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Thromb Haemost 2014; 111(04): 570-574
DOI: 10.1160/TH13-10-0812
Theme Issue Article
Schattauer GmbH

New players in haemostasis and thrombosis

Julia E. Geddings
1   Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
,
Nigel Mackman
1   Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
2   UNC McAllister Heart Institute, University of North Carolina, Chapel Hill, North Carolina, USA
3   Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
› Author Affiliations
Further Information

Publication History

Received: 01 October 2013

Accepted after major revision: 10 February 2014

Publication Date:
29 November 2017 (online)

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Summary

The blood coagulation cascade is essential for haemostasis, but excessive activation can cause thrombosis. Importantly, recent studies have identified factors that contribute to thrombosis but not haemostasis. These include factor XII (FXII), tissue factor-positive microparticles (MPs) and neutrophil extracellular traps (NETs). Studies have shown that FXII plays a role in thrombosis but not haemostasis. FXII is activated in vivo by a variety of negatively-charged polyphosphates, which include extracellular RNA, DNA and inorganic polyphosphate (PolyP) that are released during cell damage and infection. These findings have led to the development of nucleic acid-binding polymers as a new class of anticoagulant drug. Other studies have analysed the role of MPs in experimental thrombosis. MPs are small membrane vesicles released from activated or apoptotic cells. We and others have found that tissue factor-positive MPs enhance thrombosis in mouse models and are elevated in the plasma of pancreatic cancer patients. Finally, NETs have been shown to contribute to experimental venous thrombosis in mouse models and are present in human thrombi. NETs are composed of chromatin fibers that are released from neutrophils undergoing cell death. NETs can capture platelets and increase fibrin deposition. The recent advances in our understanding of the factors contributing to thrombosis in animal models provide new opportunities for the development of safer anticoagulant drugs.

Keywords

Coagulation factors - deep-vein thrombosis - arterial thrombosis - microparticles - thrombosis
 

