What is the recommended work‑up for a patient presenting with thrombocytopenia?

Low Platelet Work-Up: Evidence-Based Diagnostic Algorithm

Begin by confirming true thrombocytopenia through peripheral blood smear review by a hematopathologist, then proceed with a structured evaluation based on patient age, bleeding manifestations, and CBC findings to exclude life-threatening conditions before diagnosing primary immune thrombocytopenia.

Step 1: Confirm True Thrombocytopenia

• Repeat the platelet count in a citrate or heparin tube to exclude EDTA-dependent pseudothrombocytopenia, which occurs in approximately 0.1% of samples and falsely lowers automated counts 1, 2.
• Obtain manual peripheral blood smear review by a qualified hematopathologist or pathologist before proceeding with further workup, as automated counters miss critical findings including platelet clumping, giant platelets, and schistocytes 3, 1, 2.

Step 2: Assess Clinical Context and Bleeding Risk

Physical Examination Red Flags

• Normal examination except for bleeding manifestations (petechiae, purpura, ecchymoses) supports primary ITP 3, 1, 2.
• Moderate or massive splenomegaly, hepatomegaly, or lymphadenopathy excludes primary ITP and mandates investigation for HIV, systemic lupus erythematosus, lymphoproliferative disorders, or portal hypertension 3, 1, 2.
• Fever, weight loss, night sweats, bone pain, or syndromic features (hearing loss, skeletal dysmorphisms, mental retardation) require immediate bone marrow examination 3, 1.

Bleeding Risk Stratification

• Platelet count >50 × 10⁹/L: Patients are generally asymptomatic; observation is appropriate 4, 5.
• Platelet count 20-50 × 10⁹/L: Mild skin manifestations (petechiae, purpura) may occur; avoid contact sports and antiplatelet agents 1, 4.
• Platelet count 10-30 × 10⁹/L: Bleeding with minimal trauma is possible 5.
• Platelet count <10 × 10⁹/L: High risk of serious spontaneous bleeding; constitutes a hematologic emergency requiring hospitalization 6, 4, 5.

Step 3: Review Complete Blood Count and Peripheral Smear

Expected Findings in Primary ITP

• Isolated thrombocytopenia (platelet count <100 × 10⁹/L) with otherwise normal CBC 3, 1, 2.
• Platelets normal-sized or mildly enlarged; consistently giant platelets (approaching red cell size) indicate inherited thrombocytopenias such as MYH9-related disease or Bernard-Soulier syndrome 3, 1, 2.
• Normal red cell morphology without schistocytes; presence of schistocytes suggests thrombotic microangiopathy (TTP, HUS, DIC) with >90% mortality if untreated 1, 2, 4.
• Normal white cell count and morphology; immature cells, blasts, or Döhle-like inclusion bodies suggest leukemia, myelodysplastic syndrome, or MYH9-related disease 3, 1, 2.

Findings That Mandate Alternative Workup

• Any cytopenia beyond isolated thrombocytopenia (unexplained anemia, leukopenia, leukocytosis) requires bone marrow examination 3, 1, 2.
• Schistocytes on smear: Urgent ADAMTS13 activity, LDH, haptoglobin, and coagulation studies to rule out TTP/HUS 1, 2, 4.
• Leukocyte inclusion bodies: Suggests MYH9-related disease 3, 1.

Step 4: Mandatory Infectious Disease Testing (All Adults)

• HIV antibody testing is required in all adults with suspected ITP, regardless of risk factors or geographic location, because HIV-associated thrombocytopenia may precede other manifestations by years and is clinically indistinguishable from primary ITP 3, 1, 2.
• Hepatitis C virus serology is mandatory in all adults; chronic HCV can cause secondary ITP that resolves with antiviral therapy 3, 1, 2.
• Helicobacter pylori testing (urea-breath test or stool antigen preferred over serology) should be performed in adults, as eradication normalizes platelet counts in a subset of patients, particularly in high-prevalence regions 3, 1, 2.

Step 5: Age-Based Stratification for Bone Marrow Examination

Bone Marrow Examination is MANDATORY When:

• Age ≥60 years to exclude myelodysplastic syndrome, leukemia, or other malignancies 3, 1, 2.
• Systemic constitutional symptoms (fever, unexplained weight loss, night sweats, bone pain) 1, 2.
• Abnormal CBC parameters beyond isolated thrombocytopenia (anemia not proportional to bleeding, leukopenia, leukocytosis) 1, 2.
• Atypical peripheral smear findings (schistocytes, immature white cells, giant platelets, leukocyte inclusion bodies) 1, 2.
• Organomegaly or lymphadenopathy on physical examination 1, 2.
• Treatment failure: Persistent thrombocytopenia lasting >6-12 months or minimal/no response to first-line therapies (IVIg, corticosteroids, anti-D) 1, 2.
• Pre-splenectomy evaluation in patients with chronic ITP 3, 1.

