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What Is PNH?

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... an Abnormal Clone The Beginning of PNH The change that occurs in PNH stops the production of an anchor that ties some protein ... symptoms such as fatigue ... – PowerPoint PPT presentation

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Title: What Is PNH?


1
What Is PNH?
  • And What Can Be Done About It.

2
PNH Is
  • A disorder of blood
  • Rare
  • Due to a glitch (a mutation) in a gene in a
    single cell
  • Manifest in a variety of ways
  • Able to be treated

3
What We Will Cover Today
  • How does PNH get started?
  • What are the ways PNH affects the patient?
  • What can be done to treat PNH?

4
How Does PNH Get Started?
  • PNH is due to a change (a mutation) in a gene in
    a blood stem cell

5
What A Gene Does
Makes a protein
Gene
Protein
Copies itself for a new cell
In egg and sperm, carries characteristics to
next generation
6
What Is A Mutation?
  • A mutation is a mistake in a gene that arises
    during copying and is not corrected

7
What A Mutation Does
Makes a protein
Gene
Protein
Copies itself for a new cell
8
What A Mutation Does
Makes an altered protein
Gene
Protein
Copies itself for a new cell
9
What A Mutation Does
Makes less protein
Gene
Protein
Copies itself for a new cell
10
What A Mutation Does
Makes no protein
Gene
Protein
Copies itself for a new cell
11
When Mutations Occur in Stem Cells

12
Stem Cells
Egg
Sperm
Embryonic Stem Cell
Egg or Sperm
Blood
Muscle
Nerve
Etc.
Somatic Stem Cells
The Cells of Each Specific Organ
13
A Genetically-transmitted Mutation
Egg
Sperm
Mutation
Embryonic Stem Cell
Egg or Sperm
Blood
Muscle
Nerve
Etc.
Somatic Stem Cells
The Cells of Each Specific Organ
14
A Germ Line (Genetically-transmitted) Mutation
Egg
Sperm
Embryonic Stem Cell
Egg or Sperm
Blood
Muscle
Nerve
Etc.
Somatic Stem Cells
The Cells of Each Specific Organ
15
A Somatic Mutation
Egg
Sperm
Embryonic Stem Cell
Egg or Sperm
Blood
Muscle
Nerve
Etc.
Somatic Stem Cells
The Cells of Each Specific Organ
16
  • A Blood Stem Cell Can Give Rise To All The
    Different Cells Of The Blood

T LYMPHOCYTES
BLOOD STEM CELL
B LYMPHOCYTES
ERYTHROCYTES
GRANULOCYTES
MONOCYTES
PLATELETS
17
  • In PNH, a single mutation occurs in one blood
    stem cell

T LYMPHOCYTES
STEM CELL
B LYMPHOCYTES
ERYTHROCYTES
GRANULOCYTES
MONOCYTES
ALTERED GENE
PLATELETS
18
  • That Altered Stem Cell Can Give Rise to an
    Abnormal Clone

NORMAL
CLONES
ABNORMAL
CLONE
19
The Beginning of PNH
  • The change that occurs in PNH stops the
    production of an anchor that ties some protein
    molecules to the cell

20
Molecules Are Attached to the Surface of Cells
21
How Molecules Are Attached
Molecule Stuck Through Membrane
Molecule Attached To Anchor in Membrane
Anchor
Cell Membrane
22
The Defect in PNH
The Cell Cannot Make The Anchor
23
  • The GPI Anchor Defect in PNH

PNH
O
O-P-O
O
CH
CH
CH
2
2
O
O
CO
(180,1)
(224,5)
24
PNH and Aplastic Anemia

25
What Does PNH Have To Do With Aplastic Anemia
  • Many PNH patients have aplastic anemia or a
    history of aplastic anemia
  • Many PNH patients show signs of inadequate blood
    cell formation
  • Low granulocyte (white cell) and low platelet
    counts are such signs

