Overview
Definition:
Immune Thrombocytopenia (ITP) is an autoimmune disorder characterized by isolated thrombocytopenia (low platelet count) due to antibody-mediated destruction of platelets and impaired platelet production
Chronic ITP in children is defined as lasting longer than 12 months from diagnosis, although a significant proportion of children achieve spontaneous remission.
Epidemiology:
ITP is the most common acquired bleeding disorder in childhood, with an incidence of approximately 5-10 cases per 100,000 children per year
While most cases are acute and resolve spontaneously, a minority develop chronic ITP, which can significantly impact quality of life and require long-term management.
Clinical Significance:
Chronic ITP poses a challenge due to persistent risk of bleeding, often exacerbated by infections, trauma, or surgical procedures
The introduction of thrombopoietin receptor agonists (TPO-RAs) has revolutionized the management of chronic ITP, offering a mechanism to increase platelet production and mitigate bleeding risk, thereby improving patient outcomes and quality of life for affected children.
Tpo Receptor Agonists
Mechanism Of Action:
TPO-RAs are molecules that mimic the action of endogenous thrombopoietin (TPO), the primary regulator of platelet production
They bind to and activate the TPO receptor (c-Mpl) on megakaryocyte progenitor cells in the bone marrow, stimulating megakaryopoiesis and leading to increased platelet production.
Available Agents:
In pediatric chronic ITP, the commonly used TPO-RAs include eltrombopag (an oral small molecule agonist) and romiplostim (a peptibody, typically used in adults but with emerging pediatric data).
Indications For Use:
TPO-RAs are generally indicated for children with chronic ITP who have a significant bleeding history or a platelet count that poses a risk of serious bleeding, and who have failed or are intolerant to first-line therapies (e.g., corticosteroids, IVIG, rituximab) or splenectomy.
Management Principles With Tpo Agonists
Initial Assessment And Monitoring:
Before initiating TPO-RAs, a thorough assessment of bleeding risk, assessment for other causes of thrombocytopenia, and baseline laboratory parameters (CBC, peripheral smear, coagulation profile) are crucial
Regular monitoring of platelet counts (typically weekly initially, then less frequently) is essential to guide dosing and assess response.
Dosing And Titration:
Dosing of TPO-RAs is individualized and titrated to achieve and maintain a target platelet count that reduces bleeding risk (often 30,000-50,000/µL), avoiding unnecessarily high counts
Eltrombopag is typically initiated at a low dose (e.g., 25 mg daily) and increased based on response
Romiplostim is given subcutaneously weekly, with dose adjustments based on platelet count.
Duration Of Therapy:
Treatment duration is variable and guided by clinical response and patient tolerance
TPO-RAs are often used as long-term therapy for chronic ITP, aiming to achieve sustained platelet counts and reduce the need for rescue therapies or invasive procedures.
Assessment Of Response And Adverse Events:
Response is primarily assessed by sustained adequate platelet counts and a reduction in bleeding symptoms
Close monitoring for potential adverse events, including thrombotic events (though rare in pediatrics), bone marrow reticulin fibrosis (especially with long-term TPO-RA use), and effects on other cell lines, is paramount.
Clinical Presentation Of Chronic Itp Requiring Tpo Agonists
Symptoms:
Easy bruising
Petechiae
Mucosal bleeding (epistaxis, gingival bleeding)
Menorrhagia in adolescent females
Hematuria
Gastrointestinal bleeding
In severe cases, intracranial hemorrhage can occur, although this is rare.
Signs:
Isolated thrombocytopenia on CBC (platelets typically <100,000/µL, often <30,000/µL)
Normal or mildly elevated WBC and RBC counts
Peripheral smear may show large platelets (megathrombocytes)
Absence of splenomegaly or lymphadenopathy (unless secondary to another condition)
Signs of active bleeding (e.g., purpura, ecchymoses).
