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.