Download Organ Specific (sp) Autoimmunity:

PATHOPHYSIOLOGY OF ITP
o Autoimmune thrombocytopenic purpura (ITP) is a bleeding
disorder : autoantibodies are directed against an individual’s own
platelets
o Enhanced destruction by macrophages within spleen.
o Immune causes are unknown but: theories of autoimmunity .
o Most research : characterization of antiplatelet autoantibodies.
o Last 15 years,
research has suggested abnormal T cells are
responsible for stimulating and controlling B cells to produce
antiplatelet autoantibodies.
o Cytotoxic T cells (CTL) may be involved in platelets destruction
o Cell-mediated immunology of AITP
Organ Specific Autoimmunity:
o
o
Deficiency of central tolerance induction
mechanisms
Failure to eliminate or deactivate self reactive
lymphocytes.
Factors That Regulate
Central Tolerance:
Strength of Signals initiated by
antigen receptor
a.
b.
c.
d.
Avidity of interaction between antigen and
antigen receptor
Affinity of interaction between antigen and
antigen receptor
Co-stimulatory signals that enhance signal
strength (CD28)
Signals that attenuate signal strengthinhibitory receptors (CD5)
Factors That Regulate
Peripheral Tolerance:
Not all self-reactive T or B cells are deleted
during development:
a.
b.
c.
d.
e.
Need for a peripheral repertoire that will protect from
pathogens.
Peripheral tissue specific antigens not expressed in the
thymus.
Expression of neo-antigens occurring as a result of tissue
damage.
Expression of specific endopeptidases that modify
peptides in thymus.
Positive selection of specificities that exhibit weak selfreactivity
but
with
propensity
for
pathogenic
autoreactivity.
Control of autoreactive T cells in the periphery is
termed Peripheral Tolerance
Central Tolerance
o
o
Negative selection of immature lymphocytes by clonal
deletion of self reactive clones during development in
the thymus.
T cells – thymus
B cells – bone marrow
Clonal deletion occurs by induction of programmed cell
death or apoptosis.
Peripheral Tolerance:
o
Clonal deletion, clonal energy or clonal
ignorance of mature self-reactive T and
mature or transitional
B cells.
Regulated by:
Co-stimulatory molecules
Cytokines
Inhibitory molecules
T-Regulatory cells (Tr), T-suppressor cells (Ts)
Dendritic cells
Platelet count: <150X109/L
Acute:
o
o
o
o
o
Childhood disorder
Abrupt onset
Usually
follows
infectious illness
Spontaneous remission
Th0/Th 1 bias
Chronic:
o
o
o
o
o
>6 month duration
Organ
specific
autoimmune
disease
Autoantibodies
enhance
platelet
destruction
Presence of GPillareactive T cell
Cytokine abnormalities
ITP:
o
o
o
Acute AITP :Good example of molecular mimicry. Cross
reactivity of anti-viral antibodies with normal platelet
epitopes.
Chronic AITP: Immunodominat epitopes on GPllb-llla
recognized by autoreactive T cells in patients with
immune thrombocytopenic purpura
M. Kuwana, J. Kaburaki, H. Kitasato, M. Kato S. Kawai, Y.
Kawakami, and Y. Ikeda Blood 98:130, 2001
T Cell Characteristics:
o
o
o
o
o
o
Specificity of platelet-reactive T cell
lines from children with chronic ITP.
JW Semple, ER Speck, M Kim, V Blanchette, J Freedman
Blood 98 (11):441a, 2001
CD 4+ T cells>CD8+ T cells
Trend toward Th 1 (IFN) activation
Line primarily react with GPllb-llla
Antigen presenting cell dependent
T regulatory cells (TREG)
Transforming Growth Factor-:

Platelets are the largest source (mg amounts)

Also produced by CD4 T cells (TREG), especially by the Th3 subtype

Inhibits growth of B cells.

Inhibits activation of macrophages

Genetics knockouts are lethal at – 10 weeks of age
Platelet destruction in AITP
Many (=40%) patients with chronic AITP
have no detectible antibodies on their platelets
or in their plasma.
Why?
How are their platelets being destroyed?
Apoptosis
Apoptosis
Non-inflammatory cell death.
The body’s way of removing senescent cells
and cells that are not useful without reaction.
In chronic AITP, autoreactive CD4+ T cells
against platelet autoantigens are resistant to apoptosis.
This may explain why some chronic AITP patients
become refractory.
Apoptosis (non-inflammatory)
Necrosis (inflammatory)
Patterns of death
Single cells
Groups of neighboring cells
Cell shape changes
*Apoptosis bodies*
Shrinkage Fragmentation
Swelling disrupted
Plasma Membrane
Preserved continuity blabbed
Smoothing, early lysis, integrity lost
Mitochondria
Contents released into cytoplasm
Cytochrome c, Apart I
Non to limited role
Organelle
shape
Contracted
Swelling
Nuclei
Chromatin
Clumps & Fragmented
Membrane disruption
DNA
degradation
Fragmented
Intemudeosomal cleavage
DNA appears in cytoplasm
None to random
Conclusions

Chronic AITP is associated with a pro-inflammatory Th0/Th 1 cytokine
phenotype that appears responsible for antibody production.
 Autoreactive T cells from chronic AITP patients primarily react with
GPIIIa.

CD8+ T cells may also be responsible for platelet destruction in AITP.

Apoptosis-resistant T cells may be associated with refractoriness in
chronic AITP.
Targeting T cells in chronic AITP may be an effective therapy for
refractory patients.
