clinical study insights

Thrombopoietin Receptor Agonists Maintain Platelet Counts and Induce Remission in Patients With Chronic Immune Thrombocytopenia

by Howard A. Liebman, MD

Overview

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


Clinical Study 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.

Reference:
Garabet L, Ghanima W, Monceyron Jonassen C, Skov V, Holst R, Mowinckel MC, Hans CH, Torben AK, Thomassen M, Liebman H, Bussel JB, Sandset PM. Effect of thrombopoietin receptor agonists on markers of coagulation and P-selectin in patients with immune thrombocytopenia. Platelets. 2017:1-7. doi: 10.1080/09537104.2017.1394451. [Epub ahead of print]

Expert Commentary

Howard A. Liebman, MD

Donald I Feinstein Chair in Medicine
Professor of Medicine and Pathology
Jane Anne Nohl Division of Hematology
USC Norris Cancer Hospital
Los Angeles, CA

“The TPO-RAs romiplostim and eltrombopag have changed second-line treatment regimens in ITP due to their safety and efficacy. They allow patients to maintain a safe platelet count for longer periods of time.”

Howard A. Liebman, MD

The TPO-RAs romiplostim and eltrombopag have changed second-line treatment regimens in ITP due to their safety and efficacy. They allow patients to maintain a safe platelet count for longer periods of time. In some long-term clinical trials, thromboembolic events have been reported with both TPO-RAs in a small percentage (6%) of adults with ITP. The events were not found to be related to type of TPO-RA, dosage of drug, or patient platelet count. An increased rate of venous thrombosis has also been reported with splenectomy, steroids, and intravenous immunoglobulin. It is unclear whether the disease, its treatment, or both trigger venous thrombosis in some adults with ITP. We conducted a study to assess what contributes to the risk of venous thrombosis in ITP. We found that, after treatment with TPO-RA, only sP-selectin, platelet count, and PAI-1 increased, and TPO-RA treatment had no effect on thrombin generation. Also, patients with ITP had elevated levels of F1+2, D-dimer, and PAI-1 before starting treatment with TPO-RA. We found that increased sP-selectin with TPO-RA treatment could contribute to the increased risk of venous thrombosis with the use of these agents in patients with ITP. Despite this small risk, the advantage of TPO-RAs is that they allow most patients to maintain a safe platelet count and can be combined with immune-modulating agents to induce remission in patients with chronic ITP.

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