The acceleration of the propagation phase of thrombin generation in patients with steady-state sickle cell disease is associated with circulating erythrocyte-derived microparticles

Abstract

<jats:title>Summary</jats:title><jats:p>Sickle cell disease (SCD) is linked to hypercoagulability and is characterised by high concentrations of erythrocyte-derived microparticles (Ed-MPs). However, the impact of procoagulant cell-derived microparticles on the thrombin generation process remains unclear. We analysed the alterations of each phase of thrombin generation (TG) in relation to the concentration of erythrocyte- or platelet-derived microparticles (Ed-MPs and Pd-MPs) in a cohort of patients with steady-state SCD. We studied 92 steady-state SCD patients, 19 of which were under treatment with hydroxyurea, and 30 healthy age- and sex-matched individuals. TG was assessed by calibrated automated thrombogram. Ed-MP and Pd-MP expressing or not phosphatidylserine (PS) were determined by means of flow cytometry. Procoagulant phospholipid-dependent activity in the plasma was evaluated by the Procoag-PPL assay. Levels of thrombomodulin and haemoglobin in the plasma as well as red blood cell and reticulocyte counts were measured. SCD patients, independently of the administration of hydroxyurea, were marked by a significant acceleration in the propagation phase of TG which correlated with the Ed-MP/PS+ concentration. TG was significantly attenuated in hydroxyurea-treated patients. In conclusion, the acceleration of the propagation phase of TG, driven by Ed-MP/PS+, is a major functional alteration in blood coagulation in patients with steady-state SCD. Treatment with hydroxyurea, in addition to the regulation of haemolysis, lowers Ed-MPs and attenuates thrombin generation. The thrombogram could be a useful tool for the diagnosis of hypercoagulability and optimisation of the treatment in patients with SCD.</jats:p>

Hydroxyurea Increases Plasma Concentrations of Microparticles and Reduces Coagulation Activation and Fibrinolysis in Patients with Sickle Cell Anemia

“…These results were not able to unveil the effect of HU treatment on concentrations of total and specific MPs. In another study, Gerotziafas et al [26] demonstrated that HU significantly reduced thrombin generation in sickle cell disease patients, as well as erythrocyte-derived MP concentrations. Recently, Nebor et al [27] showed that HU treatment was associated with a decrease in MPs derived from erythrocytes and platelets.…”

Coagulation abnormalities of sickle cell disease: Relationship with clinical outcomes and the effect of disease modifying therapies

“…There are conflicting reports on the effect of hydroxyurea on total, specific blood cell-derived and TF-bearing microparticles (31,78,91,173). A reduction in plasma D-dimer level in patients treated with hydroxyurea has been reported (78,174), with these studies reporting conflicting effects of hydroxyurea on circulating TAT complexes.…”

“…A reduction in plasma D-dimer level in patients treated with hydroxyurea has been reported (78,174), with these studies reporting conflicting effects of hydroxyurea on circulating TAT complexes. Adult patients treated with hydroxyurea also manifest a longer lag time, slower rate and reduced peak of ex vivo thrombin generation in TGA compared with untreated patients (31). One study of pediatric patients with SCD reported a negative correlation between ETP and peak ex vivo thrombin generation normalized for age and duration of hydroxyurea treatment, suggesting a time-dependent effect of hydroxyurea on overall coagulation potential in children with SCD (146).…”

Impact of blood hypercoagulability on in vitro fertilization outcomes: a prospective longitudinal observational study

“…Among them, the Calibrated Automated Thrombogram® and the minimal TF-triggered whole blood thromboelastometry allow the evaluation of thrombin generation and clot formation processes [12–14]. The measurement of the procoagulant phospholipid dependent clotting time (Procoag-PPL®) reflects the plasma concentration of procoagulant membrane vesicles of cellular origin [15, 16]. Biomarkers of endothelial cell activation such as thrombomodulin activity (TMa) and TF activity (TFa) measured in plasma offer information on the status of the endothelial cells at the vasculature.…”