Diagnostic Criteria:
Diagnosis of chronic ITP requires: 1
Isolated thrombocytopenia (<100,000/µL)
2
Absence of other causes of thrombocytopenia (e.g., infections, medications, inherited disorders, malignancy)
3
Presence of anti-platelet antibodies (though not always detectable and not essential for diagnosis)
4
Normal or enlarged spleen
Chronic ITP is diagnosed when thrombocytopenia persists beyond 12 months from diagnosis.
Diagnostic Approach In Chronic Itp
History Taking:
Detailed history of bleeding episodes (onset, frequency, severity), family history of bleeding disorders, antecedent infections (viral illnesses are common triggers for acute ITP), vaccination history, medication history, and any other medical conditions
Assess impact of ITP on quality of life and school attendance.
Physical Examination:
Thorough examination focusing on signs of bleeding (purpura, petechiae, mucosal bleeding), assessing for lymphadenopathy, hepatosplenomegaly, and signs of other systemic diseases
Rule out signs of malignancy or other causes of cytopenias.
Investigations:
Complete Blood Count (CBC) with differential and platelet count
Peripheral blood smear for platelet morphology and to rule out pseudothrombocytopenia or other abnormal cells
Coagulation profile (PT, aPTT) to rule out other coagulopathies
Consider assays for anti-platelet antibodies (GP Ib/IX, GP IIb/IIIa) or anti-nuclear antibodies (ANA) if other autoimmune disorders are suspected
Bone marrow aspiration and biopsy may be considered in specific situations, particularly if there are atypical features, refractory disease, or suspicion of other bone marrow pathology, but are not routine for diagnosis of ITP.
Differential Diagnosis:
Other causes of isolated thrombocytopenia: viral infections (HIV, EBV, CMV), drug-induced thrombocytopenia, inherited thrombocytopenias (e.g., Wiskott-Aldrich syndrome, Bernard-Soulier syndrome), hypersplenism, systemic lupus erythematosus (SLE), thrombotic thrombocytopenic purpura (TTP) / hemolytic uremic syndrome (HUS), leukemia, aplastic anemia, vitamin deficiencies (B12, folate).
Complications And Monitoring With Tpo Agonists
Thrombotic Events:
Although TPO-RAs increase platelet counts, the risk of arterial or venous thrombosis is generally low in pediatric ITP
However, patients with other thrombophilic risk factors should be closely monitored
Thrombotic events are a rare but serious potential adverse effect.
Bone Marrow Changes:
Long-term use of TPO-RAs, particularly eltrombopag, has been associated with increased reticulin deposition in the bone marrow
Regular monitoring via bone marrow biopsy (if indicated for other reasons or after prolonged therapy) may be considered
Evidence of significant fibrosis leading to marrow failure is rare.
Other Adverse Effects:
Other potential side effects include headache, nausea, vomiting, diarrhea, and elevated liver enzymes
Some patients may experience rebound thrombocytopenia upon discontinuation of the medication, necessitating careful tapering and transition to other therapies if needed.
Monitoring Frequency:
Initial monitoring of platelet counts is typically weekly
Once stable, platelet counts can be monitored every 2-4 weeks
Liver function tests, CBC, and assessment for signs of thrombosis or bleeding should be performed regularly
The frequency of bone marrow assessment is individualized.
Key Points
Exam Focus:
TPO-RAs (eltrombopag, romiplostim) are indicated for chronic ITP in children refractory to or intolerant of standard therapies
They work by stimulating platelet production via the TPO receptor
Monitoring platelet counts is crucial for dose titration to achieve target ranges and avoid complications.
Clinical Pearls:
Always consider the risk-benefit ratio when initiating TPO-RAs
Start with the lowest effective dose and titrate upwards
Educate parents/patients about potential side effects and the importance of regular follow-up
Be vigilant for signs of thrombotic events or bone marrow changes with long-term use.
Common Mistakes:
Initiating TPO-RAs without ruling out other causes of thrombocytopenia
Using excessively high target platelet counts, increasing thrombotic risk
Failing to adequately monitor for adverse events or bone marrow changes
Discontinuing medication abruptly without a plan for alternative management, potentially leading to severe rebound thrombocytopenia.