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American Journal of Medicine
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American Journal of Medicine
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This final Figure shows the process of venous thrombosis and its treatment. Whereas atherothrombosis usually occurs at a site where the endothelium is disrupted, this is not the case in venous thrombosis. In venous thrombosis, slow blood flow, accumulation of procoagulant proteins, and/or disrupted regulation of coagulation are more important mediators of clotting.
Although in these situations we do not have evidence of vascular disruption, we do have evidence for vascular activation. In this case what happens is that the endothelial cells can become activated on the venous endothelial surface
There is also evidence that neutrophils cannot produce tissue factor (TF) but that they can release their DNA content to create neutrophil extracellular traps (NETs) of DNA, which can then bind red cells, activate platelets, and induce clotting. Activation of clotting results in the generation of factor Xa, which then converts prothrombin to thrombin and the thrombin induces fibrin formation.
Thrombin generation can be blocked with vitamin K antagonists such as warfarin. Warfarin works by lowering the levels of the vitamin K-dependent clotting factors and attenuating thrombin formation.
The alternative approach is to use specific inhibitors of either factor Xa or of thrombin factor IIa. The newest inhibitors of factor Xa include the oral factor Xa inhibitors, rivaroxaban, apixaban, and edoxaban; on the other hand, we can target thrombin directly with dabigatran, an oral direct thrombin inhibitor -- and all of these novel oral anticoagulants (NOACs) are described in more detail in the presentations of Dr Eikelboom and Dr Hylek.
As opposed to the oral agents just mentioned, injectable drugs include heparin and low molecular weight heparin (LMWH), which work through antithrombin to inhibit factor Xa and thrombin. As a result, the approaches to therapy on the arterial side are similar to those on the venous side, in that we can inhibit coagulation by targeting one or several steps in the coagulation process.
What about platelets? The platelets are not shown in Figure 6, because it is believed that platelets are less important to venous thrombosis than they are to artherothrombosis. Nevertheless, platelets must not be forgotten, because they are activated by the thrombin that is generated in this cascade. Very recent data have shown that aspirin (a platelet inhibitor) attenuates the risk of recurrent thrombosis but it does not do it as effectively as anticoagulants, suggesting that the platelets are playing a role – just not as major a role – as the coagulation system.[3]
In summary, this has been an overview of the coagulation cascade, the integration of coagulation with platelet activation, the critical role of thrombin in both these processes, and the stepwise progression to the platelet–fibrin “plug” formation, as well as the targeted approach to inhibition of these processes with specific drugs. Weitz JI. Am J Med 2013; published on-line at http://education.amjmed.com/00000.
[3] Becattini C, Agnelli G, Schenone A, et al; WARFASA Investigators. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med. 2012;366:1959-1967.