Thrombosis — localized clotting of the blood — can occur in the arterial or the venous circulation and has a major medical impact. Acute arterial thrombosis is the proximal cause of most cases of myocardial infarction (heart attack) and of about 80% of strokes, collectively the most common cause of death in the developed world. Venous thromboembolism is the third leading cause of cardiovascular-associated death. The pathogenic changes that occur in the blood vessel wall and in the blood itself resulting in thrombosis are not fully understood. Understanding these processes is crucial for developing safer and more effective antithrombotic drugs.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Journal of Medical Case Reports Open Access 02 March 2021
Communications Chemistry Open Access 15 February 2021
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Hartwig, J. & Italiano, J. The birth of the platelet. J. Thromb. Haemost. 1, 1580–1586 (2003).
Ruggeri, Z. M. & Mendolicchio, G. L. Adhesion mechanisms in platelet function. Circ. Res. 100, 1673–1685 (2007).
Denis, C. V. & Wagner, D. D. Platelet adhesion receptors and their ligands in mouse models of thrombosis. Arterioscler. Thromb. Vasc. Biol. 27, 728–739 (2007).
Savage, B., Almus-Jacobs, F. & Ruggeri, Z. M. Specific synergy of multiple substrate–receptor interactions in platelet thrombus formation under flow. Cell 94, 657–666 (1998).
Coughlin, S. R. Protease-activated receptors in hemostasis, thrombosis and vascular biology. J. Thromb. Haemost. 3, 1800–1814 (2005).
Marmur, J. D. et al. Identification of active tissue factor in human coronary atheroma. Circulation 94, 1226–1232 (1996).
Tremoli, E., Camera, M., Toschi, V. & Colli, S. Tissue factor in atherosclerosis. Atherosclerosis 144, 273–283 (1999).
Misumi, K. et al. Comparison of plasma tissue factor levels in unstable and stable angina pectoris. Am. J. Cardiol. 81, 22–26 (1998).
Mackman, N. Role of tissue factor in hemostasis, thrombosis, and vascular development. Arterioscler. Thromb. Vasc. Biol. 24, 1015–1022 (2004).
Meadows, T. A. & Bhatt, D. L. Clinical aspects of platelet inhibitors and thrombus formation. Circ. Res. 100, 1261–1275 (2007). This recent review describes the targets of the various antiplatelet drugs and their clinical use.
Gilbert, J. C. et al. First-in-human evaluation of anti von Willebrand factor therapeutic aptamer ARC1779 in human volunteers. Circulation 116, 2678–2686 (2007).
Oney, E. S. et al. Antidote-controlled platelet inhibition targeting von Willebrand factor with aptamers. Oligonucleotides 17, 265–274 (2007).
Lord, S. T. Fibrinogen and fibrin: scaffold proteins in hemostasis. Curr. Opin. Hematol. 14, 236–241 (2007).
Intracerebral hemorrhage after intravenous t-PA therapy for ischemic stroke. Stroke 28, 2109–2118 (1997).
Brass, L. F., Zhu, L. & Stalker, T. J. Minding the gaps to promote thrombus growth and stability. J. Clin. Invest. 115, 3385–3392 (2005).
Febbraio, M., Hajjar, D. P. & Silverstain, R. L. CD36: a class B scavenger receptor involved in angiogenesis, atherosclerosis, inflammation, and lipid metabolism. J Clin. Invest. 108, 785–791 (2001).
Podrez, E. A. et al. Platelet CD36 links hyperlipidemia, oxidant stress and a prothrombotic phenotype. J Clin. Invest 13, 1086–1095 (2007). This paper shows that oxidized low-density lipoproteins activate platelets by binding to CD36, providing a possible explanation for the link between hyperlipidaemia and thrombosis.
Ratnikov, B. I., Partridge, A. W. & Ginsberg, M. H. Integrin activation by talin. J. Thromb. Haemost. 3, 1783–1790 (2007).
Petrich, B. G. et al. The antithrombotic potential of selective blockade of talin-dependent integrin αIIbβ3 (platelet GPIIb-IIIa) activation. J Clin. Invest. 117, 2250–2259 (2007).
