Disseminated Intravascular Coagulopathy

Pathophysiology

To maintain normal hemostasis, three primary components of the coagulation system—vascular integrity, coagulation factors, and platelets—are very well coordinated to result in a delicate balance between bleeding (anticoagulation) and clotting (procoagulation). Any disruption of this balance can cause DIC. The most common conditions underlying DIC are sepsis and cancer; other less common causes include significant trauma and burns, obstetrical complications (e.g., retained products of conception, placental abruption), large vascular malformations, severe allergic reactions, and envenomation. Any of these conditions can cause a generalized, unregulated activation of the coagulation system leading to widespread thrombin generation and deposition of fibrin-rich microthrombi throughout the circulation. Resultant obstruction of microvasculature causes hypoxic end-organ damage, mainly to the vital organs such as liver, kidney, and brain. Additionally, excessive consumption of endogenous anticoagulant proteins (protein C, protein S, and antithrombin [AT]), and disruption of hemostatic anticoagulant pathways, contributes to the coagulation disarray. This is aggravated by the relative insufficiency of the fibrinolytic system to clear the microthrombi from the circulation.

During normal hemostasis, tissue factor (TF) expression is restricted to the surface of cells not exposed to flowing blood (subendothelium, fibroblasts). Microvascular injury exposes TF to circulating FVII, initiating coagulation. In DIC, inflammatory cytokines (TNF-alpha, IL-1, IL-6) induce intravascular monocytes and macrophages to express TF. This intravascular expression of TF initiates exaggerated, pathologic coagulation, ultimately leading to the depletion of coagulation factors, which in turn can predispose to hemorrhage. It is this simultaneous development of pathologic thrombosis and hemorrhage that is the hallmark of DIC. The generation of thrombin also leads to the exposure of negatively charged phospholipids on the surface of platelets, which plays a role in sustaining thrombin generation, in addition to the platelet microparticles generated by cell damage.

Clinical Manifestations

Clinical presentation of DIC is heterogeneous and to some extent, reflective of the underlying pathophysiology. Severity ranges from isolated laboratory derangements (often referred to as compensated or nonovert DIC) to multiorgan failure and death, indicative of the dynamic nature of DIC. Microvascular occlusion leads to renal, cardiac, central nervous system, and/or pulmonary failure. Digital gangrene and purpura fulminans can occur as a result of widespread skin necrosis. A subset of patients present with primarily hemorrhagic symptoms, most commonly, generalized mucocutaneous bleeding. Mortality rates are high, ranging from 34% to 86%.

Diagnosis

There is no gold standard single test for the diagnosis of DIC. The presence of a triggering condition, clinical signs/symptoms, and supportive laboratory data aids in the diagnosis, and this can be supported by the use of a five-step scoring algorithm developed by the ISTH ( Fig. 124.1 ). This scoring system was designed to assist in diagnosis and to be utilized as a reference standard. Since its inception, it has proven both sensitive and specific for the diagnosis of overt DIC, and increasing scores strongly correlate with patient mortality.

The complete blood count is used to assess platelet number and the degree of anemia associated with the underlying illness. In more advanced DIC, the peripheral smear will show evidence of thrombotic microangiopathy (schistocytes, thrombocytopenia, anemia). Varying degrees of thrombocytopenia may be present in DIC; however, thrombocytopenia may also be present as a result of many of the underlying causes of DIC such as malignancy or sepsis.

The activated partial thromboplastin time (aPTT) and prothrombin time (PT) are in vitro measurements of the coagulation pathway and can be used to assess factor activation and consumption during DIC. In nearly half of the patients, aPTT and PT would be normal or shortened, reflecting the accelerated thrombin generation phase of DIC. The PT is typically more affected than the PTT in patients with DIC.

Fibrinogen levels below 150 mg/dL are typically the result of consumption (e.g., DIC) or decreased production (e.g., liver failure). Levels less than 100 mg/dL significantly increase the risk of bleeding. Fibrinogen is also an acute-phase reactant, and caution must be used when interpreting fibrinogen levels in early DIC, where plasma levels can remain normal or even be elevated.

The thrombin time measures the time to conversion of fibrinogen to fibrin. Decreased concentrations of fibrinogen, decreased clearance of fibrin degradation products, and the presence of heparin prolong the thrombin time.

Fibrin degradation products (FDPs) are formed when fibrinogen, cross-linked fibrin, and non–cross-linked fibrin are degraded by plasmin. The extent of fibrin formation in DIC can be assessed indirectly by the generation of FDPs. D-dimers are a result of plasmin breakdown of cross-linked fibrin and are proposed by the ISTH as the FDP marker of choice when diagnosing DIC. The D-dimer test has a high negative predictive value but is limited by a low positive predictive value.

Levels of the endogenous coagulation inhibitor AT are typically decreased in DIC. Levels less than 80% may be associated with thrombosis. Protein C and S may also be reduced in patients with DIC. The current ISTH criteria concluded that routine testing of these parameters showed no additional value to the 4 test scoring system. However, in selected circumstances, testing may prove beneficial.