HOT TOPICS AND ONGOING STUDIES IN ITP
James Bussel, MD
Professor of Pediatrics
The Weill Medical College of Cornell University, New York, NY
Immune thrombocytopenic purpura (ITP) is a chronic autoimmune disease characterized
by
autoantibody-mediated destruction of platelets. This increased platelet destruction is Fcdependent and classically assumes that there is increased platelet production that is overwhelmed by the rapid platelet destruction. However this appears not always of autologous
platelets all suggested that platelet survival might be longer than anticipated and turnover
(production) much lower.
Studies of one thrombopoietic agent, AMG531, have demonstrated remarkable efficacy
in
increasing the platelet count in 4 separate studies in ITP. One study in the US (presented at
ASH 2003) and one in Europe (poster presentation in 2004) have both demonstrated clear
efficacy in increasing the platelet count and minimal toxicity with single dose injections. A
follow-up study (to be presented orally at ASH) used 6 consecutive treatments and sustained
increased platelet counts in responders over the 6 weeks of treatment. Finally, a long-term
extension study enrolling patients entered into the initial studies has demonstrated continued
efficacy, little toxicity, and considerable individual variability in dose response. A second
molecule has increased the platelet count in healthy individuals and is entering clinical trial in
ITP.
Cont.
Another complex and confusing area in which a considerable number of studies have been
recently performed in the relationship of H pylori and ITP. Approximately 10-15 studies have
been published in which groups of patients with ITP have been examined for the presence of
H pylori infection by the Breath Test; the antibody test is neither as sensitive nor as specific
and is susceptible to being made falsely positive by IVIg. Many of these studies have suggested
that the eradication of H pylori. Eg by the PrevPak, will result in a substantial platelet increase
Within several months of treatment of the H pylori in approximately 50% of treated patients.
There are many uncertainties highlighted by the inability to predict response in individual
patients. Preliminary it would seem that being treated in Italy or Japan, having a higher
platelet count, and a shorter duration of disease all may be associated with a better likelihood
of response.
WHY IS IT ITP?
Eight years after the publication of the ASH guidelines (Goerge JN et al. Blood
1996;88:3-40), the diagnosis of ITP is still based principally on the history, physical
examination, complete blood count (CBC), and examination of the peripheral smear. Although
in the last years, a number of surrogate markers of platelet turnover including reticulated
platelets, glycocalicin, the mean platelet volume, and serum thrombopoietin have been tested
in patients with ITP, none of them has entered into routine clinical practice.
In the present case, the occurrence of thrombocytopenia in a 31 year-old woman is highly
suggestive of ITP. The estimated incidence of ITP is 1/10,000 per year and in ITP, the
female/male ratio is 1.7 to 2. Moreover, although the disease can occur in the elderly and
children, young adults (20 to 40 years) are preferentially affected.
By definition, except for the presence of bleeding symptoms of increased severity
(petechiae, bruising, “wet purpura,” nose bleeding) that are usually present when the platelet
count is equal to or below 30 x 109/L, no other abnormalities are found on physical examination
in ITP. If splenomegaly and/or lymphadenopathy are present, another cause of thrombocytopenia
must be considered.
Cont.
A low platelet count of 30 x 109/L without any other abnormality on the CBC is also strong
evidence for ITP. This implies not only a normal white cell count and a normal hemoglobin
level, but also a normal MCV. Checking standard coagulation tests (ie, PT, APTT, and
fibrinogen) and a liver test are helpful to rule out other causes of thrombocytopenia, such as
coagulopathy and liver disease. An accurate examination of the peripheral smear is also of
paramount importance. Pseudo-thrombocytopenia as well as many other causes of acquired
or hereditary thrombocytopenia can indeed be excluded if the blood smear shows no
abnormalities. A bone marrow aspirate is usually unnecessary when both the CBC and the
peripheral smear are normal. However, a bone marrow analysis is appropriate in patients aged
over 60 years to rule out a myelodysplastic syndrome and, whatever the age, if a patient does
not respond to corticosteroids or to intravenous immunoglobulin or when a splenectomy is
considered.
In this young woman, assuming that the CBC is, except for the low platelet count,
completely normal and the blood smear shows no atypical findings. I would definitely retain the
diagnosis of ITP as very likely and would consider treatment with steroids.
Why is it ITP?
Other clinical evidence for ITP in adults
 No medications known to cause thrombocytopenia
 No family history of thrombocytopenia
 afebrile
 No splenomegaly and/or lymphadenopathy
 Normal clinical examination (except for bleeding symptoms)
Why is it ITP?
Other useful biological tests
 Peripheral blood smear +++
 Normal reticulocyte count
 Normal coagulation tests )PT and APTT)
 Normal liver tests (AST)
 Bone marrow examination (?)
Why is it ITP?
Clinical evidence (case report)
 Woman => sex ratio (M/F)= 1 / 1.7 – 2
 Age 31 => 2 peaks, 2-4 years and young adults
(i.e 15-40)
 Frequency => incidence = 1/10 000/year
 Mild bruising (platelet-related bleeding)
Why is it ITP?
Biological evidence (case report)
 Thrombocytopenia <50 x 109/L
 Normal WBC and Hb level
 Normal MCV
Bone Marrow aspirate
USA (ASH 1996 guidelines)
“Europe”
- Age > 60 (MDS)
- If splenectomy is considered
- Age > 60 years
- other abnormality on CCBC
- atypical findings
- no response to standard
therapy
- prior to splenectomy
Markers of Platelet turnover
 Platelet survival study:
Isotopic studies with indium-labeled platelets
for the evaluation of platelet turnover:


Reduced life-span (accelerated
destruction)
Site of destruction (spleen vs liver)


Limitations:
Technically difficult (plt 30,000/L)
Very few centers available
ITP diagnosis (1996-2004)
In the absence of a “gold standard”, the
diagnosis
of ITP is still based on the exclusion of other
causes of thrombocytopenia……
Other tests that can appropriate/useful in
adult’s ITP
 Antinuclear
anti-DNA ds antibodies
 Anticardiolipin Abs / Lupus anticoagulant
 Ig levels (CVID, IgA deficiency)
 DAT
 Consider HIV and HCV tests
 Thyroid function tests
 EBV test
 H pylori testing
 Platelet antigen-specific antibody
 Platelet associated IgG(PAIgG)
Surrogate markers of platelet turnover
(increased production)
 Reticulated platelets
 MPV
 Large platelets (4-7 m)
 Glycocalicin
 TPO level
 Immature Platelet Fraction.
