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What Is PNH

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In egg and sperm, carries. characteristics to next generation. What Is A Mutation? ... Sperm. The Cells of Each Specific Organ. A Stem Cell Can Give Rise To ... – 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 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 one?
  • What can be done to treat PNH?

4
How Does PNH Get Started?
  • PNH is due to a change 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
  • The mutation is transmitted to daughter cells
  • The effect of a mutation
  • None
  • An altered protein
  • No protein is produced

7
Stem Cells
Egg
Sperm
Egg
Embryonic Stem Cell
Egg or Sperm
Blood
Muscle
Nerve
Etc.
Somatic Stem Cells
The Cells of Each Specific Organ
8
Stem Cells
Egg
Sperm
Egg
Embryonic Stem Cell
Egg or Sperm
Blood
Muscle
Nerve
Etc.
Somatic Stem Cells
The Cells of Each Specific Organ
9
Stem Cells
Egg
Sperm
Egg
Embryonic Stem Cell
Egg or Sperm
Blood
Muscle
Nerve
Etc.
Somatic Stem Cells
The Cells of Each Specific Organ
10
  • A Stem Cell Can Give Rise To All The Cells Of The
    Blood

T LYMPHOCYTES
STEM CELL
B LYMPHOCYTES
ERYTHROCYTES
GRANULOCYTES
MONOCYTES
PLATELETS
11
  • In PNH, a single mutation occurs in one blood
    stem cell

T LYMPHOCYTES
STEM CELL
B LYMPHOCYTES
ERYTHROCYTES
GRANULOCYTES
MONOCYTES
ALTERED GENE
PLATELETS
12
  • Evolution of PNH in Marrow

NORMAL
CLONES
ABNORMAL
CLONE
13
The Beginning of PNH
  • The change that occurs in PNH stops the
    production of an anchor that ties protein
    molecules to the cell
  • Sometimes the stop is only partial and PNH II
    cells occur

14
  • The GPI Anchor Defect in PNH

PNH
O
O-P-O
O
CH
CH
CH
2
2
O
O
CO
(180,1)
(224,5)
15
The Beginning of PNH
  • The change that occurs in PNH stops the
    production of an anchor that ties protein
    molecules to the outside of the cell
  • Sometimes the stop is only partial and PNH II
    cells occur
  • About 25 molecules are not attached but only one
    plays a major role in causing PNH
  • This is CD59, which protects the cells from
    complement

16
How Do These Abnormal Cells Take Over The Bone
Marrow?
  • Many normal people have blood stem cells with the
    abnormality characteristic of PNH in very small
    numbers (perhaps 6 per 1,000,000 bone marrow
    cells)
  • In PNH, something allows the abnormal cells to
    become a major population in the marrow and blood
    (anywhere from 1 to over 90)
  • This something may be related to aplastic
    anemia, a disease of poor production of blood
    from the marrow

17
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
  • All patients have evidence of a lazy bone
    marrow
  • Therefore, whatever causes aplastic anemia
    (immune suppression?) may allow PNH to develope

18
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
  • One of the ways it does this is by penetrating
    the membrane (outside surface) of the invading
    organism
  • When this happens to red cells, they burst,
    releasing their hemoglobin

19
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20
(No Transcript)
21
What is Complement?
  • Complement circulates in an inactive form
  • It is activated spontaneously and by a variety of
    events (infections, trauma, etc.)
  • It is normally activated more at night

22
How Are Our Cells Normally Protected From
Complement
  • Proteins in the serum inactivate complement when
    it is activated
  • Proteins on the cell surface inactivate
    complement to prevent breakdown (lysis)
  • The most important of these is CD59, which is
    missing on the abnormal cells of PNH
  • For this reason, PNH red cells are extremely
    sensitive to very small amounts of activated
    complement

23
What Happens in PNH When Complement Is Activated?
  • Complement successfully attacks the red cells and
    they break up (hemolysis)
  • This releases hemoglobin (the red pigment in red
    cells) into the plasma (the fluid part of the
    blood)
  • The red cells are destroyed, resulting in anemia

24
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
  • Free hemoglobin binds nitric oxide

25
Action of Nitric Oxide (NO)
NO
NO
Smooth Muscle Relaxation
Smooth Muscle Contraction
26
Free Hemoglobin Binds NO
NO
NO
Smooth Muscle Relaxation
NO
Free Hemoglobin
Smooth Muscle Contraction
27
What Are The Effects of Nitric Oxide Trapping by
Hemoglobin
  • Spasm of the esophagus
  • Abdominal pain
  • Erectile dysfunction
  • Other symptoms such as fatigue

28
What Happens in PNH When Complement Is Activated?
  • Platelets are attacked and become activated
  • They stick together and form clots

29
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30
What Happens in PNH When Complement Is Activated?
  • Platelets are attacked and become activated
  • They stick together and form clots
  • These clots are often in unusual places
  • Liver veins (Budd-Chiari syndrome
  • Other abdominal veins
  • Veins covering the brain

31
The Clinical Picture in PNH
  • Hemolytic anemia due to complement activation
  • Hemoglobinuria and, eventually, kidney damage
  • Anemia to a variable degree
  • Effects of NO trapping
  • Thrombosis due to complement activation
  • Often in unusual places (liver veins, abdominal
    veins, etc)
  • Lazy bone marrow (not related to complement
    activation)

32
What Can Be Done For PNH?
  • Symptomatic treatment
  • Iron supplementation
  • Folic acid
  • Transfusion

33
What Can Be Done For PNH?
  • Treatment of thrombosis
  • Prevention by coumadin
  • Acute treatment by clot busters
  • Use of coumadin or heparin
  • Stopping the effect of complement activation
  • Prednisone
  • Eculizumab (Soliris), an antibody that
    inactivates one of the components of complement
    (C5)

34
What Does Soliris Do?
  • Quickly and markedly reduces hemolysis
  • Stops hemoglobinuria
  • Increases hematocrit and hemoglobin level
  • Reduces transfusions
  • Hematocrit may not be quite normal

35
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
PI All patients sustained a reduction in
intravascular hemolysis over a total SOLIRIS
exposure time ranging from 10 to 54
months.
TRIUMPH placebo patients switched to SOLIRIS
after week 26. All TRIUMPH patients entered the
long term extension study.
36
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
37
Effect of Soliris on Ability to Maintain a Good
Hemoglobin
38
Effect of Soliris on Transfusion in PNH
10
8
Plt0.0000001
Transfused Units/Patient (median)
6
4
2
0
Soliris
Placebo
39
What Does Soliris Do?
  • Stops the symptoms associated with hemolysis
  • Fatigue
  • Esophageal and abdominal spasm
  • Erectile dysfunction
  • Improves sense of well being

40
What Does Soliris Do?
  • Appears to reduce thrombosis
  • May change role of chronic blood thinning

41
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.
42
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

43
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

44
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

45
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
46
The End
  • Any Questions?
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