Disseminated Intravascular Coagulation

1 What is disseminated intravascular coagulation (DIC)?

DIC occurs because of aberrant activation of the clotting cascade, leading to fibrin deposition in small vessels, combined with activation of fibrinolytic mechanisms, leading to bleeding. DIC is usually a common final hemostatic disorder caused by other conditions such as sepsis, pancreatitis, or trauma. Because they are consumed by the ongoing prothrombotic and fibrinolytic processes, coagulation proteins and platelets can become depleted, leading to bleeding. Thus, in DIC, hemorrhage and thrombosis can occur simultaneously. DIC can be an acute or a chronic disorder, and the latter is seen mostly in obstetric and oncology patients. Hereafter, the discussion will focus primarily on acute DIC, the form most likely to be encountered in the critical care setting.

2 Why is DIC important?

DIC is a common cause of concurrent thrombocytopenia and prolonged clotting times (activated partial thromboplastin time [aPTT] and prothrombin time [PT]) in hospitalized patients. It can also be an independent predictor of mortality. DIC leads to fibrin and platelet deposition in small vessels, which can cause tissue ischemia and result in organ dysfunction (Figure 56-1). The consumptive coagulopathy can also lead to clinically significant bleeding.

Figure 56-1 Microvascular thrombosis in skin of patient with severe disseminated intravascular coagulation. Lumen of blood vessel is partly occluded by fibrin-platelet thrombosis.

3 What is the pathophysiology of acute DIC?

Although the pathophysiology of DIC remains incompletely understood, it is thought to begin at the level of the microvasculature. As a result of widespread endothelial damage due to an underlying illness (i.e., sepsis, trauma, or pancreatitis), tissue factor is released into the circulation, where it combines with factor VIIa to produce thrombin via the extrinsic pathway. The thrombin activates platelets and cleaves fibrinogen such that platelets and fibrin are deposited in the microvasculature. Concurrently, fibrinolytic pathways are activated. As platelets and coagulation proteins are consumed, bleeding can occur as the result of a consumptive coagulopathy. Thus DIC is characterized by simultaneous clotting and hemorrhage.

4 In critical care patients, what conditions are associated with DIC?

5 How does DIC present clinically?

In acutely ill hospitalized patients, DIC usually presents with prolongation of the PT and aPTT along with decreased fibrinogen and platelets; systemic bleeding may or may not be present. Typically, bleeding manifests as ecchymoses, purpura, petechiae; it also occurs at surgical incisions or insertion sites of vascular access catheters. Mucosal and urinary bleeding are common, whereas pulmonary, gastrointestinal, and central nervous system bleeding occur less frequently. Because of widespread intravascular coagulation, tissue ischemia can occur, resulting in cyanosis, delirium, oliguria, hypoxia, and frank tissue necrosis (Figure 56-2).

Figure 56-2 Ischemic necrosis of fingers (A) and feet (B) of patient with disseminated intravascular coagulation as a result of bacterial sepsis.

6 What laboratory abnormalities are typical of acute DIC?

Thrombocytopenia; prolongation of the PT, aPTT, and thrombin time; and hypofibrinogenemia are characteristic. Early in the course of DIC, the platelet count may be in the normal range but is often decreased from baseline. Platelet counts are rarely less than 20,000/mcL. D-dimer and fibrin degradation product (FDP) levels are almost always markedly elevated. The haptoglobin level is variably affected and is not helpful in confirming the diagnosis of DIC.

7 Is the peripheral blood smear useful in the diagnosis of DIC?

The peripheral blood smear from a patient typically shows mild to moderate thrombocytopenia. The finding of schistocytes (red blood cell fragments created by intravascular hemolysis) (Figure 56-3) is neither sensitive nor specific, and schistocytes are present in only 10% to 50% of cases of acute DIC. If present in DIC, there are usually only one to four per high-power field, in contrast to thrombotic thrombocytopenic purpura where they are much more abundant.

Figure 56-3 Schistocytes in peripheral blood smear of patient with severe acute disseminated intravascular coagulation. Note also the absence of platelets.

8 What conditions make interpretation of laboratory abnormalities in DIC more difficult?

Fibrinogen is an acute-phase reactant. As such, it can be within the normal range in occasional patients with acute DIC, especially if an underlying inflammatory disorder exists; comparison with a baseline value would therefore be useful. In addition, the D-dimer can be chronically elevated in patients with cancer and in those with recent clots or liver disease (see later).

9 Why is it difficult to make the diagnosis of DIC in patients with advanced liver disease?

The liver produces most coagulation proteins, and most cases of advanced liver disease are characterized by a prolonged PT and aPTT with decreased fibrinogen. The liver is also responsible for clearing D-dimers, which are therefore often elevated in liver disease. Additionally, the platelet count may be reduced in patients with cirrhosis due to hypersplenism and reduced production of thrombopoietin by the liver.

