrick, Hematology 2003, 8:53-6) Anticoagulant prophylaxis reduced VTE risk. In an analysis of 36 hemolytic episodes, VTE occurred in 5/15 without prophylaxis and only in 1/21 with (Hendrick, Hematology 2003, 8:53-6) Not known if AIHA pts should be given VTE prophylaxis during hemolytic crises (particularly high risk pts with antiphospholipid abs?)
26 TREATMENT OPTIONS FOR AIHA steroids azathioprine, CTX, VCR splenectomy Cyclosporine Rituximab Campath-1 Mycophenolate BMT
27 Rituximab (anti-cd20) therapy in AIHA PubMed (ITP + Rituximab) 133 reports PubMed (AIHA + Rituximab) 39 reports Most studies are case reports, larger studies have a limited number of patients Low levels of evidence Clinically heterogeneous patients Response to treatment not univocally defined
28 Rituximab (anti-cd20) therapy in AIHA
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30 Rituximab (anti-cd20) therapy in AIHA Frame & Lee: Blood, 2004; 104: abstract # pts; 34 case report, 5 case series CR definition: stable increase of Hb = >2 g/dl and Hb = >12 g/dl and DAT-, resolution of symptoms of anemia, transfusion independence PR definition: increase of Hb = >2 g/dl but Hb = >10 <12 g/dl and 50% decrease in abs titer, improvement of symptoms of anemia, transfusion indepence
31 Frame & Lee: Blood, 2004; 104: abstract # 3721 Conclusions Efficacy: - OR 61% (19% CR + 42% PR) in monotherapy (52 pts) - significant mean Hb increase (CR: 5.6 g/dl, PR 4.0 g/dl) even in NRs (2.1 g/dl) - effective in all AIHA (Warm, Cold, Idiopathic and Secondary) indipendently on the disease stage Mean time to response : 22 d (5-120) Mean response duration: 10.5 mo (1.5-42) Well tolerated
32 OR = 83% CR = 66% Norton A & Roberts I. Br J Haemat 132: ,2005
33 13 studies with > 5 pts treated with rituximab (375 mg/m 2 x 4w): median overall response 60% (40-100%) independently on AIHA type and age. Durable responses up to > 3 yrs. 2008
34 A SINGLE-ARM PILOT STUDY WITH LOW-DOSE RITUXIMAB PLUS STANDARD ORAL PREDNISONE IN AIHA single-arm prospective pilot study aimed to evaluate the safety, activity and the duration of the response of LD rituximab associated with standard oral prednisone (PDN) as first line therapy in newly diagnosed WAIHA and CHD, and as second line therapy in WAIHA relapsed after standard oral PDN. LD rituximab was administered at 100 mg fixed dose weekly on days +7, +14, +21, +28 along with standard oral PDN (1 mg/kg/die p.o. from day +1 to + 30, followed by quick tapering: 10 mg/week until 0.5/mg/kg/die, then 5 mg/week until stop). Complete and partial initial responses (icr and ipr)) were defined as Hb > 12 g/dl and > 10 g/dl at month +2 from the beginning of therapy, respectively; sustained response (SR) was defined as Hb > 10 g/dl at month +6, in the absence of any treatment. Steroid Rituximab m2 m3 m4 m6 m9 m12 m15 m18 m21 m24
