1. Updates in the Management of ITP
Dr. K.C Usha
Professor & Head - Dept of Transfusion Medicine
Sree Mookambika Institute of Medical Sciences,
Kulasekharam, Kanyakumari Dist:
Tamil Nadu

2. ITP “Idiopathic Thrombocytopenic Purpura”
“Immune Thrombocytopenic Purpura”

3. Introduction Inherited autoimmune disorder
Abs against pl: Ags llb / llla
↑ Destruction of platelets
Macrophages & cytotoxic T cells involved
↓ Levels of thrombopoietin in plasma
↓ Production of platelets
Impaired megakaryocyte function

4. ITP ( Contd….) International ITP Working group
Removed the terminology “A/c ITP”
Since diagnosis made retrospectively
Proposed term “Newly diagnosed ITP”
ITP classified into 3 groups
Newly diagnosed : First 3 months
Persistent ITP : Symptoms last b/w 3-12 months
Chronic ITP : Symptoms persist > 12 months
According to international guidelines :
Thrombocytopenia : Pl: count < 100 x 109 / L

5. Another Classification
ITP
Primary
Secondary

6. Primary ITP
Diagnosed by exclusion
Constitutes 80 % of ITP

7. Secondary ITP Due to various underlying diseases Auto immune SLE
Anti phospholipid antibody syndrome(
APLA)
Infections
HIV
HCV
H. Pylori
Drugs
Heparin
Penicillin
Non steroidal anti- inflammatory drugs
Vaccination
Measles
Mumps
Rubella
Varicella
Secondary ITP

8. Treatment of ITP Guidelines published by ASH (2011)
American Society of Hematology
Valid reference for conventional Rx
Rx modalities divided into :
I line therapy
II line therapy
III line therapy
Treatment of ITP

9. Treatment Modalities First Line Therapy Corticosteroids IV Ig
Anti D Immunoglobulin
Second Line Therapy
Splenectomy
Rituximab
Third Line Therapy
TPO RAS / TRAS
(Thrombopoietin Receptor Agonists)
Commonly used TRAS
Eltrombopag
Romiplostim

10. ITP in Children I & II line Rx as in adults
Rituximab suggested as II line
Splenectomy contraindicated
Splenectomy not preferred
Significant bleeding
Need for better quality of life
III line : Initially, TPO RAS not recommended
After successful trials
Now Eltrombopag recommended

11. Corticosteroids First choice for initial Rx Ease of administration
Lower cost
↓ Ab production
Prevent platelet destruction
Available corticosteroids
Prednisone
Prednisolone
Methyl prednisolone
Dexamethasone
Corticosteroids

12. Corticosteroids (Contd)
Oral administration
Dose :
0.5-2 mg / kg / day for wks
Gradual tapering
Platelet count to be monitored
Avoid long term use

13. Corticosteroids (Contd)
Adverse effects :
Osteoporosis
Diabetes
Hypertension
Cataract
Weight gain
Avascular necrosis of bones
Growth retardation in children
Personality changes
Opportunistic infections

14. IV Ig Pooled plasma gamma globulin One of the safer options
Neutralise auto antibodies & cytokines
↑ Clearance of anti pl: Abs
Faster response rate compared to corticosteroids
Generally well tolerated
Costly but ↓ hospital stay
Transmission of viruses; theoretical risk

15. IV Ig (Contd) Dose : 2mg/kg (single dose)
Repeated based on platelet count
Non responders : 3mg /kg
Response transient
Lasting no longer than 3-4 wks
Adequate hydration required
To reduce A/c renal injury

16. IV Ig (Contd) Products not interchangeable
Due to numerous differences in
Osmolality
Immunoglobulin A content
Different stabilizers
(Sucrose/glucose/maltose)

17. IV Ig (Contd) Adverse effects Depends on rate of infusion
Specific products
Headache
Chills
Arthralgia
Back pain
Thrombotic events
Renal impairment
IV Ig (Contd)

18. Anti D Immunoglobulin Gamma globulin against Rh (D) ag
Approved by FDA for Rx of ITP
Oposonize Rh D + RBCs
Opsonised RBC & opsonised platelets
Compete for sequestration in spleen
Blocks macrophage system
↓ Platelet destruction
Neutralise anti platelet Abs
Patients monitored at least for 8 hours

19. Anti D Immunoglobulin (Contd)
Dose :
50-75 mg / kg IV
75 mg / kg preferred
Adverse effects :
Headache, fever, chills
Nausea, vomiting
Fatal intravascular hemolysis
Hemoglobinuria ( rare)
Multi organ dysfunction

20. Splenectomy Historically gold standard Rx for C/c ITP
Newer Rx regimens ↓ splenectomy rates
Higher response rates in younger pts
Limiting factor : bleeding associated with surgery
Mortality rate :
0.2 % with laparoscopic procedure
1 % with open laparotomy
↑ Chance for infections
To be vaccinated against various infections .

