Pnh & Aaa
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PNH & Aplastic Anaemia
By Najmaldin Saki
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Paroxysmal nocturnal haemoglobinuria
PNH
Paroxysmal nocturnal haemoglobinuria
PNH
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•Clinical features
PNH
Haemolytic anaemia
thrombosis
pancytopenia
AA PNH (PNH_AA Syndrome )
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•Laboratory findings & diagnosis
1.Haemoglobinuria
2.Hemosiderinuria
Ham test & Flow cytometry( gold standard)
Anti-CD59
Bilirubin levelLDH (U/L)HaptoglobinSerum iron &TSIBM
In a typical patient there may be,for instance 30% CD59- RBC & 90% CD59- granulocytes
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•Pathogenesis and pathophysiology
Inositol-P + GlcNAc = GPI
Acetylglucosaminyl transferase
Complement receptoroCD55 (DAF)oCD59 (MIRL)Adhesion moleculesCD48CD58(LFA3)CD66b & CD66cEnzymesAcetylcholinesteraseLeucocyte alkaline phosphataseCD157Receptors CD14 CD16U-PAR(CD87)OthersCD52CD90Prion protein
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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
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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
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Inherited aplastic anaemia &bone marrow failure syndromes
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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)
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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.
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Cell and molecular biology
Increased chromosomal breakage after exposure DEB & MMC
Abnormal cell cycle kineticshypersensitivity to oxygenincreased apoptosisaccelerated telomere shortening
(FA-A, FA-B, FA-C, FA-D1,FA-D2, FA-E, FA-F and FA-G)
EACGF
EACGF
D2D2
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Treatment
SCTAndrogens (oxymetholone)Corticosteroids (prednisolone)Dyskeratosis congenita
X-linked & autosomal recessive and dominant
DKC1 geneX-linked
40%
hTR gene Dominant
5%
hTR gene Dominant
5%
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Acquired aplastic anaemiaAAA
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Aplastic anaemia
a hypocellular marrow(i)haemoglobin < 10 g/dL(ii) platelet count < 100 x 10⁹/L(iii) neutrophil count < 1.5 x 10⁹/L
Busulphan
ChloramphenicolSulphonamidesCotrimoxazole
Gold salts
Benzene
B19EBVHIV
SLEpregnancy
PathogenesisPathogenesis
autoimmune mechanism
human leucocyte antigen (HLA)DR2, specifically the DR15 split
cytotoxic suppressor (T cell release cytokines)
most persuasive evidence forthe autoimmune pathogenesis for aplastic anaemia remains theclinical response to antilymphocyte globulin (ALG) in abouttwo-thirds of patients
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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 myelofibrosismycobacterial infections anorexia nervosa prolonged starvation