26
What Does PNH Have To Do With Aplastic Anemia
  • All PNH patients have evidence of a lazy bone
    marrow
  • Therefore, whatever causes aplastic anemia
    (immune suppression?) may allow PNH to develop

27
Aplastic Anemia and PNH
PNH Cell
Aplastic Marrow
Normal Marrow
PNH Marrow
28
Diagnosing PNH

29
Monoclonal Antibody in the Diagnosis of PNH
Fluorescein
Anti-CD59
CD59
GPI Anchor
30
FLAER in the Diagnosis of PNH
Fluorescein
GPI Anchor
Aerolysin
31
Flow Cytometric Analysis of Red Blood Cells from
Patients with PNH
Control
Counts
PNH III
Normal
CD59
32
(No Transcript)
33
FLAER and Anti CD24 on Granulocytes
34
FLAER and Anti CD24 on Granulocytes
A B
35
A Small Population of Red Cells
36
Distribution of PNH-type Granulocytes in Healthy
Females and Patients With Bone Marrow Failure
Ishiyama, K. et al. Blood. 20031021211-1216.
37
Percent of Each Type of PNH Granulocyte
100
PNH III
80
60
Percent Cells in Population
PNH II
40
20
0
0
20
40
60
80
Cumulative Patients
38
Percent of Each Type of PNH Red Cell
100
80
60
Percent Cells in Population
40
PNH III
20
PNH II
0
0
20
40
60
80
100
Cumulative Patients
39
Complement and PNH

40
What is Complement and What Does It Have To Do
With PNH?
  • Complement is the name given to a group of blood
    proteins that act together to help the body get
    rid of microbiological invaders

41
Complement Attacks a Bacterium
42
(No Transcript)
43
Complement Attacks a Bacterium
44
What is Complement?
  • Complement circulates in an inactive form

45
Things That Activate Complement In Vivo
  • Tick-over activation
  • Endotoxin from gastrointestinal tract
  • Nocturnal periodicity
  • Massive hemolysis with gastrointestinal illness
  • Almost any infection, surgery, or trauma
  • External immune reactions

46
Complement Attacks a Red Cell
Complement
47
The Normal Red Cell Defends Itself with CD59
CD59
48
The PNH Red Cell Cannot Defend Itself
49
And Is Destroyed
50
What Are The Effects of Releasing Hemoglobin?
  • Some of the hemoglobin passes through the kidneys
    and into the urine, causing red to dark brown
    urine
  • This causes a marked loss of iron from the body
  • In the long run, this damages the kidney

51
What Are The Effects of Releasing Hemoglobin?
  • Free hemoglobin binds an important regulator of
    smooth muscle activity - nitric oxide (NO)

52
Action of Nitric Oxide (NO)
NO
NO
Smooth Muscle Relaxation
Smooth Muscle Contraction
53
Free Hemoglobin Binds NO
NO
NO
Smooth Muscle Relaxation
NO
Free Hemoglobin
Smooth Muscle Contraction
54
What Are The Effects of Nitric Oxide Trapping by
Hemoglobin
  • Spasm of the esophagus
  • Abdominal pain
  • Erectile dysfunction
  • Kidney dysfunction
  • High blood pressure in arteries to the lung
  • ? Other symptoms such as fatigue

55
What Happens in PNH When Complement Is Activated?
  • Platelets are attacked and become activated
  • They stick together and form clots

56
Where Are The Clots in PNH?
  • The clots may be in common places
  • Veins of the leg
  • The clots are often in unusual places
  • Liver veins (Budd-Chiari syndrome
  • Other abdominal veins
  • Veins covering the brain
  • Skin veins

57
The Clinical Picture in PNH
  • Hemolytic anemia due to complement activation
  • Hemoglobin in the urine and, eventually, kidney
    damage
  • Anemia to a variable degree
  • Effects of nitric oxide (NO) trapping

