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 and Management

Initial Diagnostic Approach

For any patient presenting with thrombocytopenia, immediately obtain a complete blood count with differential and peripheral blood smear review to confirm true thrombocytopenia, exclude pseudothrombocytopenia from platelet clumping, and identify isolated thrombocytopenia versus pancytopenia. 1, 2

Step 1: Confirm True Thrombocytopenia

• Exclude pseudothrombocytopenia first by requesting manual peripheral blood smear examination by a qualified hematologist or pathologist to identify platelet clumping, which occurs in 0.1% of patients due to EDTA-dependent platelet agglutination 2, 3
• If pseudothrombocytopenia is suspected, redraw blood in a tube containing heparin or sodium citrate and repeat the platelet count 3

Step 2: Assess Bleeding Risk and Severity

The bleeding risk stratifies as follows:

• Platelet count >50 × 10⁹/L: Generally asymptomatic, minimal bleeding risk 3
• Platelet count 20-50 × 10⁹/L: Mild skin manifestations only (petechiae, purpura, ecchymosis) 3
• Platelet count 10-20 × 10⁹/L: Moderate bleeding risk, mucosal bleeding may occur 1
• Platelet count <10 × 10⁹/L: High risk of serious bleeding including intracranial hemorrhage 1, 3

Step 3: Distinguish Isolated vs. Multi-lineage Cytopenias

• If isolated thrombocytopenia with normal hemoglobin and white blood cell count: Most likely immune thrombocytopenia (ITP) or drug-induced thrombocytopenia 3, 4
• If pancytopenia or other cytopenias present: Consider bone marrow disorders, infections, or systemic diseases 2, 4

Essential Laboratory Workup

Mandatory Testing for 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, 2

Additional mandatory testing includes:

• HIV antibody testing 1, 2
• Hepatitis C virus testing 1, 2
• H. pylori testing (particularly in adults with persistent thrombocytopenia, as eradication can resolve thrombocytopenia) 2, 5

Peripheral Blood Smear Findings

The smear must show these features for ITP diagnosis:

• Normal-sized or slightly enlarged platelets (not giant platelets approaching red blood cell size) 2
• Normal red blood cell morphology without schistocytes or poikilocytosis 2
• Normal white blood cell morphology without immature or abnormal cells 2

Red flags on smear requiring expanded workup:

• Schistocytes suggest thrombotic microangiopathy 2, 5
• Giant platelets suggest inherited thrombocytopenias 2
• Abnormal white cells suggest bone marrow disorders 2

When to Obtain Coagulation Studies

Obtain PT, aPTT, fibrinogen, and D-dimers when:

• Severe thrombocytopenia with concern for disseminated intravascular coagulation (DIC) 1, 2
• Active bleeding disproportionate to platelet count 5
• Suspicion of thrombotic microangiopathy 5

When Bone Marrow Examination is Required

Bone marrow examination is NOT necessary in patients with typical ITP features (isolated thrombocytopenia, normal physical exam except bleeding manifestations, normal peripheral smear). 1

Bone marrow examination IS mandatory in these situations:

• Age ≥60 years (to exclude myelodysplastic syndromes, leukemias, or other malignancies) 1, 2
• Systemic symptoms present (fever, weight loss, bone pain) 1, 2
• Abnormal blood count parameters beyond thrombocytopenia (anemia, leukopenia, leukocytosis) 1, 2
• Atypical peripheral smear findings (schistocytes, abnormal white cells) 2
• Splenomegaly, hepatomegaly, or lymphadenopathy on exam 1, 2
• Minimal or no response to first-line ITP therapies 2
• Before splenectomy in patients with persistent disease 1, 2

Physical Examination Red Flags

Physical examination should be normal aside from bleeding manifestations in primary ITP. 2

The following findings exclude primary ITP and mandate investigation for secondary causes:

• Splenomegaly, hepatomegaly, or lymphadenopathy 1, 2
• Non-petechial rash 2
• Fever or constitutional symptoms 2
• Skeletal or soft-tissue morphologic abnormalities 6

Treatment Thresholds and Indications

Pediatric Patients (Children and Adolescents)

For children with no bleeding or mild bleeding (skin manifestations only such as bruising and petechiae), manage with observation alone regardless of platelet count. 1

Treatment is indicated only when:

• Clinically significant bleeding occurs (mucosal bleeding, epistaxis lasting >15 minutes, oral bleeding) 1
• Lifestyle or psychosocial factors significantly impact quality of life 2
• Invasive procedures are planned 2

First-line treatment options for pediatric patients requiring treatment:

• Single dose of IVIg 0.8-1 g/kg (preferred when rapid response needed) 1
• Short course of corticosteroids (prednisone 1-2 mg/kg/day for 2 weeks then tapered) 1
• Anti-D immunoglobulin 50-75 μg/kg (only in Rh-positive, non-splenectomized children without hemolysis or anemia from bleeding) 1

Critical point: The risk of intracranial hemorrhage in children with ITP is only 0.1-0.5%, with most occurring within the first 5 weeks of diagnosis 2

