Causes of Thrombocytopenia in Children
Thrombocytopenia in children is most commonly caused by primary immune thrombocytopenia (ITP), an autoimmune disorder characterized by isolated platelet destruction following viral infections, but secondary causes including autoimmune diseases, viral infections (HIV, HCV, EBV, CMV), medications, inherited thrombocytopenias, and bone marrow disorders must be systematically excluded. 1
Primary Immune Thrombocytopenia (ITP)
Primary ITP is the leading cause of acute thrombocytopenia in otherwise healthy children, typically occurring between ages 1-7 years. 2, 3
- Mechanism: Autoimmune destruction of platelets through antibody-mediated clearance, with newer evidence showing impaired platelet production also contributes. 1
- Typical presentation: Sudden onset of bruising and petechiae following a viral illness in an otherwise healthy child with no organomegaly or lymphadenopathy. 2, 3
- Natural history: Two-thirds of children recover spontaneously within 6 months; 20-30% develop chronic ITP (>12 months duration). 1, 2
- Prognosis: Benign and self-limiting in most cases, with intracranial hemorrhage risk of only 0.1-0.5%. 1, 4
Secondary Causes of Thrombocytopenia
Autoimmune Disorders
Systemic lupus erythematosus (SLE) is a critical secondary cause that presents with thrombocytopenia plus additional autoimmune features. 1, 5
- Antiphospholipid antibody syndrome (APS): Causes immune-mediated platelet destruction; requires testing for lupus anticoagulant, anticardiolipin antibodies, and anti-beta-2 glycoprotein I. 1, 6, 5
- Autoimmune lymphoproliferative syndrome (ALPS) and common variable immunodeficiency (CVID): Should be suspected in children with persistent thrombocytopenia and recurrent infections or lymphoproliferation. 1
- Evans syndrome: Concurrent autoimmune hemolytic anemia and thrombocytopenia. 5
Infectious Causes
Viral infections are common triggers and secondary causes of thrombocytopenia in children. 1, 5
- HIV and Hepatitis C (HCV): Cause thrombocytopenia through multiple mechanisms including antibody cross-reactivity, immune complex formation, megakaryocyte infection, and decreased thrombopoietin production. 1, 5
- Acute viral infections: EBV, CMV, varicella zoster, and post-viral syndromes (especially after MMR vaccination) can trigger acute ITP-like presentations through cross-reacting antibodies. 5, 2
- Helicobacter pylori: Generates antibodies that cross-react with platelet antigens. 1, 5
Drug-Induced Thrombocytopenia
Certain medications cause immune-mediated platelet destruction and must be identified through careful medication history review. 1
Inherited Thrombocytopenias
Familial inherited thrombocytopenias are frequently misdiagnosed as ITP and should be suspected when: 1
- Thrombocytopenia has been present since early life
- Positive family history of similar disorder exists
- Characteristic morphologic features are present on blood smear
Bone Marrow Disorders
Malignancies and bone marrow failure syndromes must be excluded, particularly when atypical features are present. 1
- Acute leukemia: Suspect when systemic features (fever, bone pain, hepatosplenomegaly) or abnormalities beyond isolated thrombocytopenia exist. 1
- Myelodysplastic syndromes and chronic myelomonocytic leukemia: Consider when persistent unexplained cytopenias or cytoses with abnormal counts beyond isolated thrombocytopenia are present. 7
Diagnostic Approach to Exclude Secondary Causes
Initial Evaluation (All Children)
Complete blood count with peripheral blood smear is mandatory to identify abnormalities beyond isolated thrombocytopenia. 1
- Normal hemoglobin, white blood cell count, and differential support primary ITP
- Abnormalities in other cell lines mandate bone marrow examination 1
Patient and family history must specifically assess for: 1
- Duration of thrombocytopenia (lifelong suggests inherited disorder)
- Family history of bleeding or thrombocytopenia
- Recent viral infections or vaccinations
- Medication exposures
- Symptoms of autoimmune disease (rash, arthritis, fever)
Physical examination must identify: 1
- Hepatosplenomegaly or lymphadenopathy (suggests secondary cause or malignancy)
- Dysmorphic features or skeletal abnormalities (inherited syndromes)
- Signs of other autoimmune diseases
When Bone Marrow Examination is Required
Bone marrow examination is NOT necessary in children with typical ITP features (isolated thrombocytopenia, no organomegaly, normal other cell lines). 1
Bone marrow examination IS mandatory when: 1
- Abnormalities exist beyond isolated thrombocytopenia in blood count or smear
- Systemic features are present (bone pain, fever, weight loss)
- Unexplained splenomegaly exists
- Patient fails to respond to first-line therapies
- Persistent thrombocytopenia beyond 3-6 months without prior response 1
Additional Testing for Persistent/Chronic Cases (3-6 months)
For children with ITP persisting beyond 3-6 months, perform comprehensive evaluation: 1
- HIV, HCV, H. pylori testing (if clinical suspicion or high local prevalence)
- Antinuclear antibodies (ANA) to screen for SLE
- Antiphospholipid antibodies (anticardiolipin, lupus anticoagulant) for APS
- Serum immunoglobulins (IgG, IgA, IgM) to identify CVID
- Direct antiglobulin test to exclude Evans syndrome
- Thyroid antibodies and function for autoimmune thyroid disease
- Bone marrow examination if not previously performed and no response to treatment 1
Critical Pitfalls to Avoid
Do not assume ITP without excluding secondary causes when atypical features exist (organomegaly, abnormal cell lines, systemic symptoms). 1
Do not perform routine bone marrow examination in typical ITP cases, as this exposes children to unnecessary procedures without changing management. 1
Do not delay bone marrow examination when abnormalities beyond isolated thrombocytopenia exist, as this delays diagnosis of potentially life-threatening malignancies. 1, 7
Do not overlook inherited thrombocytopenias by failing to obtain family history and review blood smear morphology carefully. 1
Do not forget to reassess children with persistent thrombocytopenia at 3-6 months with expanded testing for secondary causes, as some autoimmune conditions evolve over time. 1