Thrombopoietin Receptor Agonists

Thrombopoietin receptor agonists (TPO-RAs) stimulate megakaryocyte production to raise platelet counts in immune thrombocytopenia (ITP), aplastic anaemia, thrombocytopenia of chronic liver disease before procedures, and some other settings. They are not first-line, and they do not cure ITP; platelet counts fall when treatment stops.

Mechanism. Romiplostim (a peptibody) and the oral small molecules eltrombopag, avatrombopag, lusutrombopag and hetrombopag bind and activate the thrombopoietin receptor (c-Mpl), driving megakaryocyte growth and platelet production. Effect begins after 1 to 2 weeks.

Pharmacokinetics. Romiplostim: subcutaneous weekly. Eltrombopag: oral, half-life 21 to 32 hours, hepatic metabolism, chelates polyvalent cations. Avatrombopag: oral with food, half-life 19 hours.

Romiplostim. 1 microgram/kg subcutaneously once weekly; increase by 1 microgram/kg weekly until platelets reach 50 x 10^9/L or more; maximum 10 micrograms/kg weekly. Reduce when platelets exceed 200 x 10^9/L and stop over 400 x 10^9/L.

Eltrombopag.

• 50 mg orally once daily (25 mg for East and South-East Asian ancestry, hepatic impairment, or children under 6 years); increase by 25 mg every 2 weeks to a maximum of 75 mg daily.
• Take at least 2 hours before or 4 hours after calcium-rich food, antacids, iron or other polyvalent cations.
• Aplastic anaemia (specialist): 50 mg daily, up to 150 mg.
• Chronic hepatitis C: 25 mg daily start.

Avatrombopag. ITP: 20 mg orally daily with food, adjusted in steps to 40 mg; chronic liver disease before a procedure: 60 mg daily for 5 days if platelets are under 40 x 10^9/L, 40 mg if 40 to under 50 x 10^9/L.

Lusutrombopag. 3 mg orally daily for 7 days before a procedure in chronic liver disease.

Treatment target. Platelets 50 x 10^9/L or more to reduce bleeding; do not aim for normal counts.

• First-line. Not first-line; first-line ITP treatment is glucocorticoid (prednisolone 1 mg/kg daily, or dexamethasone 40 mg daily for 4 days), with intravenous immunoglobulin 1 g/kg for urgent rises.
• Alternative. Persistent or chronic ITP (usually over 6 to 12 months) after steroids, or when steroids are contraindicated; oral options preferred for convenience, romiplostim when oral drugs fail or adherence is poor.
• Specialist. Aplastic anaemia (eltrombopag with immunosuppression); thrombocytopenia in chronic liver disease before procedures (avatrombopag, lusutrombopag); selected chemotherapy-related thrombocytopenia.
• Emergency. Not suitable for acute bleeding (delayed effect); use platelet transfusion, intravenous immunoglobulin and glucocorticoid.

Selection. Consider H. pylori eradication and treatment of hepatitis C or HIV in ITP before TPO-RAs; rule out other causes (drugs, myelodysplasia, lymphoproliferative disease, pseudothrombocytopenia). Splenectomy and rituximab are alternatives.

Contraindications. Hypersensitivity; eltrombopag with hepatic impairment in some uses (specialist dose reduction); romiplostim and eltrombopag in myelodysplastic syndrome (risk of progression); pregnancy (avoid unless essential); portal vein thrombosis risk in chronic liver disease (caution).

Serious adverse effects.

• Thrombosis, including portal vein thrombosis in chronic liver disease.
• Hepatotoxicity (eltrombopag): monitor alanine transaminase.
• Rebound thrombocytopenia and bleeding on stopping.
• Bone marrow reticulin and collagen fibrosis.
• Cataracts (eltrombopag in children), headache, nausea, arthralgia.

Major interactions. Polyvalent cations (calcium, iron, magnesium, aluminium, zinc) reduce eltrombopag absorption; eltrombopag inhibits OATP1B1 and BCRP (raises rosuvastatin); anticoagulants and antiplatelets with low platelets; strong CYP3A4/CYP2C9 inducers and inhibitors alter avatrombopag.

Common prescribing errors.

• Missing the cation separation for eltrombopag.
• Starting at 50 mg in patients of East Asian ancestry or with liver disease.
• Aiming for normal platelet counts.
• Stopping abruptly.
• Prescribing before excluding other causes of low platelets.

Special groups.

• Pregnancy: avoid unless benefit exceeds risk; limited data.
• Breastfeeding: not known to pass; avoid if possible.
• Children: eltrombopag and romiplostim licensed for chronic ITP in some regions; weight-based dosing.
• Older adults: caution because of thrombosis.
• Kidney: no adjustment for oral agents.
• Liver: eltrombopag starting dose 25 mg; avoid in decompensated disease for ITP.
• East Africa: cost and availability are limited; first-line glucocorticoid with H. pylori and HIV testing is more accessible; ancestry-related dose reduction applies to East and South-East Asian patients, not for African ancestry.

Monitoring. Platelet count weekly during titration, then monthly; alanine transaminase and bilirubin before and every 2 weeks during dose adjustment (eltrombopag); blood film for marrow changes; signs of thrombosis.

Referral and escalation. Rapid fall in platelets after stopping; thrombosis; liver enzyme rise over three times normal; new cytopenias or abnormal film; suspected marrow disease.

Comparison with alternative classes. TPO-RAs raise platelets reliably in chronic ITP and avoid immunosuppression, but need continuous treatment and are costly. Glucocorticoids, intravenous immunoglobulin, rituximab and splenectomy remain alternatives.