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2200 Part XII: Hemostasis and Thrombosis Chapter 129: Disseminated Intravascular Coagulation 2201

giving rise to platelet aggregation and augmenting platelet functions activated by thrombin through cleavage of a specific aminoterminus bond
in coagulation; (2) it activates factors VIII, V, and XI, yielding fur- creating a tethered ligand that activates the receptor. PAR-2 can be cleaved
ther thrombin generation; (3) it activates proinflammatory factors via by factor Xa–TF–factor VIIa complex and by other proteases. Activated
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protease-activated receptors (PARs); (4) it activates factor XIII to factor PARs then lead through mitogen-activated protein kinase and NF-κB
XIIIa, which crosslinks fibrin clots; (5) it activates thrombin-activatable signaling pathways to cell motility, shape change, proliferation, endoge-
fibrinolysis inhibitor (TAFI), making clots resistant to fibrinolysis; and nous secretagogue release, and apoptosis. The activated protein C (APC)–
(6) it increases expression of adhesion molecules, such as L-selectin, endothelial protein C receptor complex (see “Role of Natural Antico-
thereby promoting the inflammatory effects of leukocytes. 41 agulant Pathways” below) appears to be the “off switch” for PAR activa-
Paradoxically, at low concentrations, thrombin exhibits both anti- tion by the proteases. These counterbalances determine the magnitude
inflammatory and anticoagulant effects because it binds to thrombo- of coagulation and inflammatory upregulation by PARs. For exam-
modulin and activates protein C to the activated form, which, in turn, ple, factor VIIa–TF binding to PAR-2 in the lungs is proinflamma-
downregulates inflammation and serves as an “off switch” for further tory and appears to play a role in acute respiratory distress syndrome
thrombin generation (Chap. 116). (ARDS), raising the possibility that TFPI might be therapeutic in this
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circumstance. This finding is consistent with data from animal stud-
ies demonstrating that TFPI can protect baboons from a LD100 of
ROLE OF COAGULATION PROTEASES IN Escherichia coli, likely by impeding factor VIIa–TF activation of PAR-2
UPREGULATING INFLAMMATION and thereby attenuating release of IL-6 and other proinflammatory agents.
Coagulation proteases and protease inhibitors not only interact with
coagulation proteins, but also with specific cell receptors to induce sig- ROLE OF FIBRINOGEN AND FIBRIN
naling pathways. In particular, protease interactions that affect inflam- Fibrinogen and fibrin directly influence the production of proinflamma-
matory processes may be important in critically ill patients. Coagulation tory cytokines and chemokines (including TNF-α, IL-1β, and MCP-1)
of whole blood in vitro results in a detectable expression of IL-1β mRNA by mononuclear cells and endothelial cells. Fibrinogen-deficient mice
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in blood cells, and thrombin markedly enhances endotoxin-induced display inhibition of macrophage adhesion and less thrombin-mediated
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IL-1 activity in culture supernatants of guinea pig macrophages. Simi- cytokine production in vivo. The effects of fibrinogen on mononuclear
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larly, clotted blood produces IL-8 in vitro. 44 cells seem to be mediated by toll-like receptor-4, which is also the recep-
Factor Xa, thrombin, and fibrin can also activate endothelial cells, tor of endotoxin.
eliciting the synthesis of IL-6 and IL-8. 45,46 Coagulation proteases such
as thrombin, factor Xa, and factor VIIa–TF complex induce inflamma- ROLE OF NATURAL ANTICOAGULANT
tory upregulation via leukocyte, endothelial cell, and platelet PAR-1,
PAR-2, PAR-3, and PAR-4, which are located on leukocytes, endothelial PATHWAYS
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cells, and platelets. PARs have an extracellular domain, seven trans- Procoagulant activity is regulated by three important anticoagulant
membrane domains, and an intracellular domain that is coupled to spe- pathways: AT, the protein C system, and TFPI. In DIC, the function of
cific G-proteins that transmit signaling. PAR-1, PAR-3, and PAR-4 are all three pathways can be impaired (Fig. 129–2). 51

Figure 129–2. Schematic of the three important physiologic
anticoagulant mechanisms and their point of impact in the coagu-
Thrombomodulin
Protein C lation system. In sepsis, these mechanisms are impaired by various
mechanisms (green arrows). The protein C system is dysfunctional
as a result of low levels of zymogen protein C, downregulation of
Thrombin thrombomodulin and the endothelial protein C receptor, and low
levels of free protein S because of acute phase-induced high levels
of its binding protein (i.e., C4b-binding protein). There is a relative
insufficiency of the endothelial cell-associated tissue factor pathway
Activated Protein S inhibitor. The antithrombin system is defective because of low lev-
protein C Factor Va & els of antithrombin and impaired glycosaminoglycan expression on
factor VIIIa perturbed endothelial cells.
Endothelial
protein C receptor
Tissue factor
pathway inhibitor

Tissue factor

Glycosaminoglycans

Thrombin &
Antithrombin factor Xa

Kaushansky_chapter 129_p2199-2220.indd 2201 17/09/15 3:45 pm