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Published in: International Journal of Hematology 5/2017

01-11-2017 | Original Article

Elevated plasma levels of procoagulant microparticles are a novel risk factor for thrombosis in patients with myeloproliferative neoplasms

Authors: Yasuhiro Taniguchi, Hirokazu Tanaka, Espinoza J. Luis, Kazuko Sakai, Takahiro Kumode, Keigo Sano, Kentarou Serizawa, Shinya Rai, Yasuyoshi Morita, Hitoshi Hanamoto, Kazuo Tsubaki, Kazuto Nishio, Itaru Matsumura

Published in: International Journal of Hematology | Issue 5/2017

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Abstract

Myeloproliferative neoplasms (MPNs), including polycythemia vera and essential thrombocythemia, are frequently associated with thrombotic complications. Prevention of thrombotic events is thus a primary aim of the current treatment for these disorders. Although it is known that microparticles (MPs), which are small vesicles released from cell membranes and circulate in the blood, directly contribute to thrombosis via their procoagulant activity, potential associations between plasma levels of MPs and the risk of thrombotic events in MPNs have not been reported. In the present study, we characterized plasma levels of MPs and assessed their potential association with the occurrence of thrombotic events in 59 patients with MPNs. Plasma levels of procoagulant MPs expressing tissue factor (TF+ MPs) were significantly higher in patients suffering thrombotic events than in patients without such events (median/μl plasma: 33.8 vs 47.2, p = 0.02). Among patients who developed thrombotic events, irrespective of patients’ blood counts, TF+ MP were significantly higher in patients without cytoreductive therapy than in those receiving cytoreductive therapy (101.2 vs. 42.5, p < 0.001). These results suggest that elevated levels of TF+ MP may be considered as a novel surrogate marker for thrombotic events in MPN patients. Further studies are needed to clarify the mechanism involved.
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Literature
1.
go back to reference Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, Bloomfield CD, Cazzola M, Vardiman JW. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391–405.CrossRefPubMed Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, Bloomfield CD, Cazzola M, Vardiman JW. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391–405.CrossRefPubMed
2.
go back to reference Schnittger S, Bacher U, Haferlach C, Geer T, Müller P, Mittermüller J, Petrides P, Schlag R, Sandner R, Selbach J, et al. Detection of JAK2 exon 12 mutations in 15 patients with JAK2V617F negative polycythemia vera. Haematologica. 2009;94(3):414–8.CrossRefPubMedPubMedCentral Schnittger S, Bacher U, Haferlach C, Geer T, Müller P, Mittermüller J, Petrides P, Schlag R, Sandner R, Selbach J, et al. Detection of JAK2 exon 12 mutations in 15 patients with JAK2V617F negative polycythemia vera. Haematologica. 2009;94(3):414–8.CrossRefPubMedPubMedCentral
3.
go back to reference Milosevic JD, Kralovics R. Genetic and epigenetic alterations of myeloproliferative disorders. Int J Hematol. 2013;97(2):183–97.CrossRefPubMed Milosevic JD, Kralovics R. Genetic and epigenetic alterations of myeloproliferative disorders. Int J Hematol. 2013;97(2):183–97.CrossRefPubMed
4.
go back to reference Nangalia J, Massie CE, Baxter EJ, Nice FL, Gundem G, Wedge DC, Avezov E, Li J, Kollmann K, Kent DG, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013;369(25):2391–405.CrossRefPubMedPubMedCentral Nangalia J, Massie CE, Baxter EJ, Nice FL, Gundem G, Wedge DC, Avezov E, Li J, Kollmann K, Kent DG, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013;369(25):2391–405.CrossRefPubMedPubMedCentral
5.
go back to reference Imai M, Araki M, Komatsu N. Somatic mutations of calreticulin in myeloproliferative neoplasms. Int J Hematol. 2017;105(6):743–7.CrossRefPubMed Imai M, Araki M, Komatsu N. Somatic mutations of calreticulin in myeloproliferative neoplasms. Int J Hematol. 2017;105(6):743–7.CrossRefPubMed
6.
