What is the recommended workup and treatment for a patient with thrombocytopenia (low platelet count), particularly those presenting with symptoms such as bruising, petechiae, or bleeding?

Thrombocytopenia Workup

Initial Diagnostic Steps

Begin by confirming true thrombocytopenia with a complete blood count with differential and peripheral blood smear review to exclude pseudothrombocytopenia, which occurs in 0.1% of patients due to EDTA-dependent platelet agglutination. 1

Immediate Exclusion of Pseudothrombocytopenia

• Collect blood in a tube containing heparin or sodium citrate and repeat the platelet count if pseudothrombocytopenia is suspected 2
• Request manual peripheral blood smear examination by a qualified hematologist or pathologist to identify platelet clumping, which definitively excludes pseudothrombocytopenia 3

Determine Isolated vs. Multi-lineage Cytopenias

• The peripheral blood smear must confirm isolated thrombocytopenia versus pancytopenia, as this distinction fundamentally alters the differential diagnosis 1, 3
• Isolated thrombocytopenia (platelet count <100 × 10⁹/L) with otherwise normal CBC suggests immune thrombocytopenia (ITP) or drug-induced thrombocytopenia 3, 2
• Pancytopenia or other cytopenias mandate immediate consideration of bone marrow disorders, including myelodysplastic syndromes, leukemias, or aplastic anemia 3

Bleeding Risk Stratification

Assess bleeding risk based on platelet count: >50 × 10⁹/L are generally asymptomatic, 20-50 × 10⁹/L may have mild skin manifestations, 10-20 × 10⁹/L indicates moderate bleeding risk, and <10 × 10⁹/L indicates high risk of serious bleeding including intracranial hemorrhage. 1, 2

• Patients with platelet counts >50 × 10⁹/L rarely require urgent intervention unless undergoing invasive procedures 1
• Active hemorrhage or platelet counts <10 × 10⁹/L require immediate hospitalization and consideration of platelet transfusion 2

Mandatory Laboratory Workup

Infectious Disease Screening (All Adults)

• Test all adults with suspected ITP for HIV and hepatitis C virus, regardless of risk factors, as these infections can be clinically indistinguishable from primary ITP and may precede other symptoms by years 1, 3
• H. pylori testing should be performed, particularly in adults with persistent thrombocytopenia, as eradication therapy can resolve thrombocytopenia 1, 3

Peripheral Blood Smear Findings to Identify

• Normal-sized or slightly enlarged platelets with normal red blood cell and white blood cell morphology support ITP 3
• Schistocytes indicate thrombotic microangiopathy (TTP, HUS, DIC) and require emergency hospitalization 3, 2
• Giant platelets approaching red blood cell size suggest inherited thrombocytopenias 3
• Immature or abnormal white blood cells suggest bone marrow disorders requiring bone marrow examination 3

Coagulation Studies (When Indicated)

• Obtain PT, aPTT, fibrinogen, and D-dimers if disseminated intravascular coagulation is suspected, particularly in patients with severe thrombocytopenia and systemic illness 1, 3

Medication History Review

Perform a detailed medication history including over-the-counter medications and herbal supplements, as drug-induced thrombocytopenia is a common reversible cause. 3

Heparin-Induced Thrombocytopenia (HIT) Assessment

• HIT typically presents 5-10 days after heparin exposure with moderate thrombocytopenia (30-70 × 10⁹/L) and paradoxical thrombosis risk 1, 3
• Calculate the 4T score immediately if the patient has received any heparin within the past 3 months, based on degree of thrombocytopenia, timing, presence of thrombosis, and absence of other causes 1, 3
• Test anti-PF4 antibodies immediately when clinical probability is intermediate or high based on the 4T score 1, 3

Bone Marrow Examination Indications

Bone marrow examination is not necessary in patients with typical ITP features (isolated thrombocytopenia, normal physical exam, no systemic symptoms), but is mandatory in specific situations. 1, 3

