In the normal person, the process of coagulation is finely controlled at many levels to ensure the appropriate amount of hemostasis at the appropriate location. Broadly defined, disseminated intravascular coagulation (DIC) is the name given to any process that disrupts this fine tuning, leading to unregulated coagulation. Defined this way, DIC may be found in a variety of patients with a variety of disease states, and can present with a spectrum of findings ranging from asymptomatic abnormal laboratory results to florid bleeding or thrombosis. It is important to remember that DIC is always a consequence of an underlying pathological process and not a disease in and of itself. This article first reviews concepts common to all forms of DIC, and then reviews the more common disease states that lead to DIC.
At the most basic level, DIC is the clinical manifestation of inappropriate thrombin activation.1–5 Inappropriate thrombin activation can be due to underlying conditions such as sepsis and obstetric disasters. The activation of thrombin leads to (1) conversion of fibrinogen to fibrin, (2) activation of platelets (and their consumption), (3) activation of factors V and VIII, (4) activation of protein C (and degradation of factors Va and VIIIa), (5) activation of endothelial cells, and (6) activation of fibrinolysis (Table 1). Thus, with excessive activation of thrombin one can see the following processes:
1. Conversion of fibrinogen to fibrin, which leads to the formation of fibrin monomers and excessive thrombus formation. These thrombi are rapidly dissolved by excessive fibrinolysis in most patients. In certain clinical situations, especially cancer, excessive thrombosis will occur. In patients with cancer, this is most often a deep venous thrombosis. Rare patients, especially those with pancreatic cancer, may have severe DIC with multiple arterial and venous thromboses. Nonbacterial thrombotic endocarditis can also be seen in these patients, leading to widespread embolic complications.
2. Activation of platelets and their consumption. Thrombin is the most potent physiologic activator of platelets, so in DIC there is increased activation of platelets. These activated platelets are consumed, resulting in thrombocytopenia. Platelet dysfunction is also present. Platelets that have been activated and have released their contents but still circulate are known as “exhausted” platelets; these cells can no longer function to support coagulation. The fibrin degradation products (FDP) in DIC can also bind to GP IIb/IIIa and inhibit further platelet aggregation.
3. Activation of factors V, VIII, XI, and XIII. Activation of these factors can promote thrombosis, but they are then rapidly cleared by antithrombin (XI) or activated protein C (V and VIII) or by binding to the fibrin clot (XIII). This can lead to depletion of all the prothrombotic clotting factors and antithrombin, which in turn can lead to both thrombosis and bleeding.
4. Activation of protein C further promotes degradation of factors Va and VIIIa, enhances fibrinolysis, and decreases protein C levels.
5. Activation of endothelial cells, especially in the skin, may lead to thrombosis, and in certain patients, especially those with meningococcemia, purpura fulminans. Endothelial damage will down-regulate thrombomodulin, preventing activation of protein C and leading to further reductions in levels of activated protein C.56. Activation of fibrinolysis leads to the breakdown of fibrin monomers, formation of fibrin thrombi, and increased circulating fibrinogen. In most patients with DIC, the fibrinolytic response is brisk.6 This is why most patients with DIC present with bleeding and prolonged clotting times.
PATTERNS OF DIC
The clinical manifestations of DIC in a given patient depend on the balance of thrombin activation and secondary fibrinolysis plus the patient’s ability to compensate for the DIC. Patients with DIC can present in 1 of 4 patterns:1–3
1. Asymptomatic. Patients can present with laboratory evidence of DIC but no bleeding or thrombosis. This is often seen in patients with sepsis or cancer. However, with further progression of the underlying disease, these patients can rapidly become symptomatic.
2. Bleeding. The bleeding is due to a combination of factor depletion, platelet dysfunction, thrombocytopenia, and excessive fibrinolysis.1 These patients may present with diffuse bleeding from multiple sites (eg, intravenous sites, areas of instrumentation).
3. Thrombosis. Despite the general activation of the coagulation process, thrombosis is unusual in most patients with acute DIC. The exceptions include patients with cancer, trauma patients, and certain obstetrical patients. Most often the thrombosis is venous, but arterial thrombosis and nonbacterial thrombotic endocarditis have been reported.7
4. Purpura fulminans. This form of DIC is discussed in more detail later (see Specific DIC Syndromes section).
There is no one test that will diagnose DIC; one must match the test to the clinical situation (Table 2).8