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3 4 5 6 Gene CEINGE – Biotecnologie Avanzate Dipartimento di Biochimica e Biotecnologie Mediche Università Federico II, Napoli Ruolo della citometria nello studio del clone EPN Luigi Del Vecchio Firenze, 25 novembre 2010 PNH PATHOGENESIS PIG-A 1 2 3 4 5 6 gene PROTEIN C=O NH NH 2 PHOSPHO- NH2 CH GPI-anchor ETHANOLAMINE 2 CH2 O GLYCAN CORE O-P-O- O O O MAN Extracellular MAN COOH (α 1-2) (α 1-6) space (α 1-4) MAN O PHOSPHATIDYL GLU -INOSITOL N O- O=P-O INOS H C H2C CH2 O O O C=O C=O Cytoplasm COOH Transmembrane GPI-Anchored protein Protein GPI Linked Proteins in Blood Cells CD59, CD90, CD109 RBC B cells CD48 CD59 CD24 CD55 CD73 CD58 CD55 CD58 Stem Cell CD59 CD108 CD48 CD55 CD52 CD58 CD73 CD59 CD55 CD109 CD58 Platelets CD59 Monocytes CD87 CD24 CD108 CD66b T cells CD109 CD16 PMN CD66c CD87 CD55 CD58 CD48 CD59 CD55 CD48 CD58 CD109 CD14 CD55 CD58 CD59 CD59 CD157 CD48 CD52 CD87 CD109 CD52 CD157 CD16 NK cells PATHOPHYSIOLOGY OF PNH The dual hypothesis (Rotoli and Luzzatto, Baillieres Clin Haematol 1989) Mutazioni fisiologiche Danno autoimmune Prevalenza del clone Espansione del clone THE CLINICAL TRIAD OF PNH 1. Chronic hemolytic anemia with paroxistic crises Intravascular hemolysis, complement mediated Deficiency of CD55/CD59 2. Propensity to thromboembolisms Often at unusual site, especially veins (cerebral veins, hepatic veins, splenic vein) As a consequence of hemolysis. Deficiency of CD87 on neutrophils and of CD55/CD59 on PLT. 3. Variable cytopenia Condition allowing the growth of PNH clone Fate of PNH clone L.Luzzatto 1996 What patients to test for PNH? Usually 3 types of patients: . Cytopenias • Genuine aplastic anaemia (established on BM trephine biopsy) • Pancytopenia/neutropenia/isolated cytopenia . Thrombosis • Budd-Chiari, hepatic/mesenteric vein thrombosis • Other more likely causes of thrombosis must be investigated . Haemolysis/anaemia • Intravascular haemolysis and haemoglobinuria (paroxysmal & nocturnal!) PNH screening by flow cytometry Main cell lineages Red blood cells Granulocytes and monocytes RBC analysis a b . Log amplification for FSC/SSC . MoAbs to CD59 (MEM43) g r a n u l o c y t e s M o n o c y t e s Colors Lab Cells First Second Third Fourth Fifth Sixth Gating strategy 3 color G FLAER CD24 CD15 CD15/SSChi 3 color M FLAER CD14 CD33 CD33hi/SSCint 4 color G FLAER CD24 CD15 CD45 CD15hi/SSChi 4 color M FLAER CD14 CD33 CD45 CD33hi/SSClo 4 color G+M FLAER CD24 CD14 CD33 CD33hi/SSClo 5 color G+M FLAER CD24 CD14 CD15 CD33 CD15hi/CD33low/SSChi (grans) and CD33hi/SSCint (monos) 6 color G+M FLAER CD24 CD14 CD15 CD33 CD45 CD15hi/CD45int/SSChi/C D33lo (grans) and CD45hi/SSCint/CD33hi (monos) L. Del Vecchio, 2010 Assessment of PNH clone size Red cell clone size a) Type III and/or Type II red cells b) Proportion of PNH red cells is related to recent transfusion and hemolysis 1. PNH granulocytes a) More accurate reflection of PNH clone size 2. PNH monocytes a) Validates the size of clone Reporting results . Normal cases –report normal expression of GPI-linked antigens – no PNH clones detected. New cases – report GPI deficiency, cell lineages tested & PNH clone sizes. Monitoring – report PNH clone sizes and any changes . Proposal of reporting format in ClonePNH Magazine (www.clonePnh.com) . Cut-off point? Detection of PNH clone is cytometric, but final diagnosis is not only cytometric Classification of PNH Definition Haemolysis BMF Classic PNH + - PNH in the setting of + + other BM disorders Subclinical PNH - + www.clonePnh.com 26 ottobre 2010.
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