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2212 Part XII: Hemostasis and Thrombosis Chapter 129: Disseminated Intravascular Coagulation 2213

Intensive support of vital functions is required. Volume replace- shock, or both. All trials have shown some beneficial effect in terms
ment and correction of hypotension, acidosis, and oxygenation may of improvement of laboratory parameters, shortening of the duration
improve blood flow and oxygen delivery to the microcirculation. of DIC, or even improvement in organ function. 6,321,322 In several small
Careful monitoring of pulmonary, cardiac, and renal function enables clinical trials, use of very high doses of AT concentrate showed a modest
prompt institution of supportive measures, such as use of a respirator for reduction in mortality, but without being statistically significant. 323–325
respiratory support, inotropic and vasoactive drugs for improvement of A large-scale, multicenter, randomized controlled trial also showed no
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organ perfusion, renal function, and maintenance of electrolyte balance. significant reduction in mortality of patients with sepsis. Interestingly,
post hoc subgroup analyses of the latter study indicated some benefit in
BLOOD COMPONENT THERAPY patients who did not receive concomitant heparin, but this observation
Treatment of the underlying disease and vital support are necessary but needs validation. In a small randomized trial in patients with burns and
usually insufficient to treat DIC or forestall progression of nonovert DIC, AT administration decreased mortality, reduced multiple organ
DIC to overt DIC. Additional supportive treatment directly aimed at failure, and improved coagulation parameters compared to placebo-
327
the coagulation system may be required. These interventions include control patients.
replacing the coagulation factors, natural anticoagulant, fibrinolytic Because a decreased function of the protein C system contributes
proteins, and platelets that are actively consumed during DIC. 317 to the pathogenesis of DIC, therapy by an APC concentrate was pre-
328
Low levels of platelets and coagulation factors may increase the risk dicted to be beneficial. Indeed, a dose-ranging controlled trial using
of bleeding. However, plasma or platelet substitution therapy should not continuous infusion of recombinant human APC disclosed that a dose
be instituted on the basis of laboratory results alone; it is indicated only of 24 mcg/kg per hour was optimal, judged by a decrease of D-dimer
329
in patients with active bleeding and in those requiring an invasive pro- level in plasma. A subsequent phase III trial of APC concentrate in
cedure or are at risk for bleeding complications. 318,319 The suggestion that patients with sepsis was prematurely stopped because of efficacy in
330
administration of blood components might “add fuel to the fire” has reducing mortality in these patients. All-cause mortality at 28 days
never been proven in clinical or experimental studies. The presumed after inclusion was 24.7 percent in the APC group versus 30.8 percent
efficacy of treatment with plasma, fibrinogen concentrate, cryopre- in the control group (a 19.4 percent relative risk reduction). Amelio-
cipitate, or platelets is not based on randomized controlled trials but ration of coagulation abnormalities and less organ failure were noted
331
appears to be rational therapy in bleeding patients or in patients at risk in patients who received the concentrate. However, meta-analyses
of bleeding who have a significant depletion of these hemostatic fac- of subsequent trials concluded that the basis for treatment with APC,
332,333
tors. One of the major challenges of infusion of fresh-frozen plasma in even in patients with a high disease severity, was not very strong.
319
these dire circumstances is the propensity of the added volume, which is A recently completed placebo-controlled trial in patients with severe
necessary to correct the coagulation defect, to exacerbate capillary leak. sepsis and septic shock was prematurely stopped because of the lack
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This situation can increase the risk of inducing or worsening pulmo- of any significant benefit of APC. Subsequently, the manufacturer of
nary edema and, by extension, predispose to ARDS, and induce ascites. APC has decided to withdraw the product from the market, which has
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Coagulation factor concentrates, such as prothrombin complex concen- resulted in a revision of current guidelines for treatment of DIC.
trate, may partially overcome this obstacle, but do not contain essen-
tial factors, such as factor V. Moreover, caution is advocated with the HEPARIN ADMINISTRATION AND OTHER
use of prothrombin complex concentrates in DIC, as it may worsen the ANTICOAGULANTS
coagulopathy because of traces of activated factors that are present in
these concentrates. Specific deficiencies of coagulation factors, such as Although the question of heparin therapy in patients with DIC has
fibrinogen, may be corrected by administration of purified coagulation been studied by several investigators, this therapy remains controver-
factor concentrates. sial. Experimental studies show that heparin can at least partly inhibit
Platelet transfusion is often required in patients with DIC to pre- the activation of coagulation in DIC. 336,337 However, a beneficial effect
vent bleeding into already ischemic or damaged organs (particularly of heparin on clinically important outcome events in patients with
338
the central nervous system). The threshold platelet count that should DIC has not been demonstrated in controlled clinical trials. Also, the
prompt transfusion is patient and disease specific. Cryoprecipitate can safety of heparin treatment is debatable in DIC patients who are prone
be used to rapidly raise the fibrinogen and factor VIII levels, particularly to bleeding. A large trial in patients with severe sepsis showed a slight,
when bleeding is part of the DIC and fibrinogen level is less than 1 g/L. but nonsignificant benefit, of low-dose heparin on 28-day mortality in
Cryoprecipitate has at least four to five times the mass of fibrinogen patients with severe sepsis. 339
per milliliter of infusate compared to fresh-frozen plasma. Fresh-fro- Notwithstanding these considerations, administration of heparin
zen plasma contains fibrinogen in sufficient amounts for treatment of is beneficial in some categories of chronic DIC, such as metastatic car-
patients with mild to moderate hypofibrinogemia. cinomas, purpura fulminans, and aortic aneurysm (prior to resection).
Replacement therapy for thrombocytopenia should consist of 5 to Heparin also is indicated for treating thromboembolic complications in
10 units of platelet concentrate or single-donor apheresis-derived plate- large vessels and before surgery in patients with chronic DIC (see Fig.
lets to raise the platelet count to 20 to 30 × 10 /L, and in patients who 129–4). Heparin administration may be helpful in patients with acute
9
need an invasive procedure, to 50 × 10 /L. DIC when intensive blood component replacement fails to improve
9
excessive bleeding or when thrombosis threatens to cause irrevers-
RESTORATION OF PHYSIOLOGIC ible tissue injury (e.g., acute cortical necrosis of the kidney or digital
gangrene).
ANTICOAGULANT PATHWAYS Heparin should be used cautiously in all these conditions. In
Because the levels of the physiologic anticoagulants are reduced in patients with chronic DIC because of metastatic carcinoma or aortic
patients with DIC, restoration of these inhibitors may be a rational aneurysm, continuous infusion of heparin 500 to 750 U/h without a
approach. 49,320 Based on successful preclinical studies, the use of AT con- bolus injection may be sufficient. If no response is obtained within 24
centrates and heparin in patients with DIC has been examined mainly in hours, escalating dosages can be used. In hyperacute DIC cases, such
randomized controlled trials, that included patients with sepsis, septic as mismatched transfusion, amniotic fluid embolism, septic abortion,

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