What are the diagnostic steps and treatment options for a patient suspected of having Immune Thrombocytopenic Purpura (ITP)?

Diagnosis of Immune Thrombocytopenic Purpura (ITP)

ITP is a diagnosis of exclusion requiring isolated thrombocytopenia (platelet count <100 × 10⁹/L) without anemia or leukopenia, confirmed by peripheral blood smear showing normal or slightly enlarged platelets, with all secondary causes systematically ruled out. 1, 2, 3

Essential Diagnostic Workup

Mandatory Initial Tests

• Complete blood count with differential to confirm isolated thrombocytopenia versus pancytopenia—any additional cytopenias beyond isolated thrombocytopenia require investigation for alternative diagnoses 1, 2

• Peripheral blood smear examination is the cornerstone of diagnosis and serves three critical functions: 1, 2, 4

  • Excludes pseudothrombocytopenia from EDTA-dependent platelet clumping (a common pitfall that falsely lowers counts) 1, 2
  • Confirms normal or slightly enlarged platelets with normal morphology 4, 3, 5
  • Identifies red flags suggesting alternative diagnoses: schistocytes (suggesting TTP-HUS), leukocyte inclusion bodies (MYH9-related disease), excessive giant or small platelets (inherited thrombocytopenias) 1, 2

• HIV and hepatitis C virus testing in all adults with suspected ITP, regardless of risk factors or local prevalence, because these infections can be clinically indistinguishable from primary ITP and may precede other symptoms by years 1, 2

• Helicobacter pylori testing (preferably urea breath test or stool antigen test, not serology) should be considered in adults where eradication may impact clinical outcomes 1, 2

Physical Examination Red Flags

The physical examination should be entirely normal except for bleeding manifestations. 2, 4, 3 The presence of any of the following mandates investigation for secondary causes and excludes primary ITP: 1, 2

• Splenomegaly, hepatomegaly, or lymphadenopathy
• Non-petechial rash
• Fever, weight loss, or bone/joint pain
• Any systemic symptoms beyond bleeding

When Bone Marrow Examination Is Required

Bone marrow examination is NOT necessary in patients with typical ITP features (isolated thrombocytopenia, normal physical exam except bleeding, normal peripheral smear). 1, 2, 3 However, bone marrow biopsy and aspirate with flow cytometry and cytogenetic testing are mandatory in: 1, 2

• Age >60 years (to exclude myelodysplastic syndromes, leukemias, or other malignancies) 1, 2
• Systemic symptoms present (fever, weight loss, bone pain) 1, 2
• Abnormal blood count parameters beyond isolated thrombocytopenia (anemia not explained by blood loss, leukopenia, leukocytosis) 1, 2
• Atypical peripheral smear findings (schistocytes, leukocyte abnormalities, dysplastic features) 1, 2
• Minimal or no response to first-line ITP therapies (IVIg, corticosteroids, anti-D) 2
• When splenectomy is being considered 1, 2

Additional Testing Based on Clinical Context

• Blood group Rh(D) typing if anti-D immunoglobulin is being considered as treatment 1

• Antithyroid antibodies and thyroid function tests may be useful, as 8-14% of ITP patients develop clinical thyroid disease longitudinally 1, 2

• Coagulation studies (PT, aPTT, fibrinogen, D-dimer) to exclude disseminated intravascular coagulation if clinical suspicion exists 2, 4

• Antiphospholipid antibodies (anticardiolipin, lupus anticoagulant) are found in ~40% of adult ITP patients but do not affect treatment response and are not routinely recommended unless antiphospholipid syndrome symptoms are present 1

• Antinuclear antibodies may predict chronicity in childhood ITP but are not routinely indicated 1

• Immunoglobulin levels to exclude common variable immune deficiency, as ITP can be a presenting feature 2

Tests That Should NOT Be Routinely Ordered

• Antiplatelet antibody assays (glycoprotein-specific antibody testing) are not routinely recommended because platelet-associated IgG is elevated in both immune and non-immune thrombocytopenia and does not change management 1, 2, 4

• Immature platelet fraction (IPF) has uncertain diagnostic value—while typically elevated in ITP, severe ITP can present with low IPF, and this test cannot replace bone marrow examination when indicated 2, 6

Diagnostic Classification by Duration

Once ITP is diagnosed, classify by duration: 3

• Newly diagnosed ITP: <3 months from diagnosis
• Persistent ITP: 3-12 months from diagnosis
• Chronic ITP: ≥12 months from diagnosis

Critical Diagnostic Pitfalls to Avoid

• Missing secondary causes that have different natural histories and treatment responses (HIV, HCV, H. pylori, autoimmune diseases, lymphoproliferative disorders, drug-induced thrombocytopenia) 2

• Mistaking pseudothrombocytopenia for true ITP—always review the peripheral smear to exclude EDTA-dependent platelet clumping 1, 2

• Overlooking inherited thrombocytopenias that may present similarly—family history and platelet size on smear provide critical clues 1, 2

• Failing to recognize myelodysplastic syndrome with isolated thrombocytopenia (MDS-IT), which is a predominant misdiagnosis of refractory ITP, particularly in patients >60 years 2, 7

• Not reassessing the diagnosis if atypical features develop during treatment or if there is minimal response to standard ITP therapies 2

• Assuming elevated IPF confirms ITP—severe ITP can present with low IPF, and age >60 years mandates bone marrow examination regardless of IPF 2, 6