Any of these tests has entered in routine clinical practice
WHY ISN’T IT ITP?
OR, NOT EVERY LOW PLATELET COUNT MEANS ITP
Thormbocytopenia is defined as a platelet count of less than 150,000/L. However,
significant thrombocytopenia can occur in individuals with minimal symptoms and caution
must
be used in concluding that a low platelet count represents an acute or even a new finding.
Due
to increased use of routine platelet counts, significant numbers of patients are now known to
have incidental thrombocytopenia. This is generally mild, 50,000-150,000/L, and is usually
of
little clinical significance. Factitious thrombocytopenia, a laboratory artifact caused by
platelet
clumping in the presence of EDTA, must be excluded by examining the blood smear and/or
repeating the measurement in the presence of a different anticoagulant.
Inherited thrombocytopenia may be quite mild and careful inquiry will often identify a
long
history of symptoms dating back to childhood and a family history consistent with autosomal
dominant transmission. Unlike the severe thrombocytopenias that present during infancy
(i.e. congenital amegakaryocytic thrombocytopenia, Wiskott-Aldrich syndrome) less severe
genetic mutations may be undetected until adulthood. Genetic tests and screening methods
Cont:
Acquired thrombocytopenia can occur at any time in a person’s life and can be broadly
divided into inadequate platelet production (i.e. bone marrow disorders) or increased platelet
consumption/destruction. The first category includes bone marrow suppression (i.e. alcohol,
drugs, chemotherapy, chronic viral infection) and primary hematopoietic disroders.
(i.e. myelodysplastic syndrome, leukemia, myeloproliferative disorder, fibrosis, bone marrow
metastases). Increased platelet consumption occurs due to immune mechanisms (ITP,
neonatal alloimmune thrombocytopenic purpura, post-transfusion purpura) as well as platelet
destruction (thrombotic thrombocytopenic purpura, heparin induced thrombocytopenia, trauma,
disseminated intravascular coagulopathy, vascular malformations), and splenic sequestration.
Since there is still no diagnostic test for ITP, it is important to keep this broad differential
Diagnosis in mind whenever evaluating “new onset” thrombocytopenia.
Thrombocytopenia: Not
Necessarily ITP
Jonathan Drachman MD
Medical Director
Seattle Genetics
Clin. Assoc. Prof., Div. Hematology
University of Washington
December 3, 2004
Factitious thrombocytopenia
 Platelet
clumping in vitro
- Often caused by EDTA anticoagulant
- Visible on peripheral blood smear
- Does not represent thrombocytopenia in vivo
 Repeat
CBC with alternative anticoagulant
Thrombocytopenia:
Inadequate production
 Bone marrow suppression
- Drugs, alcohol, chemotherapy, chronic viral infection
 Bone marrow failure
- Aplastic anemia, myelodysplasia, leukemia, PNH, CAMT,
DBA
 Bone marrow invasion (myelophthisis)
- Metastatic disease, lymphoma, CLL, myelofibrosis
Inherited Thrombocytopenias
 Mild-moderate thrombocytopenia
 No significant platelet dysfunction
- May-Hegglin Anomaly (MYH9 mutations)
 Giant platelets, nuetrophil inclusions, cataracts, nephritis,
sensorineural hearing loss
- FDP/AML (AML 1 mutation)
 Autosomal dominant, aspirin-like aggregation defect,
predisposition to myeloid malignancies
 Others- rare and/or poorly understood
What’s wrong with this case?
 Symptoms resolved spontaneously
 Easy bruising is nonspecific
-petechiae, nose bleeds, prolonged menses
Inherited Thrombocytopenia:
Abnormal Megakaryocytes
 Congenital
- Has there ever been a normal platelet count?
- Have symptoms changed significantly?
 Inherited
- Are there family members with similar symptoms or platelet
counts?
- Is there a recognizable inheritance pattern?
 Autosomal dominant, autosomal recessive, X-linked
recessive.
Thrombocytopenia:
Increased Consumption
 Platelet activation/thrombosis
-Trauma, TTP, DIC, Heparin Induced Thrombocytopenia
 Immune destruction
- aITP, NaITP, Post Transfusion Purpura (PTP)
 Splenic sequestration
- Splenomegaly, hepatic, cirrhosis, increased portal pressure
There is no definitive test for aITP
 Peripheral smear; platelets normal-large, normal granularity, no
clumping
 Bone marrow; increased number of morphologically
megakaryocytes
 Good response to ITP treatments (e.g. IV IgG, anti-D, steroids,
splenectomy)
 Anti-platelet antibodies: neither sensitive nor specific
 Effect of plasma on megakaryocytes growth in vitro
It could be ITP if….
Disease that are associated with aITP
- Lupus (+ANA)
- Autoimmune thyroiditis (elevated TSH)
- AIHA (Evan’s Syndrome)
- Low-grade lymphoma
- Chronic Lymphocytic Leukemia (CLL)
- Chronic H. pylori infection (?)
It may not be ITP if….
