Immune thrombocyopenia.

1. Immune Thrombocytopenia
Dr Ankit Raiyani (MD Medicine , DNB Hematology)
Consultant hematologist and BMT physician
Qure hematology oncology center
Ellisbridge, Ahmedabad

2. Outline
• Overview
• Demographics
• Pathophysiology
• Clinical Manifestations
• Differential Diagnosis
• Management
– Goals of therapy
– First-line therapy
– Selection of second-line therapies
• Future directions

3. Overview

4. Platelets
• Normal platelet count - 150000 to
450000/cmm
• Lifespan of Platelets : typically 5 to 9
days
• Eliminated via phagocytosis in the
spleen and liver by Kupffer cells
• Thrombopoiesis is the process by
which new platelets are formed from
megakaryocytes in the bone marrow.
• Average daily production of platelets -
100,000,000,000
• Platelet production can increase up to
20-fold during periods of high demand

5. ITP
• Idiopathic thrombocytopenic purpura
• Immune Thrombocytopenia
– Immune-mediated
– Acquired disease
– Transient or persistent decrease of the platelet
count
– Increased risk of bleeding

6. • Newly diagnosed ITP: ≤ 3 months from diagnosis
• Persistent ITP: 3-12 months from diagnosis
– Describes patients lacking spontaneous remission or
complete response after treatment
• Chronic ITP: lasting > 12 months
• Severe ITP: Bleeding symptoms requiring
treatment
• Refractory ITP: disease that does not respond to
or relapses after splenectomy and that requires
treatment to reduce the risk of clinically
significant bleeding

7. • Primary ITP: Isolated thrombocytopenia (peripheral
blood platelet count < 100000/cmm) in the absence
of other causes or disorders. The diagnosis of
primary ITP remains one of exclusion
• Secondary ITP: All other immune-mediated
thrombocytopenia
• Infection-associated HCV, HIV, H pylori
• Immunodeficiency- CVID, WAS
• Autoimmune disorders - SLE, others
• Lymphoproliferative - CLL, others
• Drug-induced

8. • Accounts for estimated 20% of total ITP cases
SLE 5%
APS 2%
CVID 1%
CLL 2%
Evan’s 2%
ALPS, post-tx 1%
HIV 1%
HCV 2%
H pylori 1%
Postvaccine 1%
Misc systemic infection 2%
Primary
80%
Cines DB, et al. Blood. 2009;113:6511-6521.
Secondary ITP

9. Demographics

10. Incidence of ITP in Adults
• Retrospective cohort analysis of adult pts
Abrahamson PE, et al. Eur J Haematol. 2009;83:83-89. Slide credit: clinicaloptions.com
12
10
8
6
4
2
0
18-19 20-29 30-39 40-49 50-59 60-69 70-79 80-89 90-99
Age, Yrs
3.6
1.6
4.9
0.6
3.5
1.3
3.0
1.8
4.2
3.0
5.5
3.9
6.4
10.5
9.2 9.3
10.8
8.1
Female
Male
Rateper100,000Person-Yrs

11. Pathophysiology of ITP

12. Harrington’s Classic Experiment
Harrington WJ, et al. J Lab Clin Med. 1951;38:1-10.
1000
800
600
400
200
1 2 3 1 2 3 4 5 6 7 8 9
Platelets(Thousands)
Hrs Days

14. Increased destruction of platelets
1. Loss of immune tolerance
of Helper T cells
2. Differentiation of
autoreactive B cells
producing antiplatelet
antibodies
3. Antiplatelet antibodies
target glycoprotein IIb/IIIa,
and cause platelet
destruction by
macrophages or cytotoxic
T cells
3 step process

15. Decreased platelet production
• Megakaryocytes and platelets share common
surface antigens
• Most anti-platelet antibodies may also target
megakaryocytes

16. Clinical manifestations

17. • History
– Preceding episode of fever
– Sudden onset ecchymosis, mucosal bleeding,
petechiae, purpura
– Joint pain, skin rashes, oral ulcers
– Night sweats, bone pain, weight loss
• Examination
– Lymphadenopathy
– Organomegaly

18. Bleeding Manifestations in ITP
Wet Purpurae
Ecchymoses and petechiae
CNS hemorrhage

19. Estimated Annual Bleeding Incidence in
ITP by Age
Fatal Hemorrhages Major Nonfatal Hemorrhages
Age, Yrs
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0
< 40 40-60 > 60
0.130
0.012
0.004
EventsperPt-Yr
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0
EventsperPt-Yr
Age, Yrs
< 40 40-60 > 60
0.025
0.0725
0.719

20. Adult ITP Presenting Symptoms by
Platelet Count
Neylon AJ, et al. Br J Haematol. 2003;122:966-974.
Symptom, n (%) Platelet Count
0-9 x 109/L
(n = 114)
10-19 x
109/L
(n = 51)
20-29 x
109/L
(n = 26)
30-49 x
109/L
(n =54)
Any
(N = 245)
Hemorrhage 18 (16) 6 (12) 4 (15) 2 (4) 30 (12)
Purpura 75 (66) 34 (67) 12 (46) 23 (43) 144 (59)
Asymptomatic 21 (18) 11 (22) 10 (38) 29 (54) 71 (29)