58
The Clinical Picture in PNH
  • Thrombosis due to complement activation
  • Often in unusual places (liver veins, abdominal
    veins, etc)
  • Lazy bone marrow (not related to complement
    activation)

59
What Can Be Done For PNH?
  • Symptomatic treatment of anemia
  • Iron supplementation
  • Folic acid
  • Transfusion
  • Prednisone
  • Specific treatment of anemia
  • Stopping complement effects by eculizimab

60
What Is Eculizimab (Soliris)?
  • It is an inactivating antibody to C5, a component
    of complement involved in destroying the cell
  • It prevents the formation of the complex
    responsible for breaking down the membrane of the
    cell

61
Soliris Inactivates Complement
62
What Does Soliris Do?
  • Quickly and markedly reduces hemolysis
  • Stops hemoglobinuria
  • Increases hematocrit and hemoglobin level
  • Reduces transfusions
  • Hematocrit may not be quite normal

63
Reduction in LDH During Soliris Treatment in
TRIUMPH and SHEPHERD
3000
TRIUMPH Placebo/extension
TRIUMPH SOLIRIS/extension
2500
SHEPHERD SOLIRIS
2000
Lactate Dehydrogenase (U/L)
1500
1000
500
0
0
10
20
30
40
50
Time, Weeks
64
D.T., urine score 2 weeks before after
Eculizumab
4
7
7
5
5
8
8
5
8
4
1
1
8
1
1
1
1
1
1
1
1
1
1
1
1
1
1
4
Pre-eculizumab
Post-eculizumab
65
Effect of Soliris on Ability to Maintain a Good
Hemoglobin
66
Effect of Soliris on Transfusion in PNH
10
8
Plt0.0000001
Transfused Units/Patient (median)
6
4
2
0
Soliris
Placebo
67
What Does Soliris Do?
  • Stops the symptoms associated with hemolysis
  • Fatigue
  • Esophageal and abdominal spasm
  • Erectile dysfunction
  • Improves sense of well being

68
What Can Be Done For PNH?
  • Treatment of thrombosis
  • Prevention and treatment by coumadin or heparin
    (blood thinners)
  • Acute treatment by clot busters
  • Stopping the effect of complement activation
  • Prednisone
  • Eculizumab (Soliris),

69
What Does Soliris Do?
  • Appears to reduce thrombosis
  • May change role of chronic blood thinning

70
Clots in Patients With and Without Soliris
7.37
8.00
7.00
6.00
5.00
(Events per 100 Pt-Years)
Thrombosis Event Rate
4.00
(Plt0.0000000000001)
3.00
2.00
1.07
1.00
0.00
Pre-Soliris Treatment
Soliris Treatment
Hillmn P, et al. Blood. First Edition Papr,
prepublished online August 16, 2007.
71
What Does Soliris Do?
  • Improves kidney function
  • May in part be due to reduced hemoglobinuria
  • May in part be due to availability of nitric
    oxide
  • Improves hypertension

72
What Does Soliris NOT Do?
  • Does not appear to improve impaired hematopoiesis
    (lazy bone marrow)
  • Low white count or low platelet count will
    persist
  • Other treatments may be indicated
  • Bone marrow transplantation
  • ATG and other immunosuppressives

73
Downside of Soliris Treatment
  • Susceptibility to sepsis by meningococcal
    organism
  • All patients must be vaccinated
  • All patients must know to seek medical help at
    once when fever happens
  • All patients must carry cards describing this
    complication
  • Cost
  • Inconvenience
  • Must be given every 12-14 days by vein

74
Who Should Get Soliris?
  • Patients with significant anemia, especially
    those requiring transfusion
  • Patients with clots or a history of clots,
    especially of the abdomen or brain
  • Patients incapacitated by symptoms of PNH

In all cases, the decision should be made
by doctors and patients that understand PNH and
its treatment
75
The End
  • Any Questions?
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