How is immune thrombocytopenic purpura (ITP) diagnosed?

Diagnosis of Immune Thrombocytopenic Purpura (ITP)

ITP is diagnosed by confirming isolated thrombocytopenia (platelet count <100 × 10⁹/L) through peripheral blood smear review by a hematopathologist, combined with mandatory exclusion of secondary causes—particularly HIV and hepatitis C in all adults—without requiring bone marrow examination in patients with typical features. 1, 2

Core Diagnostic Requirements

Essential Initial Testing

• Complete blood count with differential – Confirms isolated thrombocytopenia versus pancytopenia; the presence of unexplained anemia or leukopenia excludes primary ITP and mandates bone marrow examination. 1, 2

• Peripheral blood smear reviewed by a hematopathologist – This is the single most critical diagnostic test and must never be omitted, as automated counters miss pseudothrombocytopenia in up to 0.1% of samples. 2, 3

Expected Smear Findings in ITP

• Platelets of normal size or only mildly enlarged (giant platelets approaching red cell size suggest inherited thrombocytopenias like MYH9-related disease or Bernard-Soulier syndrome). 1, 2

• Normal red blood cell morphology without schistocytes (schistocytes indicate thrombotic microangiopathy—TTP, HUS, or DIC—which carries >90% mortality if untreated). 2

• Normal white blood cell morphology without immature cells, blasts, or leukocyte inclusion bodies (these findings suggest leukemia, myelodysplastic syndrome, or MYH9-related disease). 1, 2

• Absence of EDTA-dependent platelet clumping (if pseudothrombocytopenia is suspected, repeat the count in heparin or citrate tubes). 2, 4

Mandatory Testing to Exclude Secondary Causes

Required in All Adults (Regardless of Risk Factors)

• HIV antibody testing – HIV-associated thrombocytopenia is clinically indistinguishable from primary ITP and may precede other HIV manifestations by years. 1, 2

• Hepatitis C virus serology – Chronic HCV can cause thrombocytopenia that resolves with successful antiviral therapy; HCV may appear years before other symptoms. 1, 2

• Helicobacter pylori testing (urea-breath test or stool antigen preferred over serology) – Eradication therapy normalizes platelet counts in a subset of adult ITP patients, particularly in endemic regions. 2

Additional Context-Specific Testing

• Pregnancy test in women of childbearing potential – Differentiates gestational thrombocytopenia, pre-eclampsia, or HELLP syndrome from primary ITP. 1, 2

• Direct antiglobulin test (DAT) – Excludes Evans syndrome (combined autoimmune hemolytic anemia and ITP). 2

• Quantitative immunoglobulin levels – Identifies common variable immune deficiency (CVID), as ITP can be its presenting feature. 1, 2

Physical Examination Red Flags

The physical examination should be entirely normal except for bleeding manifestations (petechiae, purpura, mucosal bleeding). 1, 2 The presence of any of the following excludes primary ITP and mandates immediate investigation for secondary causes:

• Splenomegaly, hepatomegaly, or lymphadenopathy (suggests HIV, systemic lupus erythematosus, lymphoproliferative disorders, or chronic liver disease). 1, 2, 4

• Constitutional symptoms including fever, unexplained weight loss, night sweats, or bone pain (indicates underlying malignancy, infection, or bone marrow infiltration). 2

• Non-petechial rash (suggests systemic autoimmune disease or viral infection). 2

When Bone Marrow Examination Is Mandatory

Bone marrow examination is not required in patients with typical ITP features but becomes mandatory in the following scenarios: 1, 2

• Age ≥60 years – To exclude myelodysplastic syndrome, leukemia, or other malignancies (these conditions carry catastrophic mortality if missed). 1, 2

• Systemic symptoms present – Fever, weight loss, night sweats, or bone pain require exclusion of marrow infiltrative or malignant processes. 2

• Abnormal CBC parameters beyond isolated thrombocytopenia – Unexplained anemia, leukopenia, or leukocytosis suggests bone marrow failure or infiltration. 1, 2

