Immune Thrombocytopenic Purpura in Children

Dr. Priti S. Mehta
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Immune Thrombocytopenic Purpura In Children - Treatment
There is not enough evidence to prove that treatment alters the final outcome in any way. IWG has given the definitions of response to treatment as mentioned in Table 1.17

TABLE 1: Definitions of response to treatment by ITP*
Complete response (CR) A platelet count = 100 × 109/L measured on 2 occasions > 7 days apart and the absence of bleeding.
Response (R) A platelet count = 30 × 109/L and a greater than 2-fold increase in platelet count from baseline measured on 2 occasions > 7 days apart and the absence of bleeding.
No response (NR) A platelet count < 30 × 109/L or a less than 2-fold increase in platelet count from baseline or the presence of bleeding. Platelet count must be measured on 2 occasions more than a day apart.
Loss of complete response A platelet count < 100 × 109/L measured on 2 occasions more than a day apart and/or the presence of bleeding.
Loss of response A platelet count < 30 × 109/L or a less than 2-fold increase in platelet count from baseline or the presence of bleeding. Platelet count must be measured on 2 occasions more than a day apart.
?* Based on the recommendations of the International Working Group.17


ITP requires a personalized treatment depending on factors like age, clinical presentation, duration, economic and lifestyle issues, parental and patient compliance. Treatment is categorized into medical and surgical management. Medical management includes first and second lines of pharmacotherapeutic drugs.
It is recommended that children can be managed with observation alone regardless of the platelet count when they present with no bleeding symptoms or only mild bleeding symptoms (skin bleeds in the form of petechiae and ecchymosis). 6 Medical drug therapy initially includes corticosteroids, Intravenous immunoglobulin (IVIg) and IVRh anti-D.7

Corticosteroids
Not only reduce autoantibody formation but also impair the clearance of opsonised platelets in the bone marrow and peripheral organs. Steroids increase platelet levels more rapidly than no treatment as confirmed by many prospective, randomized studies. High dose prednisolone at 4 mg/kg/day for 4 days maintains therapeutic significance and minimizes side effects. Children with platelet count < 10× 109 /L or with mucosal hemorrhage are considered for steroid therapy by many physicians without any significant evidence. No steroid regimen has an advantage over other regimens. Long term steroids should be avoided because of side effects. Tapering the dose of steroids or terminating them on subsidence of bleeding or achieving a platelet count > 20× 109 /L are important.7

Intravenous Immunoglobulin (IVIg)
Acts through Fc?R11b receptor by impairing the clearance of opsonised platelets. Other studies suggest increased clearance of antiplatelet antibodies via saturation of the neonatal Fc salvage receptor for IgG. IVIg had a faster response rate as compared to steroids when the target platelet count was 50× 109 /L as observed by 2 Canadian clinical trials. They also observed that single dose of 0.8 mg/kg was as effective as the dose of 1gm/kg for 2 days. It also worked better than IV Rh anti-D to achieve a platelet count of 20× 109 /L. IVIg shortens the hospital stay because of the rapid response usually within 24-48 hours and is considered a safer option except for the exorbitant cost. Rare side effects of IVIg are aseptic meningitis, renal impairment or failure and thromboembolic events.7

Intravenous Anti-D
IV anti-D coats the rhesus D antigen positive RBCs and these opsonised RBCs compete with opsonised platelets for splenic sequestration. A dose of 75 µg/kg over 3-5 minutes is more effective than a dose of 50 µg/kg but not without side effects. Common side effects related to infusion of IV anti-D are fever, chills, nausea and headache. An important adverse effect related to infusion of IV anti D is a drop in haemoglobin due to hemolysis. Usually the drop is upto 2 gm/dl but at times can be severe leading to renal failure and disseminated intravascular coagulation.7 American Society of Hematology 2011 guidelines recommend that anti-D can be used as first line therapy in Rh positive, non-splenectomized children requiring treatment.

Second –Line Pharmacotherapy.
If treatment with first line agents like corticosteroids, IVIg, IV anti-D have been successful than these can be used during the first 12 months of persistent disease recurrently to prevent bleeding, especially while waiting for a possible spontaneous remission.6
The drugs in the armamentarium include Rituximab, high dose Dexamethasone therapy and immunosuppressants. The latest which have been approved in children are TPO mimetics. Immunosuppressants act at the level of T cells. In children and adolescents with chronic or persistent ITP who failed to respond to more conventional therapy, options of drugs like Azathioprine, Danazol, interferon, mycophenolate mofetil, cyclosporine, anti-CD 52 monoclonal antibody exist. However apart from Dapsone, or combination of agents, data is insufficient for specific recommendations.6

Rituximab6
It is a human-murine monoclonal antibody against the CD20 antigen on B lymphocytes. The effect of rituximab has been analyzed in children with persistent or chronic ITP by several prospective and retrospective studies. None of these were randomized, placebo controlled trials. Rituximab at a dose of 375mg/m2 every weekly for 4 weeks in a prospective, multicentre trial over 1 year was effective in only 8 of 36 children in maintaining their platelet counts above 50 x 109/ L.6 A trial in which the dose was doubled including some other trials showed a higher response rate if initially there was no response. Some children suffered from serum sickness 8. Data about long term adverse events such as progressive multifocal leukoencephalopathy is not known.9

High dose dexamethasone therapy
Studies have not been on more than 25 children with persistent or chronic ITP. In a prospective randomized trial in 20 patients, 6 cycles of high dose dexamethasone (0.6 mg/kg/day for 4 days every 4 weeks) and IVIg (800 mg/kg with a second dose if platelet count less than 30 x109/L at 48 hrs for 6 cycles), complete or partial remissions occurred in 5(25%) patients. Results have been similar with small prospective observational studies.10

Dapsone
A response rate of 66% and continuous response rate (maintenance of a platelet count > 50 x 109/ L with or without dapsone) of 31% was found in a retrospective analysis on 35 children.11 The dose recommended is 25 to 100 mg/day.

