Page 2325 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 139 Disseminated Intravascular Coagulation 2067

Va and VIIIa by proteolytic cleavage, thereby downregulating the levels of uPA. In contrast to wild-type mice challenged with endo-
coagulation cascade. Endothelial cells, primarily of large blood vessels, toxin, PAI-1 knockout mice do not develop thrombi in the kidney.
express endothelial protein C receptor (EPCR) on their surface. Endotoxin administration to mice with a functionally inactive
EPCR augments protein C activation by binding protein C and thrombomodulin gene (TMProArg mutation) and defective protein
presenting it to the thrombin–thrombomodulin complex on the cell C activator cofactor function caused fibrin plugs in the pulmonary
surface. APC has antiinflammatory effects on mononuclear cells and circulation, whereas wild-type mice did not develop macroscopic
granulocytes, which may be distinct from its anticoagulant activity. fibrin. This phenomenon in thrombomodulin deficient mice proved
Administration of APC prevented thrombin-induced thromboembo- to be temporary; thrombi developed 4 hours after endotoxin admin-
lism in mice, mainly through its antithrombotic effect. istration and disappeared at 24 hours in animals killed at that time
Defects in the protein C mechanism enhance the vulnerability to point. These experiments demonstrate that the fibrinolytic system is
inflammatory reactions and DIC. In patients, reduced levels of essential for clearance of intravascular fibrin.
protein C and protein S are associated with increased mortality. Mice Fibrinolytic activity is regulated by PAI-1, the principal inhibitor
with a one-allele targeted disruption of the protein C gene, causing of this system. Previous studies have shown that a functional muta-
heterozygous protein C deficiency, developed a more severe form of tion in the PAI-1 gene, the 4G/5G polymorphism, not only influ-
DIC and associated inflammatory response compared with their ences plasma levels of PAI-1, but also affects the clinical outcome of
wild-type counterparts. Blockade of protein C activity by infusion of meningococcal septicemia. Patients with the 4G/4G genotype had
C4 binding protein converted a sublethal model of E. coli in baboons significantly higher PAI-1 concentrations in plasma and an increased
into a lethal model. In addition, blockade of EPCR with a neutral- risk of death. Further investigations demonstrated that the PAI-1
izing monoclonal antibody also increased mortality in the E. coli polymorphism did not influence the risk of contracting meningitis,
baboon model, whereas infusion of PC protected against DIC and but probably increased the likelihood of developing septic shock from
lethality. Therefore the protein C pathway is important in the host meningococcal infection. These studies provide the first evidence that
defense against sepsis and DIC. In situations associated with DIC genetically determined differences in the level of fibrinolysis influence
and systemic inflammation, cell culture experiments suggest that the risk of developing complications of gram-negative infection. In
TNF-α and IL-1 may downregulate thrombomodulin expression. other clinical studies in cohorts of patients with DIC, high plasma
However, in vivo studies suggest that EPCR is upregulated in sepsis; levels of PAI-1 were one of the best predictors of mortality. These
an effect mediated by thrombin. The generation of thrombin may data suggest that DIC contributes to mortality in this situation, but
also trigger EPCR shedding due to the activation of metalloprotein- as indicated earlier, because PAI-1 is an acute-phase protein, higher
ases by thrombin. It is presently unknown whether thrombomodulin plasma levels may also be a marker of disease rather than a causal
is also cleaved by similar mechanisms. factor.
TFPI provides a third inhibitory mechanism. TFPI exists in
several pools including endothelial cell associated and lipoprotein
bound in plasma. It inhibits the TF–factor VIIa complex by forming CLINICAL MANIFESTATIONS
a quaternary complex in which factor Xa is the fourth component.
Clinical studies in patients with sepsis have not provided clues as to The clinical manifestations of DIC vary depending on the underlying
its importance because in the majority of patients the TFPI levels are disorder. At the extreme end of the spectrum is acute, severe DIC,
normal. This may be explained by the lack of downregulatory effects which often occurs in the setting of sepsis, major trauma, obstetric
of inflammatory mediators on cultured endothelial cells. The relevance calamities, and severe immunologic responses. Diffuse multiorgan
of TFPI in DIC is illustrated by two lines of experimentation. First, bleeding, hemorrhagic necrosis, microthrombi in small blood vessels,
depletion of TFPI sensitizes rabbits to DIC induced with tissue factor and thrombi in medium and large blood vessels are common find-
infusion. Second, TFPI infusion protects against the harmful effects ings at autopsy, although patients with unequivocal clinical and
of E. coli in primates. TFPI not only blocks DIC in baboons given laboratory signs of DIC may not have confirmatory postmortem
lethal doses of E. coli, but improves vital functions and survival. A findings. Conversely, some patients in whom clinical and laboratory
study in human volunteers confirmed the potential of TFPI to block signs were not consistent with DIC have typical autopsy findings.
the procoagulant effects of endotoxin. Although this occasional lack of correlation among clinical, labora-
In general, normal levels and function of inhibitors is important tory, and pathologic findings can partly be explained by excessive
in the defense against DIC. It should be noted, however, that there fibrinolysis post mortem, this does not account for all cases. The
are no strong indications that patients with congenital deficiencies of organs most frequently involved by diffuse microthrombi are the
inhibitors are at increased risk of DIC, but this issue requires greater lungs and kidneys, followed by the brain, heart, liver, spleen, adrenal
exploration. In addition, the capacity of inhibitors to modify the glands, pancreas, and gut. Specific immunohistological techniques
interaction between coagulation and inflammation deserves further and ultrastructural analysis have revealed that most thrombi consist
attention. of fibrin monomers or polymers in combination with platelets. In
addition, involvement of activated mononuclear cells and other
signs of inflammation are frequently present. In cases of long-lasting
Fibrinolysis DIC, organization and endothelialization of the microthrombi are
often observed. Acute tubular necrosis is more frequent than renal
In experimental models of DIC, fibrinolysis is activated, demon- cortical necrosis. Clinically, thrombotic occlusive events occur first
strated by an initial activation of plasminogen, followed by impair- as a consequence of microvascular obstruction by microthrombi
ment caused by the release of type 1 plasminogen activator inhibitor consisting of fibrin or platelets. These thrombi result from clots that
(PAI-1). This results in a net procoagulant state. The molecular basis form either in the circulation or in situ in arterioles, capillaries, or
for this procoagulant state is cytokine-mediated activation of vascular venules. Circulatory obstruction reduces organ perfusion and may
endothelial cells, thus TNF-α and IL-1 decrease tPA production and lead to ischemia, infarction, and necrosis. The process is disseminated
increase PAI-1 production. Although TNF-α increases urokinase throughout the microcirculation, therefore all organs are potentially
type plasminogen activator (uPA) production by endothelial cells, vulnerable.
endotoxin and TNF-α stimulate PAI-1 production in the liver, In contrast to acutely ill patients with severe DIC, others may
kidney, lung, and adrenals of mice. have mild or protracted clinical manifestations of consumption or
1
The net procoagulant state is manifested by a late rise in fibrin even subclinical disease manifested only by laboratory abnormalities.
breakdown fragments after E. coli challenge in baboons. Experimental The clinical picture of subacute to chronic DIC generally occurs in
data also suggest that the fibrinolytic mechanism is active in clearing patients with malignancy, in particular those with mucin-producing
fibrin from organs and the circulation. Endotoxin-induced fibrin adenocarcinomas or acute promyelocytic leukemia (APL). The latter
formation in the kidneys and adrenals is most dependent on decreased usually is dominated by a hemorrhagic presentation, whereas venous