REVIEWBasic mechanisms and pathogenesis of venous thrombosis
Introduction
Virchow’s triad predicts that the causes of thrombosis are changes in blood coaguability, changes in the vessel wall or stasis (Fig. 1). More recent studies have provided a mechanistic understanding for some of the processes that cause each of these alterations to contribute to thrombosis. A combination of genetically manipulated mouse models and human epidemiology have revealed that a variety of genetic risk factors can contribute to venous thrombosis, but the site of the thrombotic risk varies depending on the defect.[1], [2]
One of the major concepts involved in either hemostasis or thrombosis is that the processes are localized. Simply increasing coagulation enzyme concentrations with or without added negatively charged phospholipid vesicles leads to thrombin generation, but this thrombin generation is widespread, usually leading to disseminated intravascular coagulation rather than either hemostasis or thrombosis.[3], [4]
Section snippets
Where does venous thrombosis begin and why?
Except in thrombosis associated with surgery, examination of the thrombus in the human veins seldom indicates evidence of injury,5 raising the question of how venous thrombosis is initiated. Venous thrombosis is believed to begin at the venous valves.[1], [6] These valves play a major role in helping with blood circulation in the legs. They are also areas where stasis and hypoxia may occur. Direct evidence from autopsy studies and phlebography have established the venous valvular sinus as a
The role of blood cells versus vascular contribution to venous thrombosis
In addition to modulating the pro and anticoagulant properties of the endothelium, hypoxia also up regulates the expression of P-selectin on endothelium leading to the recruitment of leukocytes or leukocyte microparticles containing tissue factor which can serve as the nidus for initiation of the thrombotic response[18], [19] (Fig. 2). Microparticles bearing tissue factor appear to play a role in thrombus formation.[20], [21] This contrasts to the conventional notion that initiation of
Additional potential mechanisms for stasis induced venous thrombosis
Many of the anticoagulant pathways are triggered by endothelial cell surface components including thrombomodulin, EPCR, tissue factor pathway inhibitor and heparin like proteoglycans. EPCR and thrombin bound to thrombomodulin initiate the protein C pathway responsible for the inactivation of critical cofactors Va and VIIIa, tissue factor pathway inhibitor blocks tissue factor initiated coagulation and heparin like protoglycans stimulate antithrombin’s inhibitor activity toward coagulation
Changes in blood coaguability
Increased levels of coagulation factors, particularly factor VIII, von Willebrand factor, factor VII and prothrombin are associated with an increased risk of thrombosis, reviewed in.[2], [35] The increased risk of thrombosis with the elevation in factor VIII may be due to its inherent instability following activation and hence the need for replenishment to obtain a stable thrombus. In the case of prothrombin, in addition to the potential increase in thrombin generation, prothrombin is also an
The influence of aging on thrombosis risk
The risk of thrombosis increases dramatically with aging (Fig. 3). The basis for this increase in thrombotic risk with aging remains uncertain. From a population perspective, all of the following increase with age: there are increases in procoagulant levels with age without concomitant increases in natural anticoagulants like protein C,45 there is an increase in body mass with age,46 activity decreases often with extended periods of immobilization due to illness, the frequency of acute serious
Venous thrombosis
A single factor abnormality is seldom enough to cause venous thrombosis leading to “the multiple hit hypothesis.” Although based on human population studies, it is clear that coagulation factor or natural anticoagulant factor levels influence the risk of venous thrombosis, it is equally clear that other factors contribute to thrombotic risk. For example, in some families with protein C deficiency, the incidence of thrombosis is low whereas in other families it is high. In one extended family,
Pregnancy
Like oral contraceptives,55 pregnancy carries an increased risk of developing venous thrombosis56 that is increased still further in patients with thrombophilia. This increased risk is present in all trimesters of pregnancy and in the post partum period. Potential contributing factors might be disturbed blood flow and hormonal changes.56
Cancer
Cancer is a major risk factor for venous thrombosis, increasing the risk about 6–10-fold.[57], [58], [59], [60] Patients with cancer contribute approximately 20% of the new cases of venous thrombosis occurring in the community.61 Tumors shed membrane particles that contain procoagulant activity62 including tissue factor63 and membrane lipids that propagate the coagulation response. Adhesion molecules on the shed particles can help to concentrate the particles at sites where the appropriate
Lupus anticoagulants
Paradoxically the presence of lupus anticoagulants in patients is associated with an increased risk of thrombosis despite the fact that these lupus anticoagulant antibodies increase coagulation times in vitro. There are two major mechanisms that might contribute to the thrombotic risk. The antibodies bind to the platelets and endothelium possibly eliciting an inflammatory response.[64], [65] These antibodies also lead to complement activation which appears to contribute to fetal loss.66 These
Post operative thrombosis
Post operative thrombosis is a complication of surgery especially knee, hip and cancer surgery.[61], [72] In the case of knee and hip surgery, damage to the veins in combination with stasis are thought to be major contributing factors.72 In addition, materials released into the blood stream from the surgical sites can augment coagulation. In the case of cancer surgeries, candidates for contributing to thrombosis include the release of tumor procoagulants, host inflammatory responses and
Conclusion
While epidemiology has identified factors which predispose to venous thrombotic risk, we still lack fundamental knowledge of the basis for the initiation of thrombosis, how exactly the valves are involved in the process and what specific factors are altered with advancing age that contribute so markedly to thrombotic risk. Given the increased risk of major bleeding in the elderly on oral anticoagulants, a better understanding of the basis for the increased risk of thrombosis in the elderly
Research agenda
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Prediction of thrombotic risk in the elderly.
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Underlying mechanisms of increasing thrombotic risk with age.
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Basis for increased bleeding risk on oral anticoagulants with age.
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The role of the venous valves in thrombus initiation.
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Establishing better animal models of venous thrombosis.
Conflict of interest statement
The author serves as a consultant for Portola Pharmaceuticals, Inc., Cardiome Pharma Corp., Artisan Therapeutics, Teva Pharmaceuticals, and has a license for the production of protein C.
Acknowledgement
Portions of the research discussed above were funded by a Transatlantic Network for Excellence in Cardiovascular Research grant from the Leducq Foundation, Paris, France.
References (72)
Vascular bed-specific thrombosis
J Thromb Haemost
(2007)- et al.
Role of hemostatic gene polymorphisms in venous and arterial thrombotic disease
Blood
(2000) - et al.
P-selectin and leukocyte microparticles are associated with venous thrombogenesis
J Vasc Surg
(2003) - et al.
Nuclear translocation of human angiogenin in cultured human umbilical artery endothelial cells is microtubule and lysosome independent
Biochem Biophys Res Commun
(1997) - et al.
Decreased venous thrombosis with an oral inhibitor of P selectin
J Vasc Surg
(2005) - et al.
Venous thrombosis prophylaxis by inflammatory inhibition without anticoagulation therapy
J Vasc Surg
(2000) - et al.
Antithrombin III stimulates prostacyclin production by cultured aortic endothelial cells
Biochem Biophys Res Commun
(1989) - et al.
Macrovascular thrombosis is driven by tissue factor derived primarily from the blood vessel wall
Blood
(2005) The roles of protein C and thrombomodulin in the regulation of blood coagulation
J Biol Chem
(1989)- et al.
Inhibition of activated protein C anticoagulant activity by prothrombin
Blood
(1999)