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Idiopathic Thrombocytopenic Purpura (ITP) - MD Pathology Exam Notes

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Definition & Nomenclature

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Classification

• Acute ITP - children; follows viral infection; spontaneous remission in ~80%
• Chronic ITP - adults; predominantly females (F:M = 2:1 to 4:1); persists >6 months

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Pathogenesis

1. Antibody-Mediated Platelet Destruction (Primary Mechanism)

• IgG autoantibodies (most commonly anti-GPIIb/IIIa, also anti-GPIb/IX) bind to platelet surface glycoproteins
• Antibody-coated platelets are recognized by Fc receptors on splenic macrophages and undergo phagocytosis (reticuloendothelial destruction)
• The spleen is the primary site of both antibody production and platelet destruction
• The rate of destruction exceeds the bone marrow's compensatory capacity

2. T-Cell-Mediated Destruction

• Cytotoxic T lymphocytes (CD8+) can directly lyse platelets
• T-helper cell dysregulation promotes autoreactive B-cell clones producing antiplatelet IgG

3. Impaired Platelet Production

• Autoantibodies also bind to megakaryocyte surface antigens, impairing megakaryocyte maturation and thrombopoiesis
• Paradoxically, thrombopoietin (TPO) levels are low or normal (not elevated as expected), suggesting impaired megakaryocyte response

4. Net Result

• Accelerated platelet destruction + impaired platelet production = thrombocytopenia
• Despite thrombocytopenia, bone marrow shows normal to increased megakaryocytes (compensatory response, though functionally impaired)

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Clinical Features

Symptoms

• Petechiae - pinpoint (<3 mm), non-blanching, flat red/purple spots; appear first on dependent areas and pressure points
• Purpura / Ecchymoses - larger areas of spontaneous bruising on skin and mucous membranes
• Mucosal bleeding - epistaxis (common), gingival bleeding, hemorrhagic bullae in the mouth
• Menorrhagia - may be the presenting complaint in young women
• Prolonged bleeding from minor wounds
• GI bleeding (melena, hematemesis) - less common
• Hematuria - rare

Signs

• Petechial hemorrhages on skin and mucous membranes
• Positive tourniquet test (Hess/Rumpel-Leede test) - indicates capillary fragility
• Splenomegaly in <10% of cases - important: gross splenomegaly should raise suspicion of an alternative diagnosis (lymphoma, portal hypertension)
• No lymphadenopathy, no hepatomegaly in primary ITP
• Conjunctival hemorrhages may be present

Age and Sex Distribution

• Adults: predominantly females aged 15-50 years
• Children: equal sex distribution; peaks before age 5; often follows viral URI by 2 weeks (range 1-4 weeks)
• Elderly: more difficult to manage; higher major bleeding complication rates

Serious Complications

• Intracranial hemorrhage - rare but most serious; leading cause of death in ITP
• Mortality also from treatment complications (especially in elderly)

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Diagnostic Approach

Step 1: Clinical History

• Prior viral illness (especially in children)
• Drug history (heparin, quinidine, sulfonamides, NSAIDs, vancomycin)
• Family history of bleeding disorders
• Symptoms of SLE, HIV risk factors
• Pregnancy status

Step 2: Complete Blood Count (CBC)

• Isolated thrombocytopenia (platelet count <100,000/mm³, often <60,000/mm³ in symptomatic cases)
• Normal WBC and hemoglobin (anemia only if significant blood loss)
• If anemia + thrombocytopenia → consider Evans syndrome (autoimmune hemolytic anemia + ITP)

Step 3: Peripheral Blood Smear (KEY TEST)

Step 4: Coagulation Studies

• PT: Normal
• aPTT: Normal
• Thrombin time: Normal
• Bleeding time: Prolonged (platelet number-dependent)
• Clot retraction: Abnormal (platelet-dependent)
• Capillary fragility: Increased (positive Hess test)
• Normal coagulation studies differentiate ITP from DIC and von Willebrand disease

Step 5: Bone Marrow Examination

• Indicated when: diagnosis uncertain, age >60 years, atypical findings, failure to respond to first-line therapy
• Findings in ITP:
  • Normal to increased megakaryocytes (compensatory, morphologically normal or slightly immature)
  • Normal erythroid and myeloid lineages
  • Normal cellularity
• Rules out: aplastic anemia, leukemia, myelodysplastic syndrome, metastatic malignancy

Step 6: Additional Tests (As Indicated)

Antiplatelet Antibody Testing - Exam Point

• Most ITP patients have platelet-associated IgG (direct) and many have circulating antiplatelet antibodies (indirect)
• However, these assays are NOT recommended for routine diagnosis due to:
  • Multiple different assays, high interlaboratory variation
  • High background rate of platelet-associated IgG
  • Cannot distinguish ITP from incidental thrombocytopenia of pregnancy

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Differential Diagnosis

A. Falsely Low Platelet Count (Pseudothrombocytopenia)

• EDTA-dependent pseudothrombocytopenia - in vitro platelet clumping; repeat count in citrate tube
• Cold-dependent agglutinins
• Giant platelets miscounted as WBC by automated counters
• GPIIb/IIIa inhibitors (abciximab)

B. Decreased Production

C. Increased Destruction - Non-Immune

D. Increased Destruction - Immune (Secondary ITP)

E. Sequestration

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Key Lab Summary Table (Exam Memory Aid)

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Treatment (Brief - For Context)

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High-Yield Points for MD Pathology Exam

1. Pathognomonic bone marrow finding: Normal to increased megakaryocytes with normal erythroid/myeloid lineage - the "hallmark" exam answer
2. ITP is a diagnosis of exclusion - no single confirmatory test
3. Autoantibodies target GPIIb/IIIa most commonly (also GPIb/IX)
4. Coagulation studies are normal - key differentiator from DIC, liver disease, hemophilia
5. Spleen is <10% palpable - gross splenomegaly suggests alternative diagnosis
6. Peripheral smear shows large platelets (megathrombocytes) - young platelets from compensatory marrow response
7. Children: acute, post-viral, 80% spontaneous remission; Adults: chronic, female predominance, requires treatment
8. Antiplatelet antibody assays are not recommended for routine diagnosis
9. Intracranial hemorrhage - most serious but uncommon complication; most common cause of death
10. Secondary ITP associations: SLE, HIV, HCV, H. pylori, drugs (esp. heparin), lymphoma, CLL, Hodgkin's

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Important Note on Sources

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