go back to reference Ma W, Zhang X, Wang X, Zhang Z, Yeh CH, Uyeji J, Albitar M. MPL mutation profile in JAK2 mutation-negative patients with myeloproliferative disorders. Diagn Mol Pathol. 2011;20(1):34–9.CrossRefPubMed Ma W, Zhang X, Wang X, Zhang Z, Yeh CH, Uyeji J, Albitar M. MPL mutation profile in JAK2 mutation-negative patients with myeloproliferative disorders. Diagn Mol Pathol. 2011;20(1):34–9.CrossRefPubMed
7.
go back to reference Kim SY, Im K, Park SN, Kwon J, Kim JA, Lee DS. CALR, JAK2, and MPL mutation profiles in patients with four different subtypes of myeloproliferative neoplasms: primary myelofibrosis, essential thrombocythemia, polycythemia vera, and myeloproliferative neoplasm, unclassifiable. Am J Clin Pathol. 2015;143(5):635–44.CrossRefPubMed Kim SY, Im K, Park SN, Kwon J, Kim JA, Lee DS. CALR, JAK2, and MPL mutation profiles in patients with four different subtypes of myeloproliferative neoplasms: primary myelofibrosis, essential thrombocythemia, polycythemia vera, and myeloproliferative neoplasm, unclassifiable. Am J Clin Pathol. 2015;143(5):635–44.CrossRefPubMed
8.
go back to reference Casini A, Fontana P, Lecompte TP. Thrombotic complications of myeloproliferative neoplasms: risk assessment and risk-guided management. J Thromb Haemost. 2013;11(7):1215–27.CrossRefPubMed Casini A, Fontana P, Lecompte TP. Thrombotic complications of myeloproliferative neoplasms: risk assessment and risk-guided management. J Thromb Haemost. 2013;11(7):1215–27.CrossRefPubMed
9.
go back to reference Barbui T. How to manage thrombosis in myeloproliferative neoplasms. Curr Opin Oncol. 2011;23(6):654–8.CrossRefPubMed Barbui T. How to manage thrombosis in myeloproliferative neoplasms. Curr Opin Oncol. 2011;23(6):654–8.CrossRefPubMed
10.
go back to reference Barbui T, Finazzi G, Carobbio A, Thiele J, Passamonti F, Rumi E, Ruggeri M, Rodeghiero F, Randi ML, Bertozzi I, et al. Development and validation of an International Prognostic Score of thrombosis in World Health Organization-essential thrombocythemia (IPSET-thrombosis). Blood. 2012;120(26):5128–33 (quiz 5252).CrossRefPubMed Barbui T, Finazzi G, Carobbio A, Thiele J, Passamonti F, Rumi E, Ruggeri M, Rodeghiero F, Randi ML, Bertozzi I, et al. Development and validation of an International Prognostic Score of thrombosis in World Health Organization-essential thrombocythemia (IPSET-thrombosis). Blood. 2012;120(26):5128–33 (quiz 5252).CrossRefPubMed
11.
go back to reference Carobbio A, Thiele J, Passamonti F, Rumi E, Ruggeri M, Rodeghiero F, Randi ML, Bertozzi I, Vannucchi AM, Antonioli E, et al. Risk factors for arterial and venous thrombosis in WHO-defined essential thrombocythemia: an international study of 891 patients. Blood. 2011;117(22):5857–9.CrossRefPubMed Carobbio A, Thiele J, Passamonti F, Rumi E, Ruggeri M, Rodeghiero F, Randi ML, Bertozzi I, Vannucchi AM, Antonioli E, et al. Risk factors for arterial and venous thrombosis in WHO-defined essential thrombocythemia: an international study of 891 patients. Blood. 2011;117(22):5857–9.CrossRefPubMed
12.
go back to reference Görtzen J, Hunka LM, Vonnahme M, Praktiknjo M, Kaifie A, Fimmers R, Jansen C, Heine A, Lehmann J, Goethert JR, et al. γ-Glutamyl transferase is an independent biomarker of splanchnic thrombosis in patients with myeloproliferative neoplasm. Medicine (Baltimore). 2016;95(20):e3355.CrossRef Görtzen J, Hunka LM, Vonnahme M, Praktiknjo M, Kaifie A, Fimmers R, Jansen C, Heine A, Lehmann J, Goethert JR, et al. γ-Glutamyl transferase is an independent biomarker of splanchnic thrombosis in patients with myeloproliferative neoplasm. Medicine (Baltimore). 2016;95(20):e3355.CrossRef
13.
