What are the causes and recommended management for idiopathic thrombocytopenic purpura (immune‑mediated thrombocytopenia)?

Immune Thrombocytopenic Purpura (ITP): Etiology and Management

Etiology

ITP is an autoimmune disorder characterized by antibody-mediated destruction of otherwise normal platelets, resulting in isolated thrombocytopenia (platelet count <100 × 10⁹/L). 1

Primary Mechanisms

• Increased platelet destruction occurs through autoantibodies targeting platelet glycoproteins (primarily GPIIb/IIIa and GPIb/IX), leading to accelerated clearance by splenic macrophages. 2
• Impaired platelet production results from antibody-mediated suppression of megakaryocytes in the bone marrow, contributing to insufficient compensatory platelet generation. 2
• Cellular immune dysregulation involves abnormalities in T-cell function and cytokine production that perpetuate the autoimmune response. 2

Secondary Causes That Must Be Excluded

• HIV and hepatitis C virus can cause clinically indistinguishable thrombocytopenia and may precede other manifestations by years; mandatory testing is required in all adults. 1
• Helicobacter pylori infection is associated with ITP, and eradication therapy produces platelet responses in approximately 50% of infected patients. 1
• Drug-induced thrombocytopenia from heparin, quinine, sulfonamides, antiplatelet agents, and numerous other medications must be ruled out through careful medication history. 1
• Antiphospholipid syndrome and other autoimmune disorders (SLE, common variable immunodeficiency) are common secondary causes. 1
• Viral infections (EBV, CMV, varicella, parvovirus B19) can trigger acute ITP, particularly in children. 3

Clinical Presentation Patterns

• In children, ITP typically follows viral infection with acute onset; two-thirds achieve spontaneous remission within 6 months. 1, 3
• In adults, ITP usually has insidious onset without preceding illness and follows a chronic course requiring long-term management. 1

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Diagnostic Approach

ITP remains a diagnosis of exclusion requiring isolated thrombocytopenia on CBC, normal peripheral blood smear morphology (except for thrombocytopenia), and mandatory exclusion of secondary causes. 1

Essential Initial Testing

• Complete blood count with differential confirms isolated thrombocytopenia; any unexplained anemia or leukopenia mandates bone marrow examination. 1
• Peripheral blood smear reviewed by a hematopathologist is the single most critical test, excluding pseudothrombocytopenia (EDTA-dependent clumping in ~0.1% of samples), identifying giant platelets (suggesting inherited thrombocytopenias), and detecting schistocytes (indicating thrombotic microangiopathy with >90% mortality if untreated). 1
• HIV antibody testing is mandatory in all adults regardless of risk factors. 1
• Hepatitis C serology is mandatory in all adults. 1
• Helicobacter pylori testing (urea-breath test or stool antigen preferred over serology) should be performed in adults. 1

When Bone Marrow Examination Is Required

• Age ≥60 years to exclude myelodysplastic syndrome, leukemia, or other malignancies. 1
• Systemic symptoms (fever, weight loss, night sweats, bone pain). 1
• Abnormal CBC parameters beyond isolated thrombocytopenia. 1
• Atypical smear findings (schistocytes, immature cells, giant platelets, leukocyte inclusion bodies). 1
• Splenomegaly, hepatomegaly, or lymphadenopathy on physical examination—these findings exclude primary ITP. 1
• Before splenectomy in chronic ITP. 1
• Failure to respond to first-line therapies (IVIg, corticosteroids, anti-D). 1

Tests That Should NOT Be Ordered Routinely

• Platelet-associated IgG and glycoprotein-specific antiplatelet antibodies lack diagnostic specificity and do not influence management. 1
• Thrombopoietin levels, reticulated platelet counts, and bleeding time have no proven clinical utility. 1

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Management Strategy

Treatment decisions must be based on bleeding severity and clinical context, not platelet count alone; the goal is to maintain a hemostatically safe platelet count (≥30–50 × 10⁹/L), not to normalize counts. 4, 5

Observation vs. Treatment Algorithm

Platelet Count	Bleeding Status	Recommendation	Evidence
>50 × 10⁹/L	No bleeding	Observation; no treatment or activity restrictions	[4,5]
30–50 × 10⁹/L	No bleeding or minor purpura	Observation strongly preferred over corticosteroids; harm from steroid exposure outweighs benefit	[5]
<30 × 10⁹/L	Minor mucocutaneous bleeding	Consider corticosteroids	[5]
<20 × 10⁹/L	Any bleeding	Initiate first-line therapy; hospitalization recommended	[5]
Any count	Severe bleeding (CNS, GI, GU)	Emergency treatment (corticosteroids + IVIg ± platelet transfusion)	[5,3]

First-Line Therapies

Corticosteroids are the standard initial treatment, with prednisone or high-dose dexamethasone as the two primary options. 4

Prednisone (Standard First-Line)

• Dose: 0.5–2 mg/kg/day until platelet count increases to 30–50 × 10⁹/L (may require several days to weeks). 4
• Response rate: 70–80% initial response within 2–7 days. 4, 3
• Taper rapidly and stop by 4 weeks in non-responders to avoid corticosteroid-related complications (hyperglycemia, hypertension, osteoporosis, infections, mood alterations). 4, 5
• Long-term sustained remission: Only 10–15% at 2–5 years. 3

High-Dose Dexamethasone (Alternative First-Line)

• Dose: 40 mg/day for 4 days, repeatable every 2–4 weeks for 1–4 cycles. 4
• Response rate: Up to 90% initial response; 50–80% sustained remission. 4, 3
• Superior long-term outcomes: ~50% sustained remission at 2–5 years compared to 10–15% with prednisone. 3
• Equivalent to 400 mg prednisone per day, but given in short pulses to minimize toxicity. 4

