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Classification of venous thromboembolism (VTE)

2005; Elsevier BV; Volume: 3; Issue: 11 Linguagem: Inglês

10.1111/j.1538-7836.2005.01661.x

1538-7933

Paola E. J. van der Meijden, Johan W. M. Heemskerk, Karly Hamulyák, Hugo Ten Cate,

Platelet Disorders and Treatments

The blood coagulation system serves at least two main functions in physiology: controlling bleeding because of trauma and protecting the organism against infections as part of the innate immune system [1Spronk H.M. Govers-Riemslag J.W. ten Cate H. The blood coagulation system as a molecular machine.Bioessays. 2003; 25: 1220-8Crossref PubMed Scopus (120) Google Scholar]. These functions are accomplished by multiple interactions between cellular elements (platelets, leukocytes and endothelial cells) and proteins of the coagulation and fibrinolytic pathways. In case of bleeding, the traditional view is that the cells provide the first line of defense, i.e. aggregated platelets form the primary hemostatic plug after which the coagulation process permits fibrin clot formation (secondary hemostasis). The modern view is slightly different in the sense that we consider these mechanisms as cooperative and acting in parallel, in fact behaving as an integrated cell-protein clotting machinery. Why and how, then, have platelets and the coagulation system still different functions? Excessive activity of the blood coagulation system can result in excess fibrin formation at sites of blood stasis or vascular damage, where it is potentially harmful. This situation may lead to venous thrombosis, in which a fibrin and cellular meshwork partially or completely obstructs a major vein. On the other hand, rupture of an atherosclerotic plaque can result in arterial thrombosis. Thrombosis by itself is a cause of serious clinical complications; venous thrombosis leads to pulmonary embolism and post-thrombotic syndrome, while arterial thrombosis causes impaired oxygenation of a critical organ, resulting in e.g. a myocardial infarction or stroke. From early studies by Virchov and other pathologists, it is known that venous and arterial thrombi typically differ in their composition. While venous thrombi appear as 'red' clots because of numerous red cells intermingled with fibrin, arterial thrombi are 'white' in appearance because of a predominance of platelets with associated fibrin [2Tan K.T. Lip G.Y. Red vs. white thrombi: treating the right clot is crucial.Arch Intern Med. 2003; 163: 2534-5Crossref PubMed Scopus (0) Google Scholar]. Consequently, it has been surmized for long that particularly platelets play a distinct role in the thrombotic processes, in the sense that their participation is critically important in arterial thrombosis, but not apparent in venous thrombosis [3Ten Cate H. Brandjes D.P. Smits P.H. van Mourik J.A. The role of platelets in venous thrombosis: a patient with Glanzmann's thrombasthenia and a factor V Leiden mutation suffering from deep venous thrombosis.J Thromb Haemost. 2003; 1: 394-5Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 4Ten Cate H. Aird W.C. Lessons from venous thrombosis and disseminated intravascular coagulation: a synthesis of pathophysiological mechanisms of prothrombotic states.in: Ten Cate H Levi M Molecular Mechanisms of Disseminated Intravascular Coagulation. Landes Bioscience, 2003: 7-28Google Scholar]. This corresponds well to the experimental evidence ex vivo that tissue factor is a primary trigger for thrombus formation under (coagulant) conditions resembling those of venous thromboembolism (VTE) [5Mann K.G. Jenny R.J. Krishnaswamy S. Cofactor proteins in the assembly and expression of blood clotting enzyme complexes.Annu Rev Biochem. 