PNH & Aplastic Anaemia

By Najmaldin Saki

Paroxysmal nocturnal haemoglobinuria

PNH

Paroxysmal nocturnal haemoglobinuria

PNH

•Clinical features

PNH

Haemolytic anaemia

thrombosis

pancytopenia

AA PNH (PNH_AA Syndrome )

•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

•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

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

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

Inherited aplastic anaemia &bone marrow failure syndromes

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)

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.

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

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%

Acquired aplastic anaemiaAAA

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

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