go back to reference Barbui T, Thiele J, Passamonti F, Rumi E, Boveri E, Ruggeri M, Rodeghiero F, d’Amore ES, Randi ML, Bertozzi I, et al. Survival and disease progression in essential thrombocythemia are significantly influenced by accurate morphologic diagnosis: an international study. J Clin Oncol. 2011;29(23):3179–84.CrossRefPubMed Barbui T, Thiele J, Passamonti F, Rumi E, Boveri E, Ruggeri M, Rodeghiero F, d’Amore ES, Randi ML, Bertozzi I, et al. Survival and disease progression in essential thrombocythemia are significantly influenced by accurate morphologic diagnosis: an international study. J Clin Oncol. 2011;29(23):3179–84.CrossRefPubMed
14.
go back to reference Rumi E, Pietra D, Ferretti V, Klampfl T, Harutyunyan AS, Milosevic JD, Them NC, Berg T, Elena C, Casetti IC, et al. JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes. Blood. 2014;123(10):1544–51.CrossRefPubMedPubMedCentral Rumi E, Pietra D, Ferretti V, Klampfl T, Harutyunyan AS, Milosevic JD, Them NC, Berg T, Elena C, Casetti IC, et al. JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes. Blood. 2014;123(10):1544–51.CrossRefPubMedPubMedCentral
15.
16.
17.
go back to reference Lacroix R, Dubois C, Leroyer AS, Sabatier F, Dignat-George F. Revisited role of microparticles in arterial and venous thrombosis. J Thromb Haemost. 2013;11(Suppl 1):24–35.CrossRefPubMed Lacroix R, Dubois C, Leroyer AS, Sabatier F, Dignat-George F. Revisited role of microparticles in arterial and venous thrombosis. J Thromb Haemost. 2013;11(Suppl 1):24–35.CrossRefPubMed
19.
go back to reference Trappenburg MC, van Schilfgaarde M, Marchetti M, Spronk HM, ten Cate H, Leyte A, Terpstra WE, Falanga A. Elevated procoagulant microparticles expressing endothelial and platelet markers in essential thrombocythemia. Haematologica. 2009;94(7):911–8.CrossRefPubMedPubMedCentral Trappenburg MC, van Schilfgaarde M, Marchetti M, Spronk HM, ten Cate H, Leyte A, Terpstra WE, Falanga A. Elevated procoagulant microparticles expressing endothelial and platelet markers in essential thrombocythemia. Haematologica. 2009;94(7):911–8.CrossRefPubMedPubMedCentral
20.
go back to reference Kissova J, Ovesna P, Bulikova A, Zavřelova J, Penka M. Increasing procoagulant activity of circulating microparticles in patients with Philadelphia-negative myeloproliferative neoplasms: a single-centre experience. Blood Coagul Fibrinolysis. 2015;26(4):448–53.CrossRefPubMed Kissova J, Ovesna P, Bulikova A, Zavřelova J, Penka M. Increasing procoagulant activity of circulating microparticles in patients with Philadelphia-negative myeloproliferative neoplasms: a single-centre experience. Blood Coagul Fibrinolysis. 2015;26(4):448–53.CrossRefPubMed
21.
go back to reference Dey-Hazra E, Hertel B, Kirsch T, Woywodt A, Lovric S, Haller H, Haubitz M, Erdbruegger U. Detection of circulating microparticles by flow cytometry: influence of centrifugation, filtration of buffer, and freezing. Vasc Health Risk Manag. 2010;6:1125–33.PubMedPubMedCentral Dey-Hazra E, Hertel B, Kirsch T, Woywodt A, Lovric S, Haller H, Haubitz M, Erdbruegger U. Detection of circulating microparticles by flow cytometry: influence of centrifugation, filtration of buffer, and freezing. Vasc Health Risk Manag. 2010;6:1125–33.PubMedPubMedCentral
22.
go back to reference Hemker HC, Al Dieri R, De Smedt E, Béguin S. Thrombin generation, a function test of the haemostatic-thrombotic system. Thromb Haemost. 2006;96(5):553–61.PubMed Hemker HC, Al Dieri R, De Smedt E, Béguin S. Thrombin generation, a function test of the haemostatic-thrombotic system. Thromb Haemost. 2006;96(5):553–61.PubMed
23.
