Thromb Haemost 2018; 118(04): 734-744
DOI: 10.1055/s-0038-1637733
Cellular Haemostasis and Platelets
Schattauer GmbH Stuttgart

Factors Involved in Maintaining Haemostasis in Patients with Myelodysplastic Syndrome

Ihosvany Fernández Bello
1   Hematology and Hemotherapy Unit, University Hospital La Paz, Madrid, Spain
2   Hospital La Paz Institute for Health Research (IdiPaz), Madrid, Spain
,
Víctor Jiménez-Yuste
1   Hematology and Hemotherapy Unit, University Hospital La Paz, Madrid, Spain
2   Hospital La Paz Institute for Health Research (IdiPaz), Madrid, Spain
3   Universidad Autónoma de Madrid, Madrid, Spain
,
Raquel de Paz
1   Hematology and Hemotherapy Unit, University Hospital La Paz, Madrid, Spain
2   Hospital La Paz Institute for Health Research (IdiPaz), Madrid, Spain
,
Mónica Martín Salces
1   Hematology and Hemotherapy Unit, University Hospital La Paz, Madrid, Spain
2   Hospital La Paz Institute for Health Research (IdiPaz), Madrid, Spain
,
Raul Justo Sanz
1   Hematology and Hemotherapy Unit, University Hospital La Paz, Madrid, Spain
2   Hospital La Paz Institute for Health Research (IdiPaz), Madrid, Spain
,
Elena Monzón Manzano
1   Hematology and Hemotherapy Unit, University Hospital La Paz, Madrid, Spain
2   Hospital La Paz Institute for Health Research (IdiPaz), Madrid, Spain
,
Elena G. Arias-Salgado
4   Advanced Medical Projects Madrid, Madrid, Spain
,
María Teresa Álvarez Román
1   Hematology and Hemotherapy Unit, University Hospital La Paz, Madrid, Spain
2   Hospital La Paz Institute for Health Research (IdiPaz), Madrid, Spain
,
María Isabel Rivas Pollmar
1   Hematology and Hemotherapy Unit, University Hospital La Paz, Madrid, Spain
2   Hospital La Paz Institute for Health Research (IdiPaz), Madrid, Spain
,
Isabel Goyanes
1   Hematology and Hemotherapy Unit, University Hospital La Paz, Madrid, Spain
,
Nora V. Butta
1   Hematology and Hemotherapy Unit, University Hospital La Paz, Madrid, Spain
2   Hospital La Paz Institute for Health Research (IdiPaz), Madrid, Spain
› Author Affiliations
Further Information

Publication History

10 August 2017

26 January 2018

Publication Date:
19 March 2018 (online)

Abstract

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.

Note

This work was supported by grants from the FIS-FONDOS FEDER (PI15/01457, N.V.B.). NVB holds a Miguel Servet II tenure track grant from FIS-FONDOS FEDER (CP14/00024).


Authors' Contribution

I.F.B., R.J.S., E.M.M. and E.G.A-S. performed the experiments. R.d.P., M.T.A.R., M.M.S., M.I.R.P. and V.J-Y. diagnosed and provided clinical care to MDS patients. I.G. collected and verified patient information. I.F.B., R.d.P., V.J-Y. and N.V.B. analysed the results. N.V.B. was the principal investigator, designed the experiments and wrote the manuscript. All authors approved the manuscript.