 Peripheral smear
- Giant platelets are present
- Neutrophils have cytoplasmic inclusions
- Small platelets, abnormal granulation
 Physical exam
- Splenomegaly, signs of hepatic cirrhosis
-Large vascular malformation, telangiectasias
Drug-induced Thrombocytopenia
 Oral contraceptives
- No association with ITP
- ? Thrombisis/consumption
 Claritin  (loratidine)
- No known association
 Ask about over-the counter medications, nutritional
supplements, alcohol quinine, antibiotics
WHY NOT DO SPLENOCTOMY
Nichola Cooper, MD
Specially Registrar, University College Hospital, NHS Trust
London, UK
While the majority of adults with immune thrombocytopenic, purpura (ITP) will have an
initial response to a short course of steroids, most adults will subsequently relapse. Longterm
steroids have many side effects, therefore alternative therapies must be sought in those who
do relapse. While a number of therapies can transiently increase the platelet count, there are
few options that will restore the platelet count to continuously normal levels. Traditionally,
splenectomy has been recommended for those patients refractory to steroids. This restores a
normal platelet count in 60%-70% of patients. However, these patients are otherwise well,
typically with few symptoms despite a low platelet count. Furthermore, at least half of all
deaths in adults with ITP are caused by the immunosuppressive effects of treatment, and the
morbidity associated with surgery and post splenectomy sepsis should not be ignored.
Alternative, less immunosuppressive therapies are therefore increasingly being sought.
There are a variety of options for patients not wanting to undergo splenectomy. Both
IVIg
and IV and-D transiently increase the platelet count in the majority of patients. However,
patients require repeated infusions and regular attendance in the hematology clinic. However,
Cont.
both of these treatments have few adverse side effects and no immunosuppressive effects.
Furthermore, we have recently reported that a number of patients go into a late remission after
many months of intermittent IV and and-D. Another longer lasting and potentially curable therapy
is rituximab. This anti-CD20 monoclonal antibody depletes peripheral B cells for 3-6 months and
induces a lasting platelet increment in 55% of patients. In those patients who have a complete
response (28% of patients), this response lasts for 1-3 years, with a few patients in continued
response for >4 years. Other treatments including MMF, azathioprine, and danazol have
variable responses in patients, but require long-term therapy, which many patients are reluctant
to choose. In summary, there are a number of therapies available that obviate the need of
splenectomy. In this particular patient, who is a young female of childbearing age, it must
be remembered that pregnancy can exacerbate ITP, that a number of therapies are
contraindicated in pregnancy, and that splenectomy is unlikely to cure ITP. Hence circulating
antibodies may still cause thrombocytopenia in the neonate. I think this patient should not
immediately undergo splenectomy but does require steroid-sparing agents. In this particular
case, rituximab may be an appropriate second-line therapy.
Avoiding Splenectomy
Nichola Cooper
Department of Haematology
UCLH, London UK
Can splenectomy be avoided?
 Depends on
1. Safe treatments to induce a platelet increment
2. What is a safe platelet count?
3. Whether a number of patients go into a late
remission
How many patients goNumber
into CR?
Initial CR,
Steroids
Alone
CR Maintained
After
Discontinuing
Treatment
Year
Country
Treated
With
Steroids
Thomson et al3
1972
US
57
13 (23%)
Difino et al4
1980
US
59
Pizzuto et al5
1984
S.Am
JiJi et al5
1984
Stasi et al7
Ikkala et al8
Late CR
Total CR
13 (23%)
3
16(28%)
25 (43%)
13 (22%)
3
16 (27%)
818
386 (47%)
262 (32%)
US
91
22 (24%)
21 (23%)
1995
Italy
121
52 (30%)
11 (9%)
1978
Finland
40
16 (40%)
10 (25%)
262(32%)
5
26 (29%)
11 (9%)
10 (25%)
Pre-splenectomy Therapies
+
-
Steroids
Cheap, short term
effective
Multiple toxicities
Anti-D
Short term effective
No immunosuppressive
Effects, bolus
Requires recurrent
treatment
IVIG
Short term effective.
No immunosuppressive
effects
Requires recurrent
Treatment, long infusion
time
Rituximab
Long term response
(1-3 yr CR)
? Consequence of B
cell depletion
Azathioprine
Cheap, easy to use
Frequent side effects/
toxicities
Rituximab in ITP
 9 of 26 (35%) pre-splenectomy patients CR
 1 relapse at 32 weeks
 71% respond to re-treatment
 No infectious complications
 Return of B cells in all patients
 No long-term adverse events so far….
What to do next?
 Not appropriate to continue with high doses of
steroids
 Response to anti-D, though transitory
Reasons not to splenectomize
 Newly diagnosed: allow more time to go in to remission
 Has been responsive to both steroids and anti-D therefore
has responsive disease
 ? Symptomatic with reasonable platelet counts
 Many treatment options available
Treatment with rituximab
This patient
 31 year old woman
 Initially responsive to steroids
 Refractory after 4 months, requiring unacceptably high doses
of prednisolone
 transiently responsive to anti-D
What to do next?
 Repeated doses of Anti-D or IVIG
 Rituximab
 Continuous low dose steroids
 Azatghioprine
 MMF
 Other
Disadvantages
 Young woman
 may require a more definitive therapy
? Pregnancy related issues
- relapse
- treatment with rituximab not recommended to get
pregnant
Decision?
 If no intention to get pregnant within the
next year. rituximab
 Alternatively, holding methods with intermittent
anti-D, IVIG azathioprine
WHY DO SPLENECTOMY?
An adult ITP patient should be treated with the goal of obtaining a stabl, safe platelet
count (>25-30,000/L) on no treatment. There is now good evidence that if the platelet count
can be be supported in some manner, some adult ITP patients will achieve safe platelet
counts
without splenectomy. What therapy should be used to maintain the platelet count, awaiting a
spontaneous remission? IVIg and anti-D have each been compared to corticosteroids for ITP
maintenance treatment. Each treatment was associated with spontaneous remissions, but
there was no significant difference in terms of the ultimate remission rate or the need for
splenectomy. From these observations, it is clear that some adult chronic ITP patients will
remit without splenectomy. The following need to n determined: (a) what percentage will
remit
and how will this subgroup be identified; (b) are remissions permanent; © how long should
treatment continue before advising splenectomy and (d) is there a “best” agent to maintain
the
platelet count.