35 A SINGLE-ARM PILOT STUDY WITH LOW-DOSE RITUXIMAB PLUS STANDARD ORAL PREDNISONE IN AIHA PRELIMINAR RESULTS 9 patients (5 female, 4 male; median 49 yrs, range 28-65) enrolled A icr and ipr were observed in 5 and 3 out of 9 patients, respectively the median Hb level increased from 9.25 g/dl (range ) at enrolment to 11.7 g/dl (range ) at month +2. A sustained response (SR) at month +6 was observed in 5 out 5 evaluable patients. No side effects or serious adverse events were observed.. Steroide Rituximab m2 m3 m4 m6 m9 m12 m15 m18 m21 m24
36 Campath-1H (anti-cd52) therapy in AIHA In 4 pts with refractory AIHA 1 CR, 2PR and 1 NR with death (median follow up 10 mo.) were observed F. Willis J. British Journal of Haematology, 2001; 114: 891, In 14/20 pts with immune cytopenias (AIHA, ITP, PRCA) a therapeutical response was obtained. Marsh JC. Cytotherapy. 2001;3: In 1 pt refractory to steroid, splenectomy, rituximab: RC Cheun WW, Haematologica 2006, 91 (5 Suppl) In 1 pt with AIHA & CLL: RC Ludin J, Med Oncol 2006; 23:137-9 In 5 pts with AIHA & CLL: RC Karlsson C, Leukemia 2007; 21: cumulative response 24/31 (77%)
37 Mycophenolate therapy in AIHA 4 pts with AIHA and 6 with ITP showed a CR or a good PR Howard, Br J Haematol. 2002;117: pts with AIHA secondary to MDS showed CR Lin JT, Ann Hematol. 2002; 81: pts with AIHA secondary to ESL showed a good PR Alba P, Lupus. 2003;12: pts with AIHA (1 Evans S.) + 9 ITP showed 100% and 78% response respectively Koth R, Eur J Hematol 2005; 75: 60-4
38 Authors Diagnosis Age /sex Outcome AUTOLOGOUS Tx Martino et al (1997) Evans S. 25/F PBSC death Musso et al (1998) Evans S. + LES 17/F PBSC CR Jindra et al (1999) AIHA+ LLC 48/M PBSC CR De Stefano et al (1999) AIHA + Thal. Int. 12/M PBSC relapse Paillard et al (2000) AIHA 8/M PBSC CR Seeliger S et al (2001) AIHA 6/M PBSC PR Huhn et al (2003) Evans S. (5 pts) 35-52/3M,2F PBSC 3CR, 2 NR ALLOGENEIC Tx BMT IN AIHA Raetz et al (1997) Evans S. 5/M HLA-id CR De Stefano et al (1999) AIHA + Thal. Int. 12/M unrel CR Oyama et al (2001) Evans S. CR Marmont (2003) Evans S. M/HLA-id CR Passweg et al (2004) Evans S. (5 pts) PBSC 1CR, 2 deaths Urban (2006) Evans S. 7/M Unrel Cord CR
39 TREATMENT OPTIONS FOR AIHA steroids azathioprine, CTX, VCR splenectomy Cyclosporine Rituximab Campath-1 Mycophenolate BMT danazol i.v. immunoglobulins plasmapheresis vincristine-loaded plts blood transfusion
40 Therapy of AIHA Conclusions Usually, AIHA are easy to diagnose and cure and have a favourable prognosis. However, in rare cases the diagnosis may be difficult, or the disease particularly severe and refractory to standard treatments. These cases may represent a critical problem. Diagnostic and therapeutic protocols, and controlled clinical trials with most recently available drugs are needed.