21. Thrombocytopenia in pregnancy

22. Diagnosis
• Thrombocytopenia (Platelet < 1,00,000/cmm)
– Spurious
• Platlelet aggregation – EDTA
• Large platlelets – Harris syndrome
– True thrombocytopenia
• Manual platelet counts

23. Diagnosis
• CBC
– Anemia
• Iron deficiency anemia – Low MCV, high RDW
• Hemolytic anemia – Evans syndrome
• RBC morphology – schistocytes, nucleated RBC
– WBC
• Differential WBC count
• Reactive lymphocytes
• Abnormal cells – Atypical lymphocytes, blasts

24. Diagnosis
• Bone marrow aspiration and biopsy
– Should be done before steroids administration
– To establish normal hematopoiesis and platelet production
– To rule out bone marrow involvement by hematological
malignancies
• HIV, HCV
• H Pylori antibodies
• ANA, APLA, Direct coombe’s test
• PT, APTT, D-dimer
• Quantitative immunoglobulins
• Imaging – CXR, USG Abdomen

25. Differential diagnosis
• Hypersplenism
• Malignancies
– Leukemia
– Lymphoma
• Thrombotic thrombocytopenic purpura (TTP)
• Disseminated Intravascular coagulation (DIC)
• Evolving Aplastic anemia

27. Goals of ITP Therapy
• Maintain a safe platelet count with minimal
toxicity
– Toxicity of therapy, particularly long-term steroid
exposure, may be significant
• Individualize therapy based on bleeding risk

28. Recommended “Safe” Platelet Ranges
Clinical Situation Platelets
General dentistry
 Extractions
 Regional dental block
≥ 10 x 109/L
≥ 30 x 109/L
≥ 30 x 109/L
Surgery
 Minor
 Major
≥ 50 x 109/L
≥ 80 x 109/L
Pregnancy
 Vaginal delivery
 Caesarean section
 Spinal/epidural anesthesia
> 50 x 109/L
> 80 x 109/L
> 80 x 109/L

29. Therapy Options for ITP
Clinical Situation Therapy Options
First line (initial treatment for
newly diagnosed ITP)
Anti-D
Corticosteroids: dexamethasone, methylprednisolone,
prednisolone
IVIg
Second line
Azathioprine
Cyclosporin A
Cyclophosphamide
Danazol
Dapsone
Mycophenolate mofetil
Rituximab
Splenectomy
TPO receptor agonists (romiplostim and eltrombopag)
Vinca alkaloids
Treatment for patients failing
first- and second-line
therapies
Category A*: TPO receptor agonists
Category B†: campath-1 H, combination of first- and second-line
therapies, combination chemotherapy, HSCT
*Sufficient data to support recommendation.
†Minimal data to support recommendation; potential for considerable toxicity.

31. First-line therapy

32. Corticosteroids
• Prednisone
– Dose: 1-2 mg/kg/day, then
taper
– Clinical responses in 65-85%
patients
• Responses in 4-14 days;
peak in 7-28 days[1]
• Only 5-30% sustain response
after discontinuation
– Toxicity: glucose
intolerance, psychosis,
osteoporosis, Cushingoid
habitus, weight gain
• Dexamethasone
– Dose: 40 mg daily x 4 days
– 1 or more cycles, every 2 wks
– Higher incidence of sustained
remissions?

33. 80
High-Dose Dexamethasone vs
Prednisone in Newly Diagnosed ITP
Wei Y, et al. Blood. 2016;127:296-302. Slide credit: clinicaloptions.com
100
60
40
20
0
0 6 12 18 24 30 36
Mos
95
97
60
57
40
45
39
40
37
32
21
15
31
24
12
10
7
4
PtsResponding(%)
Pts at Risk, n
High-dose
dexamethasone
Prednisone
High-dose dexamethasone
Prednisone

34. Intravenous Immunoglobulin (IVIg)
• Dose: 0.5-2.0 g/kg over 2-5 days
Efficacy
 65% achieve platelet count > 100,000/µl, 85% > 50,000/µ
 Most responses transient
 30% become refractory
Toxicity
 Headache
 Positive DAT
 Anaphylaxis in IgA-deficient patients
 Thrombosis
 Renal
Mechanisms
 Modulation of Fc receptors
 Attenuation of complement mediated damage
 Induction of anti-inflammatory cytokines
 Anti-cytokine antibodies
 Neutralization of autoantibodies by anti-idiotypes
 Modulation of T-cell activity
 Inhibition of lymphocyte proliferation
 FcRn

35. Intravenous Anti-Rh(D)
• Creates RBC hemolysis and Fcγ
receptor blockade
• Initial dose: 50 µg/kg IV over 2-5
minutes
– Reduce if Hgb < 10 g/dL
• > 70% responders; duration > 21
days in 50%
• All patients drop Hgb (0.8 g/dL)
• Recommended only for Rh-positive
pts with no history of splenectomy
• Rare but severe AE: intravascular
hemolysis and disseminated
intravascular coagulation[1]
• Severe DIC in 1 in 20,232
infusions[2]
 Patients should be closely
monitored in a health care setting
for at least 8 hrs after
administration
 Dipstick urinalysis should be
performed at baseline, 2 hrs, 4 hrs
post administration and prior to
end of monitoring period
FDA Black Box Warning

36. Second-Line Therapies
• Azathioprine
• Danazol
• Dapsone
• Rituximab
• Thrombopoietin
receptor agonists
– Romiplostim
– Eltrobopag
• Cyclosporine A
• Cyclophosphamide
• Splenectomy
• Mycophenylate mofetil
• Vinca alkaloids
Provan et al. Blood. 2010;115:168-186.