  • References

  • 1 Butenas S, Orfeo T, Mann KG. Tissue factor in coagulation: Which?. Where? When? Arterioscler Thromb Vasc Biol 2009; 29: 1989-1996.
    CrossrefPubMedGoogle Scholar
  • 2 Gailani D, Renne T. Intrinsic pathway of coagulation and arterial thrombosis.. Arterioscler Thromb Vasc Biol 2007; 27: 2507-2513.
    CrossrefPubMedGoogle Scholar
  • 3 Muller F, Gailani D, Renne T. Factor XI and XII as antithrombotic targets.. Current opinion in hematology 2011; 18: 349-355.
    CrossrefPubMedGoogle Scholar
  • 4 Konings J, Govers-Riemslag JW, Philippou H. et al. Factor XIIa regulates the structure of the fibrin clot independently of thrombin generation through direct interaction with fibrin.. Blood 2011; 118: 3942-3951.
    CrossrefPubMedGoogle Scholar
  • 5 Renne T, Pozgajova M, Gruner S. et al. Defective thrombus formation in mice lacking coagulation factor XII.. J Exp Med 2005; 202: 271-281.
    CrossrefPubMedGoogle Scholar
  • 6 Kannemeier C, Shibamiya A, Nakazawa F. et al. Extracellular RNA constitutes a natural procoagulant cofactor in blood coagulation.. Proc Natl Acad Sci USA 2007; 104: 6388-6393.
    CrossrefPubMedGoogle Scholar
  • 7 Muller F, Mutch NJ, Schenk WA. et al. Platelet polyphosphates are proinflam-matory and procoagulant mediators in vivo.. Cell 2009; 139: 1143-1156.
    CrossrefPubMedGoogle Scholar
  • 8 Fuchs TA, Brill A, Wagner DD. Neutrophil extracellular trap (NET) impact on deep vein thrombosis.. Arterioscler Thromb Vasc Biol 2012; 32: 1777-1783.
    CrossrefPubMedGoogle Scholar
  • 9 Kleinschnitz C, Stoll G, Bendszus M. et al. Targeting coagulation factor XII provides protection from pathological thrombosis in cerebral ischemia without interfering with haemostasis.. J Exp Med 2006; 203: 513-518.
    CrossrefPubMedGoogle Scholar
  • 10 Xu Y, Cai TQ, Castriota G. et al. Factor XIIa inhibition by Infestin-4: in vitro mode of action and in vivo antithrombotic benefit.. Thromb Haemost 2014; 111: 694-704.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 Hagedorn I, Schmidbauer S, Pleines I. et al. Factor XIIa inhibitor recombinant human albumin Infestin-4 abolishes occlusive arterial thrombus formation without affecting bleeding.. Circulation 2010; 121: 1510-1517.
    CrossrefPubMedGoogle Scholar
  • 12 Yamashita A, Nishihira K, Kitazawa T. et al. Factor XI contributes to thrombus propagation on injured neointima of the rabbit iliac artery.. J Thromb Haemost 2006; 4: 1496-1501.
    CrossrefPubMedGoogle Scholar
  • 13 Schumacher WA, Seiler SE, Steinbacher TE. et al. Antithrombotic and haemostatic effects of a small molecule factor XIa inhibitor in rats.. Eur J Pharmacol 2007; 570: 167-174.
    CrossrefPubMedGoogle Scholar
  • 14 Tucker EI, Marzec UM, White TC. et al. Prevention of vascular graft occlusion and thrombus-associated thrombin generation by inhibition of factor XI.. Blood 2009; 113: 936-944.
    CrossrefPubMedGoogle Scholar
  • 15 Crosby JR, Marzec U, Revenko AS. et al. Antithrombotic effect of antisense factor XI oligonucleotide treatment in primates.. Arterioscler Thromb Vasc Biol 2013; 33: 1670-1678.
    CrossrefPubMedGoogle Scholar
  • 16 Leung PY, Hurst S, Berny-Lang MA. et al. Inhibition of Factor XII-Mediated Activation of Factor XI Provides Protection Against Experimental Acute Ischemic Stroke in Mice.. Translat Stroke Res 2012; 3: 381-389.
    CrossrefPubMedGoogle Scholar
  • 17 Lowenberg EC, Meijers JC, Monia BP. et al. Coagulation factor XI as a novel target for antithrombotic treatment.. J Thromb Haemost 2010; 8: 2349-2357.
    CrossrefPubMedGoogle Scholar