Bone Marrow Examination is NOT Required When:

• Age <60 years with typical ITP features: isolated thrombocytopenia, normal physical exam except bleeding manifestations, normal smear, no systemic symptoms 3, 1, 2.
• Children and adolescents with typical ITP presentation (recent viral prodrome, skin-only bleeding, no organomegaly) 3, 1, 2.

Components of Bone Marrow Testing (When Performed)

• Both aspirate and core biopsy are required 1, 2.
• Flow cytometry to identify chronic lymphocytic leukemia-associated ITP 1.
• Cytogenetic testing to exclude clonal disorders 1.

Step 6: Additional Context-Specific Testing

• Direct antiglobulin test (DAT) to exclude Evans syndrome (combined autoimmune hemolytic anemia and ITP) 1, 2.
• Pregnancy test in women of childbearing potential to differentiate gestational thrombocytopenia, pre-eclampsia, or HELLP syndrome 3, 1, 2.
• Rh(D) blood group typing if anti-D immunoglobulin therapy is being considered 3, 1, 2.
• Quantitative immunoglobulin levels in children with ITP, especially those with persistent or chronic disease, to exclude common variable immunodeficiency 3, 1.
• Coagulation studies (PT, aPTT, fibrinogen, D-dimer) in patients with severe thrombocytopenia to evaluate for disseminated intravascular coagulation 3, 1.

Step 7: Assess for Heparin-Induced Thrombocytopenia (HIT)

• Calculate the 4T score immediately in any patient who received heparin (including heparin flushes) within the past 3 months 3, 1, 2.
• If 4T score ≥4 (intermediate/high probability): Discontinue all heparin immediately and obtain anti-PF4 antibody testing without awaiting results 3, 1, 2.
• Initiate non-heparin anticoagulant (argatroban, bivalirudin, fondaparinux) promptly; do not delay for laboratory confirmation 3, 1, 2.
• HIT typically presents 5-10 days after heparin exposure with moderate thrombocytopenia (30-70 × 10⁹/L) and paradoxical thrombosis risk, not bleeding 3, 1, 2.

Step 8: Medication Review

• Document all current and recent medications, including prescription drugs, over-the-counter products, herbal supplements, and quinine-containing beverages 1, 2, 6.
• Common culprits: Heparin, quinidine/quinine, sulfonamides, vancomycin, cefazolin, clindamycin, doxycycline, trimethoprim-sulfamethoxazole, GPIIb/IIIa inhibitors, alcohol 3, 1, 2.
• Drug-induced thrombocytopenia typically occurs 5-14 days after drug exposure 1, 2.

Tests That Should NOT Be Ordered Routinely

• Platelet-associated IgG (PaIgG) and glycoprotein-specific antiplatelet antibodies lack diagnostic specificity and do not change management 3, 1, 2.
• Thrombopoietin (TPO) levels have insufficient evidence for routine use 1, 2.
• Reticulated platelets (immature platelet fraction) cannot replace bone marrow examination in patients meeting mandatory criteria 1.
• Bleeding time has no proven clinical utility 1, 2.
• Antiphospholipid antibodies only if clinical features of antiphospholipid syndrome are present 1, 2.
• Antinuclear antibodies (ANA) only when systemic lupus erythematosus is suspected 3, 1, 2.

Critical Pitfalls to Avoid

• Never diagnose ITP without personal review of the peripheral blood smear by a hematopathologist, as automated counters miss pseudothrombocytopenia, giant platelets, and schistocytes 1, 2.
• Never omit HIV and HCV testing in adults, even in perceived low-risk populations, as these infections can masquerade as primary ITP for years 3, 1, 2.
• Missing TTP, HIT, or DIC carries catastrophic mortality risk (untreated TTP >90% mortality; HIT thrombosis risk 30-50%); prompt exclusion is essential 1, 2, 4.
• Presence of any organomegaly or lymphadenopathy excludes primary ITP and mandates investigation for secondary causes 3, 1, 2.
• Delaying bone marrow examination in patients ≥60 years risks missing myelodysplastic syndrome or leukemia 3, 1, 2.

Special Populations

Children

• Bone marrow examination is not necessary in children with typical ITP features (isolated thrombocytopenia, recent viral illness, normal exam except bleeding) 3, 1, 2.
• Observation alone is appropriate for children with no or minor bleeding, regardless of platelet count, as 60-74% achieve spontaneous remission within 6 months 3, 1, 2.
• Intracranial hemorrhage risk is 0.1-0.5% in pediatric ITP, with most occurring within the first 5 weeks of diagnosis 1, 2.

Pregnancy

• Gestational thrombocytopenia is the most common cause in pregnancy, typically presenting with mild thrombocytopenia (platelet count >70 × 10⁹/L) 2.
• Distinguish from pre-eclampsia, HELLP syndrome, and ITP through clinical context and laboratory findings 2, 4, 5.

Liver Disease

• Cirrhosis causes thrombocytopenia through decreased thrombopoietin production, bone marrow suppression, and splenic sequestration from portal hypertension 1, 2.
• Approximately 80% of cirrhotic patients have platelet counts below normal, but severe thrombocytopenia (<50 × 10⁹/L) is uncommon in compensated disease 1.