A variety of clinical conditions may cause systemic activation of coagulation, ranging from insignificant laboratory changes to severe
disseminated intravascular coagulation (
DIC).
DIC consists of a widespread systemic activation of coagulation, resulting in diffuse
fibrin deposition in small and midsize vessels. There is compelling evidence from clinical and experimental studies that
DIC is involved in the pathogenesis of microvascular dysfunction and contributes to organ failure. In addition, the massive and ongoing activation of coagulation, may result in depletion of platelets and
coagulation factors, which may cause
bleeding. Recent understanding of important pathogenetic mechanisms that may lead to
DIC has resulted in novel preventive and therapeutic approaches to patients with
sepsis and a derangement of coagulation.
Thrombin generation proceeds via the (extrinsic)
tissue factor/
factor VIIa route and simultaneously occurring depression of inhibitory mechanisms, such as
antithrombin III and the
protein C system. Also, impaired
fibrin degradation, due to high circulating levels of the fibrinolytic
inhibitor plasminogen activator inhibitor, type 1 (PAI-1), contributes to enhanced intravascular
fibrin deposition. Interestingly, an extensive cross-talk between activation of
inflammation and coagulation exists, where inflammatory mediators (such as
cytokines) not only activate the coagulation system, but vice versa activated coagulation
proteases and
protease inhibitors may modulate
inflammation through specific cell receptors. Supportive strategies aimed at the inhibition of coagulation activation may theoretically be justified and have been found beneficial in experimental and initial clinical studies. These strategies comprise inhibition of
tissue factor-mediated activation of coagulation or restoration of physiological
anticoagulant pathways, for example by means of the administration of recombinant human activated
protein C.