Immune Thrombocytopenic Purpura In Children

Dr. Priti S. Mehta
FNB (DNB),MD, DNB, DCH
Paediatric Hematologist-Oncologist
S.L.Raheja Hospital, Saifee Hospital, Surya Children Hospital

First Created: 02/27/2001  Last Updated: 02/27/2001

Abstract

Immune thrombocytopenia (ITP) is commonly encountered by general physicians and pediatricians in their day to day practice. With rapid advances in the field of hematology, not only the insight as to the pathophysiology has changed but the terminologies to have changed. Approval of the use of Thrombopoietin mimetics in children has added a ray of hope for children suffering from chronic ITP.

Definitions

The International Working Group (IWG) consensus panel has defined primary ITP as a platelet count less than 100 × 109/L in the absence of other causes or disorders that may be associated with thrombocytopenia.

IWG also defines ITP as newly diagnosed (diagnosis to 3 months), persistent (3 to 12 months from diagnosis), or chronic (lasting for more than 12 months). These definitions have not been formally validated and may not apply to patients with secondary forms of ITP.6

Introduction

The terminology of ITP is now known as Immune Thrombocytopenic Purpura unlike Idiopathic Thrombocytopenic Purpura in the past and indicates an underlying autoimmune disease in Children.1 The common age of presentation in children is between 1-7 years of age with an incidence of approximately 5 per 100,000 children and 2 per 100,000 adults.2

Children have varied manifestations like petechiae, ecchymosis, mucosal bleeds but the percentage of children presenting with life-threatening bleeds is negligible (0.2-0.9%).3 This is because the platelets in circulation are relatively young platelets adequate in function unlike in aplastic anemia. The latest concept is that in addition to increased peripheral platelet destruction there is also a decreased platelet production.ITP may occur either as an isolated phenomenon (primary) or secondary to other disorders (secondary) such as antiphospholipid syndrome, SLE, autoimmune thrombocytopenia (e.g. Evan’s syndrome - which is associated with autoimmune thrombocytopenia with coincident hemolytic anemia), common variable immune deficiency, drug administration, Infection with cytomegalovirus, Helicobacter pylori, hepatitis C, human immunodeficiency virus, varicella-zoster, lymphoproliferative disorders, bone marrow transplantation, post-vaccination.

Pathophysiology

The pathophysiology is postulated to be twofold:

  • Immune-mediated destruction of platelets.
  • ITP is an autoimmune disorder in which immunologic destruction of otherwise normal platelets occurs in response to an unknown stimulus. Antiplatelet antibodies opsonize the platelets and with the help of Fc? receptors are attached to antigen-presenting cells. Macrophages then phagocytose these opsonized platelets. Some cryptic epitopes from platelet antigens stimulate platelet-specific T cells which in turn stimulate B cells to produce more antiplatelet antibodies.

  • Decreased production of platelets

    A rise in platelet count after administering TPO mimetics confirms the role of thrombopoietin (TPO) in reduced thrombopoiesis in ITP and stimulation with TPO mimetics.

Presentation

The pattern of presentation varies from skin bleeds like petechiae, ecchymosis, mucosal bleeds to intracranial hemorrhage with minimal or no trauma. A history of preceding illness like a viral illness or immunizations especially MMR should be asked for. Also, a history of any insect bites or allergic reactions should be noted. The seasonal nature of this illness (in winters more than summers) supports an environmental immune trigger.

Diagnosis

Bone marrow examination is no longer mandatory to confirm the diagnosis of ITP. A careful history, physical examination, complete blood count, and review of the peripheral blood smear are the key factors in diagnosing ITP. The routine use of antiphospholipid, antinuclear antibodies, thrombopoietin levels or platelet parameters is not routinely required in the diagnosis of ITP. A bone marrow examination to rule out other disorders is required in children presenting clinically with fever, bone or joint pain, skeletal or soft tissue abnormalities, non-petechial rash, and lymphadenopathy. A family history of low platelets or easy bruising and HIV infection should be asked for. An abnormal hemoglobin level, abnormal WBC morphology, or count is not typical of ITP and also requires a bone marrow examination.6 This is to avoid missing leukemias before starting steroids but not required before giving Intravenous Immunoglobulin.

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 the 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 opsonized 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 x 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 x 109 /L are important.7

Intravenous Immunoglobulin (IVIg)

Acts through the Fc?R11b receptor by impairing the clearance of opsonized 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 a single dose of 0.8 mg/kg was as effective as the dose of 1 gm/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 opsonized RBCs compete with opsonized 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 the infusion of IV anti D is a drop in hemoglobin due to hemolysis. Usually, the drop is up to 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 has been approved in children is 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 a 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 375 mg/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 a continuous response rate (maintenance of a platelet count >50x109/L with or without dapsone) of 31% was found in a retrospective analysis of 35 children.11 The dose recommended is 25 to 100 mg/day.

Single agents

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

TPO Mimetics (Eltrombopag and Romiplostim)

Thrombopoietin (TPO) is the principal cytokine involved in the regulation of megakaryopoiesis and platelet production. Eltrombopag, non-peptidyl thrombopoietin (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 pediatric chronic ITP where the risk of bleeding is significant. Pediatric 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 months following the 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 occurs 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 ophthalmologic 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

Surgical Management

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, an unresponsive disease affecting the quality of life.6 Post splenectomy sepsis is the most dreaded complication. A laparoscopic approach with the 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 up to 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 a supranormal dose of platelets (up to 30 ml/kg) is recommended. 15 Antifibrinolytics such as tranexamic acid 10-15 mg/kg IV every 6 hours 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 the involvement of B and T lymphocytes i.e. both humoral and cellular arms are involved. The addition of TPO Mimetics for chronic ITP patients has raised the hope of parents tackling this prolonged frustrating disease in their children.


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