Intravenous Immunoglobulin (IVIg)

• Dose: 0.8–1 g/kg as a single infusion (repeatable if needed). 4, 5, 3
• Indication: When rapid platelet rise is needed (pre-procedure, severe bleeding) or corticosteroids are contraindicated. 5, 3
• Response rate: >80% in children and adults; platelet recovery within 1–2 days (many within 24 hours). 3
• Duration: Transient effect; platelets return to baseline in 2–4 weeks. 3
• Toxicities: Severe headache and fever (common); renal failure and thrombosis (rare but serious). 3

Anti-D Immunoglobulin (Rh-Positive, Non-Splenectomized Only)

• Dose: 50–75 µg/kg. 4, 3
• Response rate: 50–77% depending on dose; ≥50% of responders achieve platelet rise within 24 hours. 3
• Contraindications: Autoimmune hemolytic anemia, Rh-negative status, prior splenectomy. 4, 3
• Main toxicity: Dose-limiting hemolysis; rare intravascular hemolysis can cause renal failure. 3
• Avoid in patients with decreased hemoglobin from bleeding. 5

Emergency Management of Life-Threatening Bleeding

• Combine prednisone with IVIg for rapid control. 3
• High-dose methylprednisolone (30 mg/kg/day for 7 days) achieves 95% response rate in severe cases. 3
• Platelet transfusion (often with concurrent IVIg) for immediate hemostasis in CNS, GI, or GU bleeding. 5, 3
• Emergency splenectomy or vincristine may be considered for refractory life-threatening hemorrhage. 3

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Second-Line Therapies (Chronic/Refractory ITP)

Second-line therapy is indicated for patients who fail first-line treatment, require ongoing corticosteroids after initial therapy, or have persistent thrombocytopenia >6–12 months. 5

Splenectomy (Gold-Standard Second-Line)

• Highest durable remission rates: ~66–67% complete remission; 67% freedom from relapse at 5 years. 3
• Laparoscopic approach preferred when feasible; similar efficacy to open surgery. 3
• Pre-operative vaccination against encapsulated organisms (pneumococcus, meningococcus, Haemophilus influenzae) is mandatory. 3
• Risks: Surgical complications, lifelong infection risk, thrombosis. 5

Rituximab

• Dose: 375 mg/m² weekly × 4 doses. 5
• Response rate: 60% overall. 5
• Long-term outcomes: Only 19% freedom from relapse at 5 years when used as second-line after steroids; better outcomes (73% 2-year relapse-free) when used after splenectomy failure. 3
• Indication: Patients at bleeding risk who have failed one line of therapy or cannot undergo splenectomy. 3

Thrombopoietin Receptor Agonists (TPO-RAs)

• Agents: Romiplostim (subcutaneous), eltrombopag (oral). 5, 6
• Indication: Third-line therapy for patients who relapse after splenectomy or have contraindications to splenectomy and have failed at least one prior therapy. 3
• Eltrombopag response: 70–81% achieve platelet count >50 × 10⁹/L by day 15 at doses of 50–75 mg daily. 5
• Advantages: Non-immunosuppressive, effective. 3
• Disadvantages: High cost, need for ongoing administration. 3
• Critical monitoring: Check platelet counts weekly for at least 2 weeks after discontinuation due to risk of worsening thrombocytopenia. 5

Other Immunosuppressive Options (Refractory Disease)

• Azathioprine 1–2 mg/kg/day: Response up to 40% after 3–6 months. 3
• Cyclosporine A 5 mg/kg/day for 6 days then 2.5–3 mg/kg/day: Response 50–80%. 3
• Cyclophosphamide 1–2 mg/kg/day orally: Response 24–85%. 3
• Danazol 200 mg 2–4 times daily: Response ~40% after 3–6 months. 3

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Special Populations

Pregnancy

• Mode of delivery should be determined by obstetric indications, not platelet count. 1
• Epidural anesthesia has been reported safe with platelet counts as low as 50 × 10⁹/L, though formal guidelines suggest 75–80 × 10⁹/L. 1
• Neonatal thrombocytopenia occurs in ~25% of infants born to thrombocytopenic mothers, but major bleeding is rare. 1

Pediatric ITP

• Observation alone is recommended for children with no bleeding or only mild bleeding, regardless of platelet count. 1, 3
• Spontaneous remission occurs in two-thirds of children within 6 months. 1, 3
• Severe bleeding occurs in only 3% of children; intracranial hemorrhage risk is ~0.1–0.5%, mostly within first 5 weeks. 1
• Bone marrow examination is not necessary in children with typical ITP features. 1

Viral-Associated ITP

• HIV-associated ITP: Prioritize antiretroviral therapy before other ITP-directed treatments unless there is active significant bleeding. 3
• HCV-associated ITP: Consider antiviral therapy, but monitor platelets closely as interferon may worsen thrombocytopenia. 3
• Acute viral infections (EBV, CMV, varicella): Manage the viral illness per standard protocols without specific ITP-targeted antivirals. 3

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Critical Pitfalls to Avoid

• 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. 1
• Do not treat based on platelet count alone; treatment is indicated only for clinically significant bleeding. 4, 5
• Limit corticosteroid exposure to ≤4 weeks in non-responders to avoid severe toxicity (hyperglycemia, hypertension, osteoporosis, infections). 4, 5
• Do not normalize platelet counts as a treatment goal; target is ≥30–50 × 10⁹/L to reduce bleeding risk. 5
• Missing secondary causes (HIV, HCV, H. pylori, medications, antiphospholipid syndrome) leads to misdiagnosis and inappropriate treatment. 1