Babapulle, M. N., Joseph, L., Belisle, P., Brophy, J. M. & Eisenberg, M. J. A hierarchical Bayesian meta-analysis of randomised clinical trials of drug-eluting stents. Lancet 364, 583–591 (2004).
Finn, A. V. et al. Pathological correlates of late drug-eluting stent thrombosis: strut coverage as a marker of endothelialization. Circulation 115, 2435–2441 (2007).
Bavry, A. A. et al. Late thrombosis of drug-eluting stents: a meta-analysis of randomized clinical trials. Am. J. Med. 119, 1056–1061 (2006).
Wiviott, S. et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N. Engl. J. Med. 357, 2001–2015 (2007). This paper describes the results of a recent clinical trial of prasugrel, a new antiplatelet drug.
Virchow, R. Gesammelte Abhandlungen zur Wissenschaftlichen Medizin (Meidinger, Frankfurt, 1856).
Cushman, M. Epidemiology and risk factors for venous thrombosis. Semin. Hematol. 44, 62–69 (2007).
Heit, J. A. Venous thromboembolism: disease burden, outcomes and risk factors. J. Thromb. Haemost. 3, 1611–1617 (2007).
Segers, K., Dahlback, B. & Nicolaes, G. A. Coagulation factor V and thrombophilia: background and mechanisms. Thromb. Haemost. 98, 530–542 (2007).
Hron, G. et al. Tissue factor-positive microparticles: cellular origin and association with coagulation activation in patients with colorectal cancer. Thromb. Haemost. 97, 119–123 (2007).
Tesselaar, M. E. et al. Microparticle-associated tissue factor activity: a link between cancer and thrombosis? J. Thromb. Haemost. 5, 520–527 (2007).
Polgar, J., Matuskova, J. & Wagner, D. D. The P-selectin, tissue factor, coagulation triad. J. Thromb. Haemost. 3, 1590–1596 (2005).
Weitz, J. I. & Linkins, L. A. Beyond heparin and warfarin: the new generation of anticoagulants. Expert Opin. Investig. Drugs 16, 271–282 (2007).
Hirsh, J., O'Donnell, M. & Eikelboom, J. W. Beyond unfractionated heparin and warfarin: current and future advances. Circulation 116, 552–560 (2007). This review summarizes the anticoagulants that are in clinical use and the development of new anticoagulant drugs.
Eriksson, B. I. et al. Oral rivaroxaban compared with subcutaneous enoxaparin for extended thromboprohylaxis after total hip arthroplasty. Blood 110, abstr. 6 (2007). This abstract describes the recent clinical trial assessing the effect of the factor-Xa inhibitor rivaroxaban on rates of thrombosis.
Snyder, L. A. et al. Expression of human tissue factor under the control of the mouse tissue factor promoter mediates normal hemostasis in knock-in mice. J. Thromb. Haemost. 6, 306–314 (2008).
Mackman, N. Tissue-specific hemostasis in mice. Arterioscler. Thromb. Vasc. Biol. 25, 2273–2281 (2005).
Bolton-Maggs, P. H. & Pasi, K. J. Haemophilias A and B. Lancet 361, 1801–1809 (2003).
Galiani, D. & Renne, T. The intrinsic pathway of coagulation: a target for treating thromboembolic disease? J. Thromb. Haemost. 5, 1106–1112 (2007).
Howard, E. L., Becker, C. D., Rusconi, C. P. & Becker, R. C. Factor IXa inhibitors as novel anticoagulants. Arterioscler. Thromb. Vasc. Biol. 27, 722–727 (2007).
Weitz, J. I. & Buller, H. R. Direct thrombin inhibitors in acute coronary syndromes: present and future. Circulation 105, 1004–1011 (2002).
Turpie, A. G. Oral, direct factor Xa inhibitors in development for the prevention and treatment of thromboembolic diseases. Arterioscler. Thromb. Vasc. Biol. 27, 1238–1247 (2007).
Li, W. X., Kaplan, A. V., Grant, G. W., Toole, J. J. & Leung, L. L. A novel nucleotide-based thrombin inhibitor inhibits clot-bound thrombin and reduces arterial platelet thrombus formation. Blood 83, 677–682 (1994).
