* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Ina AIHA
Survey
Document related concepts
Psychopharmacology wikipedia , lookup
Compounding wikipedia , lookup
Neuropsychopharmacology wikipedia , lookup
Pharmacognosy wikipedia , lookup
Pharmacogenomics wikipedia , lookup
Theralizumab wikipedia , lookup
Pharmaceutical industry wikipedia , lookup
Prescription costs wikipedia , lookup
Drug discovery wikipedia , lookup
Neuropharmacology wikipedia , lookup
Prescription drug prices in the United States wikipedia , lookup
Drug design wikipedia , lookup
Transcript
AUTOIMMUNE HAEMOLYTIC ANAEMIA American Journal of Hematology 69:258-271 (2002) Bradley C. Gehrs and Richard C. Friedberg University of Alabama, Birmingham INTRODUCTION •Ig G and/or Ig M bind to rbc surface ag – initiate rbc destruction via C system and RES •IHA – classification – autoimmune, alloimmune, drug induced •AIHA – a/b directed against self rbc cont •AIHA – incidence 1-3 cases/100,000 per year •Auto a/b usually reacted against high frequency ag – exhibit reactivity against allogeneic rbc as well PATHOGENESIS •Degree of haemolysis depends on : 1. Characteristic of antibodyquantity specificity T ability to fix C ability to bind to tissue machrophage. 2. target ag – density expression age of pt cont Ig G a poor activator for classical C p/way Generally Ig G sensitized rbc are eliminated by phagocyte of RES RES also have receptor for C3b and iC3b – can potentiate e/v hemolysis Ig M -- sensitized rbc ass with e/v and i/v hemolysis cont I/v – Ig M readily activated by classical C p/way Regulatory rbc protein DAF and MIRL – overwhelming C activation is req. to produce clinically evident i/v hemolysis More common Ig M sensitized rbc u/go e/v hemolysis cont REC have receptor for rbc bound C3b and iC3b resulting fr C activation Spleen – site for Ig G ass e/v hemolysis Liver (kupper cell) – site for Ig M ass e/v CLASSIFICATION OF AIHA 1. 1. 1. 1. Warm AIHA Idiopathic Secondary (LPD, A/ Immune) Cold AIHA Cold Agglutinin syndrome PCH Mixed AIHA Idiopathic secondary Drug induced Autoimmune type Drug adsorption type Neoantigen type cont Classification according to T reactivity of a/b Warm react strongly near 37 c Cold bind rbc strongly near 0-4 c d/o – about half of cases of secondary cold and warm AIHA Idiopathic more in female, peak at 4 and 5 decade Lymphoproliferative LAB EVALUATION criteria to dx AIHA – serologic evidence and clinical or lab evidence 2 WARM AIHA Intro 48% - 70% of AIHA incidence increase around 40 y/o children peak incidence at first 4 years of life cont variable clinical presentation fulminant hemolysis – jaundice, pallor, edema, dark urine, hepatosplenomrgaly pregnancy – 5x risk of dev auto a/b Lab Evaluation Hb, HCT – N in pt with indolent hemolysis Low in pt wt fulminant hem. Reticulocytosis Reticulocytopenia – early in d/o, secondary to a/I d/o, inadequate BM response Cont. WBC – mild leucocytosis FBP – Polychromasis, macrocytosis, NRBC Erythrophagocytosis, microspherocytes – a/I hemolysis BM – erythriod hyperplasis, Cont. IB – increase LDH – Increased Se haptoglobin – reduced Positive urine Hb and hemosiderin DAT – positive in 95% cases of WAIHA Ig G (20-66% Ig G + C3 (24 – 63%) C3 ( 7-14%) Cont. DAT – neg in small percentage A/b – in lower quantity than the detectable threshold Ig A or Ig M Warm auto a/b - panagglutination cont Risk of hemolysis: Presence of bound Ig G1, Ig G3 Presence of concomitantly bound Ig A and/or Ig M Quality of bound rbc auto a/b Strength of DAT Cont. Quantity of bound C Characteristic of boubd rbc ag Affinity of auto a/b to these ag No of Ig G fc and c receptor on machrophage Functional status of phagocyte system – Treatment If Bm can compensate – monitor Anaemia develop – steroids – first line of tx. 70 – 80% improve within 3 mo Splenectomy –fail steroid, second line of tx Removal primary site of e/v hem and site of a/b production. Response rate 60 – 75% Cont. Cytotoxic drug - fail steroid and splenectomy Response rate 40 – 60% Recently reported cases fail to steroid and chemo response to Rituximab ( anti CD 20) Plasma pheresis benefit in fulminant