41 FINE
42 Therapy with danazol in warm antibody AIHA N. Response (%) very good/good poor idiopathic AIHA secondary AIHA Ahn Ys. Acta Hematol, 1990; 84:122
43 Chan & Sack, J rheumatol 1991; 18: 280 CR to danazol in one AIHA-SLE patient refractory to cortocosteroids, splenectomy, azathioprine, chlorambucil and Ig i.v. Lugassy et al., Ann Hematol. 1993, 67: 143 Severe autoimmune hemolytic anemia with cold agglutinin and sclerodermic features--favorable response to danazol. Pignon et al., Br J Hematol. 1993, 83: % long lasting response in 7 AIHA refractory or relapsed after initial response to prednison
44 73 cases with warm antibodies AIHA treated with iv. Ig (Flores G., et al, Am J Hematol, 1993; 44:237) Only 9 of 62 (14.8%) had a good response Global efficacy of 40%, better in pediatric patients (54,5%) than in adults (37%)
45 Relationship between pretreatment Hb levels and response to i.v. Ig therapy in AIHA patients Hb I type response II type response No response g/dl % % % < I type response : ΔHb 2 g/dl within 10 d II type response: ΔHb 2 g/dl within 10 d, with Hb > 10g/dL Flores et al, AM J Hemat, 1993; 44:237
46 Relationship between hepatomegaly and response to i.v. Ig therapy Response type I type II None Hepatomegaly alone Hepatosplenomegaly All hepatomegaly Splenomegaly Flores et al, AM J Hemat, 1993; 44:237
47 Ratko et al, consensus conference on Intravenous immunoglobulin preparations (1999) - evaluated 77 patients with AIHA - most Ig i.v recipients had WAIHA refractory to other therapies. - The report concludes by stating that is difficult to evaluate the clinical value of Ig i.v therapy for AIHA adequately, primarily because no data from randomised, comparative trials are available. Sacher RA. Intravenous immunoglobulin consensus statement, J Allergy Clin Immunol AIHA not mentioned in the report of this panel Anderson D.Guidelines on the use of i.v. Ig for hematological conditions (Transf. Med. Rev.) - i.v. Ig not recommended for use in AIHA, except under certain life threatening circumstances-
48 Plasmapheresis in AIHA Therapeutic benefit of plasmapheresis is sustained by level V evidence No controlled clinical studies, only anecdotal reports von Baeyer H. Plasmapheresis in immune hematology: review of clinical outcome data with respect to evidence-based medicine and clinical experience. Therap Apher Dial. 2003;7:127-40
49 Shnaider et al, Am J Nephrol, 2001; 21:494 Severe Coombs'-negative autoimmune hemolytic anemia in a kidney transplant patient. Javeed et al, Transfusion, 2002;42:1217 Durable response to combination therapy including staphylococcal protein A immunoadsorption in life-threatening refractory autoimmune hemolysis. Roy-Burman & Glader, Crit Care Med, 2002 ;30:931 Resolution of severe Donath-Landsteiner autoimmune hemolytic anemia temporally associated with institution of plasmapheresis. von Baeyer Ther Apher Dial, 2003; 7 :127 Plasmapheresis in immune hematology: review of clinical outcome data with respect to evidence-based medicine and clinical experience.
50 Hct 0,4 TREATMENT WITH PLASMA-EXCHANGE IN A PATIENT WITH AIHA TYPE IgG P.E. 0,3 0,2 0,1 0 Retics (%) days trasfusions (N.) PREDNISONE (MG/day)
51 Vincristine-loaded platelet infusion for treatment of refractory autoimmune hemolytic anemia and chronic immune thrombocytopenia: rethinking old cures. Shvidel L, Sigler F, Shtalrid M, Berrebi A. Am J Hematol Jun;81(6): AIHA, 3 ITP, 3 Evans syndrome The response was prompt in all pts, occurring 3-8 days after vincristine-loaded platelet infusion. Two patients with AIHA are still in remission 9 and 8 years posttreatment with no maintenance treatment. Three ITP patients achieved persisted partial response for 6 years, 5 years, and 11 months; in the remaining 5 patients the response lasted for 2-5 months. No side effects were seen.
