We did a comprehensive literature search by using electronic bibliographic databases (ie, Medline, Embase, DARE, Cochrane database), scanning reference lists from included articles, and hand searching abstracts from national and international cardiovascular meetings. We used search terms including “atrial fibrillation”, “hypercoagulability”, “inflammation”, “anti-thrombotic treatment”. Bibliographies of all selected articles and review articles were reviewed for other relevant articles.
ReviewMechanisms of thrombogenesis in atrial fibrillation: Virchow's triad revisited
Introduction
The association between atrial fibrillation and the risk of stroke and thromboembolism has long been recognised. The pathogenesis of thrombus formation (thrombogenesis) in atrial fibrillation is multifactorial and is not only related to stasis in a poorly contractile left atrium. Indeed, there is an increasing body of evidence to support the presence of a prothrombotic or hypercoagulable state.1
More than 150 years ago, Rudolf Virchow proposed a triad of events needed for thrombus formation—ie, abnormal changes of the vessel wall, blood flow, and blood constituents.2 In the 21st century, we now recognise Virchow's triad as: endothelial or endocardial damage or dysfunction (and related structural abnormal changes); abnormal blood stasis; and abnormal haemostasis, platelets, and fibrinolysis. Extensive abnormal changes of these variables are clearly evident in atrial fibrillation. Thus, atrial fibrillation could in fact drive a prothrombotic or hypercoagulable state, by virtue of its fulfilment of Virchow's triad for thrombogenesis.3
Section snippets
Anatomical and structural considerations
Attached to each atria is a blind-ended passage known as an appendage. The left atrial appendage (LAA) is long with a narrow inlet, thereby predisposing to blood stasis. Thus, the LAA is the most common site of intra-atrial thrombus formation, not only in atrial fibrillation, but also in patients with sinus rhythm.4, 5
Changes in the dimensions of the left atrium and LAA occur as a consequence of atrial fibrillation, with some correlation to subsequent thromboembolism. Detailed descriptions of
Abnormal blood stasis
In addition to stasis consequent on the failure of atrial systole, the presence of non-valvular atrial fibrillation seems to promote progressive left atrial (LA) dilatation,25 thus amplifying the potential for stasis. In the presence of mitral stenosis, LA dilatation is increased and leads to further stasis and propensity to thrombosis.26 The contribution of LA dilatation to thrombogenesis (at least, in non-valvular atrial fibrillation) is indicated by the finding that atrial size corrected for
Abnormal blood constituents
The main intravascular promoters of thrombogenesis are platelets and the various proteins of the coagulation cascade. In atrial fibrillation, abnormal changes in both these promoters and other blood constituents (eg, inflammatory cytokines, growth factors) are evident, thereby completing Virchow's triad.
What drives the prothrombotic state in atrial fibrillation?
Several mechanisms have been purported to drive the prothrombotic state in atrial fibrillation (figure 2), but recent evidence has focused on the potential role of inflammation and the release of various growth factors.
Future directions
There is increasingly strong evidence for the presence of a prothrombotic or hypercoagulable state in atrial fibrillation. The presence of various flow and structural defects has been used to refine clinical risk stratification models for stroke and thromboembolism, or to help predict the likelihood of success for cardioversion and the long-term maintenance of sinus rhythm.162
However, the clinical role of indices of the prothrombotic or hypercoagulable state is emerging, although more data are
Conclusion
The mechanisms underlying thrombogenesis in atrial fibrillation are clearly complex and remain only partly understood. Abnormal changes in flow, vessel wall, and blood constituents in atrial fibrillation fulfil Virchow's triad for thrombogenesis, and accord with a prothrombotic or hypercoagulable state in this arrhythmia. That this process is related purely to blood stasis is no longer accepted. Various abnormal changes related both to atrial fibrillation and its comorbidities impart a
Search strategy and selection criteria
References (165)
Does atrial fibrillation confer a hypercoagulable state?
Lancet
(1995)- et al.
Appendage obliteration to reduce stroke in cardiac surgical patients with atrial fibrillation
Ann Thorac Surg
(1996) - et al.
Von Willebrand factor, fibrinogen, and soluble P-selectin levels after mitral valve replacement versus mitral valve repair
Am J Cardiol
(2000) Atrial stunning: determinants and cellular mechanisms
Am Heart J
(2003)- et al.
The L-type Ca2+-channel subunits alpha1C and beta2 are not downregulated in atrial myocardium of patients with chronic atrial fibrillation
J Mol Cell Cardiol
(2003) - et al.
The fibrosis and atrial fibrillation: is the transforming growth factor-beta(1) a candidate etiology of atrial fibrillation
Med Hypotheses
(2008) - et al.
Matrix metalloproteinase-9 contributes to human atrial remodeling during atrial fibrillation
J Am Coll Cardiol
(2004) - et al.
Selective induction of matrix metalloproteinases and tissue inhibitor of metalloproteinases in atrial and ventricular myocardium in patients with atrial fibrillation
Am J Cardiol
(2006) - et al.
Atrial fibrillation and atrial enlargement in patients with mitral stenosis
Am Heart J
(1987) - et al.
Antithrombotic therapy in valvular heart disease—native and prosthetic: the seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy
Chest
(2004)