Mechanism of Action of IVIG in ITP
IVIG works in ITP primarily by blocking Fc gamma receptors on reticuloendothelial cells, preventing the clearance of antibody-coated platelets by the spleen and liver. 1
Primary Mechanism: Fc Receptor Blockade
The dominant mechanism through which IVIG raises platelet counts involves saturating Fc gamma receptors (FcγR) on macrophages and other reticuloendothelial cells. 1 When these receptors are blocked by the high concentration of immunoglobulin, platelets that are sensitized with anti-platelet IgG antibodies cannot be recognized and destroyed by the reticuloendothelial system. 1
Evidence supporting this mechanism comes from studies demonstrating that Fc gamma fragments alone (without the Fab portion) are sufficient to produce clinical responses in ITP patients. 1 In a study of 12 children with acute ITP treated with intravenous Fc gamma fragments, 11 patients (92%) showed rapid increases in platelet counts above 50 × 10⁹/L, with no adverse reactions observed. 1
Supporting Evidence for Fc Receptor Blockade
- In responders with detectable platelet-associated IgG before treatment, platelet-bound IgG levels fell substantially during IVIG therapy, indicating reduced platelet destruction. 1
- Serum soluble CD16 (sFcγRIII) concentrations increased transiently or stably in treated patients, correlating with the rise in platelet count. 1
- This increase in soluble CD16 suggests additional immunoregulatory mechanisms may be triggered by IVIG beyond simple receptor blockade. 1
Additional Proposed Mechanisms
While Fc receptor blockade is the primary mechanism, IVIG likely exerts multiple immunomodulatory effects in ITP:
- Modulation of autoantibody production: IVIG may interfere with B-cell function and autoantibody synthesis, though this is a secondary effect. 2
- Anti-idiotypic antibodies: The pooled immunoglobulin preparation may contain antibodies that neutralize anti-platelet autoantibodies. 2
- Complement modulation: IVIG can interfere with complement-mediated platelet destruction. 2
Clinical Implications of the Mechanism
The mechanism of action explains why IVIG produces such rapid clinical responses—typically within 24 hours—compared to other ITP treatments. 2, 3, 4 The immediate blockade of Fc receptors prevents ongoing platelet destruction, allowing circulating platelet counts to rise quickly. 2, 3
However, this mechanism also explains the transient nature of IVIG's effect: once the infused immunoglobulin is metabolized (typically over 2-4 weeks), Fc receptors become available again, and platelet destruction resumes if the underlying autoimmune process persists. 2, 4 This is why platelet counts usually return to pretreatment levels within 2-4 weeks after IVIG administration. 2, 4
Dosing Considerations Based on Mechanism
The standard dose of 1 g/kg (given as a single dose or over 1-2 days) is designed to achieve sufficient Fc receptor saturation to block platelet clearance. 2, 3, 4 Lower doses (0.4 g/kg/day for 5 days or 0.6 g/kg total) may not achieve adequate receptor blockade as rapidly, explaining why the 1 g/kg regimen produces faster platelet increases within 24 hours. 2, 5
Studies comparing different IVIG doses confirm that higher total doses (2 g/kg) produce more rapid and pronounced platelet count increases in the first 72 hours compared to lower doses (0.6 g/kg), supporting the dose-dependent nature of Fc receptor blockade. 5, 6
Enhancement with Corticosteroids
Concomitant corticosteroids may enhance the IVIG response through complementary mechanisms—while IVIG blocks Fc receptors, corticosteroids suppress autoantibody production and reduce macrophage activity. 2, 3, 4 This combination is particularly recommended for emergency situations requiring urgent platelet count elevation. 3, 4