52 BLOOD TRANSFUSION IN AIHA Blood should never be denied a patient with a justifiable need, even though the compatibility test may be strongly positive Probably the most common mistake is reluctance to transfuse those patients with severe anemia
53 Risks of blood transfusion in AIHA Autoantibody will cause short survival of transfused RBCs Alloantibodies may be present in addition to the antibody
54 RBC alloantibodies in patients with warm autoantibodies. REFERENCE % of sera alloantibodies Morel et al, Branch & Petz, Wallhermfechtel et al, Laine & Beattie, James et al, Zanella & Rossi, Issit et al (alloadsorptions), Liger & Garratty, total 34
55 Petz & Garratty, 2004
56 Detection of alloantibodies in AIHA Testing patient s serum against RBC panel Dilution technique: will be accurate only if alloantibody is in higher titer than autoantibody Allogeneic adsorption procedure Warm autoadsorption procedure Leger & Garratty, Transfusion 1999
57 Warm autoadsorption procedure The optimal technique when feasible Rule of thumb IAT of 1+ : one adsorption IAT of 2+ : two adsorptions IAT of 3+ : three adsorptions IAT of 4+ : three or more adsorptions Technique should not be used if patient has been transfused in the last three months, unless pre-transfusion RBC are avaiilable
58 antibody specificity red cell phenotyping
59 Autoantibody specificity Identifying alloantibodies is more critical If the autoantibody demostrates specificity, including Rh relative specificity, and if appropriate blood can be found, it may help the survival of transfused RBCs
60 Warm N. cases Cold N. cases autoantibodies autoantibodies e 99 I 478 E 15 i 40 c 10 Pr 13 D 8 Tj a 4 C 4 A I 2 Mix 30 other 3 Total pts 706 Total transfused units 2954 Hemolytic transf. reactions 0 Sokol et al, 1995
61 Red cell phenotyping For all patients with warm antibody AIHA who require transfusion, the patient s extended phenotype should be determined prior to the initial transfusion If time does not allow, it is nevertheless advisable to obtain blood specifmen for subsequent typing Once the patient has been transfused, it may be impossible to determine the patient s phenotype
62 Using phenotypically matched RBCs If one knows the patient s extended phenotype (D,C,E,c, e,k,jka,jkb,fya,fyb,s ans s) and if the blood supplier can provide units negative for all these antigens not present on the patient s RBC, this method appears to be as safe as using antigenic adsorptions.
63 Least incompatible units Identifying less strongly reactive units from among incompatible units may erroneously be considered as an acceptable alternative to detecting and determining the specificity of alloantibody If alloantibodies have been excluded, it may provide a measure of satisfaction to select least incompatible unit. However, there are no data indicating significance of selecting least incompatible units
64 Communicating with clinicians Message should be: We have attempted to exclude alloantibodies to minimize the possibility of an alloantibody-induced hemolytic transfusion reaction. RBC survival will not be normal because the autoantibody will cause the RBC survival to be shortened, but acute and severe reactions are not likely.
65 Optimal volume of blood to be transfused Avoid aggressive transfusion practices, since the number of RBC hemolyzed per unit time is related to the number of RBC present Augmented amount of hemolysis may cause post-transfusion hemoglobinuria and lead to DIC with subsequent morbidity and mortality
66 FINE
67 AIHA in CLL
68 Autoimmune complications in CLL 194 complications / 3150 cases of CLL = 6.15% Other (30/194, 15.45%) AITP (35/194, 18.04%) bullous pemphigus (n=9), Hashimoto s thyroiditis (n=8), rheumatoid arthritis (n=4), systemic lupus erythematosus (n=1), autoimmune glomerulonephritis (n=1), autoimmune gastritis (n=1), Sjögren s syndrome (n=1), polymyositis-dermatomyositis (n=1), vasculitis (n=1), autoimmune polyneuropathy (n=1), ulcerative colitis(n=1), Raynaud s disease (n=1). AIHA (129/194, 66.49%) Prevalence of AIHA in CLL 4%