Mandatory Bone Marrow Examination

• Age ≥60 years (to exclude myelodysplastic syndromes, leukemias, or other malignancies) 1, 3
• Systemic symptoms present (fever, weight loss, bone pain) 1, 3
• Abnormal blood count parameters beyond thrombocytopenia (anemia, leukopenia, leukocytosis) 1, 3
• Atypical peripheral smear findings (schistocytes, leukocyte inclusion bodies) 1, 3
• Minimal or no response to first-line ITP therapies (IVIg, corticosteroids, anti-D) 1, 3
• Before splenectomy in patients with persistent disease 3

Physical Examination Red Flags

Physical examination should be normal aside from bleeding manifestations; presence of splenomegaly, hepatomegaly, or lymphadenopathy excludes primary ITP and mandates investigation for secondary causes. 3

• Splenomegaly suggests portal hypertension, lymphoproliferative disorders, or storage diseases 3
• Lymphadenopathy suggests lymphoma, leukemia, or autoimmune disorders 3
• Non-petechial rash suggests vasculitis or other systemic disorders 3

Emergency Situations Requiring Immediate Hospitalization

• Active bleeding with any platelet count 2, 4
• Platelet count <10 × 10⁹/L (or <30 × 10⁹/L if on anticoagulation or antiplatelet therapy) 4
• Biological signs of disseminated intravascular coagulation 4
• Acute renal failure with thrombocytopenia (suggests TTP/HUS) 4
• Significant and/or brutal onset pancytopenia 4
• Suspected heparin-induced thrombocytopenia with intermediate or high 4T score 1, 3
• Suspected thrombotic microangiopathy (schistocytes on smear) 3, 2
• HELLP syndrome in pregnant patients 2

Treatment Thresholds

Treatment should be based on bleeding severity, bleeding risk factors, activity level, and patient preferences, rather than solely on platelet count. 1

Observation Without Treatment

• Patients with platelet count ≥30 × 10⁹/L and no or minor mucocutaneous bleeding can be observed without treatment 3
• Children with ITP who have no bleeding or only mild bleeding should be observed regardless of platelet count 3

First-Line Treatment Options (When Treatment Required)

• For pediatric patients: single dose of IVIg (0.8-1 g/kg), short course of corticosteroids, or anti-D immunoglobulin (50-75 μg/kg) 1, 3
• For adults: longer courses of corticosteroids, IVIg for rapid platelet increase, or anti-D therapy 1, 3

Second-Line Treatment Options

• Romiplostim (Nplate): initiate at 1 mcg/kg subcutaneously weekly, adjust by 1 mcg/kg increments to achieve platelet count ≥50 × 10⁹/L, maximum 10 mcg/kg weekly 5
• Eltrombopag (ALVAIZ): initiate at 36 mg orally once daily (18 mg for East-/Southeast-Asian ancestry or hepatic impairment) to achieve platelet count ≥50 × 10⁹/L 6
• Splenectomy for patients who have failed corticosteroid therapy and have persistent bleeding risk 3

Common Pitfalls to Avoid

• Never diagnose ITP without reviewing the peripheral blood smear personally, as automated counts can miss pseudothrombocytopenia, giant platelets, or schistocytes 3
• Never skip HIV and HCV testing in adults, as these infections can be clinically indistinguishable from primary ITP 3
• Do not use medications that impair platelet function (aspirin, NSAIDs) in patients with thrombocytopenia, as these increase bleeding risk 3
• Do not assume ITP when platelet counts are normal or high-normal with petechiae, as this suggests alternative diagnoses such as vasculitis or platelet function disorders 7
• Do not rely solely on platelet count in older patients; age >60 years mandates bone marrow examination regardless of other features 1, 3
• Do not use thrombopoietin receptor agonists to normalize platelet counts; use the lowest dose to achieve platelet count ≥50 × 10⁹/L to reduce bleeding risk 5, 6

Outpatient vs. Inpatient Management

• Platelet count 50-100 × 10⁹/L: outpatient investigation without urgency 4
• Platelet count 30-50 × 10⁹/L without anticoagulation or antiplatelet therapy: rapid outpatient evaluation 4
• Platelet count <30 × 10⁹/L (or <50 × 10⁹/L on anticoagulation/antiplatelet therapy): immediate hospitalization 4