ITP

What is Changing in Pediatric ITP?

• The I in ITP no longer mean Idiopathic; in fact it stands for Immune

Nomenclature in ITP:

• Definition of ITP:

  • Platelet count < 100 x 109/L

  • Previously it was platelet count < 150 x 109/L. Only 6.9% of cases with platelet count between 100 to 150 x 109/L progressed to ITP in 10 yrs.

Newly Diagnosed ITP: < 3 mths duration

Persistent ITP: 3 mths to 1 yr.

Chronic ITP: > 1 yr. duration

Definition of Primary ITP:

Isolated thrombocytopenia in absence of identifiable & specific precipitants. WBC is Normal with Normal Hb; if there is anemia it must be commensurate with the degree of Blood Loss.

Definition of Secondary ITP: when ITP occurs in association with secondary causes

(HIV infection, HCV, Anti Phospholipid Antib0dies & Others)

Table: Secondary causes of ITP:

Definition of response to treatment:

CR: Complete Response

Platelet count > 100 x 109/L on 2 occasions. Done > 7 days apart & Absence of Bleeding

R : Response

Platelet count > 30 x 109/L or 2 fold increase in platelet count Done > 7 days apart & Absence of bleeding

NR: No Response

Platelet count < 30 x 109/L

< 2 fold increase in platelet from base line or the presence of bleeding

Platelets must be measured on 2 occasions more than a day apart

Loss of Complete Response

Platelet count < 100 x 109/L measured on 2 occasion a day apart & or presence of Bleeding

Loss of Response

Platelet count < 30 x 10/L& or a < 2 fold increase from baseline or the presence of Bleeding. Platelets must be measured on 2 occasions more than a day apart

Recommendations of IWG (International Working Group) in ITP

Childhood ITP:

• • Commonly preceded by viral infection 4 to 6 weeks before onset of ITP

  • Very often acute,

  • 75 to 85% resolve with in 6 weeks

  • Only 5 to 10% progress to chronic ITP

  • In India we believe incidence of chronicity is more say 15 to 25%

  • Child has the potential to achieve spontaneous remission with in 2 yrs.

Diagnosis of Childhood ITP can be made with reasonable certainty if

• Child has thrombocytopenia; Normal Hb & WBC count with a Normal Differential count.(Confirmed by a Hematologist)

• No organomegaly

Are Additional testing necessary in ITP?

ASH (American Society of Hematology) guidelines 2011 for ITP;

• Additional testing is ONLY necessary if there is a pointer to its presence like

• Presence of anemia, leucopenia, joint pains, bone pains, infections, LNpathy, Hepatosplenomegaly, family history or high-risk behavior should prompt additional work up.

Additional work up suggested is:

• HIV, HCV, ANA, APLA, ACLA, LA by Dilute Russell Viper Venom, Coombs test, Bone Marrow Aspiration, Serum Immunoglobulin levels (to r/o Common Variable Immune Deficiency)

• In INDIA it is important to rule out Familial Macro platelet Syndrome that is very common among people from Bengal, Bihar, Assam & the Northeast.

• H/o Vaccination especially with MMR or Hepatitis B is important and ITP may be post vaccination.

• In a child with thrombocytopenia with out fever please do not ask for Anti Dengue Antibodies, Anti Leptospira Antibodies & Rapid Tests for Malaria as they will invariably have fever prior to thrombocytopenia. These patients also have associated Leucopenia.

Is it necessary to do BMA + Biopsy in newly suspected ITP

ASH (American Society of Hematology) guidelines 2011 for ITP;

• BMA is not necessary in children & Adolescent with features of classic ITP

• BMA is not necessary in children who fail IVGG therapy

• BMA is not necessary in Children before initiation of Corticosteroids or splenectomy.

In India there is indiscriminate use of steroids hence BMA in children with suspected ITP would be appropriate if you are going to start steroids. BMA is done to r/o Acute Lymphoblastic Leukemia. The prognosis of ALL is excellent (>80% chance of cure) thus it should not be missed.

