PATHOPHYSIOLOGY OF ITPo 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 Deficiency of central tolerance induction mechanisms

o Failure to eliminate or deactivate self reactive lymphocytes.

Factors That Regulate Central Tolerance:

Strength of Signals initiated by antigen receptor

a. Avidity of interaction between antigen and antigen receptor

b. Affinity of interaction between antigen and antigen receptor

c. Co-stimulatory signals that enhance signal strength (CD28)

d. Signals that attenuate signal strength-inhibitory receptors (CD5)

Factors That Regulate Peripheral Tolerance:

Not all self-reactive T or B cells are deleted during development:

a. Need for a peripheral repertoire that will protect from pathogens.

b. Peripheral tissue specific antigens not expressed in the thymus.

c. Expression of neo-antigens occurring as a result of tissue damage.

d. Expression of specific endopeptidases that modify peptides in thymus.

e. Positive selection of specificities that exhibit weak self-reactivity but with propensity for pathogenic autoreactivity.

Control of autoreactive T cells in the periphery is termed Peripheral Tolerance

Central Tolerance

o Negative selection of immature lymphocytes by clonal deletion of self reactive clones during development in the thymus.

T cells – thymusB cells – bone marrow

o 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

CytokinesInhibitory moleculesT-Regulatory cells (Tr), T-suppressor cells (Ts)Dendritic cells

Platelet count: <150X109/L

Acute:o Childhood disordero Abrupt onseto Usually follows

infectious illnesso Spontaneous

remissiono Th0/Th 1 bias

Chronic:o >6 month durationo Organ specific

autoimmune disease

o Autoantibodies enhance platelet destruction

o Presence of GPilla-reactive T cell

o Cytokine abnormalities

ITP:

o Acute AITP :Good example of molecular mimicry. Cross reactivity of anti-viral antibodies with normal platelet epitopes.

o Chronic AITP: Immunodominat epitopes on GPllb-llla recognized by autoreactive T cells in patients with immune thrombocytopenic purpura

o M. Kuwana, J. Kaburaki, H. Kitasato, M. Kato S. Kawai, Y. Kawakami, and Y. Ikeda Blood 98:130, 2001

T Cell Characteristics:

o Specificity of platelet-reactive T cell lines from children with chronic ITP.

o JW Semple, ER Speck, M Kim, V Blanchette, J Freedman Blood 98 (11):441a, 2001

o CD 4+ T cells>CD8+ T cellso Trend toward Th 1 (IFN) activationo Line primarily react with GPllb-lllao 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 deathSingle cellsGroups of neighboring cells

Cell shape changes*Apoptosis bodies*

Shrinkage Fragmentation

Swelling disrupted

Plasma MembranePreserved continuity blabbedSmoothing, early lysis, integrity lost

Mitochondria Contents released into cytoplasm

Cytochrome c, Apart I

Non to limited role

Organelle

shape

ContractedSwelling

NucleiChromatin

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 ITPJames Bussel, MD Professor of PediatricsThe 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 Fc-dependent and classically assumes that there is increased platelet production that is over-whelmed by the rapid platelet destruction. However this appears not always of autologousplatelets 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 inincreasing the platelet count in 4 separate studies in ITP. One study in the US (presented atASH 2003) and one in Europe (poster presentation in 2004) have both demonstrated clearefficacy in increasing the platelet count and minimal toxicity with single dose injections. Afollow-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-termextension study enrolling patients entered into the initial studies has demonstrated continuedefficacy, little toxicity, and considerable individual variability in dose response. A second mole-cule 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) - Age > 60 years

- If splenectomy is considered - 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

Are being developed to help recognize these familial syndromes.

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: NotNecessarily ITP

Jonathan Drachman MD Medical Director Seattle Genetics

Clin. Assoc. Prof., Div. HematologyUniversity 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 SPLENOCTOMYNichola Cooper, MDSpecially Registrar, University College Hospital, NHS TrustLondon, 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. Long-term

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 SplenectomyNichola Cooper

Department of HaematologyUCLH, 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 go into CR?YearCountry

Number Treated

With

Steroids

Initial CR,

Steroids

Alone

CR Maintained

After

Discontinuing

Treatment

Late CRTotal CR

Thomson et al31972US5713 (23%)13 (23%)316(28%)

Difino et al41980US5925 (43%)13 (22%)316 (27%)

Pizzuto et al51984S.Am818386 (47%)262 (32%)262(32%)

JiJi et al51984US9122 (24%)21 (23%)526 (29%)

Stasi et al71995Italy12152 (30%)11 (9%)11 (9%)

Ikkala et al81978Finland4016 (40%)10 (25%)10 (25%)

Pre-splenectomy Therapies

+-

SteroidsCheap, short term

effective

Multiple toxicities

Anti-DShort term effective

No immunosuppressive

Effects, bolus

Requires recurrent

treatment

IVIGShort term effective.

