Abstract
In the majority of patients with severe sepsis, systemic activation of coagulation
is present. Increasing evidence points to an extensive cross-talk between coagulation
and inflammation that may play an important role in the pathogenesis of sepsis. Inflammation
not only leads to activation of coagulation, but coagulation also considerably affects
inflammatory activity. Molecular pathways that contribute to inflammation-induced
activation of coagulation have been precisely identified. Proinflammatory cytokines
and other mediators are capable of activating the coagulation system and downregulating
important physiological anticoagulant pathways. Activation of the coagulation system
and ensuing thrombin generation is dependent on expression of tissue factor on activated
mononuclear cells and endothelial cells, and is insufficiently counteracted by TFPI.
Simultaneously, endothelial-bound anticoagulant mechanism, in particular the protein
C system, is shutoff by proinflammatory cytokines. In addition, fibrin removal is
severely inhibited, because of inactivation of the fibrinolytic system, caused by
an upregulation of its main inhibitor, plasminogen activator inhibitor type 1 (PAI-1).
Increased fibrin formation and impaired removal lead to (micro)vascular thrombosis,
which may result in tissue ischemia and subsequent organ damage. The cornerstone of
the management of coagulation in sepsis is the specific and vigorous treatment of
the underlying disorder. Strategies aimed at the inhibition of coagulation activation
may theoretically be justified and have been found beneficial in experimental and
initial clinical studies. Heparin may be an effective anticoagulant approach and alternative
strategies comprise restoration of physiological anticoagulant pathways.
Keywords
coagulation - inflammation - sepsis - tissue factor - antithrombin - protein C - fibrinolysis
