Paroxysmal nocturnal haemoglobinuria (PNH) and aplastic anaemia (AA) are conditions characterized by haemolytic anaemia, thrombosis, and pancytopenia. PNH results from a somatic mutation in the PIG-A gene, impairing glycosylphosphatidylinositol (GPI) anchoring of proteins on cell surfaces. AA is an autoimmune disease causing bone marrow failure. Both conditions can involve defects in complement regulation and coagulation due to loss of GPI-anchored proteins. PNH and AA may occur together due to both an autoimmune attack on stem cells and a PIG-A mutation.

1. PNH & Aplastic Anaemia By Najmaldin Saki

2. Paroxysmal nocturnal haemoglobinuria PNH

3. Clinical features PNH Haemolytic anaemia thrombosis pancytopenia AA PNH (PNH_AA Syndrome )

4. Laboratory findings & diagnosis 1.Haemoglobinuria 2.Hemosiderinuria Ham test & Flow cytometry( gold standard) Anti-CD59 Bilirubin level LDH (U/L) Haptoglobin Serum iron &TSI BM In a typical patient there may be,for instance 30% CD59- RBC & 90% CD59- granulocytes

5. Pathogenesis and pathophysiology Inositol-P + GlcNAc = GPI Acetylglucosaminyl transferase Complement receptor CD55 (DAF) CD59 (MIRL) Adhesion molecules CD48 CD58(LFA3) CD66b & CD66c Enzymes Acetylcholinesterase Leucocyte alkaline phosphatase CD157 Receptors CD14 CD16 U-PAR(CD87) Others CD52 CD90 Prion protein

6. Thrombosis Impaired fibrinolysis,because u-PAR is a GPI-linked protein C activation could cause hypercoagulability or hyperactivity of platelates ADP release procoagulant activity of cell membrane

7. BM failure & relationship between PNH and AAA Patient with PNH becames “ less haemolytic ” AAA essentially an organ-specific autoimmune disease Intensive immunosuppressive treatment is standard of care in AAA Appears that two different mechanisms co-operate in producing PNH Autoimmune damage to stem cells Somatic mutation in the PIG_A gene

8. Inherited aplastic anaemia & bone marrow failure syndromes

9. Pancytopenia Fanconi anaemia (FA) Dyskeratosis congenita (DC) Shwachman–Diamond syndrome (SDS) Reticular dysgenesis Pearson syndrome (PS) Familial aplastic anaemia (autosomal and X-linked forms) Myelodysplasia Non-haematological syndromes (Down, Dubowitz syndromes) Single cytopenia (usually) Anaemia ( Diamond–Blackfan anaemia , DBA) Neutropenia (severe congenital neutropenia, SCN, including Kostmann syndrome ) Thrombocytopenia (congenital amegakaryocytic thrombocytopenia, CAMT, amegakaryocytic thrombocytopenia with absent radii, TAR)

10. Fanconi anaemia Clinical features Pancytopenia autosomal recessive increased predisposition to malignancy, especially acute myeloid leukaemia . abnormalities including skin, skeletal , genitourinary ,gastrointestinal, cardiac and neurological anomalies. The haemoglobin (Hb) and platelet count are usually first to fall There is often a marked increase in macrophage activity with evidence of haemophagocytosis.

11. Cell and molecular biology Increased chromosomal breakage after exposure DEB & MMC Abnormal cell cycle kinetics hypersensitivity to oxygen increased apoptosis accelerated telomere shortening ( FA-A , FA-B, FA-C, FA-D1, FA-D2, FA-E, FA-F and FA-G ) E AC GF D2

12. Treatment SCT Androgens (oxymetholone) Corticosteroids (prednisolone) Dyskeratosis congenita X-linked & autosomal recessive and dominant DKC1 gene X-linked 40% hTR gene Dominant 5%

13. Acquired aplastic anaemia AAA

14. Aplastic anaemia a hypocellular marrow haemoglobin < 10 g/dL (ii) platelet count < 100 x 10⁹/L (iii) neutrophil count < 1.5 x 10⁹/L Busulphan Chloramphenicol Sulphonamides Cotrimoxazole Gold salts Benzene B19 EBV HIV SLE pregnancy Pathogenesis autoimmune mechanism human leucocyte antigen (HLA) DR2, specifically the DR15 split cytotoxic suppressor (T cell release cytokines) most persuasive evidence for the autoimmune pathogenesis for aplastic anaemia remains the clinical response to antilymphocyte globulin (ALG) in about two-thirds of patients

15. Telomere shortening Haematology relative reticulocytosis toxic granulation Reticulin is not increased trisomy 8, trisomy 6, 5q– and anomalies of chromosomes 7 and 13 Other conditions that can also present with pancytopenia and a hypocellular BM hypocellular myelodysplastic syndrome hypocellular acute myeloid leukaemia hypocellular acute lymphoblastic leukaemia hairy cell leukaemia lymphoma myelofibrosis mycobacterial infections anorexia nervosa prolonged starvation