Immune Thrombocytopenia

Widi Hersana
Hematology-Medical Oncology Division

Internal Department, Ramelan Naval Hospital

Surabaya
• Introduction
• Pathophysiology
• Diagnosis
• Management
• Summary
 Epidemiology of ITP

• ITP can affect patients of all ages and either sex1

Incidence and Prevalence of ITP in Adults ITP affects ~1.5x as many women as
Incidence2 1.6 to 3.9 per 100,000/year men1
Approximately 4 to 50 per
Prevalence1,3
100,000 (~0.04%-0.05%)a

Prevalence vs
by age1
18-49 y 30.09 per 100,000
50-64 y 58.22 per 100,000
≥65 y 93.80 per 100,000
Prevalence
by sex1
Male 40.66 per 100,000
Female 59.32 per 100,000

a Estimates of ITP prevalence in adults vary widely because of a lack of large, high-quality epidemiologic studies.

1. Bennett D et al. Adv Ther. 2011;28(12):1096-1104. 2. Terrell DR et al. Am J Hematol. 2010;85(3):174-180.

3. Kistangari G, McCrae KR. Hematol Oncol Clin North Am. 2013;27(3):495-520.
 Clinical Manifestations of ITP
Sign or Symptom Description
• Bleeding that involves the skin, oral cavity,
and gastrointestinal tract
Mucocutaneous2
• Examples include heavy periods in
women, nose bleeds, and gum bleeding
Bleeding1 • Rash-like appearance usually on the
Purpura2
Most common symptom in ITP extremities
• Bleeding that occurs within the brain
Intracranial • Serious and potentially fatal complication
hemorrhage2 • Most often occurs with platelet counts
<30 x 109/L
Fatigue1 May occur in 22%-39% of adults with ITP
• Formation of inappropriate blood clots that can lead to strokes
or heart attacks
Thrombosis1,3 • Patients with ITP may be at an increased risk for both venous
and arterial clots

Adult patients with ITP have increased morbidity and mortality compared with the general
population, particularly if they cannot maintain a platelet count above 30 x 109/L

1. Kistangari G, McCrae KR. Hematol Oncol Clin North Am. 2013;27(3):495-520. 2. Dorland's Illustrated Medical Dictionary.
32nd ed. Philadelphia, PA: Elsevier Saunders; 2012. 3. Sarpatwari A et al. Haematologica. 2010;95(7):1167-1175.
 Not all ITP is Primary ITP:

Reproduced with permission from: Cines DB et al. Blood 2009;113:6511–6521

 2019 International Working Group
Standard Definitions for ITP
• ITP can be defined as either

– Primary: platelet count <100 x 109/L in the The distinction between

absence of other causes or disorders1
primary and secondary ITP
– Secondary: ITP due to other causes, including is important, because they
drug exposure or disease (eg, secondary ITP
due to HCV, SLE, or HIV)1,2 may require different
treatment approaches1

Phases of ITP1

Newly diagnosed Within 3 months of diagnosis

Persistent Between 3 and 12 months of diagnosis

Chronic Lasting longer than 12 months
Presence of bleeding symptoms severe enough
Severe
to require treatment or additional interventions
Failed splenectomy/relapsed and exhibits severe
Refractory
risk of bleeding that requires therapy

Abbreviations: HCV, hepatitis C virus; HIV, human immunodeficiency virus; SLE, systemic lupus erythematosus.

