What is the primary goal and treatment approach for a patient with Immune Thrombocytopenic Purpura (ITP)?

Overview of Immune Thrombocytopenic Purpura (ITP)

Definition and Pathophysiology

ITP is an acquired autoimmune hemorrhagic disorder characterized by accelerated platelet destruction caused by antiplatelet autoantibodies, resulting in isolated thrombocytopenia (platelet count <100 × 10⁹/L) with variable bleeding manifestations. 1

• Autoantibodies bind to platelets, leading to their sequestration and destruction by mononuclear macrophages primarily in the spleen 2
• Bone marrow megakaryocytes attempt to compensate through increased platelet production, but when this compensation fails, thrombocytopenia and bleeding tendency (purpura) develop 2
• Many patients remain asymptomatic with only incidental thrombocytopenia discovered on routine blood work 1
• Bleeding severity does not always correlate directly with platelet count; additional factors including age, lifestyle, and comorbidities affect bleeding risk 1

Diagnosis

• Diagnosis remains one of exclusion, as there is no definitive diagnostic test despite the ability to detect anti-platelet antibodies 3
• Platelet count <100 × 10⁹/L is the most important criterion, but not the sole diagnostic criterion 4
• ITP can be classified by duration: acute, subchronic, and persistent/chronic (>6 months) 4

Primary Treatment Goal

The fundamental treatment goal is achieving a platelet count that prevents major bleeding (≥50 × 10⁹/L), NOT normalizing the platelet count. 5

• Treatment should only be initiated when the degree of thrombocytopenia and clinical condition increase the risk for bleeding, not simply based on platelet numbers alone 5
• Treatment is indicated for platelet counts <30 × 10⁹/L with bleeding symptoms, or <20 × 10⁹/L regardless of symptoms 1
• No treatment is needed if platelet count >50 × 10⁹/L unless the patient has active bleeding, requires surgery, has bleeding-predisposing comorbidities, or needs anticoagulation 1
• The decision to treat should be based on bleeding severity, bleeding risk, patient activity level, potential side effects, and patient preferences rather than platelet count alone 6

First-Line Treatment

High-dose dexamethasone 40 mg daily for 4 days offers superior initial (up to 90%) and sustained (50-80%) response rates compared to conventional prednisone, with faster response times. 1, 6

• Dexamethasone shows higher initial response rates (86-90%) with sustained responses in 50-74% of patients when given as 40 mg/day for 4 days, either as a single cycle or up to 4 cycles given every 14 days 5
• Conventional prednisone (0.5-2 mg/kg/day or 1 mg/kg for 21 days followed by tapering) remains an acceptable alternative with initial response in 70-80% of patients, but sustained responses occur in only 20-40% 5, 6
• Prednisone should be rapidly tapered and stopped in responders, and especially in non-responders after 4 weeks to avoid corticosteroid-related complications 5
• Prolonged corticosteroid use (>6-8 weeks) should be avoided due to significant side effects including weight gain, mood alterations, hypertension, diabetes, osteoporosis, and increased infection risk 5, 6

Adjunctive First-Line Therapy

• IVIg 1 g/kg as a single dose can be combined with corticosteroids for faster platelet response, particularly when rapid increase is required 1
• IVIg at 0.4 g/kg/day for 5 days or 1 g/kg/day for 1-2 days can be used when rapid platelet increase is needed or when corticosteroids are contraindicated 6
• IV anti-D (50-75 μg/kg) can be used for Rh(D) positive, non-splenectomized patients as an alternative first-line option 6

Emergency Treatment for Active Bleeding

For patients with uncontrolled bleeding or active CNS, GI, or genitourinary bleeding, combine prednisone and IVIg together rather than choosing one over the other. 5, 6

• High-dose methylprednisolone is also useful in emergency settings 5
• Platelet transfusion at larger-than-usual doses, possibly in combination with IVIg, should be considered in life-threatening situations 5
• Emergency splenectomy may be considered in extreme circumstances 6