Adult Patients

Treatment should be based on bleeding severity, bleeding risk factors (hypertension, age, previous bleeding episodes), activity level, and patient preferences—not solely on platelet count. 1

Treatment thresholds:

• Platelet count >50 × 10⁹/L with no bleeding: Observation acceptable 1
• Platelet count 30-50 × 10⁹/L with no or minor bleeding: Observation acceptable, corticosteroids may be considered 2
• Platelet count <30 × 10⁹/L or any significant bleeding: Treatment recommended 1

First-line treatment for adults:

• Longer courses of corticosteroids (prednisone 1 mg/kg orally for 21 days then tapered) are preferred over shorter courses because they provide longer time to loss of response 1
• IVIg 0.8-1 g/kg if rapid platelet increase is needed 1
• Anti-D therapy in Rh-positive, non-splenectomized individuals 1

Second-Line and Chronic ITP Treatment

For patients with insufficient response to first-line therapy:

• Rituximab may be considered for significant ongoing bleeding despite treatment 1
• High-dose dexamethasone may be considered as alternative to splenectomy 1
• Thrombopoietin receptor agonists (romiplostim, eltrombopag) for chronic ITP 7, 8

Romiplostim dosing: Initial dose 1 mcg/kg subcutaneously weekly, adjusted by 1 mcg/kg increments to achieve platelet count ≥50 × 10⁹/L, maximum 10 mcg/kg weekly 7

Eltrombopag dosing: Initial dose 36 mg orally once daily (18 mg for East/Southeast Asian ancestry or hepatic impairment), adjusted to achieve platelet count ≥50 × 10⁹/L 8

Splenectomy is recommended for patients with chronic ITP who have significant or persistent bleeding and lack of responsiveness or intolerance to other therapies. 1

Special Situations Requiring Emergency Management

Heparin-Induced Thrombocytopenia (HIT)

• Typically presents 5-10 days after heparin exposure with moderate thrombocytopenia (30-70 × 10⁹/L) 2
• Calculate 4T score immediately if patient has received any heparin within past 3 months 2
• Test anti-PF4 antibodies immediately when clinical probability is intermediate or high 2
• Paradoxically causes thrombosis, not bleeding 2, 3

Thrombotic Microangiopathies (TTP/HUS)

• Require prompt diagnosis and treatment to prevent catastrophic outcomes 2
• Look for schistocytes on peripheral smear 2
• Obtain coagulation studies, LDH, haptoglobin, indirect bilirubin 5

HELLP Syndrome in Pregnancy

• Hemolysis, elevated liver enzymes, low platelet count 3
• Requires emergency hospitalization and delivery 3

Management of Thrombocytopenia in Cancer Patients with ACS

For cancer patients with acute coronary syndrome and thrombocytopenia, life-saving interventions should not be denied because of thrombocytopenia. 1

Antiplatelet therapy guidelines:

• Platelet count >50,000/μL: Standard antiplatelet and anticoagulant therapy, response comparable to normal platelet counts 1
• Platelet count 30,000-50,000/μL: Dual antiplatelet therapy (aspirin + clopidogrel) can be used 1
• Platelet count 10,000-30,000/μL: Aspirin as single agent 1
• Platelet count <10,000/μL: Carefully evaluate bleeding risk versus thrombotic event risk 1

Heparin dosing adjustments:

• Platelet count <50,000/μL: Reduced heparin doses of 30-50 units/kg may be required 1

Platelet Transfusion Indications

Transfuse platelets when:

• Active hemorrhage is present 3
• Platelet count <10 × 10⁹/L (prophylactic) 3
• Before invasive procedures when platelet count <50 × 10⁹/L 3

Activity Restrictions

Patients with platelet counts <50 × 10⁹/L should adhere to activity restrictions to avoid trauma-associated bleeding. 3

Specific restrictions for children and adolescents:

• Avoid competitive contact sports with high risk of head trauma 2
• Avoid medications affecting platelet function (aspirin, NSAIDs) 2
• Manage menstruation in adolescent girls with antifibrinolytic agents and hormonal contraceptives 2

Common Diagnostic Pitfalls to Avoid

1. Never diagnose ITP without personally reviewing the peripheral blood smear, as automated counts can miss pseudothrombocytopenia, giant platelets, or schistocytes 2

2. Never skip HIV and HCV testing in adults, even without risk factors, as these infections may precede other symptoms by years 2

3. Do not assume ITP when platelet counts are normal or high-normal, as ITP by definition requires thrombocytopenia 5

4. Do not delay bone marrow examination in patients ≥60 years, regardless of how "typical" the presentation appears 2

5. Do not overlook drug-induced thrombocytopenia—obtain detailed medication history including over-the-counter medications and herbal supplements 2

6. Do not treat based on platelet number alone—treatment decisions should be based on bleeding severity and risk factors 1

7. Do not use prolonged corticosteroids in children due to significant toxicities including growth suppression 2