What is the appropriate workup for thrombocytopenia?

Workup for Thrombocytopenia

The workup for thrombocytopenia begins with confirming true thrombocytopenia via peripheral blood smear review by a hematopathologist to exclude pseudothrombocytopenia, followed by mandatory HIV and hepatitis C testing in all adults, with bone marrow examination reserved only for patients ≥60 years, those with systemic symptoms, additional cytopenias, or atypical smear findings. 1

Step 1: Confirm True Thrombocytopenia

• Repeat the platelet count in a heparin or citrate tube if the initial EDTA sample shows thrombocytopenia, because EDTA-dependent platelet clumping causes pseudothrombocytopenia in approximately 0.1% of samples 1, 2
• Obtain manual peripheral blood smear review by a hematopathologist—automated counters miss pseudothrombocytopenia, and this step is non-negotiable before proceeding with any further workup 3, 1

Step 2: Obtain Complete Blood Count with Differential

• Verify isolated thrombocytopenia (platelet count <100 × 10⁹/L with normal hemoglobin and white blood cell count) versus pancytopenia 1, 4
• Any unexplained anemia, leukopenia, or leukocytosis mandates immediate bone marrow examination to exclude malignancy or marrow failure 1

Step 3: Peripheral Smear Interpretation—Critical Findings

Findings Supporting Primary ITP:

• Normal-sized or mildly enlarged platelets (not giant) 1
• Normal red cell morphology without schistocytes 1
• Normal white cell morphology without immature or abnormal cells 1

Findings That Mandate Alternative Diagnoses:

• Schistocytes → thrombotic microangiopathy (TTP, HUS, DIC)—this carries >90% mortality if untreated and requires urgent ADAMTS13 activity, LDH, haptoglobin, and coagulation studies 1, 5
• Giant platelets approaching red cell size → inherited thrombocytopenias (MYH9-related disease, Bernard-Soulier syndrome) 1
• Leukocyte inclusion bodies → MYH9-related disease 1
• Immature or abnormal white cells → leukemia or myelodysplastic syndrome 1

Step 4: Physical Examination—Red Flags

• The exam should be normal except for bleeding manifestations (petechiae, purpura, mucosal bleeding) 1
• Any splenomegaly, hepatomegaly, or lymphadenopathy excludes primary ITP and mandates workup for HIV, systemic lupus erythematosus, lymphoproliferative disorders, or chronic liver disease 1

Step 5: Mandatory Infectious Disease Testing (All Adults)

• HIV antibody testing—HIV-associated thrombocytopenia is clinically indistinguishable from primary ITP and may precede other manifestations by years 1
• Hepatitis C virus serology—chronic HCV causes secondary ITP that resolves with antiviral therapy and may appear years before other symptoms 1
• Helicobacter pylori testing (urea-breath test or stool antigen, not serology)—eradication normalizes platelet counts in endemic regions 1

Step 6: Context-Specific Testing

• Pregnancy test in women of childbearing age to differentiate gestational thrombocytopenia, pre-eclampsia, or HELLP syndrome 1
• Direct antiglobulin test (DAT) to exclude Evans syndrome (combined autoimmune hemolytic anemia and ITP) 1
• Quantitative immunoglobulin levels if common variable immune deficiency is suspected 1
• Calculate 4T score immediately in any patient who received heparin within the past 3 months; if ≥4 (intermediate/high probability), discontinue all heparin and obtain anti-PF4 antibody testing without awaiting results 1

Step 7: Indications for Bone Marrow Examination

Bone marrow aspiration and core biopsy with flow cytometry and cytogenetics are mandatory when ANY of the following are present: 1

• Age ≥60 years (to exclude myelodysplastic syndrome, leukemia, or other malignancies)
• Systemic constitutional symptoms (fever, unexplained weight loss, night sweats, bone pain)
• Abnormal CBC parameters beyond isolated thrombocytopenia (anemia, leukopenia, leukocytosis)
• Atypical peripheral smear findings (schistocytes, immature cells, giant platelets, leukocyte inclusion bodies)
• Splenomegaly, hepatomegaly, or lymphadenopathy on physical exam
• Minimal or no response to first-line ITP therapies (IVIg, corticosteroids, anti-D)
• Prior to splenectomy in chronic ITP

Bone marrow examination is NOT required in patients with typical ITP features (isolated thrombocytopenia, normal physical exam except bleeding, normal smear morphology, age <60 years) 3, 1

Step 8: Tests That Should NOT Be Ordered Routinely

• Platelet-associated IgG or glycoprotein-specific antiplatelet antibodies—lack diagnostic specificity and do not alter management 3, 1, 5
• Thrombopoietin levels 1
• Reticulated platelet counts 1
• Bleeding time 1
• Antiphospholipid antibodies—only if clinical features of antiphospholipid syndrome are present 1
• Antinuclear antibodies—only when systemic lupus erythematosus is suspected 1

Critical Pitfalls to Avoid

• Missing TTP, HIT, or DIC carries high fatality risk (untreated TTP >90% mortality; HIT thrombosis risk 30-50%)—prompt exclusion of these entities is essential 1
• Never diagnose ITP without personal review of the peripheral blood smear—automated counters miss pseudothrombocytopenia, giant platelets, and schistocytes 1
• Never omit HIV and HCV testing in adults, even in low-risk populations, because these infections can masquerade as primary ITP for years 1
• Do not delay bone marrow examination in patients ≥60 years—age alone mandates marrow evaluation regardless of other features 1
• Obtain detailed medication history including over-the-counter products, herbal supplements, and quinine-containing beverages, as many agents cause drug-induced thrombocytopenia 1, 2

Bleeding Risk Stratification by Platelet Count

• Platelet count >50 × 10³/μL—generally asymptomatic, no activity restrictions needed 2
• Platelet count 20-50 × 10³/μL—mild skin manifestations (petechiae, purpura, ecchymosis); avoid contact sports and antiplatelet agents 1, 2
• Platelet count <10 × 10³/μL—high risk of serious bleeding; hospitalization and treatment typically required 3, 2