• Atypical peripheral smear findings – Schistocytes, immature white cells, giant platelets, or leukocyte inclusion bodies mandate bone marrow evaluation. 2

• Splenomegaly, hepatomegaly, or lymphadenopathy on exam – These findings exclude primary ITP. 2

• Minimal or no response to first-line ITP therapies (IVIg, corticosteroids, or anti-D) – Treatment failure warrants bone marrow examination to exclude alternative diagnoses. 2

• Before splenectomy in chronic ITP – To confirm the diagnosis and exclude underlying bone marrow pathology. 2

When performed, obtain both aspirate and core biopsy; include flow cytometry and cytogenetic studies to detect lymphoproliferative disorders. 2

Tests That Should NOT Be Ordered Routinely

The following tests have no proven clinical utility in diagnosing ITP and should not be ordered: 1, 2

• Platelet-associated IgG (PaIgG) – Elevated in both immune and non-immune thrombocytopenia; non-discriminatory. 1, 2

• Glycoprotein-specific antiplatelet antibodies – Insufficient sensitivity and specificity. 1, 2

• Thrombopoietin (TPO) levels – Does not distinguish ITP from other causes. 1, 2

• Reticulated platelets – Unproven benefit in diagnosis. 1, 2

• Bleeding time – No correlation with clinical bleeding risk. 1, 2

• Antiphospholipid antibodies – Only order if clinical features of antiphospholipid syndrome are present (thrombosis, recurrent pregnancy loss). 1, 2

• Antinuclear antibodies (ANA) – Only order when systemic lupus erythematosus is suspected based on clinical features. 1, 2

Critical Diagnostic Pitfalls to Avoid

• Never diagnose ITP without personal review of the peripheral blood smear – Automated counters miss pseudothrombocytopenia, giant platelets, and schistocytes. 2

• Never omit HIV and HCV testing in adults – These infections masquerade as primary ITP and may precede other manifestations by years. 2

• Missing thrombotic microangiopathy (TTP, HUS, DIC) carries >90% mortality – Urgent exclusion is essential; look for schistocytes on smear and obtain ADAMTS13 activity, LDH, haptoglobin, and coagulation studies if suspected. 2

• Missing heparin-induced thrombocytopenia (HIT) carries 30-50% thrombosis risk – Calculate the 4T score immediately in any patient who received heparin within the past 3 months; if intermediate/high probability, discontinue all heparin and start non-heparin anticoagulation without awaiting laboratory confirmation. 2

• Overlooking drug-induced thrombocytopenia – Review all medications including prescription drugs, over-the-counter products, herbal supplements, and quinine-containing beverages. 2

• Failing to recognize inherited thrombocytopenias – Family history and platelet size on smear provide critical clues (giant platelets suggest MYH9-related disease or Bernard-Soulier syndrome). 2, 4

Diagnostic Algorithm

1. Confirm true thrombocytopenia – Repeat platelet count in heparin or citrate tube if pseudothrombocytopenia is suspected (EDTA-dependent clumping). 2, 4

2. Obtain CBC with differential – Verify isolated thrombocytopenia; any additional cytopenias require bone marrow examination. 1, 2

3. Peripheral blood smear reviewed by hematopathologist – Confirm normal-sized or mildly enlarged platelets, absence of schistocytes, and normal white cell morphology. 1, 2

4. Physical examination – Must be normal except for bleeding manifestations; presence of organomegaly or lymphadenopathy excludes primary ITP. 1, 2

5. Mandatory infectious disease testing in all adults – HIV, HCV, and H. pylori (urea-breath or stool antigen). 1, 2

6. Additional context-specific testing – Pregnancy test, DAT, quantitative immunoglobulins as indicated. 1, 2

7. Bone marrow examination only if – Age ≥60 years, systemic symptoms, abnormal CBC beyond isolated thrombocytopenia, atypical smear findings, organomegaly, or treatment failure. 1, 2

8. If all typical features present and secondary causes excluded – Diagnosis of primary ITP is established without bone marrow examination. 1, 2