  • 18 Zhang H, Lowenberg EC, Crosby JR. et al. Inhibition of the intrinsic coagulation pathway factor XI by antisense oligonucleotides: a novel antithrombotic strategy with lowered bleeding risk.. Blood 2010; 116: 4684-4692.
    CrossrefPubMedGoogle Scholar
  • 19 Morrissey JH, Choi SH, Smith SA. Polyphosphate: an ancient molecule that links platelets, coagulation, and inflammation.. Blood 2012; 119: 5972-5979.
    CrossrefPubMedGoogle Scholar
  • 20 Smith SA, Mutch NJ, Baskar D. et al. Polyphosphate modulates blood coagulation and fibrinolysis.. Proc Natl Acad Sci USA 2006; 103: 903-908.
    CrossrefPubMedGoogle Scholar
  • 21 Smith SA, Morrissey JH. Polyphosphate enhances fibrin clot structure.. Blood 2008; 112: 2810-2816.
    CrossrefPubMedGoogle Scholar
  • 22 Smith SA, Choi SH, Davis-Harrison R. et al. Polyphosphate exerts differential effects on blood clotting, depending on polymer size.. Blood 2010; 116: 4353-4359.
    CrossrefPubMedGoogle Scholar
  • 23 Smith SA, Morrissey JH. Polyphosphate as a general procoagulant agent.. J Thromb Haemost 2008; 6: 1750-1756.
    CrossrefPubMedGoogle Scholar
  • 24 Choi SH, Smith SA, Morrissey JH. Polyphosphate is a cofactor for the activation of factor XI by thrombin.. Blood 2011; 118: 6963-6970.
    CrossrefPubMedGoogle Scholar
  • 25 Faxalv L, Boknas N, Strom JO. et al. Putting polyphosphates to the test: evidence against platelet-induced activation of factor XII.. Blood 2013; 29: 29.
    PubMedGoogle Scholar
  • 26 Nickel KF, Spronk HM, Mutch NJ. et al. Time-dependent degradation and tissue factor addition mask the ability of platelet polyphosphates in activating factor XII-mediated coagulation.. Blood 2013; 122: 3847-3849.
    CrossrefPubMedGoogle Scholar
  • 27 Morrissey JH. S.A.S. Comment on Fzxalv. et al. “Putting polyphosphates to the test: evidence against platelet-induced activation of factor XII”.. Blood. 2013 e-Letter online, August 26, 2013.
    PubMedGoogle Scholar
  • 28 Ghosh S, Shukla D, Suman K. et al. Inositol hexakisphosphate kinase 1 maintains haemostasis in mice by regulating platelet polyphosphate levels.. Blood 2013; 122: 1478-1486.
    CrossrefPubMedGoogle Scholar
  • 29 Jain S, Pitoc GA, Holl EK. et al. Nucleic acid scavengers inhibit thrombosis without increasing bleeding.. Proc Natl Acad Sci USA 2012; 109: 12938-12943.
    CrossrefPubMedGoogle Scholar
  • 30 Smith SA, Choi SH, Collins JN. et al. Inhibition of polyphosphate as a novel strategy for preventing thrombosis and inflammation.. Blood 2012; 120: 5103-5110.
    CrossrefPubMedGoogle Scholar
  • 31 Gyorgy B, Szabo TG, Pasztoi M. et al. Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles.. Cell Mol Life Sci 2011; 68: 2667-2688.
    CrossrefPubMedGoogle Scholar
  • 32 D’Souza-Schorey C, Clancy JW. Tumour-derived microvesicles: shedding light on novel microenvironment modulators and prospective cancer biomarkers.. Genes Dev 2012; 26: 1287-1299.
    CrossrefPubMedGoogle Scholar
  • 33 Owens 3rd AP, Mackman N. Microparticles in haemostasis and thrombosis.. Circ Res 2011; 108: 1284-1297.
    CrossrefPubMedGoogle Scholar
  • 34 Wolf P. The nature and significance of platelet products in human plasma.. Br J Haematol 1967; 13: 269-288.
    CrossrefPubMedGoogle Scholar
  • 35 Burnier L, Fontana P, Kwak BR. et al. Cell-derived microparticles in haemostasis and vascular medicine.. Thromb Haemost 2009; 101: 439-451.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 36 Key NS, Mackman N. Tissue factor and its measurement in whole blood, plasma, and microparticles.. Semin Thromb Haemost 2010; 36: 865-875.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 37 Ramacciotti E, Hawley AE, Wrobleski SK. et al. Proteomics of microparticles after deep venous thrombosis.. Thromb Res 2010; 125: e269-274.