My approach is as follows: begin prednisone 1mg/kg) and, if a response occurs, taper the
dose slowly with the aim of maintaining safe platelet counts on doses causing tolerable side
effects (<10-15 mg/day). In Rh+ patients, who either do not respond to prednisone or who
Cont.
cannot be tapered to safe doses, anti-D should be given whenever the platelet count falls
below 25-30,000/L. Therapy should be continued for 6-18 months, if possible, with the aim of
eventually stopping all treatment. The duration of this approach, prior to advising splenectomy,
must be decided by the patient and treating physician since there are no data that establish a
definite stopping point. Splenectomy is recommended if: (a) safe platelet counts cannot be
maintained; (b) remission is considered unlikely; © drug toxicity is severe or (d) the approach
becomes too burdensome (frequent blood tests, office visits, lost wok time, etc.).
The present patient is young (a good surgical candidate), is responsive to maintenance
therapy, has no significant mucosal bleeding, and has received maintenance treatment for only
4 months. Testing should include: thyroid studies, HIV evaluation, a hepattitis panel and
CMV-IgM serology; her medications should have been stopped or changed. The following
should be considered: (1) continue with either steroids or anti-D as needed to maintain the
platelet count for up to 18 months; (2) rituximab; or (3) splenectomy. The ultimate decision on
the need for splenectomy will depend on the patient’s lifestyle, history of compliance, and
Willingness to continue a long maintenance program hoping for a spontaneous remission.
The Spleen
Plenum mysteril organon (organ of mystery).
Source of the black bile.
“The viola is like the spleen. We have one but no one knows
why or what it is doing there” Harry Rumpler, violist.
Initial therapy – Classic Approach
Corticosteroids
Prednisone: 1 mg/kg/day (60-100 mg)
If complete response, taper over several weeks
Splenectomy indications
Uncontrolled platelet count with life-threatening bleeding
No response to steroids
Relapse on steroid taper
Initial ITP Therapy
Corticosteroids
(McMillan: Ann Int Med 126:307-314, 1997).
Total patients: 1420
Complete response: 418 (29.5%)
 Platelet count >120,000/L for duration of observation
Initial ITP Therapy-Modified approach
Pre-splenectomy Remissions at Scripps
(Advice Disregardance Methodology)
19 ITP patients, who failed steroids, were seen in consultation; splenectomy
was advised in all patients. However, the patients and/or their physicians
chose to disregard the advice, continue therapy (steroids and/or danazol) and
postpone surgery.
CR-Off Rx. 10 pts: mean follow-up- 7.7 yr (1-12 yr)
PR-Off Rx. 9 pts: mean follow-up- 10.3 yrs (3-15 yr)
First Splenectomy in Chronic ITP
Paul Kaznelson, a medical student in Prague (1916), believed that
the
“diseased spleen” removed platelets from the blood. He saw a 36
yo
woman with a long history of purpura, hemorrhage, splenomegaly
(3fb) and a platelet count of 300. He proposed a splenectomy and
Professor Schoffer performed the surgery. This resulted in a
complete
remission (5 year follow-up).
Two medical milestones:
 The first demonstration that splenectomy may be curative in
ITP.
 The first (and only) time in history that a Professor of Surgery
took
Initial Therapy – Modified approach
Hypothesis
If the platelet count can be supported for a long enough
interval, adult chronic ITP patients will remit spontaneously.
Initial ITP Therapy
Anti-D Antibody
(Cooper et al: Blood 99:1922, 2002).
28 Rh+ patients: anti-D given if platelet count
<30,000/L; Rx for 18months or until remission
occurred or splenectomy was required.
Results:
Off Rx (6-33 months): 12 pts (43%) ->100,000
(6pts);>30,000 (6pts).
On Rx: 7 pts (anti-D-3 pts; other Rx-4 pts).
Splenectomy: 8 pts (CR-6 pts).
Withdrew: 1 pt.
Pre-splenectomy IVIg vs Prednisone.
(Jacobs et al. Am J Med. 1994;97:55-59.)
Randomizes 70 patients to prednisone, IVIg or both to maintain the
platelet
count.
Results:
Therapy
Number
Remission*
Steroids
17
5
IVIg
13
2
Steroid + IVIg
13
1
*Minimum follow-up- 2 years
Total 8
(18.6%)
________________________________________________
Pre-splenectomy Anti-D vs Prednisone
(George et al.Am J Hematol 2004:74-161-169)
Randomized 70 patients to prednisone or anti-D.
Results:
 The need for splenectomy was the same: 14/37 (steroid group) and
14/33
in the anti-D group (N.S.).
 Anti-D postponed the median time to splenectomy (steroid group:
36
days, range 9-78: anti-D group: 112 days, range 19-558 p=0.045 at
100
days and 0.845 at 1 year)].
 The anti-D group required less steroid treatment.
To be determined:
 What percentage will remit spontaneously?
 How long will the remissions last?
 How long should treatment continue before splenectomy
or other therapy?
 How can we determine who will enter remission?
Splenectomy in Adult Chronic ITP
Modifying factors:
 Age
 Compliance
 Lifestyle
 Coexisting illnesses
Splenectomy in Adult Chronic ITP
 Immunizations: pneumococcal, meningocococcal and H. influenzae.
 Pre-op therapy; raise the platelet count above 50,000 prior to
surgery, if
possible (steroids, anti-D, IVIgG). Have platelets available..
 Surgical method; laparascopic splenectomy (by an experienced
surgeon)
gives the same results as standard splenectomy and has several
advantages, including shorter hospitalization and more rapid
recovery.