go back to reference Zubairova LD, Nabiullina RM, Nagaswami C, Zuev YF, Mustafin IG, Litvinov RI, Weisel JW. Circulating microparticles alter formation, structure, and properties of fibrin clots. Sci Rep. 2015;5:17611.CrossRefPubMedPubMedCentral Zubairova LD, Nabiullina RM, Nagaswami C, Zuev YF, Mustafin IG, Litvinov RI, Weisel JW. Circulating microparticles alter formation, structure, and properties of fibrin clots. Sci Rep. 2015;5:17611.CrossRefPubMedPubMedCentral
24.
go back to reference Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48(3):452–8.CrossRefPubMed Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48(3):452–8.CrossRefPubMed
25.
go back to reference Price GL, Davis KL, Karve S, Pohl G, Walgren RA. Survival patterns in United States (US) medicare enrollees with non-CML myeloproliferative neoplasms (MPN). PLoS One 2014;9(3):e90299.CrossRefPubMedPubMedCentral Price GL, Davis KL, Karve S, Pohl G, Walgren RA. Survival patterns in United States (US) medicare enrollees with non-CML myeloproliferative neoplasms (MPN). PLoS One 2014;9(3):e90299.CrossRefPubMedPubMedCentral
26.
go back to reference Hultcrantz M, Wilkes SR, Kristinsson SY, Andersson TM, Derolf Å, Eloranta S, Samuelsson J, Landgren O, Dickman PW, Lambert PC et al. Risk and Cause of Death in Patients Diagnosed With Myeloproliferative Neoplasms in Sweden Between 1973 and 2005: A Population-Based Study. J Clin Oncol. 2015;33(20):2288–95.CrossRefPubMed Hultcrantz M, Wilkes SR, Kristinsson SY, Andersson TM, Derolf Å, Eloranta S, Samuelsson J, Landgren O, Dickman PW, Lambert PC et al. Risk and Cause of Death in Patients Diagnosed With Myeloproliferative Neoplasms in Sweden Between 1973 and 2005: A Population-Based Study. J Clin Oncol. 2015;33(20):2288–95.CrossRefPubMed
27.
go back to reference Borowczyk M, Wojtaszewska M, Lewandowski K, Gil L, Lewandowska M, Lehmann-Kopydłowska A, Kroll-Balcerzak R, Balcerzak A, Iwoła M, Michalak M et al. The JAK2 V617F mutational status and allele burden may be related with the risk of venous thromboembolic events in patients with Philadelphia-negative myeloproliferative neoplasms. Thromb Res. 2015;135(2):272–80.CrossRefPubMed Borowczyk M, Wojtaszewska M, Lewandowski K, Gil L, Lewandowska M, Lehmann-Kopydłowska A, Kroll-Balcerzak R, Balcerzak A, Iwoła M, Michalak M et al. The JAK2 V617F mutational status and allele burden may be related with the risk of venous thromboembolic events in patients with Philadelphia-negative myeloproliferative neoplasms. Thromb Res. 2015;135(2):272–80.CrossRefPubMed
28.
go back to reference Tefferi A. Myeloproliferative neoplasms: a decade of discoveries and treatment advances. Am J Hematol. 2016;91(1):50–8.CrossRefPubMed Tefferi A. Myeloproliferative neoplasms: a decade of discoveries and treatment advances. Am J Hematol. 2016;91(1):50–8.CrossRefPubMed
29.
go back to reference Falchi L, Bose P, Newberry KJ, et al. Approach to patients with essential thrombocythaemia and very high platelet counts: what is the evidence for treatment? Br J Haematol. 2017;176(3):352–64.CrossRefPubMed Falchi L, Bose P, Newberry KJ, et al. Approach to patients with essential thrombocythaemia and very high platelet counts: what is the evidence for treatment? Br J Haematol. 2017;176(3):352–64.CrossRefPubMed
30.