No immunosuppressive

effects

Requires recurrent

Treatment, long infusion

time

RituximabLong term response

(1-3 yr CR)

? Consequence of B

cell depletion

AzathioprineCheap, easy to useFrequent 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 plateletcount (>25-30,000/L) on no treatment. There is now good evidence that if the platelet countcan be be supported in some manner, some adult ITP patients will achieve safe platelet countswithout splenectomy. What therapy should be used to maintain the platelet count, awaiting aspontaneous remission? IVIg and anti-D have each been compared to corticosteroids for ITPmaintenance treatment. Each treatment was associated with spontaneous remissions, butthere was no significant difference in terms of the ultimate remission rate or the need forsplenectomy. 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

remitand how will this subgroup be identified; (b) are remissions permanent; © how long shouldtreatment continue before advising splenectomy and (d) is there a “best” agent to maintain theplatelet count.

My approach is as follows: begin prednisone 1mg/kg) and, if a response occurs, taper thedose slowly with the aim of maintaining safe platelet counts on doses causing tolerable sideeffects (<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

the advice of a medical student, or for that matter, acknowledged that medical students exist.

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 remissionoccurred 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 Total CR1/Ref PCR PR NR Follow-up (yrs)___________________________________________________________________________

__

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 MedicineCase western Reserve University School of MedicineCleveland, 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 Miscellaneous

- IVIg - Cyclosporine

- Danazol - Mycophenylate mofetil

- Rituximab - Dapsone

Cytotoxics - IFN

-Vinca alkaloids - Campath 1H

- Azathioprine - Ascorbic Acid

- Cyclophosphamide - Protein A column

- Combination Experimental chemotherapy - 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 PreferenceLower

Preference

15,000-

25,000

YesIVIg

Accessory

Splenectomy

High dose

Glucorticoid

Azathioprine

Low dose glucocorticoid

Danazol

Vinca Alk

Ctx

Comb chemo

Protein A

Anti-D

Vit C

CyA

Coich

IFN

15,000-

25,000

No(None)High dose glucocorticoidVit 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 ITPStudy 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 ITPCharacteristics Relative Risk

Diagnosis - Initial diagnosis of ITP (n=150) 1.5(1.1-2-2) - ITP (n=138) 1.3 (0.9-2.0) - Reclassified as 20 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, MDProfessor of HematologyBarts and the London School of Medicine, Queen MaryLondon, UK

When a diagnosis of immune (idiopathic) thrombocytopenic purpura (ITP) has beenconfirmed, the questions remain as to whether these patients need to be treated, how theyshould be treated, and when they should be treated. The important goals of therapy are toprevent major bleeding but, in particular, to avoid the additional problem of treatment-relatedside effects. While there is a perceived risk of bleeding in adults with ITP who have notresponded to initial therapy, major bleeding episodes are relatively infrequent because theplatelets are functionally active. Patients do not usually hemorrhage unless the platelet count isless than 5,000/L or other conditions predispose them to it. Stasi et al in 995 determinedthat the incidence of death due to hemorrhage is near 2.4% and Portiejie in 2001 found it to be1.3% 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. Theincidence of this complication is relatively rare, seldom spontaneous, and can be treatedsuccessfully in most cases.

ITP patients with persistent severe thrombocytopenia require treatment to increase theplatelet count to hemostatically safe levels. There is little agreement as to what these levelsmay be, and the difficulty of producing an accurate platelet count at very low levels compoundsthe 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’ levelof physical activity and their potential risks from treatment.

Refractory ITP is more common in women and is sometimes accompanied by otherautoimmune diseases. It is this subgroup that has persistently low platelet counts, continuousbleeding, is often hospitalized, is associated with a higher incidence of mortality, and in whomearly aggressive intervention may be indicated. The decision to treat may be influenced by anumber of factors including the type of bleeding and its incidence, an active lifestyle includingtravel, the use of concomitant medications and other comorbid conditions. In considering whattreatment to offer, there are two main therapeutic strategies, one treating the symptoms, usingantifibrinolytic agents and hormonal supplements, and the other aimed at modifying the naturalhistory of the disease; treatments in this second category range from the well-knownconventional approaches to those that are in the experimental stage.

In conclusion, the ASCO guidelines of 2001, which were devised for patients with bonemarrow failure, recommended that in the absence of fever, coagulation abnormalities, andbleeding, treatment is not indicated if the platelet count is greater than 10,000/L, and thereis no reason not to adopt these guidelines in ITP, where bleeding is less of a risk. Treatmentshould be risk-adjusted and symptomatic treatment should be used when appropriate. Thosewith a potentially worse outcome should be identified and the newer treatment options considered.

ITP: Why should we treat?

Professor Adrian NewlandBarts 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 souncommon 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

1954278196.8

196111443.5

197556910.2

198418100

2001203100

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 inCohen 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 aftersplenectomy 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 deaths17 (15.7%) of ITP (bleeding in 11)6 of therapy complications15 (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 Second choice

Corticosteroids CsA/Mycohenolate

Dexamethasone Oral cyclophosphamide

Danazol Azathioprine

IVIG Combination Chemo

WinRho Experimental

Rituximab Thrombopoietic factors

Vinca alkaloids MCAB against

Vitamin C 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” plateletcounts 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