hemolysis Cont. IVIG Danazol, vincristine PC transfusion o Limited to life threatening anaemia o Least incompatible o Slow infusion cont Donor rbs are destroyed at same rate as auto rbc Exhibit specificity – ag neg unit should be transfused Transfusion may induce further auto a/b formation COLD AGGLITININ SYNDROME (CAS) Intro • 16 – 32% of AIHA • primary – older, peak incidence 70 y/o, > female • secondary – lymphoproliferative and inf cold env may exacerbate the condition pt may present with acryocyanosis, raynoud’s phenomenon Lab Evaluation FBP – rbc clumping, polychromasia, anisopoikilocytosis, occ spherocytes MCV – increase HB, HCT – mildly reduced Retic – mildly increased cont • IB,LDH – increased • Reduced se haptoglobin with hemoglobinuria – in severe exacerbation • DAT – positive for C3 and neg for Ig G • Majority of auto a/b are benign cont Pathological cold – large thermal amplitude with high titre ( > 1: 1000 at o-4 c) Primary CAS and CAS 2 t0 LPD has higher titre Pathophysiology Ig M auto a/b fix C1 – then initiate C cascade Warmer T ( at central circulation) – maximize C fixation and activation – facilitate hemolysis Dissociate cold agglutinin and allow them to bind back to rbc and rpt the cycle cont C cascade progress to MAC—i/v hemolysis Rbc bound C3d – E/V hemolysis 90% directed to I ag and remaining to i. Ag Treatment avoid cold T and tx primary ds severe hemolysis- immunosupressant steroid – rarely helpful for CAS splenectomy only benefit for pt wt Ig G cold agglutinin plasma pheresis severe hemolysis cont pc transfusion should be limited d/t 2 reason o least incompatible have higher risk if contain undetected allo a/b o most cold directed toward I ag, I ag neg donor – extremely rare o exogenous donor plasma can exacerbate hemolysis cont wash rbc – reduced exogenous C load use in line blood warmer keep pt warm PCH Intro un common 2-10% of AIHA acute cases predom in children, secondary to infection clinically presented with constitutional sx, hemoglobinuria, cold urticaria and raynoud’s phenomenon Lab Evaluation HCT,Hb – low Reticulocytopenia in acute phase later reticulocytosis FBP – agglutination, polychromasia, NRBC, Spherocytes, erythrophagocytosis Increased IB ,LDH cont Reduced se Haptoglobin Positive urine HB, hemosiderinuria ARF PCH – caused by biphasic Ig G auto a/b ( fix C at cold T and dissociate at higher T) ( Donath Landsteiner a/b) cont A/b are potent , small titre can cause hemolysis DAT – positive anti C3 , Ig G positive if performed at cold T Biphasic Ig G exhibit specificity against P ag DL test to detect biphasic auto a/b MIXED TYPE AIHA Intro ~Idiopathic or secondary to LPD or SLE ~Some pt with warm AIHA also possess cold agglutinin but not clinically significant Lab Evaluation DAT positive IgG,C3 Rbc eluate – panreactive warm Ig G auto a/b. Cold auto a/b usually exhibit specificity against I ag DRUG INDUCED AIHA Intro Produced hemolysis by immune or non immune mechanism 3 mech ~ induction of auto a/b ~ neoantigen ( i/c formation) ~ drug adsorption auto rbc cont Neoantigen formation ~ Drug bind weakly to normal rbc ~ Immune system perceive drug and rbc complex or conformational altered rbc as foreign cont Drug adsorption ~Drug strongly bound to rbc ~A/b directed against the drug interact with rbc Lab Evaluation 3 mech can be distinguished from the reaction of serum and eluate drug induced IHA 2 neoag formation or drugb adsorption has positive DAT require exogenous drug to detect the a/b cont drug induced IHA – serum and eluate a/b react with rbc panel even if drug absent Methyldopa o Induce auto a/b o Positive DAT 11%-36% of pt within 3-6 month of initiation o Positive DAT d/t bound Ig G cont Other drugs : lenodopa, mefenamic, diclofenac etc Treatment Auto a/b result in hemolysis anaemia < 1% Positive DAT alone is not indicated to stop the drugs If significant hemolysis – stop the drugs SEROLOGIC CHARACTERISTIC OF AIHA Ig type DAT Rbc eluate Specificity Warm Ig G (+A/M) Ig G+/M Ig G Panreactiv e CAS Ig M C3 NR I>i>>Pr PCH Ig G C3 NR P Mixed Ig G,M Ig G = C3 Ig G Panreactiv e Drug Ig G Ig +/C3 Ig G Often Rh related Thank You