Paroxysmal Nocturnal Hemoglobinuria (PNH) - Enerca . آ  Paroxysmal Nocturnal Hemoglobinuria

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  • 6th EUROPEAN SYMPOSIUM ON RARE ANAEMIAS 1st Dutch-Belgian meeting for patients and health professionals

    21st - 22nd November 2015

    Amsterdam - The Netherlands

    Paroxysmal Nocturnal Hemoglobinuria (PNH)

    Introduction to PNH Rosario Notaro

    Cancer Genetics and Gene Transfer

    Core Research Laboratory

    Istituto Toscano Tumori

    Florence, Italy

  • 6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

    Disclosures Company name Research

    support Employee

    Consultant Stockholder Speakers bureau Advisory board Other

    No conflicts to declare

  • 6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

    This talk is applicable for:

    Definite Probable

    Thalassemia’s

    Sickle cell disease

    Membrane disorders (e.g. sferocytosis)

    Enzym defects (e.g. PKD, G6PD)

    PNH Yes

    Other forms of hemolytic disease Yes

  • 6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

    Paroxysmal Nocturnal Hemoglobinuria

    Acquired disease (it is not transmitted to offspring)

    Prevalence: 5-10 cases per million

    Geographic distribution: worldwide

    Age: any

    Gender: same frequency in men and in women

  • 6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

    Chronic intravascular hemolysis: with crisis

    Thrombosis: Often Multiple, Venous, Abdominal

    PNH is a rare clonal acquired blood disorder

    characterized by the clinical triads:

    Cytopenias (Bone marrow failure): Common, sometimes severe

    WBC /µl Plts /µl

    Paroxysmal Nocturnal Hemoglobinuria

  • 6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

    Transmembrane Proteins and GPI-linked Proteins

    Cell Membrane

    Cytoplasm

    Proteins

    glycophosphatidylinositol- GPI Anchor

  • CD59, CD90, CD109

    CD55

    CD58*

    CD59

    CD48

    CDw52

    PrPc

    CD16*

    CD24 CD55 CD58* CD59

    CD48 PrPC

    CD73 CDw108

    CD55

    CD58*

    CD59

    CD109

    PrPC

    GP500

    Gova/b

    CD55

    CD58*

    CD59

    PrPC

    AChE

    JMH Ag

    Dombroch

    HG Ag

    CD55 CD58*

    CD59 CD14

    CD16 CD24

    CD48 CD66b

    CD66c CD87

    CD109 CD157

    LAPNB1 PrPC

    p50-80 GPI-80

    ADP-RT

    NA1/N

    A2

    CD14 CD55

    CD58* CD59

    CD48 CDw52

    CD87 CD109

    CD157 Group 8

    PrPC GPI-80

    CD16*

    CD55 CD58*

    CD59 CD48

    CDw52 CD87

    CDw108 PrPc

    ADP-RT CD73

    CD90 CD109

    CD16*

    GPI-linked Proteins Deficient on PNH Blood Cells

    Hematopoietic

    Stem Cell

    Platelets

    RBC

    PMN

    B cells

    Monocytes

    T cells

    NK cells

  • nucleus

    ER

    X chr.

    PIGA

    + GPI protein

    Etn-P GlcN

    Inositol-P

    glycan

    PIGA

    GPI anchor

    nucleus

    ER

    X chr.

    PIGA

    + GPI protein

    PIGA

    GPI anchor

    Etn-P GlcN

    Inositol-P

    glycan

    Hematopoietic Stem Cell

    Normal cell Normal cell PNH cell

    Paroxysmal Nocturnal Hemoglobinuria (PNH)