10 When and how is DIC treated?

Because DIC tends to be secondary to other disorders, addressing the underlying disorder is the mainstay of treatment. Therapy is otherwise supportive. Blood products should be administered in cases of DIC complicated by clinically significant bleeding or a significantly elevated risk of bleeding (e.g., a patient with recent vascular surgery) and are not routinely required. Blood components should not be given solely in response to laboratory abnormalities.

11 How should blood products be administered in cases of acute DIC?

Platelet transfusions should be reserved for patients with signs of clinical bleeding; a platelet goal of >30,000/mcL with minor bleeding or >50,000/mcL with major bleeding is reasonable in DIC, except in patients with recent major neurosurgical procedures where platelet counts of >100,000/mcL may be required. Cryoprecipitate may be administered to keep the fibrinogen level >80 to 100 mg/dL. Fresh frozen plasma should be given only if clinically significant bleeding is present or if a significant risk for bleeding exists (e.g., for invasive procedures); it should not be used solely to correct a prolonged PT or aPTT. It should also be noted that international normalized ratio values of up to 1.7 are not associated with an increased risk for bleeding. Paradoxically, blood products are not associated with a worsening of DIC. See Figure 56-4 for additional details.

Figure 56-4 Treatment algorithm for disseminated intravascular coagulation.

12 Are there special causes of DIC that require specific treatment?

HELLP syndrome is a peripartum form of DIC, resulting in clinically significant hepatic injury and hemolytic anemia. In addition to supportive care, treatment for HELLP includes either delivery of the fetus or dilatation and curettage to remove retained fetal or placental fragments. Acute promyelocytic leukemia is almost always associated with DIC. In addition to appropriate transfusions for the treatment of DIC, urgent initiation of chemotherapy, which should include all-transretinoic acid, is indicated.

13 In what scenarios should heparin be considered for the treatment of DIC?

In cases of acute DIC characterized by clinically significant bleeding despite administration of blood products or in thrombotic DIC with digital ischemia, heparin may be considered. Heparin should be used with caution, as it can exacerbate bleeding. The rationale for using heparin is to limit microvascular clotting in DIC and thus correct the resultant consumptive coagulopathy. Use of heparin requires that the platelet count be maintained at >50,000/mcL and that there be no concurrent gastrointestinal or central nervous system bleeding. Heparin is contraindicated in conditions that require surgical management, such as retained uterine placental tissue. In addition, its use should be avoided in patients with placental abruption.

14 How should heparin be administered?

No bolus dose should be given. A continuous infusion of unfractionated heparin, 5 to 10 units/kg per hour, is reasonable, until the bleeding has lessened or stopped and/or the underlying clinical condition has been effectively treated. Low-molecular-weight heparin has not been adequately studied for the treatment of acute DIC complicated by bleeding, and its use cannot currently be recommended.

15 What other agents have been considered for use in DIC?

Fibrinolytic inhibitors, such as ε-aminocaproic acid (Amicar) and tranexamic acid, can be used to treat DIC-associated refractory bleeding by preventing systemic fibrinolysis. However, these inhibitors should be administered with caution in DIC as they can worsen systemic fibrin deposition. Combining their use with low-dose heparin infusion is one way to avoid converting a patient with hemorrhage into one with life-threatening thrombosis. In addition, no role exists for recombinant VIIa or activated plasma-derived clotting factors in the treatment of DIC.

16 How is the efficacy of DIC treatment evaluated?

Laboratory parameters, including the PT, aPTT, fibrinogen, and platelet count, should be followed and should return to baseline levels as the disorder is effectively treated. In addition, clinical bleeding should improve. The D-dimer should also decline with treatment but may remain persistently elevated from other causes (unresolved clot, liver failure). The time course of recovery from DIC is usually linked to recovery from the underlying illness.

17 What treatments are controversial in DIC?

Randomized trials in patients with DIC are lacking. Because DIC is associated with mortality in sepsis, recombinant activated protein C (drotrecogin alfa) was approved in 2001 for use in severe sepsis with organ failure. However, use of drotrecogin alfa is associated with an increased risk of bleeding, and the agent was withdrawn from the market in 2011 after follow-up studies failed to demonstrate efficacy.

18 What new treatments may be available in the future for DIC?

A number of treatments directed against either the aberrant coagulation or fibrinolysis seen in DIC have been proposed. Recently, recombinant thrombomodulin (which operates in the same pathway as protein C) has shown promising results in an unrandomized trial using historical controls. Antithrombin concentrate has also been evaluated in small uncontrolled trials but has not demonstrated benefit. Other agents that have been proposed for the treatment of DIC include recombinant tissue factor pathway inhibitor (failed to demonstrate efficacy in a phase III trial), recombinant factor VIIa (yet to undergo large randomized trials), recombinant hirudin (animal studies only), and recombinant nematode anticoagulant c2 (animal studies only).