Initial ITP Therapy
Conclusions.
 Some adult chronic ITP patients will remit spontaneously. Patients
should
be given this opportunity.
 At present, no agent used for maintaining the platelet count
increases the
frequency of remissions.
Steroids: cheap/convenient but severe side effects
Anti-D: expensive/few side effects.
IVIg: expensive, inconvenient/view side/effects.
Splenectomy in Adult Chronic ITP
Indications:
 Failure to attain a spontaneous remission
 Inability to maintain safe platelet count
 Uncontrolled mucosal bleeding
 waiting is too burdensome (re: job, lifestyle, etc.)
Predicting Splenectomy Success
Platelet kinetic studies (hepatic sequestration)
Response to IVIg infusion (results vary)
Splenectomy in Chronic ITP
Group
(yrs)
Total
CR1/Ref
PCR
PR
NR
Follow-up
__________________________________________________________________________
___
Thompson
36
26/2
24
3
9
1-18
Jiji
51
46/10
36
2
13
1-20 (5)
DeFino
37
27/6
21
1
15
0.1-6 (5)
Ottolander
44
28/4
24
4
16
>1
Pizzuto
399
300/41
259
25
115
>0.5
Jacobs
102
41/4
37
47
18
>3
Total
669
468/67
401
82
186
% Response
66.7
59.9 12.3
27.8
__________________________________________________________
CR1-normal count after surgery; Rel-relapse; PCR-persistent complete remission;
PR-plt count >50,000; NR-plt count <30,000.
Chronic ITP-Scripps Experience Long-Term
Complete/Partial Remission
Total Patients: 45
Mean CR/PR: 8.4 yr.
Median CR/PR: 8.0 yrs.
>2 yrs: 45 pts
>5 yrs: 35 pts
>10 yrs: 18 pts
>15 yrs: 3 pts
What about splenectomy for this patient?
 She is young without other illness
 She has no mucosal bleeding.
 Other laboratory tests: hepatitis panel, CMV-IgM, HIV.
 Assume medications (OCP and Claritin) have been stopped or
changed.
 Evaluate life-style and life situation. Is she dependable?
 Consider either continuing prednisone with slow taper or
maintaining
with anti-D
 Consider rituximab pre-splenectomy.
 If I were in her situation, I would have a splenectomy.
WHY NOT TREAT REFRACTORY ITP?
Keith Mc Crae, MD
Associate Professor of Medicine
Case western Reserve University School of Medicine
Cleveland, OH
The treatment of refractory immune thrombocytopenic purpura (ITP) has long been a
perplexing problem for hematologists. The availability of an ever-broadening array of
immunosuppresive agents that may increase the platelet count in patients with refractory ITP
has led to a paradigm in which these patients are treated with a series of increasingly potent
drugs that may be associated with significant toxicity. Moreover, these patients are often
exposed to high doses of corticosteroids for prolonged intervals. One often overlooked option
for patients with refractory ITP who are not bleeding is observation alone. This discussion
will
review the natural history of adult ITP and focus on the relatively low incidence of bleeding
in
several settings associated with severe thrombocytopenia, including pediatric ITP. An
argument
for not treating refractory ITP, the absence of bleeding, will be presented.
ITP: Why NOT Treat?
Keith R. McCrae, M.D.
Associate Professor of Medicine
Is this ITP
 Additional evaluation
- Bone marrow aspiration/biopsy
 ASH guidelines: Not required to make diagnosis of ITP.
Consider
before splenectomy
 Measurement of anti-platelet glycoprotein antibodies using
phase
III assay
- Screening for Helicobacter Pylori
 Serology
 Urea breath test
- Search for accessory spleen
Other Treatment Options
 Common
- IVIg
- Danazol
- Rituximab
 Cytotoxics
-Vinca alkaloids
- Azathioprine
- Cyclophosphamide
- Combination
chemotherapy
 Miscellaneous
- Cyclosporine
- Mycophenylate mofetil
- Dapsone
- IFN
- Campath 1H
- Ascorbic Acid
- Protein A column
Experimental
- Thrombopoietin analogs
- Anti CD-154
ASH Guidelines (Blood, 1996)
 The indications for further treatment in patients who are refractory to
primary treatment
with glucocorticoids and splenectomy unclear…..there are insufficient data to develop
evidence-based recommendations……..for assessing which treatments result in
more good than harm…….
Platelet
count
Bleeding
Symptoms
Higher
Preference
Intermediate Preference
Lower
Preference
15,00025,000
Yes
IVIg
Accessory
Splenectomy
High dose
Glucorticoid
Azathioprine
Low dose glucocorticoid
Danazol
Vinca Alk
Ctx
Comb chemo
Protein A
Anti-D
Vit C
CyA
Coich
IFN
15,00025,000
No
(None)
High dose glucocorticoid
Vit C
Vinca Alk
Colch
Protein A
Anti-D
Ctx
Comb chemo
Case History
 31 year old female
 New diagnosis of ITP\
- Failed “reasonable” doses of prednisone
- Failed WinRho?
- Failed splenectomy
 Current platelet count: 15,000/l
- Petechiae
- Bruising
Refractory ITP
Definition: patients in whom treatment with
standard dose corticosteroids and
splenectomy fails, and who require further
therapy because of unsafe platelet counts
or clinical bleeding…..
Therapy…..
 Need based on risk/benefit ratio
 Benefit: decreased bleeding, but……
- Risk at current platelet count is low
 Patients with similar degree of hypoproliferative
thrombocytopenia do not bleed
 ICIS data
 ITP natural history study
 Systematic reviews/case studies
 Risk is high…..
- Immunosuppressison induced infection
- Other toxicities
What is a “Safe” Platelet Count?
