Ihosvany Fernández Bello

Factors Involved in Maintaining Haemostasis in Patients with Myelodysplastic Syndrome

Etiopathogenesis of myelodysplastic syndrome (MDS) might cause per se an anomalous haemostasis that can be even more deteriorated by thrombocytopaenia. So, evaluation of haemostasis in patients with MDS rises as a necessity.This work aimed to characterize haemostasis in non-bleeder MDS patients with a platelet count similar to healthy controls to establish differences between the two groups not related to thrombocytopaenia.Thromboelastometry in samples from MDS patients suggested the existence of at least two antagonistic processes: one of them giving a hypocoagulable pattern (prolonged clotting time and lower α angle) and another conferring a procoagulant profile (decreased fibrinolysis). Hypocoagulable state might be due to a decreased ability of platelets to be stimulated and to the presence in plasma of a factor/s that prolonged the time to initiate thrombin generation. This factor/s might be antibodies as this effect was observed in samples from MDS patients with an associated autoimmune-inflammatory condition.Otherwise, hypercoagulable state seemed to rely on an increased presence of red cell- and monocyte-derived microparticles and to the increased exposure of phosphatidylserine that served as scaffold for binding of coagulation factors.We concluded that haemostasis in MDS patients is a complex process influenced by more factors than platelet count.

Immune thrombocytopenia – in defence of the platelet count. Response to Hill

Alvarez-Roman, M.T., Fernandez-Bello, I., Jimenez-Yuste, V., Martin-Salces, M., Arias-Salgado, E.G., Rivas Pollmar, M.I., Justo Sanz, R. & Butta, N.V. (2016) Procoagulant profile in patients with immune thrombocytopenia. British Journal of Haematology, 175, 925–934. Cohen, Y.C., Djulbegovic, B., Shamai-Lubovitz, O. & Mozes, B. (2000) The bleeding risk and natural history of idiopathic thrombocytopenic purpura in patients with persistent low platelet counts. Archives of Internal Medicine, 160, 1630– 1638. Greene, L.A., Chen, S., Seery, C., Imahiyerobo, A.M. & Bussel, J.B. (2014) Beyond the platelet count: immature platelet fraction and thromboelastometry correlate with bleeding in patients with immune thrombocytopenia. British Journal of Haematology, 166, 592–600. Neunert, C.E. (2013) Individualized treatment for immune thrombocytopenia: predicting bleeding risk. Seminars in Hematology, 50, S55–S57. Neunert, C., Lim, W., Crowther, M., Cohen, A., Solberg, L. Jr & Crowther, M.A.; American Society of Hematology. (2011) The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood, 117, 4190–4207. Norgaard, M., Jensen, A.O., Engebjerg, M.C., Farkas, D.K., Thomsen, R.W., Cha, S., Zhao, S. & Sorensen, H.T. (2011) Long-term clinical outcomes of patients with primary chronic immune thrombocytopenia: a Danish population-based cohort study. Blood, 117, 3514–3520. Perneger, T.V. & Agoritsas, T. (2011) Doctors and patients’ susceptibility to framing bias: a randomized trial. Journal of General Internal Medicine, 26, 1411–1417. Portielje, J.E., Westendorp, R.G., Kluin-Nelemans, H.C. & Brand, A. (2001) Morbidity and mortality in adults with idiopathic thrombocytopenic purpura. Blood, 97, 2549–2554. Rodeghiero, F. (2016) Is ITP a thrombophilic disorder? American Journal of Hematology, 91, 39–45. Stentoft, J. (2016) ITP: from idiopathic purpura to immune thrombocytopenia and back. British Journal of Haematology, 175, 755–756.

Effect of thrombopoietin-receptor agonists on a proliferation-inducing ligand (APRIL) plasma levels in patients with immune thrombocytopaenia

Immune thrombocytopaenia (ITP) is an antibody-mediated autoimmune disease characterized by accelerated platelet destruction and suboptimal platelet production. Patients with ITP have increased plasma levels of a proliferation-inducing ligand (APRIL), a factor that can promote B-cell maturation and survival 1. Two thrombopoietin-receptor agonists [TPO-RA; romiplostim (Nplate®; Amgen, Thousand Oaks, CA, USA) and eltrombopag (Promacta®, Revolade®; GlaxoSmithKline, London, UK)] have recently been approved for the treatment of chronic ITP. They both bind to the thrombopoietin receptor (TPO-R) and activate megakaryopoiesis. We aimed to investigate whether TPO-RA treatment of patients with ITP had any effect on APRIL plasma levels and to compare these results with those observed in ITP patients treated with intravenous immunoglobulins (IVIg). Two groups of chronic ITP patients were included; one group (n = 13) was treated with a TPO-RA (two with romiplostin and 11 with eltrombopag, 46% female; mean age, 63 years) and the other group (n = 17) was treated with IVIg (82% female; mean age, 70 years). The ITP patients were studied before and after responding to therapy, defined as a platelet count ≥30 × 109 l−1 and at least twofold increase over the baseline count. Fiveteen patients with myelodysplastic syndromes who presented thrombocytopaenia (40% female; mean age, 75 years) and 35 healthy control subjects (56% female; mean age, 51 years) were also included for comparison. This study was performed in accordance with the policy of the local Ethics Committee. Blood samples were collected in EDTA. The APRIL concentration was measured by an enzyme-linked immunosorbent assay (R&D Systems, Minneapolis, MN, USA) in platelet-poor plasma. The platelet count of patients with ITP before treatment and of patients with myelodysplastic syndromes were lower than those in the control group (P < 0.001). After responding to the treatments, ITP patients had increased platelet counts (Figure ​(Figure1A1A). Figure 1 (A) Platelet count. (B) Plasma APRIL levels (C) Correlation between a proliferation inducing ligand (APRIL) plasma levels and platelet count. The Wilcoxon matched-pairs signed-ranks test was performed to compare data of patients with immune thrombocytopaenia ... All patients with ITP and thrombocytopaenia showed higher APRIL plasma levels than the control group (P < 0.01, Figure ​Figure1B),1B), which was inversely correlated with platelet count (Figure ​(Figure1C). This1C). This observation supports the proposed pathogenic role of APRIL in the development of this disease 2. Moreover, plasma APRIL levels in ITP patients were also higher than in the myelodysplastic syndrome patients (P < 0.01, Figure ​Figure1B),1B), which suggested that increased APRIL levels were not due to thrombocytopaenia but rather to the mechanism that caused the disease. Plasma levels of APRIL were reduced to control values in patients with ITP who responded to TPO-RA treatment, whereas they remained high after response to IVIg (Figure ​(Figure1B1B). Gu et al. 3 reported normal APRIL plasma levels in patients with ITP with normal platelet counts who had undergone splenectomy or been treated with corticosteroids. In our TPO-RA-treated group, only two of the patients were splenectomized and one was receiving concomitant corticosteroid treatment, so the reduced APRIL levels might be due to another cause. A beneficial effect of TPO-RA treatment on the immune system has been reported 4. Transforming growth factor-β1, an anti-inflammatory cytokine that inhibits B-cell proliferation and antibody production 5, was increased in patients with ITP who responded to TPO-RA treatment. It is therefore tempting to speculate that TPO-RAs possess immunomodulatory activity in addition to their profound effect on megakaryopoiesis. This possibility gives value to this study, despite the small size of the groups included, and gives support to the necessity of performing a study with more patients to elucidate the mechanism involved in the reduction of APRIL levels caused by TPO-RAs.