Effect of thrombopoietin receptor agonists on markers of coagulation and P-selectin in patients with immune thrombocytopenia

Abstract

Thrombopoietin-receptor-agonists (TPO-RA) are effective treatments of immune thrombocytopenia (ITP). Previous long-term TPO-RA clinical trials have shown that thrombotic events occurred in 6% of TPO-RA-treated ITP patients. To explore the increased risk of thrombosis, the effects of TPO-RA on markers of coagulation and P-selectin were studied.

The study comprised two ITP cohorts and controls. Cohort 1 included 26 patients with sequential samples acquired before and during treatment with TPO-RA. Cohort 2 included a single sample in 18 patients on TPO-RA for more than one year. Thrombin generation (endogenous thrombin potential (ETP)) prothrombin fragments 1 + 2 (F₁₊₂), D-dimer, and plasminogen-activator-inhibitor-1 (PAI-1) were measured as well as soluble P-selectin (sP-selectin). Sequential expression of encoding genes for P-selectin (SELP) and PAI-1 (SERPINE1) was determined in four patients in cohort 1.

Significantly higher levels of F₁₊₂, D-dimer, and PAI-1 were found in ITP patients before TPO-RA treatment and in patients on long-term TPO-RA treatment than in controls. Pre-treatment levels of sP-selectin did not differ from controls. Analysis of longitudinal trends showed an increase in platelet count, sP-selectin, and PAI-1 after initiation of TPO-RA, followed by gradual decline. Platelet count and sP-selectin remained at higher levels throughout the study, whereas PAI-1 did not. Levels of other studied parameters did not show significant changes after initiation of treatment. Expression of SELP was up-regulated after initiation of TPO-RA, while the expression of SERPINE1 showed no significant changes.

In conclusion, elevated pre-treatment levels of F₁₊₂, D-dimer and PAI-1 are compatible with ITP being an intrinsically pro-thrombotic condition. After TPO-RA treatment, there were no significant changes in markers of coagulation activation or fibrinolysis, except for an initial increase in PAI-1 and a significant increase in sP-selectin both of which may contribute to increased thrombotic risk associated with TPO-RA treatment in ITP.

Keywords:

• Megakaryocyte
• Platelet
• thrombin generation
• thrombosis

Declaration of Interest

Waleed Ghanima reports research support from Novartis and lecture honoraria from Novartis and Amgen, during the conduct of the study. Howard Liebman reports research support from Amgen and Bristol Myers Squibb, personal fees from Novartis, outside the submitted work. James Bussel reports research support and personal fees from Amgen, grants from Boehringer Ingelheim, grants from GlaxoSmithKline, personal fees from Momenta Pharmaceuticals, grants and personal fees from Novartis Pharmaceuticals, personal fees from Physicians Education Resource, grants and personal fees from Prophylix Pharma, grants and personal fees from Protalex, grants and personal fees from Rigel Pharmaceuticals outside the submitted work. The rest of the authors report no declarations of interest.

Supplemental data

Supplemental data for this article can be accessed here.