Rusconi, C. P. et al. RNA aptamers as reversible antagonists of coagulation factor IXa. Nature 419, 90–94 (2002).
Rusconi, C. P. et al. Antidote-mediated control of an anticoagulant aptamer in vivo. Nature Biotechnol. 22, 1423–1428 (2004). This paper describes the use of an aptamer targeting factor IXa and an 'antidote' oligonucleotide for the treatment of thrombosis.
Dyke, C. K. et al. First-in-human experience of an antidote-controlled anticoagulant using RNA aptamer technology: a phase 1a pharmacodynamic evaluation of a drug–antidote pair for the controlled regulation of factor IXa activity. Circulation 114, 2490–2497 (2006).
Monia, B. et al. ISIS 401025, a second generation antisense oligonucleotide targeting prothrombin, inhibits plasma prothrombin level and promotes anticoagulation in mice. Circulation 116 (suppl.), abstr. 716 (2007).
Berger, J. S. et al. Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials. J. Am. Med. Assoc. 295, 306–313 (2006).
Hennekens, C. H., Sechenova, O., Hollar, D. & Serebruary, V. L. Dose of aspirin in the treatment and prevention of cardiovascuar disease: current and future directions. J. Cardiovasc. Pharmacol. Ther. 11, 170–176 (2006).
Grosser, T., Fries, S. & FitzGerald, G. A. Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. J. Clin. Invest. 116, 4–15 (2006).
Gachet, C. The platelet P2 receptors as molecular targets for old and new antiplatelet drugs. Pharmacol. Ther. 108, 180–192 (2005).
The Clopidogrel in Unstable Angina To Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N. Engl. J. Med. 345, 494–502 (2007).
Sabatine, M. S. et al. Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated wilth fibrinolytics. J. Am. Med. Assoc. 294, 1224–1232 (2005).
Kong, D. F. et al. Clinical outcomes of therapeutic agents that block the platelet glycoprotein IIb/IIIa integrin in ischemic heart disease. Circulation 98, 2829–2835 (1998).
Palareti, G. et al. Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Lancet 348, 423–428 (1996).
Krynetskly, E. Building individualized medicine: prevention of adverse reactions to warfarin therapy. J. Pharmacol. Exp. Ther. 322, 427–434 (2007).
Quinlan, D. J., McQuillan, A. & Eikelboom, J. W. Low-molecular-weight heparin compared with intravenous unfractionated heparin for the treatment of pulmonary embolism: a meta-analysis of randomized, controlled trials. Ann. Intern. Med. 140, 175–183 (2004).
Turpie, A. G., Eriksson, B. I., Lassen, M. R. & Bauer, K. A. Fondaparinux, the first selective factor Xa inhibitor. Curr. Opin. Hematol. 10, 327–332 (2003).
Cines, D.B. et al. Heparin-induced thrombocytopenia: an autoimmune disorder regulated through dynamic autoantigen assembly/disassembly. J. Clin. Apher. 22, 31–36 (2007).
Eriksson, B. I. et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet 370, 949–956 (2007).
Fisher, W. D. et al. Rivaroxaban for thromboprophylaxis after orthopaedic therapy: pooled analysis of two studies. Thromb. Haemost. 97, 931–937 (2007).
I thank N. Key, R. Kasthuri and R. Stouffer for suggestions during preparation of the manuscript, and F. Church, J. Luyendyk, W. Biosvert and C. Mackman for critical reading of the manuscript.
N.M. is a consultant for Daiichi Sankyo.
Correspondence should be addressed to the author (firstname.lastname@example.org).
About this article
Cite this article
Mackman, N. Triggers, targets and treatments for thrombosis. Nature 451, 914–918 (2008). https://doi.org/10.1038/nature06797
This article is cited by
Acta Pharmacologica Sinica (2022)
Heart Failure Reviews (2022)
Efficacy and Safety of Omega-3 Fatty Acids in the Prevention of Cardiovascular Disease: A Systematic Review and Meta-analysis
Cardiovascular Drugs and Therapy (2022)
In vitro models (2022)
American Journal of Cardiovascular Drugs (2022)