Increased microvesicle-associated thrombin generation in patients with immune thrombocytopenia after initiation of thrombopoietin receptor agonists

Abstract

Immune thrombocytopenia (ITP) patients have thrombocytopenia and increased bleeding risk, but, conversely, they also have increased thrombotic risk which appears to be exacerbated by thrombopoietin-receptor agonist (TPO-RA)-treatment. Microvesicles (MVs) released from activated/apoptotic cells are prothrombotic due to exposure of phosphatidylserine (PS) and tissue factor (TF). MVs are increased in ITP patients, but their prothrombotic effect, before and during treatment with TPO-RAs, is unclear.

We studied the effect of TPO-RAs on the procoagulant activity of MVs in 11 ITP patients, before, and two and six weeks after initiation of treatment, and in 15 healthy controls. MV-associated PS-activity, TF-activity and the capacity of isolated MVs and plasma to generate thrombin in a phospholipid-dependent manner were measured.

Before treatment with TPO-RAs, prothrombotic markers in ITP patients were comparable to levels found in healthy controls. After both two and six weeks of TPO-RA-treatment, ITP patients had higher MV-associated PS-activity and phospholipid-dependent thrombin generation in plasma than controls. In addition, ITP patients had increased phospholipid-dependent MV-associated thrombin generation two weeks after initiation of TPO-RA-treatment compared with controls and pre-treatment levels. MV-associated TF-activity was low in controls and in ITP patients before and after initiation of TPO-RA-treatment.

In conclusion, TPO-RAs increase phospholipid-dependent MV-associated thrombin generation in ITP patients. This could contribute to or exacerbate a pre-existing hypercoagulable state. Phospholipid-dependent thrombin generation generated by isolated MVs, or measured directly in plasma, may be potential tools that could help in the risk-assessment of future thromboembolic events in ITP patients, both before and after initiation of TPO-RA-treatment.

Keywords:

• Immune thrombocytopenia
• microvesicles
• thrombin generation
• thrombopoietin receptor agonists

Declaration of Interest

W.G. has received research support from Novartis, and lecture honoraria from Amgen and Novartis. J.B.B. consulted and participated in advisory boards for Amgen, Novartis and Dova. H.T. has participated in advisory boards for Novartis, Abbvie, Janssen and Bayer.

Statement of Contribution

L.G. participated in study conception/design, data collection, statistical analysis and interpretation of the results, and drafted the manuscript; W.G. participated in study design and patients’ recruitment; M.H performed sample analysis; J.B.B. participated in patient inclusion and data collection; P.M.S. participated in study design and result interpretation; H.T participated in patients’ inclusion. C.E.H designed the study, participated in interpretation of the results and drafting the manuscript. All authors have reviewed the manuscript and approved its final version.