1. Rodeghiero F et al. Blood. 2009;113(11):2386-2393. 2. Kistangari G, McCrae KR. Hematol Oncol Clin North Am. 2013;27(3):495-520.
PATHOPHYSIOLOGY
 Classic Immunopathogenesis of ITP:

•autoantibodies are primarily

IgG directed against epitopes
on GPIIbIIIa (CD41) and/or
GPIbIX (CD42)

Increased
Harrington WJ et al. J Lab Clin Med 1951;38:1–10;
Harrington WJ et al. Ann Int Med 1953;38:433;
RES Destruction
Graph reproduced with permission from: Schwartz RS. N Engl J Med 2007;357:2299–301
Today: ITP is Due to Two Reasons:

Health
Increased platelet destruction
(normal platelet counts)
(Spleen)

Anti-platelet
Immunity.
(Ab + T cell)
Anti-megakaryocyte
Immunity.
(Ab + T cell)

Decreased platelet production

(Bone Marrow)

ITP effector immunity is comprised of antibodies and T cells.

 ITP Is an Immune-Mediated Disease

ITP is an acquired immune-mediated disease of both adults and children characterized by reduced
platelet counts (ie, thrombocytopenia)1
Patients with primary ITP generate antibodies to their own platelets in response to an unknown
stimulus2
Antiplatelet
Antiplatelet antibodies also bind
autoantibodies to megakaryocytes
Multiple
processes can
reduce platelet
Destruction by counts in ITP2 Impaired
immune cells such megakaryocyte
as macrophages function

Increased Decreased
Platelet Destruction Platelet Production

1. Rodeghiero F et al. Blood. 2009;113(11):2386-2393. 2. Stasi R et al. Thromb Haemost. 2008;99(1):4-13.

Modern Immunopathogenesis of ITP:
Periphery Bone Marrow

Increased Meg.
Destruction

Apoptosis
Reduced
Loss of Production
Tolerance CD8+
CTL

Faulty
Tregs

TGF-β

Modified with permission from: Cines DB, Blanchette VS. N Engl J Med 2002;346:995–1008
DIAGNOSIS
 Guidelines for diagnosis of ITP
• ITP remains a diagnosis of exclusion of other conditions or factors
that cause thrombocytopenia1
• Assessment of the following is needed to diagnose ITP:1
– Patient and family history
Results do not suggest
– Physical examination
other aetiologies for
– Complete blood count thrombocytopenia1
– Peripheral blood film
– Other laboratory investigations
• There is no robust clinical or laboratory test that can establish a
diagnosis with accuracy1
• A platelet count <100 x 109/L has been defined as the threshold for
diagnosis2
1. Provan D, et al. Blood 2010; 115: 168–86; 2. Rodeghiero F, et al. Blood 2009; 113: 2386–93
ITP = Exclusion of alternative etiologies of thrombocytopenia

George JN. Haematologica. 2009;94(6):759-62.

ICR 2019 diagnosis recommendation
Basic evaluation Tests of potential utility in Tests of unproven
the management of an ITP or uncertain
patient benefit
• Patient history • Glycoprotein-specific antibody • TPO
• Family history • Antiphospholipid antibodies • Reticulated platelets
• Physical examination (including anticardiolipin and lupus • PaIgG
• Complete blood count and anticoagulant) • Platelet survival study
reticulocyte count • Antithyroid antibodies and thyroid • Bleeding time
• Peripheral blood film function • Serum complement
• Quantitative immunoglobulin • Pregnancy test in women of
level measurement* childbearing potential
• Bone marrow examination (in • Antinuclear antibodies (ANA)
selected patients; refer to text) • Viral PCR for parvovirus and CMV
• Blood group (Rh)
• Direct antiglobulin test
• H pylori†
• HIV†
• HCV†
Rh indicates rhesus; H pylori, Helicobacter pylori; HIV, human immunodeficiency virus; HCV, hepatitis C virus; PCR,
polymerase chain reaction; CMV, cytomegalovirus;
TPO, thrombopoietin; and PaIgG, platelet-associated immunoglobulin G.
*Quantitative immunoglobulin level measurement should be considered in children with ITP and is recommended in
those children with persistent or chronic ITP as part of the reassessment evaluation.
†Recommended by the majority of the panel for adult patients regardless of geographic locale.
ASH 2019 Diagnosis Recomendation:
Newly Diagnosed ITP in Adult
Initial diagnosis of ITP
• recommendation:
– Testing patients for HBV, HCV and HIV
– DGHO (2018) and ICR(2019): H. pylori
• suggestion:
– Further investigations if there are abnormalities
(other than thrombocytopenia and perhaps findings
of iron deficiency) in the blood count or smear
– A bone marrow examination is not necessary
irrespective of age in patients presenting with typical
TREATMENT
 Treatment for ITP