21. Rituximab Anti CD 20 Cytolytic monoclonal Ab Off-label drug for ITP
Inhibits B cells from producing Abs
Reserved for patients with
High risk of bleeding
Failed treatment with corticosteroids/IVIg/Anti D
Administered early : relapse free survival
Optimal timing of administration
Yet to be determined

22. Rituximab (Contd) Adequate hydration required
Monitor serum electrolytes & renal function
Dose :
375 mg / m2 once weekly
Repeated for 4 consecutive weeks
Infused over a period of 4 hours
Initial response in days
Average 38 days

23. Rituximab(Contd) Adverse effects : Pruritis, urticaria Fever, chills
Nausea, vomiting
Serum sickness
Anti histamines / anti pyretics administered
30 mts prior to infusion
Patients treated for > 12 months
Infection
Malignancies
Pulmonary embolism
Pneumonitis
CNS hemorrhage

24. TPO-RAS / TRAS TPO Receptor Agonists Approved by FDA
Rapidly responding immunosuppressant
Acts on both platelets & megakaryocytes
↑ Platelet production
Approx 2 wks for desirable effects
Uncertainty about Rx duration
Effective in randomized trials
Enable durable remissions

25. TPO-RAS/TRAS (Contd) Rx option for Refractory ITP Cross placenta
Safety in pregnancy not demonstrated
Commonly used TPO RAS
Eltrombopag
Romiplostim
TPO-RAS/TRAS (Contd)

26. Eltrombopag Double blind randomised control trials
Assessed efficacy & safety
Route of administration : Oral
Can be used in children
Duration of remission based on
Antibody levels
Megakaryocyte pool in bone marrow
Pl: count to be measured wkly
Adverse effects
Elevated hepatic enzymes
Thromboembolic events

27. Romiplostim Used effectively in C/c ITP
Irrespective of splenectomy done or not
↑ Platelet count & ↓ bleeding
Single IV / Subcutaneous dose
Dose : 10 mcg / kg
Initial response within 5-8 days
Return to baseline by day 28
CBC to be monitored daily
Till pl: count reaches 50 x 109 / L

28. Romiplostim (Contd) Adverse effects Headache, fatigue
Epistaxis, arthralgia
Bone marrow reticulin formation
Thromboembolism
Romiplostim (Contd)

29. Other Immunosuppressive Agents
Mycophenolate Mofetil ( MMF)
Rapamycin ( Sirolumus )
Azathioprine
Cyclosporine
MMF prevents proliferation of lymphocytes
↓ Antibody production

30. Combination therapy When monotherapy fails
More effective in C / c patients
A) Triple therapy
High dose Dexamethasone
Low dose Rituximab
Cyclosporine
B) Combination of :
TPO RAS
Another immunosuppressant

31. Agents Under Trial Totrombopag Choline Thrombopoietin receptor agonist
Phase II trial
LGD 4665
New molecular entity
Small molecule
Oral administration

32. Agents Under Trial(Contd)
MDX -33
Humanized monoclonal Ab
Appears to be promising
ARK – 501
Under trial
Agents Under Trial(Contd)

33. Molecule Targeting Therapies
Anti CD 20 (Rituximab , Veltuzumab)
Anti CD 40 L (IDEC 131, CD 154)
Anti CD 52 (Alemtuzumab , Compath 1 H)
Anti CD 80 / 86 (Abatacept , CTLA4 – IG)
Anti IL 2 receptor (Daclizumab)

34. Platelet Transfusion When immediate hemostasis required
Effects transient
Transfused platelets get opsonised
Removed from circulation

35. Haematopoietic Stem Cell Transplantation
Remission seen in few cases
Newly formed pl: get opsonised
Fatal toxicities
GVHD
Septicemia
Reserved for severe refractory ITP with bleeding

36. Future Directions Targeting Neonatal Fc receptor (FcR)
↓ Half life of offending Ab
↑ Clearance of Ab
Interference with TNF signalling
TNF neutralising therapies
Using Etanarcept & Infliximab
Other ligands in TNF family :
BAFF
APRIL

37. Future Directions (Contd)
BAFF
B cell activating factor in TNF family
Monoclonal Ab used to block BAFF
↓ Production of offending Ab
↓ Platelet destruction
APRIL
Proliferation inducing ligand
Essential for B cell survival
During maturation in spleen
Produced by monocytes / macrophages
Blocking APRIL : ↓ Ab production

38. Conclusion No confirmatory tests for ITP
Novel therapies ↓ rate of splenectomy
Rx regimes to be individualised
Corticosteriod : drug of choice for initial Rx
Rituximab : Off - label Rx

39. Conclusion (Contd) Before starting Rx consider Type of ITP
Duration of disease
Cost involved
Any additional risk factors
Maintain pl: count at levels which ↓ risk of bleeding