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