• ITP is heterogeneous in its severity and clinical course, with an

unpredictable response to therapy1

• Evidence-based treatment guidelines and consensus reports

relating to ITP management have been published:

• International Consensus Report (September 2019)3

• ASH guidelines (October 2019)2

1. Stasi R, Provan D. Mayo Clin Proc 2004; 79: 504–22;

2. Neunert C, et al. Blood 2011; 117: 4190–207;
3. Provan D, et al. Blood 2010; 115: 168–86
 Goals for the Treatment of ITP

The major goal for the treatment of ITP is to provide a safe

platelet count with minimal side effects A safe platelet count
is one that prevents
Treatment should not aim to restore platelet counts to bleeding in the
normal levels individual patient

Goals in Different ITP Phases

Rapidly obtain a safe platelet count to
Newly prevent or stop bleeding and ensure an
diagnosed acceptable quality of life with minimal
side effects
Potentially try to avoid more toxic
Persistent treatments such as splenectomy,
or chronic immunosuppression, or long-term
corticosteroids
Attempt to raise platelet counts enough
Refractory to prevent clinically significant bleeding
with the fewest side effects
Rodeghiero F et al. Blood. 2009;113(11):2386-2393.
 Factors that contribute to ITP management decisions
Treatment in chronic ITP is not well defined and depends on
balancing the efficacy and adverse effects of a given treatment,
as well as the impact on quality of life1

Patient worry about disease Tolerance of

and treatment burden side effects
Accessibility of
The extent care
of bleeding Management Patient
decision factors2,3 expectations
Complications of
specific therapies
Activity and lifestyle
Potential interventions that Comorbidities
may cause bleeding predisposing to bleeding

• In patients with platelet counts >50 x 109/L treatment is not usually indicated
unless the patient has other risk factors (e.g. bleeding or surgery)3
1. Rodeghiero F, et al. Blood 2009; 113: 2386–93;
2. Neunert C, et al. Blood 2011; 117: 4190–207;
3. Provan D, et al. Blood 2010; 115: 168–86
 Immune Thrombocytopenia:
Who and When to Treat
• Treat only if platelet count < 20-30 x 109/L or symptomatic
• Bleeding risk is greatest in patients older than 60 years of
age and those with previous history of major bleeding;
consider other comorbidities
• Bleeding and infection contribute equally to mortality
• Selection of therapeutic option depends on
– Urgency of platelet increase
– Tolerated toxicity by patient, eg, steroids
– Durability of effect
– Effect of thrombocytopenia and treatment on lifestyle and
profession

Provan D, et al. Blood. 2010;115:168-186

 Treatment Goals

• Treatment goal should be individualized to the patient and

the phase of the disease
• Treatment should prevent severe bleeding episodes
• Treatment should maintain a target level > 20-30 x 1000/µl
at least for symptomatic patients (because risk of
bleeding increase below this level)
• Treatment should be with minimal toxicity
• Treatment should optimize health-related quality of life

International Consensus Report 2019

ooooo
TREATMENT OF ITP

• Wait and watch (observe)

• First-line Therapy
• Second-line Therapy
• Emergency Treatment for Patients with
major bleeding or emergency surgery
Guidelines on first-line treatment options for ITP:
International Consensus Report and ASH
First-line therapy
(initial treatment for
newly diagnosed ITP)