 
  • References

  • 1 Bejar R, Stevenson K, Abdel-Wahab O. , et al. Clinical effect of point mutations in myelodysplastic syndromes. N Engl J Med 2011; 364 (26) 2496-2506
  • 2 Matarraz S, López A, Barrena S. , et al. The immunophenotype of different immature, myeloid and B-cell lineage-committed CD34+ hematopoietic cells allows discrimination between normal/reactive and myelodysplastic syndrome precursors. Leukemia 2008; 22 (06) 1175-1183
  • 3 Lorand-Metze I, Ribeiro E, Lima CS, Batista LS, Metze K. Detection of hematopoietic maturation abnormalities by flow cytometry in myelodysplastic syndromes and its utility for the differential diagnosis with non-clonal disorders. Leuk Res 2007; 31 (02) 147-155
  • 4 Giannouli S, Voulgarelis M. A comprehensive review of myelodysplastic syndrome patients with autoimmune diseases. Expert Rev Clin Immunol 2014; 10 (12) 1679-1688
  • 5 Martín M, de Paz R, Jiménez-Yuste V. , et al. Platelet apoptosis and agonist-mediated activation in myelodysplastic syndromes. Thromb Haemost 2013; 109 (05) 909-919
  • 6 Hofmann WK, Koeffler HP. Myelodysplastic syndrome. Annu Rev Med 2005; 56: 1-16
  • 7 Nachtkamp K, Stark R, Strupp C. , et al. Causes of death in 2877 patients with myelodysplastic syndromes. Ann Hematol 2016; 95 (06) 937-944
  • 8 Alessandrino EP, Amadori S, Barosi G. , et al; Italian Society of Hematology. Evidence- and consensus-based practice guidelines for the therapy of primary myelodysplastic syndromes. A statement from the Italian Society of Hematology. Haematologica 2002; 87 (12) 1286-1306
  • 9 Shin KH, Kim IS, Lee HJ. , et al. Thromboelastographic evaluation of coagulation in patients with liver disease. Ann Lab Med 2017; 37 (03) 204-212
  • 10 Álvarez-Román MT, Fernández-Bello I, Jiménez-Yuste V. , et al. Procoagulant profile in patients with immune thrombocytopenia. Br J Haematol 2016; 175 (05) 925-934
  • 11 Harrison P, Lordkipanidzé M. Testing platelet function. Hematol Oncol Clin North Am 2013; 27 (03) 411-441
  • 12 Lacroix R, Judicone C, Poncelet P. , et al. Impact of pre-analytical parameters on the measurement of circulating microparticles: towards standardization of protocol. J Thromb Haemost 2012; 10 (03) 437-446
  • 13 Hemker HC, Giesen P, Al Dieri R. , et al. Calibrated automated thrombin generation measurement in clotting plasma. Pathophysiol Haemost Thromb 2003; 33 (01) 4-15
  • 14 Piza FM, Corrêa TD, Marra AR. , et al. Thromboelastometry analysis of thrombocytopenic dengue patients: a cross-sectional study. BMC Infect Dis 2017; 17 (01) 89
  • 15 Lak M, Scharling B, Blemings A. , et al. Evaluation of rFVIIa (NovoSeven) in Glanzmann patients with thromboelastogram. Haemophilia 2008; 14 (01) 103-110
  • 16 Gros A, Ollivier V, Ho-Tin-Noé B. Platelets in inflammation: regulation of leukocyte activities and vascular repair. Front Immunol 2015; 5: 678
  • 17 Psaila B, Bussel JB, Frelinger AL. , et al. Differences in platelet function in patients with acute myeloid leukemia and myelodysplasia compared to equally thrombocytopenic patients with immune thrombocytopenia. J Thromb Haemost 2011; 9 (11) 2302-2310
  • 18 Sandes AF, Yamamoto M, Matarraz S. , et al. Altered immunophenotypic features of peripheral blood platelets in myelodysplastic syndromes. Haematologica 2012; 97 (06) 895-902
  • 19 Fröbel J, Cadeddu RP, Hartwig S. , et al. Platelet proteome analysis reveals integrin-dependent aggregation defects in patients with myelodysplastic syndromes. Mol Cell Proteomics 2013; 12 (05) 1272-1280
  • 20 Vericel E, Croset M, Sedivy P, Courpron P, Dechavanne M, Lagarde M. Platelets and aging. I--Aggregation, arachidonate metabolism and antioxidant status. Thromb Res 1988; 49 (03) 331-342
  • 21 Terres W, Weber K, Kupper W, Bleifeld W. Age, cardiovascular risk factors and coronary heart disease as determinants of platelet function in men. A multivariate approach. Thromb Res 1991; 62 (06) 649-661
  • 22 Qiao J, Wu Y, Liu Y. , et al. Busulfan triggers intrinsic mitochondrial-dependent platelet apoptosis independent of platelet activation. Biol Blood Marrow Transplant 2016; 22 (09) 1565-1572
  • 23 Nagata S, Suzuki J, Segawa K, Fujii T. Exposure of phosphatidylserine on the cell surface. Cell Death Differ 2016; 23 (06) 952-961
  • 24 Lhermusier T, Chap H, Payrastre B. Platelet membrane phospholipid asymmetry: from the characterization of a scramblase activity to the identification of an essential protein mutated in Scott syndrome. J Thromb Haemost 2011; 9 (10) 1883-1891
  • 25 Morel O, Toti F, Hugel B. , et al. Procoagulant microparticles: disrupting the vascular homeostasis equation?. Arterioscler Thromb Vasc Biol 2006; 26 (12) 2594-2604
  • 26 Fager AM, Wood JP, Bouchard BA, Feng P, Tracy PB. Properties of procoagulant platelets: defining and characterizing the subpopulation binding a functional prothrombinase. Arterioscler Thromb Vasc Biol 2010; 30 (12) 2400-2407