Initial Management of ITP:

Goal: to achieve a platelet count associated with “adequate hemostasis” rather than “Normal” Platelet count.

Risk of ICH (Intra Cranial Hemorrhage):

• 0.17% in a registry of 2540 children

• 0.2% 1682 children with minimum 6 mths of follow up

ASH 2011 recommendation:

• Children with ITP with mild bleeding (Bleeding restricted to skin i.e. Petachiae, purpura & ecchymosis) or no bleeding be managed with OBSERVATION alone regardless of platelet count.

Initial pharmacologic management of Pediatric ITP:

ASH 2011 recommendations:

• Short Course Corticosteroids or a single dose of IVIg (0.8 gm./kg to 1 gm./kg) be used as first line therapy

• IVIg may be used if a more rapid increase desired.

• IV Anti D should not be used in children with decreased Hb or with AIHA.

• Anti D may be used in an Rh +ve, non-splenectomized children requiring treatment.

• There are some concerns about development of severe hemolysis & DIC with use of Anti D.

We in India use a short course of steroids Prednisolone 4 mg/kg for 4 days; an alternative good regimen is Prednisolone 4 mg/kg x 4 days followed by 3 mg/kg x 4 days, 2 mg/kg/day x 4 days, 1 mg/kg/day x 4 days & STOP. IVIg in Indian setting is expensive and we must use IVIg more judiciously.

Children who are treatment non-responders, and or have persistent or chronic ITP:

Appropriate second line treatment for childhood ITP:

ASH 2011 recommendations:

• Steroids, IVIg, Anti D, if previously effective, may be used to prevent bleeding.

• Since spontaneous remission can occur up to 12 mths after diagnosis.

• Rituximab be considered for children or adolescents with ITP who have significant ongoing bleeding despite treatment with IVIg, anti-D, or conventional doses of corticosteroids

• Rituximab may also be considered as an alternative to splenectomy in children and adolescents with chronic ITP or in patients who do not respond favorably to splenectomy

• High-dose dexamethasone may be considered for children or adolescents with ITP who have significant ongoing bleeding despite treatment with IVIg, anti-D, or conventional doses of corticosteroids. Dose of Dexamethasone used in high 0.6 mg/kg x 4 days every 4 weeks apart x 6 courses.

• High-dose dexamethasone may also be considered as an alternative to splenectomy in children and adolescents with chronic ITP or in patients who do not respond favorably to splenectomy.

In India we try Dapsone or high dose dexamethasone before considering use of Rituximab because of cost considerations. Dapsone in dosage of 50 mg OD has shown a response rate of 66% & a continuous complete response rate of 31%. It is mandatory to do G6PD before starting Dapsone.

When should splenectomy be considered?

ASH 2011 recommendations:

• Splenectomy for children and adolescents with chronic or persistent ITP who have significant or persistent bleeding, and lack of responsiveness or intolerance of other therapies such as corticosteroids, IVIg, and anti-D and/or who have a need for improved quality of life.

• Splenectomy or other interventions with potentially serious complications be delayed for at least 12 months, unless accompanied by severe disease defined by the IWG as unresponsive to other measures or other quality of life consideration

In India we try and delay splenectomy in children as much as possible. We consider an adolescent female who has persistent menorrhagia or a young boy who wants a career in contact sports, or someone with severe recurrent bleed inspite of other medications warrants a consideration for splenectomy.

Pre splenectomy Vaccination & penicillin prophylaxis must be done

What is the role of Helicobacter Pylori testing in children & Adolescent with Chronic or persistent ITP?

ASH 2011 recommendation:

• H. Pylori testing is NOT Recommended.

In India H. Pylori is much more common and in some cases it may be worth considering testing for H pylori as it is a treatable cause of Chronic ITP.

Management of MMR Associated ITP:

11 studies recommended the incidence of ITP following MMR to be 0.87 to 4 (median 2.6) / 100,000 vaccine dose.