go back to reference Mallat Z, Benamer H, Hugel B, Benessiano J, Steg PG, Freyssinet JM, Tedgui A. Elevated levels of shed membrane microparticles with procoagulant potential in the peripheral circulating blood of patients with acute coronary syndromes. Circulation 2000;101(8):841–43.CrossRefPubMed Mallat Z, Benamer H, Hugel B, Benessiano J, Steg PG, Freyssinet JM, Tedgui A. Elevated levels of shed membrane microparticles with procoagulant potential in the peripheral circulating blood of patients with acute coronary syndromes. Circulation 2000;101(8):841–43.CrossRefPubMed
31.
go back to reference Morel O, Hugel B, Jesel L, Lanza F, Douchet MP, Zupan M, Chauvin M, Cazenave JP, Freyssinet JM, Toti F. Sustained elevated amounts of circulating procoagulant membrane microparticles and soluble GPV after acute myocardial infarction in diabetes mellitus. Thromb Haemost. 2004; 91(2):345–53.PubMed Morel O, Hugel B, Jesel L, Lanza F, Douchet MP, Zupan M, Chauvin M, Cazenave JP, Freyssinet JM, Toti F. Sustained elevated amounts of circulating procoagulant membrane microparticles and soluble GPV after acute myocardial infarction in diabetes mellitus. Thromb Haemost. 2004; 91(2):345–53.PubMed
32.
go back to reference Bharthuar A, Khorana AA, Hutson A, Wang JG, Key NS, Mackman N, Iyer RV. Circulating microparticle tissue factor, thromboembolism and survival in pancreaticobiliary cancers. Thromb Res. 2013;132(2):180–4.CrossRefPubMed Bharthuar A, Khorana AA, Hutson A, Wang JG, Key NS, Mackman N, Iyer RV. Circulating microparticle tissue factor, thromboembolism and survival in pancreaticobiliary cancers. Thromb Res. 2013;132(2):180–4.CrossRefPubMed
33.
go back to reference Tan X, Shi J, Fu Y, Gao C, Yang X, Li J, Wang W, Hou J, Li H, Zhou J. Role of erythrocytes and platelets in the hypercoagulable status in polycythemia vera through phosphatidylserine exposure and microparticle generation. Thromb Haemost. 2013;109(6):1025–32.CrossRefPubMed Tan X, Shi J, Fu Y, Gao C, Yang X, Li J, Wang W, Hou J, Li H, Zhou J. Role of erythrocytes and platelets in the hypercoagulable status in polycythemia vera through phosphatidylserine exposure and microparticle generation. Thromb Haemost. 2013;109(6):1025–32.CrossRefPubMed
34.
go back to reference Bellucci S, Legrand C, Boval B, Drouet L, Caen J. Studies of platelet volume, chemistry and function in patients with essential thrombocythaemia treated with Anagrelide. Br J Haematol. 1999;104(4):886–92.CrossRefPubMed Bellucci S, Legrand C, Boval B, Drouet L, Caen J. Studies of platelet volume, chemistry and function in patients with essential thrombocythaemia treated with Anagrelide. Br J Haematol. 1999;104(4):886–92.CrossRefPubMed
35.
go back to reference Cacciola RR, Francesco ED, Giustolisi R, Cacciola E. Effects of anagrelide on platelet factor 4 and vascular endothelial growth factor levels in patients with essential thrombocythemia. Br J Haematol. 2004;126(6):885–6.CrossRefPubMed Cacciola RR, Francesco ED, Giustolisi R, Cacciola E. Effects of anagrelide on platelet factor 4 and vascular endothelial growth factor levels in patients with essential thrombocythemia. Br J Haematol. 2004;126(6):885–6.CrossRefPubMed
Metadata
Title
Elevated plasma levels of procoagulant microparticles are a novel risk factor for thrombosis in patients with myeloproliferative neoplasms
Authors
Yasuhiro Taniguchi
Hirokazu Tanaka
Espinoza J. Luis
Kazuko Sakai
Takahiro Kumode
Keigo Sano
Kentarou Serizawa
Shinya Rai
Yasuyoshi Morita
Hitoshi Hanamoto
Kazuo Tsubaki
Kazuto Nishio
Itaru Matsumura
Publication date
01-11-2017
Publisher
Springer Japan
Published in
International Journal of Hematology / Issue 5/2017
Print ISSN: 0925-5710
Electronic ISSN: 1865-3774
DOI
https://doi.org/10.1007/s12185-017-2302-5

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