    Pathogenesis

  • 6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

    • Intravascular hemolysis

    • Thrombosis

    • Bone marrow failure

    Paroxysmal Nocturnal Hemoglobinuria

  • 6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

    • Intravascular hemolysis

    • Thrombosis

    • Bone marrow failure

    Paroxysmal Nocturnal Hemoglobinuria

  • C5

    C3

    CD55

    CD59

    Factor H

    CD46

    CR1

    Factor I

    C5

    C3

    C4bp

    Complement Inhibitors

    Membrane Soluble

    Complement System Microorganisms Antigen-Antibody

    Constitutive/

    Microorganisms

    Classical pathway

    Lectin pathway

    Alternative pathway

    modified from Brown et al, Nat Clin Pract Nephrol 2007

    Clusterin

    Protein S

    C1 Inh

    Factor I

    Membrane

    Attack Complex

    CD55

    CD59

    in PNH

  • 6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

    Effects of intravascular hemolysis

    Hemosiderinuria

    Iron loss

    ANEMIA (low Hgb)

    Nitric oxide

    depletion

    smooth muscle

    dystonia

    • Abdominal pain

    • Fatigue

    • Dysphagia

    • Erectile disfunction

    • (Renal failure) • (Pulmonar hypertension)

    Intravascular hemolysis

    Hemoglobinemia

    Hemoglobinuria

    High LDH

    High Retics

  • 6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

    • Intravascular hemolysis

    • Thrombosis

    • Bone marrow failure

    Paroxysmal Nocturnal Hemoglobinuria

  • 6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

    • 30-40% of PNH patients suffer from at least a thrombotic event

    • 40–67% of deaths in PNH results from thromboembolisms

    • More frequent in hemolytic than in aplastic PNH patients

    • There is a rough correlation with the size of PNH population - but thrombosis can occur also in patients with small PNH population

    • More frequent in patients with congenital and acquired thrombophilic conditions

    • Substantial increased risk after the first thrombotic event

    PNH is a severe acquired thrombophilic state - thrombosis in PNH -

  • 6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

    Hillmen et al, Blood 2007

    Ictus/transient ischaemic attack (TIA)

    Myocardial infarction/unstable angina

    Arterial Thrombosis 15.3%

    Deep vein thrombosis

    - lower extremity

    - other

    Mesenteric/splenic vein thrombosis

    Hepatic/portal vein thrombosis

    Pulmonary embolus

    Cerebral/internal jugular thrombosis

    Superficial vein thrombosis

    Venous Thrombosis 84.7%

    % of Total

    33.1

    18.5

    14.5

    18.5

    16.9

    6.5

    5.6

    4.0

    13.7

    1.6

    Sites of thrombosis IN PNH

  • 6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

    Coagulation Complement

    M o

    d if ie

    d f ro

    m M

    a rk

    ie w

    s k i e

    t a

    l, T

    re n

    d s I m

    m u

    n o

    l 2

    0 0

    7

    Coagulation, Complement and PNH

    Partners in Crime?

    Coagulation Complement

  • 6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

    • Intravascular hemolysis

    • Thrombosis

    • Bone marrow failure

    Paroxysmal Nocturnal Hemoglobinuria

  • 6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

    Bone Marrow Failure and PNH Aplastic Anemia and PNH relationship

    Bone Marrow Failure and PNH

    Dual Pathogenesis of PNH

    Hemolysis

    Cytopenia

    PNH

    AA

    PNH/AA

    Bone Marrow Failure targeting GPI+ cells (?)

    Complement Susceptibility targeting GPI– cells

  • Rotoli & Luzzatto, 1989

    PIG-A+

    cells

    PIG-A null

    cells

    crippled

    PIG-A+ cells

    Noxious agent

    Time

    Paradoxical Expansion of PNH Clone (Escape Theory)

  • Y

    Y

    Y

    Y

    Y

    T Lymphocytes autoreactive T Lymphocytes Hematopoietic Stem cell

    ?? IFN

    IFN

    IFN

    IFN

    GPI protein

    GPI protein

    ID of Lymphocytes that

    damage normal cells and spare PNH cells Which is the target?

    Skewed TCR repertoire (Karadimitris et al, Blood 2000)

    Similar TCR sequences in oligoclonal T cells (Gargiulo et al, Blood 2007)

    GPI specific and CD1d restricted T cells (Gargiulo et al, Blood 2013)

  • Normal Stem Cell (GPI+) PNH Stem cell (GPI-)

    A Unified Pathogenetic Model for PNH and AA CD1d restricted autoreactive T cells target the GPI anchor

    anti-GPI TCR