 Dentistry > 10 x 109/l
 Extractions > 30 x 109/l
 Regional dental block > 30 x 109/l
 Minor surgery > 50 x 109/l
 Major surgery > 80 x 109/l
Natural History of ITP
 Patients accrued between 1974-1994
- Mean follow up of 10.5 years
- Mean age 39 years
 ITP defined as
- Platelets <100,000/l
- Normal or increased megakaryocytes
- No other causes of thrombocytopenia
 152 patients
- Within two years of diagnosis
-12 patients diagnosed with secondary thrombocytopenia
- 4 patients died
- 2 patients lost to follow up
- 85% achieved platelet count >30,000/l within 2 years off therapy
- 12 of 134 (9%) had refractory disease
 Primary endpoint: mortality
Porteiije et al. Blood 97:2549-2554
Intercontinental Childhood ITP
Study Group
 Prospective study of 2540 children with ITP
- 203 infants
-1860 children > 1 to <10 years
- 477 children > 10 to < 16 years
 Baseline and 6 month follow up
 ICH occurred in 3 of 1742 (0.17% patients
-Initial platelet counts 8,000/l, 11,000/l, 16,000/l
- Patient 1 not treated, patient 2=corticosteroids, patient
3=corticosteroids and IVIg
- Patient 2 had ICH 4 months after diagnosis without sequelae
- Patient 3 had ICH within 1 week after diagnosis, with death.
Natural History of ITP
Characteristics
Relative Risk
 Diagnosis
- Initial diagnosis of ITP (n=150)
1.5(1.1-2-2)
- ITP (n=138)
1.3 (0.9-2.0)
0
- Reclassified as 2 thrombocytopenia (n=12)
6.0 (2.5-15.0)
____________________________________________________________________________
 Presenting symptoms
- Severe thrombocytopenia (n=122)
1.5 (1.0-2.2)
- Moderate thrombocytopenia (n=28)
1.9 (0.8-4.5)
- Hemorrhagic symptoms (n=128)
1.5 (1.1-2.2)
- No hemorrhagic symptoms (n=22)
1.7 (0.4-6.8)
____________________________________________________________________________
 ITP depending on response to therapy\
- Complete response (n=90)
0.7 (0.4-1.3)
- Partial response (n=24)
1.8 (0.6-5.5)
- Response to maintenance (n=8)
1.8 (0.6-5.5)
- No response (n=12)
4.2 (1.7-10.0)
____________________________________________________________________________
 Referral
- Primary (n=73)
1.9(1.1-3.0)
- Secondary (n=77)
1.3 (0.7-2.2)
Porteije et al. Blood 97:2549-2554
Natural History of ITP: Deaths
 6 ITP related deaths
- 4 in first two years of follow-up
 40 y.o. female, plt 3,000/l, ICH
 65 y.o female, plts normal, Gm(-) sepsis after 3 months steroids
 83 y.o. female, plt 65,000/l, sepsis after 3 months steroids
 83 y.o. male, plts normal, MI and CMV pneumonia after
splenectomy/steroids
- 2 on long-term follow-up
 20 y.o. male with sepsis 3 yrs after ITP dx, 2 years after splenectomy
 35 y.o. female, plts 2,000/l, ICH
 Other causes
 Cancer (4)
 Cardiovascular disease (4)
 Alcohol abuse (1)
 Dementia (2)
 Sudden death (4)
Porteije et al. Blood 97:2549-2554
Bleeding Risk in Patients with ITP and
Persistently Low Platelet Counts
 Estimation of age-adjusted bleeding risk using
data
from 17 ITP case series of patients with platelet
<30,000/l
 49 bleeding events in 1,817 patients over 1,258
to
3,023 patients years
 Rates of fatal bleeding
- Non age-adjusted: 0.0162 to 0.0389
- Age <40 years: 0.004
- Age >40, <60 years: 0.012
- Age >60 years: 0.130
Natural History of ITP: Conclusions
 Bleeding related deaths due to ITP are uncommon, and
occur primarily at platelet counts <5,000/l
 Treatment related toxicity (infection) may be a more
important cause of death in refractory ITP than bleeding
Conclusions
 The risk of major bleeding from severe ITP is low, particularly in
younger patients
 The risk of aggressive treatment aimed at simply raising the platelet
count
is substantial
 Spontaneous bleeding may often be managed by anti-fibrinolytics
and/or
platelet transfusion
 The risk/benefit ratio in this patient favors non-treatment
WHY TREAT REFRACTORY ITP?
Adrian Newland, MD
Professor of Hematology
Barts and the London School of Medicine, Queen Mary
London, UK
When a diagnosis of immune (idiopathic) thrombocytopenic purpura (ITP) has been
confirmed, the questions remain as to whether these patients need to be treated, how they
should be treated, and when they should be treated. The important goals of therapy are to
prevent major bleeding but, in particular, to avoid the additional problem of treatment-related
side effects. While there is a perceived risk of bleeding in adults with ITP who have not
responded to initial therapy, major bleeding episodes are relatively infrequent because the
platelets are functionally active. Patients do not usually hemorrhage unless the platelet count is
less than 5,000/L or other conditions predispose them to it. Stasi et al in 995 determined
that the incidence of death due to hemorrhage is near 2.4% and Portiejie in 2001 found it to be
1.3% but that the risk of death from infection, compounded by immune suppressive treatment,
was similar. The major concern of physicians is the occurrence of intracranial bleeding. The
incidence of this complication is relatively rare, seldom spontaneous, and can be treated
successfully in most cases.
ITP patients with persistent severe thrombocytopenia require treatment to increase the
platelet count to hemostatically safe levels. There is little agreement as to what these levels
may be, and the difficulty of producing an accurate platelet count at very low levels compounds
the problem. However, in general clinically safe levels are accepted somewhere between
Cont.