69 AIHA in CLL: relationship with disease stage and therapy OD CL 70 Stage A Stage A (%) 26(23) 1.00 Ref 60 Stage B Stage B (%) Stage 26(23) C Stage C (%) 61(54) % No therapy (%) 2 (2) 1.00 Ref I line therapy (%) (51) 7 10 II line therapy (%) 0 (47) 4 CLL CLL+AIHA II line-treated with Chi fludarabine square P< (25) (%) % no therapy I line II line CLL CLL+AIHA Chi square P<0.001
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71 Conclusions
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75 AIHA classification (serological) WARM AIHA COLD AIHA (CHD, PCH) MIXED AIHA ATYPICAL AIHA ( warm IgM AIHA; DAT- AIHA)
76 ST Johnson, JT Fueger, JL Gottschall One center s experience:the serology and drugs associated with drug-induced immune hemolytic anemia-a new paradigm Transfusion 47, , pts with 73 drug-dependent antibodies to 23 different drugs 37 (51%) to cephalosporins, 12 (16%) to penicillin & derivatives, 11 (15%) NSAIDs (4 required urinary metabolyte for detection) 7 (9%) quinine and/or quinidine, 6 (8%) others DAT specificity: 17 IgG 48 IgG+C3 5 C3 only 3 DAT-Neg It is important to consider drug-induced immunohemolytic anemia when a patient presents as either warm- or cold-type AIHA
77 AIHA classification (serological) WARM AIHA COLD AIHA (CHD, PCH) MIXED AIHA ATYPICAL AIHA ( warm IgM AIHA; DAT- AIHA) DRUG-INDUCED IHA (drug-independent abs, drug-dependent abs) American Journal of Hematology. 2002; 69:
78 AIHA: hematological data WARM (286) COLD (95) MIXED (15) Hb (g/dl) ( ) (5-13) (4.5-10) WBC (x10 9 /L) (1.2-32) ( ) ( ) PLT (x10 9 /L) (9-911) (15-492) ( ) Bilirubin (mg/dl) ( ) (0.4-8) ( ) Retics (%) (0.8-46) (1-31) (4-40)
79 AIHA - CRITICAL SEROLOGICAL ASPECTS NEGATIVE DAT RESULTS IN AIHA (DAT - negative AIHA) Causes Solutions - AutoAbs of only IgA type monospecific sera - AutoAbs IgG with low affinity Wash with LISS Cold wash
80 AIHA: SEROLOGICAL DIAGNOSTIC ASPECTS NEGATIVE DAT RESULTS IN AIHA (DAT-NEGATIVE AIHA) Causes - AutoAbs of only IgA type Solutions Monospecific sera - AutoAbs IgG with low affinity Wash with LISS Cold wash - Low sensitivity of the test More sensitive Tests
81 Unusual epidemiological aspects of AIHA
82 Therapeutical aspects Rituximab Transfusion
83 WARM AIHA- Epidemiological, clinical & hematological aspects
84 DAT AIHA ALLO-IHA DRUG-induced Tot Positives Auto Auto+Allo Direct antiglobulin test (DAT) Antibody identification (serum and eluate) Complete erythrocyte phenotyping Additional serological investigations
85 DAT serum eluate interpretation + (IgG/IgG+C) + + AIHA, drug-indep. IHA transfusion reaction + (IgG/IgG+C) - - Drug-dependent IHA (neoantygen type) + (C alone) - - Drug-dependent IHA (immunocomplex type)
86 DAT - More sentive techniques RBCs washed with Lo-ion RBCs wash with LISS saline or saline at 4 C Polybrene PEG Microcolumn agglutination technique (CAT) Solid phase agglutination technique Flow cytometry Immunoenzymatic assay Monocyte/macrophage test
87 Mitogen-stimulated DAT: a new method for the diagnosis of AIHA Wilma Barcellini, Anna Zaninoni, Francesca Guia Imperiali, Alberto Zanella. IRCCS, Ospedale Maggiore Policlinico di Milano, Department of Haematology Blood Transf 2003; 2: Table II - Clinical and laboratory characteristics of DAT-negative, MS-DAT positive AIHA patients atient N Gender Hb g/dl Total bilirubin (unconjugated) µ mol/l Reticulocytes % Haptoglobin mg/l LDH U/l Steroid therapy DAT * MS-DAT IgG ng/ml 1 F (5) yes neg F (12) yes neg F (7) no neg M (9) no neg M (8) yes neg M (8) no neg M (22) no neg F (22) no neg M (18) no neg F (19) no neg M 8.8 n.d yes neg M (27) no neg F (8) no neg 314 ormal ange female male (0-12) <2% * DAT was performed with standard tube test, in solid phase and with enhancing solutions.