    CrossrefPubMedGoogle Scholar
  • 38 Mackman N, Tilley RE, Key NS. Role of the extrinsic pathway of blood coagulation in haemostasis and thrombosis.. Arterioscler Thromb Vasc Biol 2007; 27: 1687-1693.
    CrossrefPubMedGoogle Scholar
  • 39 Mackman N. New insights into the mechanisms of venous thrombosis.. J Clin Invest 2012; 122: 2331-2336.
    CrossrefPubMedGoogle Scholar
  • 40 Aleman MM, Gardiner C, Harrison P. et al. Differential contributions of mono-cyte- and platelet-derived microparticles towards thrombin generation and fibrin formation and stability.. J Thromb Haemost 2011; 9: 2251-2261.
    CrossrefPubMedGoogle Scholar
  • 41 Owens 3rd AP, Mackman N. Tissue factor and thrombosis: The clot starts here.. Thromb Haemost 2010; 104: 432-439.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 42 Mause SF, Weber C. Microparticles: protagonists of a novel communication network for intercellular information exchange.. Circ Res 2010; 107: 1047-1057.
    CrossrefPubMedGoogle Scholar
  • 43 Morrissey JH, Tajkhorshid E, Rienstra CM. Nanoscale studies of protein-membrane interactions in blood clotting.. J Thromb Haemost 2011; 9 (Suppl. 01) 162-167.
    CrossrefPubMedGoogle Scholar
  • 44 Hrachovinova I, Cambien B, Hafezi-Moghadam A. et al. Interaction of P-selectin and PSGL-1 generates microparticles that correct haemostasis in a mouse model of haemophilia A.. Nat Med 2003; 9: 1020-1025.
    CrossrefPubMedGoogle Scholar
  • 45 Jy W, Johansen ME, Bidot Jr C. et al. Red cell-derived microparticles (RMP) as haemostatic agent.. Thromb Haemost 2013; 110: 751-760.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 46 Berckmans RJ, Nieuwland R, Boing AN. et al. Cell-derived microparticles circulate in healthy humans and support low grade thrombin generation.. Thromb Haemost 2001; 85: 639-646.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 47 Biro E, Sturk-Maquelin KN, Vogel GM. et al. Human cell-derived microparticles promote thrombus formation in vivo in a tissue factor-dependent manner.. J Thromb Haemost 2003; 1: 2561-2568.
    CrossrefPubMedGoogle Scholar
  • 48 Thomas GM, Panicot-Dubois L, Lacroix R. et al. Cancer cell-derived micropar-ticles bearing P-selectin glycoprotein ligand 1 accelerate thrombus formation in vivo.. J Exp Med 2009; 206: 1913-1927.
    CrossrefPubMedGoogle Scholar
  • 49 Wang JG, Geddings JE, Aleman MM. et al. Tumour-derived tissue factor activates coagulation and enhances thrombosis in a mouse xenograft model of human pancreatic cancer.. Blood 2012; 119: 5543-5552.
    CrossrefPubMedGoogle Scholar
  • 50 Glynn RJ, Danielson E, Fonseca FA. et al. A randomized trial of rosuvastatin in the prevention of venous thromboembolism.. N Engl J Med 2009; 360: 1851-1861.
    CrossrefPubMedGoogle Scholar
  • 51 Pai M, Evans NS, Shah SJ. et al. Statins in the prevention of venous thromboembolism: a meta-analysis of observational studies.. Thromb Res 2011; 128: 422-430.
    CrossrefPubMedGoogle Scholar
  • 52 Owens 3rd AP, Passam FH, Antoniak S. et al. Monocyte tissue factor-dependent activation of coagulation in hypercholesterolemic mice and monkeys is inhibited by simvastatin.. J Clin Invest 2012; 122: 558-568.
    CrossrefPubMedGoogle Scholar
  • 53 Geddings JE, Mackman N. Tumour-derived tissue factor-positive microparticles and venous thrombosis in cancer patients.. Blood 2013; 122: 1873-1880.
    CrossrefPubMedGoogle Scholar
  • 54 Myers Jr. DD, Rectenwald JE, Bedard PW. et al. Decreased venous thrombosis with an oral inhibitor of P selectin.. J Vasc Surg 2005; 42: 329-336.
    CrossrefPubMedGoogle Scholar
