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

organs when challenged with endotoxin, whereas PAI-1 knockout mice, Endogenous lipid levels may have similar effects. Human subjects
in contrast to wild-type controls, have no microvascular thrombosis with low endogenous HDL-cholesterol plasma levels injected with small
upon endotoxin administration. 99 doses of endotoxin had a more pronounced increase in markers of coag-
TAFI, like PAI-1, may play a role in impeding fibrinolysis and ulation activation in comparison with subjects with high endogenous
in augmenting formation of microvascular thrombi. Studies in a DIC HDL levels. Also, patients heterozygous for familial hypercholester-
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cohort demonstrated very low levels of TAFI proportionate to thrombin olemia whose low-density lipoproteins level is increased were more
generation in such patients, particularly in those with infection- prone to activation of coagulation upon an inflammatory stimulus. 108
100
associated DIC. Hence, TAFI may contribute (along with PAI-1) to Hyperglycemia and hyperinsulinemia, as seen in type 2 diabetes
microvascular thrombosis-induced ischemia in organs resulting in mellitus and the associated metabolic syndrome, affect hemostasis. 109–111
multiorgan dysfunction. In these circumstances, there is a marked decrease of endogenous
fibrinolysis because of increased upregulation of plasma levels of PAI-1.
ROLE OF OXIDATIVE STRESS AND VASOACTIVE Also, a modulatory effect of glucose/insulin on coagulation in an
MOLECULES inflammatory setting has been described. Inflammation-induced TF
gene expression was elevated in the brain, lung, kidney, heart, liver, and
Superoxides and hydroxyl radicals are generated during sepsis and adipose tissues of diabetic mice compared with controls. Administra-
other organ injury states that predispose to DIC. Each is a proinflam- tion of insulin to lean mice induced enhanced inflammation-driven TF
matory agent that may lead to recruitment of neutrophils, formation mRNA in the kidney, brain, lung, and adipose tissue. In a hyperglyce-
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of chemotactic factors, lipid peroxidation, and stimulation of NF-κB, mic normoinsulinemic study in healthy subjects, there was an increased
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which induces cytokine upregulation. In addition, formation of per- sensitivity toward endotoxin exhibited by upregulation of TF expres-
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oxynitrite by these radicals exacerbates inflammation by (1) deacti- sion. Strict glucose regulation in critically ill patients improves sur-
vating superoxide dismutase, which ordinarily would eliminate these vival and reduces morbidity that is probably related to a better control
superoxides and other radicals, and (2) exerting damaging effects on of the derangement of coagulation and a faster resolution of coagulation
deoxyribonucleic acid, nicotinamide adenine dinucleotide, and ATP. abnormalities. 103
For example, evidence indicates that the poor response to pressors in
shock-like states associated with DIC may be directly related to their CONSUMPTION OF HEMOSTATIC FACTORS
deactivation by superoxides. The widespread generation of thrombin in DIC induces deposition of
Adding further insult, high levels of superoxide impair vascular fibrin, which leads to the consumption of substantial amounts of plate-
response to nitrous oxide, thereby creating an imbalance in the signal- lets, fibrinogen, factors V and VIII, protein C, AT, and components of
ing to vascular cells. Because of the strategic importance of an intact the fibrinolytic system. This situation results in massive depletion of
endothelium for attenuating any microangiopathic process, the most these components that is further aggravated because of their decreased
devastating effect of excessive generation of superoxides and associated synthesis by the liver, which frequently is affected in DIC. Depend-
free radicals may be their role in inducing endothelial apoptosis, which ing on the magnitude and nature of component depletion, bleeding,
exacerbates capillary leak. 101 enhanced thrombosis, or both can result. Bleeding can be promoted
Vasoactive substances play a critical role in the evolution of DIC. by fibrinolysis-derived fibrin degradation products (FDPs) that exhibit
The vasodilatory agent nitric oxide (NO) and the vasoconstrictor endo- anticoagulant and antiplatelet aggregation effects (see Fig. 129–1).
thelin have been measured in experimental rat models of DIC induced Microangiopathic hemolytic anemia also occurs as a result of blood
by both TF infusion and lipopolysaccharide (LPS) infusion. LPS cells passing through vessels that are partially occluded by thrombi.
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infusion increased both NO and endothelin remarkably, whereas TF
infusion increased NO more than did LPS but did not stimulate endo-
thelin significantly. The differential stimuli–response mechanisms may CLINICAL FEATURES
explain why LPS-induced DIC so prominently displays tissue infarction
leading to multiorgan dysfunction (e.g., sepsis) compared to DIC that is Numerous disorders can provoke DIC, but only a few constitute
predominately induced by TF exposure (e.g., head trauma). major causes, as can be inferred from retrospective clinical studies
(Table 129–1). Infectious diseases and malignant disorders together
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account for approximately two-thirds of DIC cases in the major series
METABOLIC MODULATION OF COAGULATION (Table 129–2). Trauma was a major cause of DIC in some series, probably
IN DISSEMINATED INTRAVASCULAR reflecting the specialized nature of the clinical practice in those centers. 115
COAGULATION Clinical manifestations are attributable to DIC, the underlying dis-
Because there is a tight relationship between plasma lipoproteins and ease, or both (Table 129–3). Bleeding manifestations were common in
all series of DIC cases, but considerable variation existed in the relative
coagulation, it has been suggested that lipoprotein metabolism mod- frequency of shock and of dysfunction of the liver, kidney, lungs, and
ulates coagulation in DIC. In vitro experiments showed that plasma central nervous system. These variations probably reflect the different
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large very-low-density lipoprotein, small very-low-density lipoprotein, nature of the underlying disorders in the respective series.
intermediate-density lipoprotein, and low-density lipoprotein stimulate
activation of coagulation by supporting factor VII activation or by stim-
ulating monocytes to express TF. Lipid infusion potentiates in animals BLEEDING
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endotoxin-induced coagulation activation, as indicated by increased Acute DIC frequently is heralded by hemorrhage into the skin at mul-
plasma levels of prothrombin fragments 1 and 2, thrombin–AT III tiple sites. Petechiae, ecchymoses, and oozing from venipunctures,
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complex, and PAI-1. High-density lipoprotein (HDL) exerts opposite arterial lines, catheters, and injured tissues are common. Bleeding also
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effects. Administration of recombinant HDL (rHDL) ameliorates the may occur on mucosal surfaces. Hemorrhage may be life-threatening,
inflammatory response, inhibits coagulation, and augments fibrinoly- with massive bleeding into the gastrointestinal tract, lungs, central ner-
sis, as reflected by reduced thrombin generation and increased levels vous system, or orbit. Patients with chronic DIC usually exhibit only
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of t-PA antigen following administration of endotoxin. minor skin and mucosal bleeding.

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