10,000/L and 30,000/L, but a safe platelet count is also dependent upon the patients’ level
of physical activity and their potential risks from treatment.
Refractory ITP is more common in women and is sometimes accompanied by other
autoimmune diseases. It is this subgroup that has persistently low platelet counts, continuous
bleeding, is often hospitalized, is associated with a higher incidence of mortality, and in whom
early aggressive intervention may be indicated. The decision to treat may be influenced by a
number of factors including the type of bleeding and its incidence, an active lifestyle including
travel, the use of concomitant medications and other comorbid conditions. In considering what
treatment to offer, there are two main therapeutic strategies, one treating the symptoms, using
antifibrinolytic agents and hormonal supplements, and the other aimed at modifying the natural
history of the disease; treatments in this second category range from the well-known
conventional approaches to those that are in the experimental stage.
In conclusion, the ASCO guidelines of 2001, which were devised for patients with bone
marrow failure, recommended that in the absence of fever, coagulation abnormalities, and
bleeding, treatment is not indicated if the platelet count is greater than 10,000/L, and there
is no reason not to adopt these guidelines in ITP, where bleeding is less of a risk. Treatment
should be risk-adjusted and symptomatic treatment should be used when appropriate. Those
with a potentially worse outcome should be identified and the newer treatment options
considered.
ITP: Why should we treat?
Professor Adrian Newland
Barts and the London School of
Medicine and Dentistry
Questions to consider
 Should we treat?
Questions to consider
 Should we treat?
 If so, how should we treat?
 When should we treat?
Why is serious bleeding so
uncommon in ITP
 Platelets in ITP large, metabolically active, “sticky”
 Actual platelet count underestimated by electronic cell counter (due
to
large platelet size)
 Patients with ITP are otherwise well and without other problems
predisposing to hemorrhage (.e., no anemia, ongoing infection,
mucositis,
organ injury, drug exposure, etc.)
Case History
 31 year old female
 Diagnosis of ITP confirmed by response to treatment
 Expose to steroids, IVIG, WinRho and splenectomy
 Continuing moderately severe thrombocytopenia with non-life
threatening symptoms
Questions to Consider
 Should we treat?
 If so, how should we treat?
ITP: Goal of Treatment
 Prevention of major bleeding
 To avoid introducing additional problems
as a side-effect of the treatment
Mortality rates – Adult ITP
 Stasi et al 1995: 208 adults
92 months median follo-up
11 deaths (5.3%)
5 due to haemorrhage
 Portieje et al 2001; 152 adults
10 year follow-up
6 deaths (4%)
2 haemorrhage, 4 infection
Mortality of “ITP”
Date of
report
Patients in
study
Deaths
recorded
% Died
1954
278
19
6.8
1961
114
4
3.5
1975
569
1
0.2
1984
181
0
0
2001
2031
0
0
Refractory ITP
 Predominantly women, median age 37
 Other autoimmune diseases more common
 The subgroup with persistently low platelet counts, continuous
bleeding
and recurrent hospitalization have a higher mortality
(17.6%)
Mc Millan & Durette, 2004, Blood; 104,956-960
 Similar observations seen in
Cohen et al, 2000, Arch Int. Med: 160, 1630-1638
What should we treat with?
Symptomatic treatment
 antifibrinolytic agents
 OCP
Disease modifying treatment
 Standard
 Second line
 experimental
Intracranial bleeding
 Is what doctors are scared of
 Is a very rare complication
 Is seldom spontaneous
 The risk of it arising is a function of time with profound
thrombocytopenia
 Can be treated successfully in most cases
Long-term outcome in adults with ITP after
splenectomy failure
 114 patients (105 with follow-up)
 75 (71.4%) attained stable CR or PR with a mean of 68.1 m
(median 48 m)
 30 (29.6%) unresponsive
 32 deaths
17 (15.7%) of ITP (bleeding in 11)
6 of therapy complications
15 (13.9%) other causes
McMillan & Durette, 2004, Blood: 104, 956-960
The decision to treat
 Bleeding manifestations
“Wet Purpura”,
Menstrual bleeding
 Lifestyle including both activity and travel
 Concomitant medications and co-morbid
conditions
Primary conditions
Other medical conditions
Treatment options
First choice
Corticosteroids
Dexamethasone
Danazol
IVIG
WinRho
Rituximab
Vinca alkaloids
Vitamin C
Second choice
CsA/Mycohenolate
Oral cyclophosphamide
Azathioprine
Combination Chemo
Experimental
Thrombopoietic factors
MCAB against
components of the
immune system
When should we treat ITP?
Initial Treatment of ITP
 No initial treatment is safe for adults with platelet counts
>30,000/L
Portieje et al, Blood: 2001; 97:2549
Neylon et al, Br J Haem: 2003; 122:966
Management if ITP in adults
 Medeiros and Buchanan 1998 (Children)
75% of major bleed, count <10 x 109/L
87% of less than 20x109/L
 ASCO guideline 200q1 (Marrow failure
In the absence of fever, coagulation abnormalities
and bleeding a count of more than 10x109/L does not
require treatment.
Conclusions II
 Use symptomatic treatment where appropriate
 The level of treatment should match the clinical picture
 Identify the sub-group who are likely to have the worst outcome
 Do not withhold treatment if it appears clinically indicated
 Consider whether some of the newer treatment options are disease
modifying e.g. Rituximab
Recommendation for “safe” platelet
counts in adults
 Dentistry > 10 x 109/L
 Extractions > 30 x 109/L
 Regional Dental Block > 30 x 109/L
 Minor Surgery > 50 x 109/L
 Major Surgery > 80 x 109/L
Evidence level IV
BCSH Guideline, BJH, 2003: 120:574-596
Conclusions I
Treatment must be risk adjusted
Risk dependent on:
 Age
 Length of history
 Symptomatology
 Level of platelet count