  • 55 Meier TR, Myers Jr. DD, Wrobleski SK. et al. Prophylactic P-selectin inhibition with PSI-421 promotes resolution of venous thrombosis without anticoagu- lation.. Thromb Haemost 2008; 99: 343-351.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 56 Ramacciotti E, Myers Jr. DD, Wrobleski SK. et al. P-selectin/ PSGL-1 inhibitors versus enoxaparin in the resolution of venous thrombosis: a meta-analysis.. Thromb Res 2010; 125: e138-142.
    CrossrefPubMedGoogle Scholar
  • 57 Fuchs TA, Abed U, Goosmann C. et al. Novel cell death program leads to neut-rophil extracellular traps.. J Cell Biol 2007; 176: 231-241.
    CrossrefPubMedGoogle Scholar
  • 58 Brinkmann V, Reichard U, Goosmann C. et al. Neutrophil extracellular traps kill bacteria.. Science 2004; 303: 1532-1535.
    CrossrefPubMedGoogle Scholar
  • 59 Yipp BG, Kubes P. NETosis: how vital is it?. Blood 2013; 5: 5.
    PubMedGoogle Scholar
  • 60 Pilsczek FH, Salina D, Poon KK. et al. A novel mechanism of rapid nuclear neut-rophil extracellular trap formation in response to Staphylococcus aureus.. J Immunol 2010; 185: 7413-7425.
    CrossrefPubMedGoogle Scholar
  • 61 Yipp BG, Petri B, Salina D. et al. Infection-induced NETosis is a dynamic process involving neutrophil multitasking in vivo.. Nat Med 2012; 18: 1386-1393.
    CrossrefPubMedGoogle Scholar
  • 62 Yousefi S, Mihalache C, Kozlowski E. et al. Viable neutrophils release mitochon-drial DNA to form neutrophil extracellular traps.. Cell Death Differ 2009; 16: 1438-1444.
    CrossrefPubMedGoogle Scholar
  • 63 von Bruhl ML, Stark K, Steinhart A. et al. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo.. J Exp Med 2012; 209: 819-835.
    CrossrefPubMedGoogle Scholar
  • 64 Fuchs TA, Brill A, Duerschmied D. et al. Extracellular DNA traps promote thrombosis.. Proc Natl Acad Sci USA 2010; 107: 15880-15885.
    CrossrefPubMedGoogle Scholar
  • 65 Fuchs TA, Bhandari AA, Wagner DD. Histones induce rapid and profound thrombocytopenia in mice.. Blood 2011; 118: 3708-3714.
    CrossrefPubMedGoogle Scholar
  • 66 Massberg S, Grahl L, von Bruehl ML. et al. Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases.. Nat Med 2010; 16: 887-896.
    CrossrefPubMedGoogle Scholar
  • 67 Martinod K, Demers M, Fuchs TA. et al. Neutrophil histone modification by peptidylarginine deiminase 4 is critical for deep vein thrombosis in mice.. Proc Natl Acad Sci USA 2013; 110: 8674-8679.
    CrossrefPubMedGoogle Scholar
  • 68 Brill A, Fuchs TA, Savchenko AS. et al. Neutrophil extracellular traps promote deep vein thrombosis in mice.. J Thromb Haemost 2012; 10: 136-144.
    CrossrefPubMedGoogle Scholar
  • 69 Saffarzadeh M, Juenemann C, Queisser MA. et al. Neutrophil extracellular traps directly induce epithelial and endothelial cell death: a predominant role of hi-stones.. PloS one 2012; 7: e32366.
    CrossrefPubMedGoogle Scholar
  • 70 Fuchs TA, Kremer Hovinga JA, Schatzberg D. et al. Circulating DNA and mye-loperoxidase indicate disease activity in patients with thrombotic microangio-pathies.. Blood 2012; 120: 1157-1164.
    CrossrefPubMedGoogle Scholar
  • 71 Diaz JA, Fuchs TA, Jackson TO. et al. Plasma DNA is Elevated in Patients with Deep Vein Thrombosis.. J Vasc Surg Ven Lymph Dis 2013; 1: 341-348.
    PubMedGoogle Scholar
  • 72 van Montfoort ML, Stephan F, Lauw MN. et al. Circulating nucleosomes and neutrophil activation as risk factors for deep vein thrombosis.. Arterioscler Thromb Vasc Biol 2013; 33: 147-151.
    CrossrefPubMedGoogle Scholar
  • 73 de Boer OJ, Li X, Teeling P. et al. Neutrophils, neutrophil extracellular traps and interleukin-17 associate with the organisation of thrombi in acute myocardial infarction.. Thromb Haemost 2013; 109: 290-297.
    Article in Thieme ConnectPubMedGoogle Scholar