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2066 Part XII Hemostasis and Thrombosis

Protein C

Thrombomodulin +
thrombin

Endothelial Activated
protein C protein C
receptor
–
Factor Va
Factor VIIIa
Endothelial Blocking
cell apoptosis NFκB
translocation
–
Tissue factor –

Decreased
TFPI – TNF-α and
IL production
in monocytes

–
Thrombin
Factor Xa
Glycosaminoglycans – Antiinflammatory
cytokines (IL-10)
Antithrombin

Increased TNF-α

Fig. 139.2 PHYSIOLOGIC ANTICOAGULANT MECHANISMS IN DISSEMINATED INTRAVASCU-
LAR COAGULATION. Physiologic anticoagulant mechanisms (activated protein C system, tissue factor
pathway inhibitor (TFPI), and antithrombin) are not only involved in blocking thrombin generation and
thrombin activity but also affect inflammatory pathways.

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pathways that elicit proinflammatory mediators. Factor Xa, throm- activity and amplify the consumptive process. Endogenous antico-
bin, and the factor VIIa–TF complex have such effects. Factor Xa agulant pathways are essential to regulate these proteases and to
injection into rats induces localized inflammation, probably as a prevent uncontrolled DIC.
result of its interaction with EPR-1 and not because of thrombin
generation. Exposure of cultured endothelial cells to factor Xa stimu-
lates the production of monocyte chemotactic protein 1 (MCP-1), Endogenous Anticoagulant Pathways in Disseminated
IL-6 and IL-8, and upregulates the expression of adhesion proteins Intravascular Coagulation
that tether neutrophils to the cell surface. Further evidence for the
crosstalk between inflammation and coagulation comes from the The development of DIC is counteracted by several mechanisms.
observations that IL-6 and IL-8 elicit TF-dependent procoagulant First, coagulation inhibitors regulate the coagulation mechanism.
activity in monocytes and the fact that IL-6 has been identified as Those inhibitors include antithrombin (AT), the protein C system,
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the critical mediator of procoagulant activity either on its own or after and TFPI (Fig. 139.2). AT, which complexes and inhibits thrombin
endotoxin challenge in vivo. Therefore cytokine production induced and factor Xa, is one of the most important inhibitors and reduced
by factor Xa may be an important driver of coagulation in DIC. AT levels are a characteristic of DIC. Reduction in AT levels reflects
In addition to its procoagulant functions, thrombin has a variety a combination of reduced protein synthesis as well as increased clear-
of noncoagulant effects. Thrombin induces the release of MCP-1 and ance through the formation of protease–AT complexes, and by deg-
IL-6 from fibroblasts, epithelial cells, and mononuclear cells in vitro. radation by neutrophil elastase. In addition, cytokines may impair
Thrombin also induces IL-6 and IL-8 production in endothelial cells. proteoglycan synthesis in the vessel wall thereby reducing the avail-
When generated in whole blood, IL-8 production has a procoagulant ability of heparan sulfate for potentiation of AT activity.
effect that is TF dependent. Cell activation by thrombin is likely In animal models of experimental bacteremia, AT concentrate
mediated by protease activated receptors (PARs). The factor VIIa–TF infusion increases survival, reduces the severity of DIC, and lowers
complex also activates cells by binding and activating PAR 2. the levels of IL-6 and IL-8. Therefore in addition to its anticoagulant
Direct evidence of the in vivo relevance of these phenomena function, AT may also have an antiinflammatory effect.
comes from a study showing that recombinant factor VIIa infusion Activated protein C and its cofactor protein S provide a second
in volunteers induces an increase in plasma levels of IL-6 and IL-8. line of defense. Thrombin binds to thrombomodulin on the endo-
Although the concentrations of factor VIIa infused far exceed those thelial cell membrane and the thrombin–thrombomodulin complex
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found in patients with sepsis, it is possible that factor VIIa-induced converts protein C to its active form, activated protein C (APC).
cytokine production is of physiologic importance. Therefore this In addition the thrombin–thrombomodulin complex converts the
information adds to the concept that several coagulation proteases latent carboxypeptidase B–like enzyme thrombin activatable fibrino-
induce proinflammatory mediators that augment procoagulant lytic inhibitor (TAFI) to its activated form. APC inactivates factors