What is the diagnostic approach for Immune Thrombocytopenic Purpura (ITP)?

Diagnostic Approach to Immune Thrombocytopenic Purpura (ITP)

ITP is a diagnosis of exclusion requiring isolated thrombocytopenia (platelet count <100 × 10⁹/L) with systematic elimination of secondary causes through targeted history, physical examination, complete blood count, peripheral blood smear review, and specific infectious disease testing. 1, 2, 3

Essential Initial Evaluation

Patient History - Specific Red Flags to Identify

• Infectious exposures: HIV, hepatitis C, recent viral illness, or history of H. pylori infection, as these can cause clinically indistinguishable secondary thrombocytopenia 1, 2
• Autoimmune conditions: Systemic lupus erythematosus, antiphospholipid syndrome, common variable immunodeficiency, or other immunodeficiency disorders 1, 2
• Medication exposure: All prescription and non-prescription drugs, quinine-containing beverages (tonic water), and environmental toxins 1
• Malignancy risk factors: Lymphoproliferative disorders, myelodysplastic syndromes, leukemias, or other bone marrow diseases 1, 2
• Recent transfusions or immunizations: Posttransfusion purpura or vaccine-associated thrombocytopenia 1, 2
• Family history: Inherited thrombocytopenias including Wiskott-Aldrich syndrome, MYH9-related disease, Bernard-Soulier syndrome, or type IIB von Willebrand disease 1
• Alcohol use: Chronic alcohol consumption causing bone marrow suppression and liver disease 1, 2

Physical Examination - Critical Findings

• Normal examination except for bleeding manifestations (petechiae, purpura, mucosal bleeding) supports ITP diagnosis 1, 2, 3
• Mild splenomegaly may occur in younger patients, but moderate or massive splenomegaly excludes primary ITP and mandates investigation for lymphoproliferative disorders, portal hypertension, or infections 1, 2
• Constitutional symptoms (fever, weight loss), hepatomegaly, or lymphadenopathy indicate underlying disorders such as HIV, SLE, or malignancy rather than primary ITP 1, 2

Mandatory Laboratory Testing

Complete Blood Count Analysis

• Isolated thrombocytopenia with otherwise normal CBC is characteristic of ITP 1, 3
• Anemia, if present, should be proportional to bleeding duration and may show iron deficiency; disproportionate anemia requires reticulocyte count to distinguish production failure from hemolysis 1
• Any abnormalities beyond isolated thrombocytopenia (leukopenia, leukocytosis, abnormal white cell morphology) mandate further investigation before diagnosing ITP 2, 3

Peripheral Blood Smear Review - Non-Negotiable

Examination by a qualified hematologist or pathologist is paramount and must be performed in every case. 1

• Exclude pseudothrombocytopenia: EDTA-dependent platelet agglutination can falsely lower platelet counts 1, 2
• Identify alternative diagnoses: Schistocytes suggest thrombotic thrombocytopenic purpura-hemolytic uremic syndrome; leukocyte inclusion bodies indicate MYH9-related disease 1
• Platelet size assessment: Excessive numbers of giant or small platelets suggest inherited thrombocytopenia 1, 2
• Normal findings: Thrombocytopenia with normal or slightly larger platelets, normal red blood cell morphology, and normal white blood cell morphology 3

Mandatory Infectious Disease Testing in Adults

• HIV testing: Required in all adults with suspected ITP regardless of risk factors, as HIV-associated thrombocytopenia can precede other symptoms by years 1, 2, 3
• Hepatitis C testing: Required in all adults with suspected ITP, as HCV-associated thrombocytopenia is clinically indistinguishable from primary ITP 1, 2, 3
• H. pylori testing: Urea breath test or stool antigen test (not serology) should be considered in adults, as eradication can resolve thrombocytopenia 1, 2, 3

Critical caveat: Serologic H. pylori testing may produce false positives after IVIg therapy and is less sensitive/specific than breath or stool tests. 1

Bone Marrow Examination - Specific Indications

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

Absolute Indications for Bone Marrow Biopsy

• Age ≥60 years: Mandatory to exclude myelodysplastic syndromes, leukemias, or other malignancies 1, 2
• Systemic symptoms: Fever, weight loss, bone pain, or night sweats 1, 2
• Abnormal blood count parameters: Any cytopenia beyond isolated thrombocytopenia or unexplained anemia 1, 2
• Atypical peripheral smear findings: Schistocytes, leukocyte inclusion bodies, or dysplastic features 1, 2
• Splenectomy consideration: Some guidelines recommend bone marrow examination before splenectomy 1, 2
• Treatment failure: Minimal or no response to first-line ITP therapies (IVIg, corticosteroids, anti-D) warrants bone marrow evaluation to exclude alternative diagnoses 2

Bone Marrow Examination Technique

• Both aspirate and biopsy should be performed when indicated 1, 2
• Flow cytometry and cytogenetic testing should be considered, particularly to identify chronic lymphocytic leukemia-associated ITP 1, 2

Important note: A 2025 case report demonstrated that severe ITP can present with low immature platelet fraction (IPF), complicating diagnosis and necessitating bone marrow biopsy in atypical presentations. 4 This underscores that elevated IPF, while typical, is not universal in ITP.

Additional Testing to Consider

• Immunoglobulin measurement: Consider to exclude common variable immunodeficiency, as ITP can be a presenting feature 2
• Antithyroid antibodies and thyroid function: May be useful, as 8-14% of ITP patients develop thyroid dysfunction 2
• Coagulation studies (PT, aPTT, fibrinogen, D-dimer): Only if disseminated intravascular coagulation is suspected; not routinely indicated in ITP 2

Anti-platelet antibody testing has insufficient evidence for routine diagnostic use and does not change management. 2, 3

Diagnostic Algorithm

1. Confirm true thrombocytopenia: Review peripheral blood smear to exclude pseudothrombocytopenia 1, 2, 3
2. Verify isolated thrombocytopenia: Ensure CBC shows no other cytopenias except proportional anemia from bleeding 1, 2, 3
3. Perform physical examination: Normal except for bleeding manifestations; any organomegaly or lymphadenopathy excludes primary ITP 1, 2, 3
4. Obtain mandatory infectious testing: HIV, HCV, and consider H. pylori in adults 1, 2, 3
5. Age-based bone marrow decision: If age ≥60 years, perform bone marrow examination regardless of other features 1, 2
6. Assess for atypical features: If systemic symptoms, abnormal blood counts beyond thrombocytopenia, or atypical smear findings present, perform bone marrow examination 1, 2
7. Diagnose ITP: If all above criteria met and secondary causes excluded, diagnosis of ITP can be made 1, 2, 3

Common Diagnostic Pitfalls

• Assuming elevated IPF confirms ITP: Severe ITP can present with low IPF, requiring bone marrow examination in atypical cases 2, 4
• Relying solely on platelet count in older patients: Age >60 years mandates bone marrow examination regardless of typical presentation 1, 2
• Missing drug-induced thrombocytopenia: Comprehensive medication history including over-the-counter drugs and supplements is essential 1, 2
• Overlooking inherited thrombocytopenias: Family history and platelet size on smear provide critical clues 1, 2
• Failing to recognize secondary ITP: HIV and HCV testing must be performed in all adults, as these infections have different natural histories and treatment responses 1, 2
• Mistaking response to ITP therapy as diagnostic confirmation: Response to ITP-specific therapy supports but does not exclude secondary ITP 3

Reassessment Triggers

If atypical features develop during treatment or monitoring, the diagnosis must be reassessed with bone marrow examination. 2 This includes treatment refractoriness, development of new cytopenias, or emergence of systemic symptoms.