88 WARM ANTIBODIES AIHA- 1 ST LINE THERAPY Prednisone 40 mg/m 2 /d ( mg/d) stable Hb >10 g/dl Response 60 mg/m 2 /d - 10 mg/w - 5 mg/w - 2,5 mg/w yes Dose tapering mg/die 15 mg/die Stop yes Follow-up no no yes Response Minimal eff. dose <15 mg/d yes 3 sett. no Therapy 2 no
89 WARM ANTIBODIES AIHA-THERAPY 2 Absent or inadequate response to steroids SPLENECTOMY - Immediate response Complete 50-60% Partial 25-30% - No predictors of outcome - Surgical risk - Risk of infections IMMUNOSUPPRESSION (CONVENTIONAL) Azathioprine 80 mg/m 2 Cyclophosphamide 60 mg/m 2 Other (Vincristine, 6-MP, 6-TG) Cyclosporine 5 mg/kg/die - Late response - Side effects
90 MS-DAT COMPARED WITH TRADITIONAL METHODS FOR THE DETECTION OF ANTI-RBC AUTOIMMUNITY. TUBE MICRO COLUMN SOLID PHASE MS- DAT N HB MEDIUM MITOGEN - STIMULATED Tube positive Tube negative and other methods positive MS-DAT positive only consecutive cases of suspected AIHA were positive by one or more tests namely 14 DATtube, 19 microcolumn, 19 solid phase and 35 MS-DAT. Among the 14 DAT-tube positive cases, 11 were confirmed by all test, and 3 by one or more (1 microcolumn, 1 solid phase, and 1 MS- DAT), eluates were positive in 11, and 10/14 patients showed haemolytic anaemia. 26 DAT-tube negative cases, 7 were positive in microcolumn and solid-phase (eluates positive in 2/8, panreactive), and 16 in MS-DAT
91 MS-DAT COMPARED WITH TRADITIONAL METHODS FOR THE DETECTION OF ANTI-RBC AUTOIMMUNITY. Tube-negative/other methods positive and MS-DAT positive only cases included patients with B-CLL, myelodysplasia/aplasia, and thalassemia intermedia, in which autoimmune phenomena are more frequently observed than overt clinical autoimmune diseases. In the last 6 years we collected 10 cases of DAT (tube, microcoumn and solid phase)-negative AIHA in which the diagnosis was made on the basis of a positive MS-DAT. These cases represent roughly 3% of the 304 DAT-tube positive cases observed in the same period. MS-DAT allowed the identification of autoantibody specificity in culture supernatants of 2 cases which gave weak positive results in microcolumn/solid phase only. We conclude that a battery of tests rather than a single test is recommended for the diagnosis of AIHA, including MS-DAT as an additional test for selected cases, although results have to be cautiously interpreted in the whole clinical context.
92 AIHA Peculiar Topics
93 ASSOCIATION OF AIHA WITH THERAPY WITH PURINE NUCLEOSIDE ANALOGUES - 1 CLL commonly complicated by AIHA Fludarabine commonly used to treat CLL But therapy with fludarabine may also induce AIHA
94 COMPLICATIONS OF AIHA AIHA & THROMBOEMBOLISM AIHA & LYMPHOPROLIFERATIVE DISORDERS
95 AIHATherapeutic aspects
96 WARM AIHA - RESPONSE TO PREDNISONE Prednisone expected to provide a response in 70-85% pts. Of them: -only 30% remain in long term remission once the drug is is discontinued -a further 50% require maintenance doses -approximately 20-30% require additional second-line therapies Petz, Immune Hemolytic Anemias, 2004
97 Cyclosporine Increasingly used in autoimmune cytopenias including AIHA Several anecdotal case reports No controlled clinical studies In long-term treatment induces remission in 3/4 AIHA Emilia G, Messora C, Longo G, Bertesi M. Long-term salvage treatment by cyclosporin in refractory autoimmune haematological disorders. Br J Haematol 1996 May;93(2):341-4 In association with steroid improves the complete response rate and reduces relapse Liu H, Shao Z, Jing L. The effectiveness of cyclosporin A in the treatment of autoimmune hemolytic anemia and Evans syndrome. Zhonghua Xue Ye Xue Za Zhi Nov;22(11): Zhang Y, Chu Y, Chen G. Clinical analysis of 164 cases Coombs test positive autoimmune hemolyticanemia. Zhonghua Xue Ye Xue Za Zhi Nov;19(11):573-5.
98 AIHA in CLL
99 Conclusions
100
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