International Consensus Report1 ASH guidelines2

• Corticosteroids (standard initial
treatment), longer courses of steroid be
avoided:
• Prednis(ol)one
• Methylprednisolon
• Dexamethasone
• Intravenous anti-D (Rho)
• IVIg (1 g/kg on 1 or 2 consecutive days
or 0,4 g/kg per day for 5 days))
• TPO-RA and rituximab are not
considered initial therapy
Suggested options (based on evidence
level 2B/2C)
• Corticosteroids: prolonged courses
(>6 weeks) not preferre d .
Prednison (0,5-2 mg/kg/day or
dexamethason 40 mg per day for 4
days (prefered >)
• IVIg: preferred where a rapid
increase is required
If corticosteroids are
contraindicated, IVIg or anti-D is
suggested
Guidelines on second-line treatment options for ITP:
International Consensus Report and ASH

Second-line therapy

International Consensus Report1 ASH guidelines2

Medical:
• Cyclosporin A, azathioprine
• Cyclophosphamide
• Danazol, Dapsone
• Vinca alkaloid regimens
• Mycophenolate mofetil
• Rituximab
• TPO-R agonists (eltrombopag ,
avatrombopag, romiplostim
• Fostamatinib:(spleen kinase) inhibitor
Surgical: Spenectomy
Recommended options – evidence level 1B
• Splenectomy for patients who have
failed corticosteroid therapy
• TPO-R agonists for patients at risk of
bleeding who relapse after
splenectomy, or who have a
contraindication to splenectomy and
who have failed at ≥1 other therapy
• Rituximab
THROMBOPOIETIN RECEPTOR (TPO-R)
AGONISTS: RATIONALE AND MECHANISM OF
ACTION
 Thrombopoietin (TPO)

Stem cell • TPO is a potent endogenous

TPO haematopoietic growth factor that plays
an integral role in platelet production1-3
Bilineal progenitor cell
– Primarily produced in the liver1
TPO
– Influences proliferation/differentiation
Committed megakaryocyte
progenitor cell of megakaryocytes2
TPO • Drives platelet production via the TPO
receptor (TPO-R)4
Immature megakaryocyte
• Decline in platelet mass causes an
TPO
increase in TPO levels to maintain
Mature megakaryocyte platelet levels
– TPO levels usually remain elevated
during any incident of persistent
Platelets
thrombocytopenia1

1. Kuter D, et al. Blood 2002; 100: 3456–69; 2. Kaushansky K. N Engl J Med 1998; 339: 746–54; 3. Wolber E, Jelkmann W. News Physiol Sci 2002; 17: 6–10;
4. Kuter D, et al. Blood 2007; 109: 4607–16. Figure adapted from Kaushansky K. N Engl J Med 1998; 339: 746–54.

©
 Thrombopoietin (TPO) signalling pathways

• TPO regulates the maturation of megakaryocytes, via

signal transduction pathways, into platelet-producing
cells
TPO
TPO-R

Cell membrane
JAK
GRB2

STAT SHC SOS

P13K RAS/RAF

AKT MAPK/ERK

NUCLEUS

Kaushansky K. J Clin Invest 2005; 115: 333947. Figure adapted from Kaushansky K. J Clin Invest 2005; 115: 333947.

©
 TPO-R agonists
• Therapeutic class of agents that bind and activate the TPO-R, stimulating
platelet production
• Agents include TPO non-peptide agonists (e.g. Eltrombopag) and TPO peptide
agonists (e.g. Romiplostim)
• Eltrombopag is indicated for chronic ITP patients aged ≥1 year who are refractory
to other treatments; romiplostim is licensed only in the adult chronic ITP setting
Eltrombopag is a small molecule, which binds deeper than endogenous TPO, in the
transmembrane domain of the TPO-R. TPO and romiplostim bind the extracellular part
of the receptor

TPO Eltrombopag romiplostim

TPO-R

Cell
membrane

TPO, thrombopoietin; TPO-R, thrombopoietin receptor.