Second-Line Treatment

Thrombopoietin receptor agonists (TPO-RAs) are the preferred initial second-line therapy for refractory ITP, with overall platelet response rates of 88% in non-splenectomized patients and 79% in splenectomized patients. 5, 1

TPO-RA Options

• Romiplostim: 1-10 µg/kg subcutaneous weekly injection, with sustained responses documented for up to 4 years with continuous administration 5, 7
• Eltrombopag: 25-75 mg oral daily dose, with up to 30% of patients achieving long-term remission after tapering and discontinuation 5
• TPO-RAs should be used only in patients whose degree of thrombocytopenia and clinical condition increases the risk for bleeding, not to normalize platelet counts 7
• For patients on TPO-RAs who achieve stable platelet counts at the lowest dose, consider holding therapy to monitor for potential remission 6
• Patients who do not respond to one TPO-RA may respond to the alternate TPO-RA 6

Splenectomy

• Splenectomy is typically deferred for at least 6-12 months to allow for potential spontaneous remission 5, 1
• Splenectomy remains the only treatment providing sustained remission off all treatments at 1 year and beyond in a high proportion of patients (approximately two-thirds) 5
• Response rates: 80% of patients respond initially, with approximately two-thirds achieving lasting remission over 5-10 years 5
• Vaccination before splenectomy is essential to prevent overwhelming post-splenectomy infection 5

Rituximab

• Rituximab (anti-CD20 monoclonal antibody) has initial response rates of 60% (40% complete response) 5, 6
• Can be dosed at 100 mg or 375 mg/m² weekly for 4 weeks 5
• Response typically occurs within 1-8 weeks of treatment initiation 6
• Long-term responses documented in 20-30% of cases 6
• Approximately two-thirds of responders maintain response without additional therapy over 5-10 years 1

Third-Line Immunosuppressive Options

Multiple immunosuppressive agents are available for patients who fail second-line therapy, though response rates vary and onset of action may be delayed.

• Azathioprine: 1-2 mg/kg/day (maximum 150 mg/day), response rate 45-67%, may take 3-6 months for effect 5, 6
• Cyclosporin A: 5 mg/kg/day for 6 days, then 2.5-3 mg/kg/day (titrate to blood levels 100-200 ng/mL), response rate 50-80% with 42% complete response, onset within 3-4 weeks 5, 6
• Mycophenolate mofetil: 1000 mg twice daily for at least 3-4 weeks, response rate up to 75% with complete response in up to 45%, onset within 4-6 weeks 5, 6
• Danazol: 200 mg 2-4 times daily, response rate 40-67%, requires 3-6 months of treatment 5, 6
• Dapsone: 75-100 mg daily, response rate up to 50% within 3 weeks, requires screening for G6PD deficiency before starting 5, 6
• Cyclophosphamide: 1-2 mg/kg orally daily or 0.3-1 g/m² IV every 2-4 weeks, response rate 24-85%, carries risk of acute myeloid leukemia 5, 6

Monitoring Requirements

Weekly CBC with platelet counts during dose adjustment phase, monthly CBC monitoring after stable dose achieved, and weekly CBC for at least 2 weeks after discontinuation. 5

• Ensure hematology follow-up within 24-72 hours of diagnosis 1
• Assess for corticosteroid side effects, health-related quality of life, and bleeding symptoms 1
• Monitor for treatment-related complications including increased reticulin in bone marrow, which may require bone marrow examination during TPO-RA therapy 7

Critical Pitfalls to Avoid

• Do not use plasmapheresis, as there is no evidence of efficacy in chronic ITP 5
• Do not continue corticosteroids beyond 6-8 weeks, as detrimental effects often outweigh benefits with extended therapy 5, 6
• Do not add rituximab to corticosteroids for initial therapy, as this increases treatment costs without sufficient evidence of benefit to justify routine use 6
• Do not use TPO-RAs in an attempt to normalize platelet counts; use only to achieve hemostatic levels 7
• Avoid abrupt interruptions of TPO-RAs or excessive dose adjustments, which may cause platelet fluctuations, especially in patients with a history of splenectomy 6
• Cytotoxic drugs should be used with extreme caution in children with chronic ITP 6