37. Splenectomy
Vianella N, et al. Haematologica. 2013;98:875-880. Slide credit: clinicaloptions.com
80
100
60
40
20
0
0 120 240 360 480 600
Mos From Splenectomy
Relapse-FreeSurvival(%)
CR (n = 180)
All pts (n = 206)
R (n = 26)
CR
R = pts who responded

38. 120 144 168
VTE and Sepsis After Splenectomy in ITP
0.25
0.20
0.15
0.10
0.05
0
0 24 48 72 96
Mos After Splenectomy
IncidenceofSepsis
0.03
0.02
0.01
0
0
Mos After Splenectomy
24 48 72 96 120
IncidenceofAbdominalVTE
Log-rank P = .0544
Splenectomized
Nonsplenectomized
0
0.01
0.02
0.03
0.04
0.05
0.07
0.06
Log-rank P < .0001
IncidenceofVTE
0 24 48 72 96 120
Splenectomized
Nonsplenectomized
Splenectomized
Nonsplenectomized

39. Rituximab Efficacy in Adult ITP:
Systematic Analysis
Platelet Count Response, x
109/L
Pooled Estimate, %
(95% CI)
Contributing
Reports, n
Pts, n
Overall response
(> 50)
62.5
(52.6-72.5)
19 313
CR (> 150)
46.3
(29.5-57.7)
13 191
PR (50-150)
24.0
(15.2-32.7)
16 284

40. • At 5 yrs, 21% to 26% of adults and children
demonstrate sustained response to rituximab
Durable ITP Remissions After Rituximab
Patel VL, et al. Blood. 2012;119:5989-5995.
n = 38 n = 72
Slide credit: clinicaloptions.com
100
80
60
40
20
0
100
80
60
40
20
0
350300250200150100500 350300250200150100500
Children Adults
Wks From Initial Treatment Wks From Initial Treatment
PtsinContinuingResponse(%)
PtsinContinuingResponse(%)
26%
21%

41. TPO Receptor Agonists
Fc Carrier Domain
Peptide Receptor-Binding
Domain
Eltrombopag[2,3]
 Peptidomimetic
 PO bioavailable
 Binds to transmembrane
portion of TPO receptor
Romiplostim[1]
 Unique platform peptibody
 Binds to ligand binding site of
TPO receptor
 SC injection
H0
0
H0
0
HN
N
N
N CH3
H3C
H3C

42. RAISE: Eltrombopag in Chronic ITP
Placebo
Eltrombopag
Placebo, splenectomized
Placebo, not
splenectomized
Eltrombopag,
splenectomized
Eltrombopag, not
splenectomized
Pts at Risk, n
Placebo
Eltrombopag
61
135
60
134
59
131
58
129
59
123
59
128
58
128
43
96
44
95
43
91
53
110
54
110
55
118
58
119
46
101
MedianPlatelet
CountperμL
(x103)
140
120
100
80
60
40
20
0
On treatment Post-
treatment
Pts at Risk, n Placebo
Eltrombopag 61
135
61
134
60
133
59
133
60
131
60
134
59
134
47
108
48
112
47
113
58
132
54
110
55
118
58
119
50
114
PtsResponding
totreatment
(%)
60
50
40
30
20
10
0
On treatment Post-
treatment
Study Wk
MedianPlateletCount
perμL(x102)
140
120
100
80
60
40
20
0
On treatment Post-
treatment
160
0 261 2 3 4 5 6 10 14 18 22 1 2 4
Placebo
Eltrombopag

43. Conclusions
• ITP is a common hematologic disorder with a complex pathogenesis involving accelerated
platelet destruction, impaired platelet production, and humoral/cellular immunity
abnormalities
• Viral and other pathogens play important roles in development of secondary ITP
• Multiple therapeutic strategies exist for the treatment of ITP and should be individualized
for each patient
– First-line
• Corticosteroids: effective, but usually do not provide long-term responses
– Second-line
• Splenectomy: remains an effective long-term therapy
• Rituximab: may potentially provide long-term remissions in a subset of patients
• Thrombopoietic agents: provide an important new treatment option
• The role of aggressive management in newly-diagnosed ITP is uncertain
• The choice of a second line therapy depends on patient characteristics and desired
outcomes

44. Thank you!!
Dr Ankit Raiyani
Hematologist & BMT physician
QURE Hematology Oncology center, Ellisbridge
Attachments- Sterling hospital, SAL hospital, HCG Hospital
Mob- 7798438250