Kuter D. Blood 2007; 109: 4607–16.
 Eltrombopag mechanism of action

Rebozet

TPO-R
TPO-R active
inactive

p p

SHC GRB2
SOS
Cell membrane JAK
RAS/RAF

STAT MAPKK

Cytoplasm P42/44

Signal transduction

Increased platelet production

Figure adapted from Kuter D. Blood 2007; 109: 4607–16.

©
 Elthrombopag was generally well tolerated
AEs in ≥10% of patients regardless of causality: 17 patients discontinued
Elthrombo treatment early due to AEs
Control • 13 patients in the Elthrombopag group:
AE, n (%) pag
(n=61) ALT increased (n=4); TEE (n=2);
(n=135) cataract, duodenal-ulcer haemorrhage,
urticaria, rash, tachycardia, headache
Any AE regardless of causality 56 (92) 118 (87) and rectosigmoid cancer (n=1 for each)
Headache 20 (33) 41 (30)
• 4 patients in the control group: cataract
Diarrhoea 6 (10) 17 (13) (n=2); fatal brain-stem haemorrhage
Nausea 4 (7) 16 (12) (n=1); abnormal renal function test
Nasopharyngitis 8 (13) 14 (10) results, ALT increased, or
Upper respiratory tract infection 7 (11) 14 (10) hyperkalaemia (n=1)
Fatigue 8 (13) 13 (10) Grade 3 or 4 (severe or
Limb pain 6 (10) 9 (7) life-threatening) AEs
Epistaxis 6 (10) 7 (5)
• Most grade 3 or 4 AEs in the
Dizziness 6 (10) 5 (4)
control group were bleeding
Peripheral oedema 6 (10) 2 (1)
events
Any grade 3 or 4 AE* 7 (11) 20 (15) • Only 2% of patients in the
Elthrombopag group had grade 3
Deaths 1 (2) 0
or 4 bleeding events

*Severity of adverse events, including bleeding adverse events, was reported according to National Cancer Institute Common
Terminology Criteria for Adverse Events (version 3.0); AE, adverse event; ALT, alanine aminotransferase; TEE, thromboembolic event.
Cheng G, et al. Lancet 2011; 377: 393–402. Erratum: Lancet 2011; 377: 382.
Table reproduced from Cheng G, et al. Lancet 2011; 377: 393–402. Erratum: Lancet 2011; 377: 382. ©
 Elthrombopag was generally well tolerated
• 277/302 patients (92%) experienced AEs • 96 (32%) patients reported
serious AEs
AEs occurring in ≥10% of patients Patients, n (%)
– These included cataracts,
Headache 86 (28) pneumonia, anaemia, increased
Nasopharyngitis 74 (25) ALT or AST, epistaxis, increased
Upper respiratory tract infection 69 (23)
bilirubin, and deep vein
thrombosis
Fatigue 50 (17)
Diarrhoea 47 (16) • 41 patients (14%) had AEs
Arthralgia 45 (15) leading to discontinuation from
Back pain 40 (13) the study
Urinary tract infection 34 (11) – These included increased ALT,
AST or bilirubin, cataract, deep
Nausea 34 (11)
vein thrombosis, cerebral
Cough 32 (11) infarction, headache and
Influenza 30 (10) myelofibrosis
Anaemia 29 (10)

The safety profile was consistent with that demonstrated in previous studies,
with no new safety findings observed with up to 8.76 years of treatment
AEs, adverse events; ALT, alanine aminotransferase; AST, aspartate aminotransferase.
Safety population. Data on file.
EXTEND
Adverse events of special interest:
hepatotoxicity and thromboembolic events

Hepatobiliary laboratory abnormalities* (HBLAs)

• HBLAs were reported in 21 patients (7%)1
– Most resolved either while on treatment or after discontinuation and none were associated
with signs of liver impairment2

– Incidence of HBLAs did not increase with longer duration of exposure to Eltrombopagt1

Thromboembolic events (TEEs)

