Page 2328 - Hematology_ Basic Principles and Practice ( PDFDrive )

2070 Part XII Hemostasis and Thrombosis

is decreased. Thrombocytopenia is common because of hypersplen- which results in high concentrations of ultralarge von Willebrand
ism and decreased hepatic production of thrombopoietin. The simi- multimers in plasma. These large multimers promote platelet-vessel
larities between the hemostatic defects of liver disease and those of wall interaction, which can lead to thrombotic microangiopathy and
DIC have evoked controversy as to the contribution of DIC to the organ dysfunction. 14
coagulopathy of liver disease. Several laboratory and clinical observa- Although determination of the fibrinogen concentration has been
tions support the concept that DIC accompanies hepatic disorders. advocated as a useful tool for the diagnosis of DIC, this test is rarely
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These include a reduced half-life of radiolabeled fibrinogen that is helpful. Fibrinogen is as an acute-phase protein whose levels increase
reversed with heparin administration; failure of replacement therapy with inflammation. Therefore the fibrinogen level may remain within
to significantly increase the levels of hemostatic factors (suggesting the normal range for a long period of time despite ongoing consump-
ongoing consumption); and increased levels of markers of activation tion. In a consecutive series of patients, the sensitivity of a low
of coagulation. All of these findings are consistent with increased fibrinogen level for the diagnosis of DIC was 28%, and hypofibrino-
thrombin generation. Against the DIC hypothesis are the observa- genemia was only found in very severe cases of DIC.
tions that microthrombi are found in only 2% of the tissues from
patients who die of liver disease, and the fact that the increased
fibrinogen turnover can be explained by extravascular accumulation. Markers of Fibrin Generation and Degradation
Current thinking is that DIC is rare in patients with liver disease, but
such patients are sensitive to the triggers of DIC because of the Plasma levels of fibrin split products are frequently used for the
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decreased synthetic capacity of the diseased liver and its inability to diagnosis of DIC. Fibrin split products were detectable in 42% of
clear activated clotting factors. In patients who undergo peritoneove- consecutive patients in the intensive care unit, in 80% of trauma
nous shunting for ascites, those with underlying liver disease are more patients, and in 99% of patients with sepsis and DIC. The levels of
likely to develop DIC than those with normal liver function. fibrin degradation products (FDP) can be quantified by immunoas-
say. Latex agglutination assays can be used for rapid point-of-care
Disseminated Intravascular Coagulation With Toxic determination in emergency cases. None of the available FDP assays
discriminate between degradation products derived from cross-linked
Reactions or Snake Bites fibrin or from fibrinogen, which may cause spuriously high levels.
Therefore the FDP assay lacks specificity because in addition to DIC,
The venom of certain snakes, particularly vipers and rattlesnakes, can high levels can be found with trauma, recent surgery, inflammation,
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produce a coagulopathy similar to DIC. Prominent among these venous thromboembolism, and many other conditions. Because FDP
species are the Vipera, Echis (E. carinatus or E. coloratus), Aspis, are metabolized in the liver and cleared by the kidneys, FDP levels
Crotalus, Bothrops, and Agkistrodon. Venoms of these snakes contain are influenced by liver and kidney function.
enzymes or peptides that (1) release fibrinopeptide A (Agkistrodon D-dimer is a degradation product of cross-linked fibrin. Therefore
rhodostoma); (2) activate prothrombin even in the absence of calcium this test is not influenced by fibrinogen degradation products.
(E. carinatus); (3) activate factors X and V (Russell viper venom); (4) D-dimer levels are high in patients with DIC, but high levels can also
degrade fibrinogen (Agkistrodon acutus); (5) induce platelet aggrega- be found in patients with venous thromboembolism, recent surgery,
tion; (6) inhibit platelet aggregation because of the presence of or inflammatory conditions. Theoretically, soluble fibrin or fibrin
arginine-glycine-aspartic acid–containing peptides; (7) activate monomers would be useful markers of intravascular fibrin formation
protein C; and (8) damage endothelial cells which leads to bleeding, in DIC. Indeed, initial clinical studies suggest that if the soluble fibrin
tissue ischemia, and edema. Interestingly, victims of snake bites rarely concentration exceeds a threshold level, a diagnosis of DIC can be
have excessive bleeding or thromboembolism despite the abnormal made. Unfortunately there are no reliable tests to quantify plasma
coagulation tests and DIC-like picture. levels of soluble fibrin. Since plasma levels of soluble fibrin reflect
intravascular fibrin formation, the test is not influenced by extravas-
cular fibrin formation, which can occur with local inflammation or
LABORATORY MANIFESTATIONS trauma.
Thrombocytopenia or a rapidly declining platelet count is an impor-
tant diagnostic hallmark of DIC. However, only 35% to 44% of Endogenous Coagulation Inhibitors
critically ill patients develop thrombocytopenia (platelet count <150
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× 10 /L). Consequently, the specificity of thrombocytopenia for the Plasma levels of physiologic coagulation inhibitors, such as protein
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diagnosis of DIC is limited. A platelet count of <100 × 10 /L is C or antithrombin, may be useful indicators of ongoing activation of
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seen in 50% to 60% of patients with DIC, whereas 10% to 15% of coagulation. Reduced levels of these inhibitors are found in 40% to
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patients have a platelet count <50 × 10 /L. In surgical or trauma 60% of critically ill patients and in 90% of DIC patients.
patients with DIC, over 80% have platelet counts less than 100 × Levels of protein C may correlate with the severity of the DIC.
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10 /L. In patients with meningococcal septicemia, plasma levels of protein
Consumption of coagulation factors leads to low levels of coagula- C are markedly reduced, which likely contributes to the purpura
tion factors in patients with DIC. In addition, impaired hepatic fulminans that occurs in these patients. Downregulation of throm-
synthesis, for example due to impaired liver function or vitamin K bomodulin and reduced levels of protein S further compromise the
deficiency, and loss of coagulation proteins, due to massive bleeding, capacity to generate APC. Therefore it is not surprising the low levels
may also play a role in DIC. Although the accuracy of the measure- of protein C are a strong predictor of poor outcome in DIC patients.
ment of one-stage clotting assays in DIC has been contested (because Plasma levels of antithrombin also are reduced in patients with
of the presence of activated coagulation factors in plasma), the levels DIC. The low levels reflect consumption due to ongoing thrombin
of coagulation factors appear to correlate with the severity of the DIC. generation, decreased synthesis, and degradation by neutrophil elas-
The low levels of coagulation factors are reflected by prolonged global tase. Like protein C, low levels of antithrombin also a strong predictor
tests of coagulation, such as the PT and the aPTT. A prolonged PT of mortality in patients with sepsis and DIC.
or aPTT is found in 14% to 28% of intensive care patients but is
present in more than 95% of patients with DIC.
Plasma levels of factor VIII are paradoxically increased in most Fibrinolytic Markers
patients with DIC, probably due to massive release of von Willebrand
factor from the endothelium in combination with the acute phase Increased fibrinolytic activity in DIC can be monitored by measur-
behavior of factor VIII. Recent studies have pointed to a relative ing plasma levels of plasminogen and α 2-antiplasmin. Low levels
deficiency of ADAMTS-13, the von Willebrand cleaving protease, may indicate consumption of these proteins. The concentration of