IVIg increases interleukin-11 levels, which in turn contribute to increased platelets, VWF and FVIII in mice and humans

Abstract

The mechanisms of action of intravenous immunoglobulins (IVIg) in autoimmune diseases are not fully understood. The fixed duration of efficacy and noncumulative effects of IVIg in immune thrombocytopenia (ITP) and acquired von Willebrand disease (AVWD) suggest other mechanisms besides immunological ones. Additionally to the peripheral destruction of platelets in ITP, their medullary hypoproduction emerged as a new paradigm with rescue of thrombopoietin receptor agonists (TPO-RA). In an ITP mouse model, interleukin (IL)-11 blood levels increase following IVIg. IL-11 stimulates the production of platelets and other haemostasis factors; recombinant IL-11 (rIL-11) is thus used as a growth factor in postchemotherapy thrombocytopenia. We therefore hypothesized that IVIg induces IL-11 over-production, which increases platelets, VWF and factor VIII (FVIII) levels in humans and mice. First, in an ITP mouse model, we show that IVIg or rIL-11 induces a rapid increase (72 h) in platelets, FVIII and VWF levels, whereas anti-IL-11 antibody greatly decreased this effect. Secondly, we quantify for the first time in patients with ITP, AVWD, inflammatory myopathies or Guillain-Barré syndrome the dramatic IL-11 increase following IVIg, regardless of the disease. As observed in mice, platelets, VWF and FVIII levels increased following IVIg. The late evolution (4 weeks) of post-IVIg IL-11 levels overlapped with those of VWF and platelets. These data may explain thrombotic events following IVIg and open perspectives to monitor post-IVIg IL-11/thrombopoietin ratios, and to assess rIL-11 use with or without TPO-RA as megakaryopoiesis co-stimulating factors to overcome the relative hypoproduction of platelets or VWF in corresponding autoimmune diseases, besides immunosuppressant.

Mechanism of increased efficacy of recombinant Fc‐μTP‐L309C compared to IVIg to ameliorate mouse immune thrombocytopenia

“…Our results raise the question as to how IVIg can effectively ameliorate ITP if it is so inferior at blocking FcγRs as our in vitro results indicate. It strongly suggests that FcγR‐blockade is not a major mechanism of IVIg efficacy for amelioration of ITP in the mouse model, that other mechanism(s) such as induction of immunomodulatory cytokines, such as interleukin‐11 [ 14 ], may be more important.…”

IVIg-exposure and thromboembolic event risk: findings from the UK Biobank

“…An hour after intravenous Ig, the increase in leucocyte and platelet trafficking and aggregation was so great in the intravenous Ig group that counting was not possible. Some of the immunomodulatory mechanism of intravenous Ig might involve increasing interleukin-11 levels which stimulate platelets and other haemostatic factors 24. In already diseased vessels, intravenous Ig may bind to Fc receptors on platelets, triggering platelet-leucocyte interactions and potentiate haemostasis 25.…”

Acquired bleeding disorders

“…The proposed mode of action of IVIG is blocking the Fc receptor of reticuloendothelial system cells, delaying the clearance of antibody-VWF complexes, but other effects have also been suggested. 29 For a therapeutic trial, doses vary from a daily dose of 400 mg/kg/day for 5 days to 1 g/kg/day for 2 days, depending on the clinical context and possible side effects in cases of renal insufficiency or hemodynamic risk related to the large infusion volume. The increase in VWF and FVIII:C levels usually occurs within 24-48 h and may last up to 3-4 weeks and this duration is usually enough for prevention of bleeding in surgeries.…”