  • 27 Owens III AP, Mackman N. Microparticles in hemostasis and thrombosis. Circ Res 2011; 108 (10) 1284-1297
  • 28 Diehl P, Fricke A, Sander L. , et al. Microparticles: major transport vehicles for distinct microRNAs in circulation. Cardiovasc Res 2012; 93 (04) 633-644
  • 29 Mackman N, Tilley RE, Key NS. Role of the extrinsic pathway of blood coagulation in hemostasis and thrombosis. Arterioscler Thromb Vasc Biol 2007; 27 (08) 1687-1693
  • 30 Steppich BA, Braun SL, Stein A. , et al. Plasma TF activity predicts cardiovascular mortality in patients with acute myocardial infarction. Thromb J 2009; 7: 11
  • 31 Aleman MM, Gardiner C, Harrison P, Wolberg AS. Differential contributions of monocyte- and platelet-derived microparticles towards thrombin generation and fibrin formation and stability. J Thromb Haemost 2011; 9 (11) 2251-2261
  • 32 Zubairova LD, Nabiullina RM, Nagaswami C. , et al. Circulating microparticles alter formation, structure, and properties of fibrin clots. Sci Rep 2015; 5: 17611
  • 33 Chiva-Blanch G, Laake K, Myhre P. , et al. Platelet-, monocyte-derived and tissue factor-carrying circulating microparticles are related to acute myocardial infarction severity. PLoS One 2017; 12 (02) e0172558
  • 34 Shet AS, Aras O, Gupta K. , et al. Sickle blood contains tissue factor-positive microparticles derived from endothelial cells and monocytes. Blood 2003; 102 (07) 2678-2683
  • 35 Aras O, Shet A, Bach RR. , et al. Induction of microparticle- and cell-associated intravascular tissue factor in human endotoxemia. Blood 2004; 103 (12) 4545-4553
  • 36 Tesselaar ME, Romijn FP, Van Der Linden IK, Prins FA, Bertina RM, Osanto S. Microparticle-associated tissue factor activity: a link between cancer and thrombosis?. J Thromb Haemost 2007; 5 (03) 520-527
  • 37 Selimoglu-Buet D, Wagner-Ballon O, Saada V. , et al; Francophone Myelodysplasia Group. Characteristic repartition of monocyte subsets as a diagnostic signature of chronic myelomonocytic leukemia. Blood 2015; 125 (23) 3618-3626
  • 38 Van Der Meijden PE, Van Schilfgaarde M, Van Oerle R, Renné T, ten Cate H, Spronk HM. Platelet- and erythrocyte-derived microparticles trigger thrombin generation via factor XIIa. J Thromb Haemost 2012; 10 (07) 1355-1362
  • 39 van Beers EJ, Schaap MC, Berckmans RJ. , et al; CURAMA study group. Circulating erythrocyte-derived microparticles are associated with coagulation activation in sickle cell disease. Haematologica 2009; 94 (11) 1513-1519
  • 40 Horne III MK, Cullinane AM, Merryman PK, Hoddeson EK. The effect of red blood cells on thrombin generation. Br J Haematol 2006; 133 (04) 403-408
  • 41 Connor DE, Ma DD, Joseph JE. Flow cytometry demonstrates differences in platelet reactivity and microparticle formation in subjects with thrombocytopenia or thrombocytosis due to primary haematological disorders. Thromb Res 2013; 132 (05) 572-577
  • 42 Wolach O, Stone R. Autoimmunity and inflammation in myelodysplastic syndromes. Acta Haematol 2016; 136 (02) 108-117
  • 43 Gañán-Gómez I, Wei Y, Starczynowski DT. , et al. Deregulation of innate immune and inflammatory signaling in myelodysplastic syndromes. Leukemia 2015; 29 (07) 1458-1469
  • 44 Adès L, Itzykson R, Fenaux P. Myelodysplastic syndromes. Lancet 2014; 383 (9936): 2239-2252
  • 45 Okamoto T, Okada M, Mori A. , et al. Correlation between immunological abnormalities and prognosis in myelodysplastic syndrome patients. Int J Hematol 1997; 66 (03) 345-351
  • 46 Marisavljević D, Kraguljac N, Rolović Z. Immunologic abnormalities in myelodysplastic syndromes: clinical features and characteristics of the lymphoid population. Med Oncol 2006; 23 (03) 385-391
  • 47 Bourgeois E, Caulier MT, Rose C, Dupriez B, Bauters F, Fenaux P. Role of splenectomy in the treatment of myelodysplastic syndromes with peripheral thrombocytopenia: a report on six cases. Leukemia 2001; 15 (06) 950-953
  • 48 van der Helm LH, Alhan C, Wijermans PW. , et al. Platelet doubling after the first azacitidine cycle is a promising predictor for response in myelodysplastic syndromes (MDS), chronic myelomonocytic leukaemia (CMML) and acute myeloid leukaemia (AML) patients in the Dutch azacitidine compassionate named patient programme. Br J Haematol 2011; 155 (05) 599-606
  • 49 Jung HA, Maeng CH, Kim M, Kim S, Jung CW, Jang JH. Platelet response during the second cycle of decitabine treatment predicts response and survival for myelodysplastic syndrome patients. Oncotarget 2015; 6 (18) 16653-16662
  • 50 Adès L, Boehrer S, Prebet T. , et al. Efficacy and safety of lenalidomide in intermediate-2 or high-risk myelodysplastic syndromes with 5q deletion: results of a phase 2 study. Blood 2009; 113 (17) 3947-3952