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2202 Part XII: Hemostasis and Thrombosis Chapter 129: Disseminated Intravascular Coagulation 2203

The serine protease inhibitor AT is the main inhibitor of thrombin Prostacyclin inhibits platelet activation and aggregation, blocks neu-
and factor Xa. Without heparin, AT neutralizes coagulation enzymes in trophil tethering to blood vessels, and decreases endothelial cell pro-
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a slow, progressive manner. Heparin induces conformational changes duction of various cytokines and chemokines. 74
in AT that result in at least a 1000-fold enhancement of AT activity. AT also interacts directly with leukocytes and lymphocytes. It
Thus, the clinical efficacy of heparin is attributed to its interaction with binds to receptors, such as syndecan-4, on the cell surfaces of neu-
AT. Endogenous glycosaminoglycans, such as heparan sulfate, also pro- trophils, monocytes, and lymphocytes, thereby blocking the adhesion
mote on the vessel wall AT-mediated inhibition of thrombin and other of these cells to endothelial cells, their activation and migration. This
coagulation enzymes. During severe inflammatory responses, AT levels effect, in turn, ameliorates the severity of capillary leakage and subse-
are markedly decreased because of impaired synthesis, degradation by quent organ damage.
elastase from activated neutrophils, and consumption as a consequence The protein C system also has an important function in modulat-
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of ongoing thrombin generation. Proinflammatory cytokines also ing inflammation. 75,76 Blocking the protein C pathway in septic baboons
cause reduced synthesis of glycosaminoglycans on the endothelial sur- exacerbates the inflammatory response, and in contrast, administration
face, thereby reducing AT function. 54 of APC ameliorates the inflammatory activation upon the intravenous
77
APC appears to play a central role in the pathogenesis of sepsis and infusion of E. coli. Support for the notion that APC has antiinflam-
associated organ dysfunction. There is ample evidence that decreased matory properties comes from in vitro observations, demonstrating an
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function of the protein C pathway contributes to the derangement of APC binding site on monocytes, that may mediate downstream inflam-
coagulation in sepsis. 49,56 The circulating zymogen protein C is activated matory processes, 78,79 and from experiments showing that APC can
by thrombin when it is bound to thrombomodulin at the endothelial cell block NF-κB nuclear translocation, which is a prerequisite for increased
surface. APC acts with its cofactor protein S and degrades the essen- proinflammatory cytokine levels and adhesion molecules. These
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80
tial cofactors Va and VIIIa, and hence, is an effective anticoagulant. The in vitro findings are supported by in vivo studies in mice with targeted
endothelial protein C receptor (EPCR) accelerates the activation of pro- disruption of the protein C gene. In these mice with genetic deficiencies
tein C several-fold, and also serves as a receptor for APC, thereby aug- of protein C, endotoxemia was associated with a more marked increase
menting APC’s anticoagulant and antiinflammatory activities. 58 in proinflammatory cytokines and other inflammatory responses as
In patients with severe inflammation, the protein C pathway mal- compared with wild-type mice. 81,82
functions at virtually all levels. Plasma levels of the zymogen protein C It is likely that the antiinflammatory effects of APC are mediated
75
are decreased because of impaired synthesis, consumption, and deg- by the EPCR. Binding of APC to EPCR influences gene expression
radation by proteolytic enzymes, such as neutrophil elastase. 59–61 Fur- profiles of cells by inhibiting NF-κB nuclear translocation. 79,80 The
thermore, a significant downregulation of thrombomodulin, caused EPCR-APC complex itself can translocate from the plasma membrane
by proinflammatory cytokines such as TNF-α and IL-1, results in into the cell nucleus, which may be another mechanism of modulat-
diminished protein C activation. 62,63 Low levels of free protein S may ing gene expression, although the relative contribution of this nuclear
further compromise the function of the protein C system. In plasma, translocation and cell surface signaling is uncertain. Like APC, EPCR
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60 percent of protein S is complexed with a complement regulatory itself may have antiinflammatory properties. Blocking the EPCR with a
protein, C4b-binding protein (C4bBP), and exhibits no activity. The specific monoclonal antibody aggravates both the coagulation and the
remaining protein S in plasma is free and functional. It was suggested inflammatory response to E. coli infusion. 65
that increased plasma levels of C4bBP caused by the acute phase reac- Apart from the effect on cytokine levels, APC causes diminished
tion in inflammatory diseases results in a relative protein S deficiency, leucocyte chemotaxis and adhesion to the activated endothelium. 83–85
which further contributes to a procoagulant state during sepsis. Indeed, A localized antiinflammatory effect of APC has been demonstrated
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infusion of C4bBP in combination with a sublethal dose of E. coli into in the lung. One mechanism for this effect may be inhibition of the
baboons resulted in a lethal response with severe organ damage because expression of platelet-derived growth factor in the lung. Also, APC
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of DIC. 64 protects against the disruption of endothelial cell barrier in sepsis. 88–90
In sepsis, the EPCR is downregulated, which further impairs the APC also inhibits endothelial cell apoptosis by a mechanism that seems
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function of the protein C pathway. Sepsis can also cause resistance to be mediated by binding of APC to EPCR and requires PAR-1. 91,92 Sig-
toward APC because of a substantial increase in factor VIII levels. 66 naling through this pathway can affect Bcl-2 homologue protein, which
A third inhibitory mechanism of thrombin generation involves can inhibit apoptosis, and further suppresses p53, that is a proapoptotic
TFPI, the main inhibitor of the TF–factor VIIa complex and factor Xa. transcription factor. 93,94
The role of TFPI in the regulation of inflammation-induced coagulation
activation is not completely clear. Administration of recombinant TFPI
blocks inflammation-induced thrombin generation in humans, and DYSREGULATION OF FIBRINOLYSIS
pharmacologic doses of TFPI prevent mortality during systemic infec- In experimental models of DIC, fibrinolysis is initially activated but
tion and inflammation in experimental animals suggesting that TFPI subsequently inhibited, because of an increased release of plasmino-
can modulate TF-mediated coagulation. 67,68 gen activator inhibitor-I (PAI-1) by endothelial cells. These effects are
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mediated by TNF-α and IL-1. 96,97 In a study of 69 DIC patients (31 with
NATURAL ANTICOAGULANTS multiorgan failure), higher levels of tissue-type plasminogen activator
(t-PA) antigen and PAI-1 with depressed levels of α -antiplasmin were
AND INFLAMMATION observed in patients with DIC and multiorgan failure compared to DIC
2
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AT possesses antiinflammatory properties, many of which are mediated patients without multiorgan failure. This finding supports the conclu-
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by its actions in the coagulation cascade. By inhibiting thrombin, AT sion that fibrinolysis is an important mechanism in preventing multi-
blunts activation of many inflammatory mediators released by plate- organ failure.
lets and endothelial cells that recruit and activate leukocytes. At high Experiments in mice with targeted disruptions of genes encod-
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concentrations, AT also possesses potent antiinflammatory properties ing components of the plasminogen–plasmin system confirm that
that are independent of its anticoagulant activity. Another effect of fibrinolysis plays a major role in inflammation. Mice with a deficiency
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AT is the induction of prostacyclin release from endothelial cells. 71–73 of plasminogen activators have more extensive fibrin deposition in

Kaushansky_chapter 129_p2199-2220.indd 2202 17/09/15 3:45 pm