With Natural infection with Measles & Rubella are 6 to 1200 / 100,000 cases.

ASH 2011 recommendations:

• Children with a history of ITP who are unimmunized should receive their scheduled first MMR Vaccine

• Children with vaccine induced or non-vaccine induced ITP who have received their MMR should have their vaccine titres done; if +ve no further MMR required; but if titres negative then child should be re-immunized with MMR vaccine at the recommended age.

Table: shows the time taken for initial response and peak response in various treatment schemas in ITP.

Treatment type Initial Response (days) Peak Response (days)

Anti D 1-3 3-7

IVIg 1-3 2-7

Prednisone 4-14 7-28

Dexamethasone 1-14 4-28

Danazol 14-90 28-180

Rituximab 7-56 14-180

Splenectomy 1-56 7-56

Eltrambopag 7-28 14-90

Romiplostim 5-14 14-60

Azathioprine 30-90 30-180

Vinblastine 7-14 7-42

Vincristine 7-14 7-42

At no point in time Platelet transfusion in the management of ITP is discussed in the ASH 2011 ITP guidelines in children.

This issue is discussed in Emergency management of ITP:

ASH 2011 recommendations:

• As standard treatment for ITP take several hours to days to work pediatricians may resort to emergency treatment with aim of increasing platelet count rapidly. Platelet transfusions along with IVIg & Steroids seem to be a reasonable strategy.

• Target platelet counts may be difficult to attain and are not yet defined for ITP.

• Recombinant Factor VIIa can be used in EMERGENCY SITUATIONS successfully; but one should be aware of risk of thrombosis associated with their use.

• Heroic deeds like an emergency splenectomy is not appropriate.

• Platelet count should not be used as a criterion for consideration for platelet Tx.

In India, most children will receive platelet Tx before being referred to a specialist.

Investigations for Dengue, Malaria & Leptospira are often already done.

We know that platelets transfused in a child with Immune thrombocytopenic purpura will also be destroyed very quickly just like their autologous platelets.

Is there an indication for platelet Tx in ITP?

The ONLY time a platelet Tx seems possibly indicated is when a child has a life threatening bleed like Intracranial Bleed.

A good policy to follow is “Rx The Patient & Not The Platelet Count”

It should be our obligation to society to prevent misuse of Blood & Blood product as the “Best Blood Is Still The One That You Have Not Received”

Lastly FFP is NOT a substitute for Platelet transfusion.

Avoid all NSAID’s; Safe Drugs in children with ITP are Paracetamol, Tramadol and Dextropropoxyphene.

Evidence based guidelines help standardize practice across spectrum of medical services and one must always use one’s discretion for an Individual case.

Based on:

The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia

*Cindy Neunert,1 *Wendy Lim,2 Mark Crowther,3 Alan Cohen,4 Lawrence Solberg Jr,5 and Mark A. Crowther2

1University of Texas, Southwestern Medical Center, Dallas, TX; 2McMaster University, Hamilton, ON; 3Worcestershire Royal Hospital, Worcester, United

Kingdom; 4Children’s Hospital of Philadelphia, Philadelphia, PA; and 5Mayo Clinic, Jacksonville, FL

Blood. 2011; 117(16):4190-4207)

Compiled by

Dr Mukesh M Desai. M.D

Prof. of Pediatric Hematology Oncology (DNB)

Hon. Hematologist, Oncologist & Immunologist.

Department of PHO;

Chief, Division of Immunology;

B. J. Wadia Hospital for Children.

Honorary Consultant Hematologist

Nanavati Hospital.

Sir H N Hospital.

Saifee Hospital.

Asian Heart Institute

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Hematology & Immunology Cell.

B1 Matru Ashish,

Next to Balbharti School; SV Road,

Kandivili west, Mumbai 400067.

Cell : +91 9820037087.

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+91 22 28092917.

Email: mmdesai007@gmail.com

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