Single agents
Data regarding use of single agents is insufficient for giving specific recommendations.

TPO Mimetics (Eltrombopag and Romiplostim)
Thrombopoeitin (TPO) is the principal cytokine involved in the regulation of megakaryopoiesis and platelet production. Eltrombopag, a non–peptidyl thrombopoeitin (TPO) receptor agonist mimics the effect of TPO to stimulate platelet production. In the U.S it is available as Promacta and in Europe and other countries across the world as Revolade (SB-497115).
Eltrombopag has been licensed for only those cases of paediatric chronic ITP where the risk of bleeding is significant. Paediatric patients with chronic ITP on eltrombopag showed a consistent platelet response for 6 of the last 8 weeks of the double blind trial compared to placebo (39.7% vs 3.4% respectively, p < 0.001)12 in the PETIT trial. Side effects of eltrombopag13 include hepatotoxicity, thrombotic/thromboembolic complications and cataracts. Recommendations are to measure serum ALT, AST, and bilirubin prior to initiation, every 2 weekly during the dose adjustment phase and monthly following establishment of a stable dose as Eltrombopag can cause derangement of liver enzymes. If SGPT levels increase to =3 X upper limit of normal (ULN) in patients with normal liver function or = 3X baseline in patients with pre-treatment elevations in transaminases and are progressively increasing; or persistent for 4 weeks; or accompanied by increased direct bilirubin; or accompanied by clinical symptoms of liver injury or hepatic decompensation, then in such cases eltrombopag has to be discontinued. Thrombotic/thromboembolic complication occur at both at low and normal platelet counts and affects both venous and arterial systems. Extra caution has to be advocated in patients with known risk factors for thromboembolism. A baseline opthalmological examination prior to administration and regular checkups during therapy with eltrombopag is recommended. Weekly complete blood counts (CBCs) with differentials until a stable platelet count is achieved and monthly thereafter while the child is on Eltrombopag. After Eltrombopag is discontinued, obtain CBCs weekly for at least 4 weeks.

Drug interactions: 13 There has to be a gap of 4 hours between taking eltrombopag and any medications or products containing polyvalent cations such as antacids, dairy products, and mineral supplements.

Adverse reactions: 13 The most common adverse reactions for eltrombopag versus placebo were: nausea (9% vs. 3%), diarrhea (9% vs. 7%), vomiting (6% vs. <1%), upper respiratory tract infection (7% vs. 6%), pharyngitis (4% vs. 2%), influenza (3% vs. 2%), increased ALT (5% vs. 3%), increased AST (4% vs. 2%),myalgia (5% vs. 2%), paresthesia (3% vs. 2%), urinary tract infection (5% vs. 3%), oropharyngeal pain (4% vs. 3%), back pain (3% vs. 2%), and rash (3% vs. 2%) as noted in 3 placebo controlled clinical trials.

Availability: It is available in 2 forms, as a tablet and powder form to be mixed with liquid for children ages one to five, to be taken once-daily.

Romiplostim at a dose of 5µg/kg subcutaneously also has shown efficacy in children by Bussel et al but not available in India as yet.14


Table 2 17 gives the time of response of individual drugs as defined by the International Working Group (IWG).

Table 2: Definitions of time to and duration of response, and the time to initial and peak response for different ITP treatments*
Time to response From start of treatment until either complete response or response
Duration of response Time from complete response or response until loss of complete response or response Measured as the proportion of the cumulative time spent in complete response or response during the period under examination as well as the total time observed from which the proportion is derived
Expected time to response Treatment type Initial response, days Peak response, days
  Anti-D 1-3 3-7
  Azathioprine 30-90 30-180
  Danazol 14-90 28-180
  Dexamethasone 2-14 4-28
  Eltrombopag 7-28 14-90
  IVIg 1-3 2-7
  Prednisone 4-14 7-28
  Rituximab 7-56 14-180
  Romiplostim 5-14 14-160
  Splenectomy 1-56 7-56
  Vinblastine 7-14 7-42
  Vincristine 7-14 7-42
• ?* Adapted from the International Working Group.17


Splenectomy: Indications for splenectomy are life threatening bleeds, severe menorrhagia and restrictions of the normal lifestyle. Splenectomy should be delayed for at least 12 months in view of the possibility of spontaneous remission unless the child has severe, unresponsive disease affecting the quality of life.6 Post splenectomy sepsis is the most dreaded complication. A laparoscopic approach with removal of accessory spleens is preferred. Presplenectomy immunization with Haemophilus influenzae type b, pneumococcus and meningococcus is mandatory at least prior to 2 weeks. Post splenectomy prophylactic penicillin upto 5 years of age (or even later) is advocated.

Platelet Transfusions: Have no role except in life threatening situations. In emergencies, a combination of IV methylprednisolone and IVIg/anti-D along with transfusion of supranormal dose of platelets (upto 30 ml/kg) is recommended. 15 Antifibrinolytics such as tranexamic acid 10-15 mg/kg IV every 6 hourly is also used during life threatening bleeding. Recombinant factor VII A is now successfully used during life threatening bleeds for hemostasis in patients with ITP. 16

CONCLUSION: ITP has both defective production and excessive destruction of platelets. Autoimmunity of ITP is due to involvement of B and T lymphocytes i.e. both humoral and cellular arms are involved. Addition of TPO Mimetics for chronic ITP patients has raised the hope of parents tackling this prolonged frustrating disease in their children.


References
Immune Thrombocytopenic Purpura in Children Immune Thrombocytopenic Purpura in Children 6/28/2016
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