• TEEs were reported in 19 (6%) patients while on treatment1
• No relationship between TEEs and elevated platelet counts was observed2
• The overall incidence of TEEs was 2.53/100 patient-years (95% CI: 1.52–3.95)3
– No increased rate of TEEs has been observed with longer treatment duration1

*Alanine aminotransferase or aspartate aminotransferase ≥3x upper limit of normal, or bilirubin >1.5x upper limit of normal.
1. Data on file; 2. Bussel J, et al. Blood 2013; 122: Abstract 2315; 3. Bussel J, et al. Poster presented at the 55th Annual Meeting of the American Society of
Hematology, New Orleans, USA, December 7–10, 2013.
 Adverse events of special interest: bone marrow fibrosis

• No clinically relevant increases in reticulin deposition were observed with up to

5.5 years of treatment
• Two patients (2%) had reticulin grade ≥MF-2 after 25 months on treatment
– Neither of these patients experienced any AE or abnormality in haematological parameters
potentially related to bone marrow findings
• Two patients were withdrawn from the study due to bone marrow findings

AE, adverse event; MF, myelofibrosis.

Brynes RK, et al. Am J Haematol 2015; 90: 598–601; Figure from Brynes RK, et al. Am J Haematol 2015; 90: 598–601. ©
 Eltrombopag: dose adjustments

Recommended starting dose in adults:*

50 mg once daily
Wait 2 weeks

<50,000/µL ≥50,000/µL to ≤150,000/µL >150,000/µL to ≤250,000/µL >250,000/µL

Increase Maintain Decrease Stop

dose by 25 mg to a use lowest dose or dose by and increase the frequency of
maximum of 75 mg/day† concomitant ITP 25 mg/day‡ platelet monitoring to twice
treatment weekly. Once the platelet count
is <100,000/μL, reinitiate
therapy at a daily dose reduced
Reassess in 2 weeks
Reassess in 2 weeks by 25 mg/day‡

*For patients of East-Asian ancestry, Rebozet should be initiated at a reduced dose of 25 mg once; †For patients taking 25 mg once every other day, increase dose to 25
mg once daily; ‡For patients taking 25 mg once daily, consideration should be taken to dosing at 12.5 mg once daily, or 25 mg once every other day.
Eltrombopag Global Data Sheet. Version 12. March 2016.
 Elthrombopag: dosing schedule

• Certain food products can affect the absorption of Elthrombopag

– Elthrombopag should be taken 2 hours before or 4 hours after
ingesting the following:

Dairy products or Antacids Some mineral and vitamin supplements,

calcium-rich foods including iron, calcium, magnesium,
aluminium, selenium and zinc

The above products should be

avoided during the highlighted time

Possible dosing schedules

Eltrombopag Global Data Sheet. Version 12. March 2016.

Elthrombopag is the first and only oral once-daily TPO-R
agonist approved for the second-line treatment of adult
chronic ITP

In adult chronic ITP patients, Elthrombopag treatment:

• Provided greater platelet responses vs control1

• Provided early and sustained platelet responses vs control1

• Reduced incidence of bleeding1,2

• Allowed reduced or discontinued use of concomitant medications1,2

• Was generally well tolerated1,2

• Had a positive impact on quality of life1,3

TPO-R, thrombopoietin receptor.

1. Cheng G, et al. Lancet 2011; 377: 393–402. Erratum: Lancet 2011; 377: 382; 2. Data on file; 3. Grotzinger K, et al. Haematologica 2012; 97:198–99.
Summary
• ITP is autoimmune disease characterized by isolated
thrombocytopenia
• Diagnosis remains one of exclusion
• New paradigm of pathophysiology is autoimmunity,
platelet destruction and decrease production platelet by
megakaryocyte
• Conventional treatment: first-line therapy, second-line
treatment, and emergency treatment.
• First-line therapy: corticosteroid, IVIG and anti-D
• Second-line therapy: splenectomy, TPO-RA, and
rituximab