1988; 57: 915-56Crossref PubMed Google Scholar]. Also, at high shear-rate conditions, as in (stenotic) arteries, collagen with deposited von Willebrand factor (VWF) is known to be an initial trigger for platelet tethering and adhesion, which predisposes for the formation of platelet-rich thrombi with a typical 'arterial' composition [6Ruggeri Z.M. Platelets in atherothrombosis.Nat Med. 2002; 8: 1227-34Crossref PubMed Scopus (1351) Google Scholar, 7Nieswandt B. Brakebusch C. Bergmeier W. Schulte V. Bouvard D. Mokhtari-Nejad R. Lindhout T. Heemskerk J.W. Zirngibl H. Fassler R. Glycoprotein VI but not alpha2beta1 integrin is essential for platelet interaction with collagen.Embo J. 2001; 20: 2120-30Crossref PubMed Scopus (0) Google Scholar]. However, the recognition that also blood-borne tissue factor can promote for arterial thrombus formation [8Giesen P.L.A. Rauch U. Bohrman B. Kling D. Roqué M. Fallon J.T. Badimon J.J. Himber J. Riederer M.A. Nemerson Y. Blood-borne tissue factor, another view of thrombosis.Proc Natl Acad Sci USA. 1999; 96: 2311-5Crossref PubMed Scopus (0) Google Scholar] has changed this black–white view. Presently, we have considerable knowledge of the molecular mechanisms of the interactions of platelets and the coagulation system [9Heemskerk J.W.M. Bevers E.M. Lindhout T. Platelet activation and blood coagulation.Thromb Haemost. 2002; 88: 186-93Crossref PubMed Google Scholar]. Activated platelets expose procoagulant phospholipids, which enhance the generation of factor Xa and thrombin by several magnitudes [10Zwaal R.F.A. Schroit A.J. Pathophysiological implications of membrane phospholipid asymmetry in blood cells.Blood. 1997; 89: 1121-32Crossref PubMed Google Scholar]. As thrombin is one of the most potent platelet agonists, this procoagulant activity of platelets results in a positive feedback loop of platelet activation, thrombin generation and fibrin formation [11Béguin S. Kumar R. Thrombin, fibrin and platelets, a resonance loop in which von Willebrand factor is a necessary link.Thromb Haemost. 1997; 78: 590-4Crossref PubMed Scopus (0) Google Scholar]. Platelets already respond at very low (sub-nanomolar) concentrations of thrombin via their receptors (PARs), i.e. well before fibrin starts to be formed. It is thus inevitable that all platelets become in an activated state at sites of venous thrombosis, where locally quite high levels of thrombin can be reached. This would imply that platelet procoagulant activity is a potent driving force for the thrombin generation in venous thrombosis, although this has not yet been demonstrated. Thus, simply the fact that thrombin is formed in thrombotic veins predicts that platelets will contribute to the thrombotic process. All of this does not necessarily mean that weak platelet antagonists (like aspirin) effectively affect the thrombotic process; for instance, the tissue factor (blood-borne?) induced thrombin generation can locally be too high to be inhibited by weak antiplatelet agents whereas anticoagulant medication is still effective. In experimental animal studies, the effect of platelet inhibitors on venous thrombosis indeed depends on the model chosen. In general, stasis-induced thrombi are insensitive to platelet inhibition, e.g. with aspirin, while inflammation related models (applying an inflammatory stimulus) may be more dependent on platelet function [4Ten Cate H. Aird W.C. Lessons from venous thrombosis and disseminated intravascular coagulation: a synthesis of pathophysiological mechanisms of prothrombotic states.in: Ten Cate H Levi M Molecular Mechanisms of Disseminated Intravascular Coagulation. Landes Bioscience, 2003: 7-28Google Scholar]. The clearest influence of platelet inhibitors is observed in models where the venous wall is directly damaged by mechanical or other forces. Under those conditions, platelets likely interact with subendothelial collagen and VWF, facilitating their adherence and activation, while aspirin or ADP receptor blockers inhibit the venous thrombus formation [12van Gestel M.A. Heemskerk J.W. Slaaf D.W. Heijnen V.V. Reneman R.S. oude Egbrink M.G. In vivo blockade of platelet ADP receptor P2Y12 reduces embolus and thrombus formation but not thrombus stability.Arterioscler Thromb Vasc Biol. 2003; 23: 518-23Crossref PubMed Scopus (0) Google Scholar]. Thus, following the argumentation above, while thrombin