It is established that the coagulation and inflammatory pathways exacerbate each other in systemic diseases such as severe sepsis, leading to disseminated intravascular coagulation with potentially catastrophic consequences.1 Reciprocal amplification arises from the ability of the products of coagulation to enhance inflammation and the ability of inflammatory mediators to favor clot formation. The latter derives from the up-regulation of platelet function and the concomitant dampening of anticoagulant and inhibitory mechanisms.1 Inflammation is increasingly recognized to represent a hallmark of atherothrombosis.2 While a similar interplay between coagulation and inflammation likely contributes to the progression of occlusive coronary artery disease, the effects are perhaps not expected to be systemic as the resultant response is localized to the site of vascular insult.
In this study, Undas et al present an analysis of peripheral coagulation in patients with acute myocardial infarction (AMI) in comparison to matched patients with stable coronary artery disease (CAD).3 Their approaches draw from the prodigious analytical abilities of the Mann laboratory, approaching blood coagulation from a systems perspective and grounded in an understanding of the biochemistry of the individual reactions. Key reactions leading to blood clot formation have been serially assessed with immunochemical approaches following damage to the peripheral microvasculature with a bleeding time device, which yields thrombin formation dependent on local tissue factor expression and platelet activation. Rather than assessing the current activation state of coagulation reactants in circulating blood by drawing directly into anticoagulants, their strategy of assessing precursor to product relationships in blood sequentially sampled from an oozing wound examines the ability of these patients to mount a procoagulant response following microvascular injury.
The authors show that in patients with AMI, the inferred rate of thrombin formation is increased approximately 2-fold in comparison to the CAD controls. This increase is associated with increased rates of consumption of the precursors of thrombin and fibrin as well as increased rates of platelet activation. Enhanced procoagulant function in the AMI patients could be correlated with the extent of myocardial necrosis and levels of the proinflammatory cytokine IL-6. Interestingly, the authors note that a similar correlation could not be established with levels of C reactive protein. Finally, based on studies of the activation and inactivation of factor V, the authors fail to correlate the increased rate of procoagulant reactions in the AMI patients with a concomitant depression in the anticoagulant path-way. These findings all point to a systemic increase in the ability of patients with AMI to form clots in response to microvascular injury. This, perhaps, does not derive from a selective depression of activated protein C-dependent mechanisms. The correlation between enhanced rates of clot formation and IL-6 levels raises the question as to whether underlying inflammatory processes predispose individuals to pathological thrombosis and occlusive coronary artery disease or whether increased inflammation accompanies atherothrombosis.
Conflict-of-interest disclosure: The author declares no competing financial interests. ■
National Institutes of Health