will activate platelets at the thrombotic sites under all these conditions, platelet inhibitors seem to be the most effective in situations where a direct trigger for platelet activation is present (LPS, collagen, VWF). Translating these animal experiments to the clinical situation, the efficacy of antiplatelet therapy in venous thrombosis may similarly depend on the underlying cause. Thus, stasis-dependent thrombosis during prolonged physical immobilization or gradual occlusion of a vein may be less inhibitable with platelet antagonists than trauma-induced thrombosis. Is this argumentation of any clinical relevance? We believe that it is for the following reasons. Firstly, there is an ongoing debate about the importance of platelet inhibitors in the prevention of VTE, where advocates claim that the 37% or 53% risk reduction observed in a meta-analysis of platelet inhibition in preventing deep venous thrombosis and pulmonary embolisms, respectively, is highly relevant [13Blann A.B. Lip G.Y.H. Platelet involvement in venous thrombosis and pulmonary embolism.in: Gresele P Page CP Fuster V Vermylen J Platelets in Thrombotic and Non-Thrombotic Disorders. Cambridge University Press, 2002: 753-60Crossref Google Scholar]. In contrast, in a recent position paper other investigators indicate that this antithrombotic effect of platelets inhibitors is of limited clinical importance when compared with the more effective low molecular weight heparins [14Geerts W.H. Pineo G.F. Heit J.A. Bergqvist D. Lassen M.R. Colwell C.W. Ray J.G. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.Chest. 2004; 126: 338S-400SAbstract Full Text Full Text PDF PubMed Scopus (2808) Google Scholar]. Here, better knowledge of the platelet triggers in relation to venous thrombosis under different conditions may help clarify the clinical arguments. Also, the use of platelet antagonists with an anticoagulant effect such as clopidogrel [15Léon C. Ravanat C. Freund M. Cazenave J.P. Gachet C. Differential involvement of the P2Y1 and P2Y12 receptors in platelet procoagulant activity.Arterioscler Thromb Vasc Biol. 2003; 23: 1941-7Crossref PubMed Scopus (0) Google Scholar, 16van der Meijden P.E.J. Feijge M.A.H. Giesen P.L.A. Huijberts M. van Raak E.P.M. Heemskerk J.W.M. Platelet P2Y12 receptors enhance signalling towards procoagulant activity and thrombin generation: a study with healthy subjects and patients at thrombotic risk.Thromb Haemost. 2005; 93: 1128-36Crossref PubMed Scopus (0) Google Scholar] and integrin blockers [17Reverter J.C. Béguin S. Kessels H. Kumar R. Hemker H.C. Coller B.S. Inhibition of platelet-mediated, tissue-factor-induced thrombin generation by the mouse/human chimeric 7E3 antibody. Potential implications for the effect of c7E3 Fab treatment on acute thrombosis and 'clinical restenosis'.J Clin Invest. 1996; 98: 863-74Crossref PubMed Google Scholar] should be considered. Secondly, and related, there is still a need for simple ways of preventing venous thrombosis in conditions like prolonged immobilization during long-term transportation such as flying. Here, it would be very helpful to estimate how effective aspirin (or perhaps even better other platelet inhibitors with anticoagulant effect) might be in limiting the risks, but it is unlikely that clinical trials will be able to answer the question, because of the low incidence of clinical VTE and consequently huge study samples required. Thirdly, new proposals for classifying idiopathic VTE [18White H. Murin S. Is the current classification of venous thromboembolism acceptable? No.J. Thromb. Haemost. 2004; 2: 2262-3Abstract Full Text Full Text PDF PubMed Google Scholar] may take into account the likely presence of a platelet trigger. Finally, it is to answer the question: what is the role of platelets in VTE? Most likely, this role is considerable, but effective inhibition may need the use of combination medication of anticoagulants and antiplatelet agents, particularly those which also have an anticoagulant potential such as clopidogrel and integrin blockers.