Disseminated Intravascular Coagulation: An Update on Pathogenesis, Diagnosis, and Therapeutic Strategies

Abstract

Disseminated intravascular coagulation (DIC) is an acquired clinicobiological syndrome characterized by widespread activation of coagulation leading to fibrin deposition in the vasculature, organ dysfunction, consumption of clotting factors and platelets, and life-threatening hemorrhage. Disseminated intravascular coagulation is provoked by several underlying disorders (sepsis, cancer, trauma, and pregnancy complicated with eclampsia or other calamities). Treatment of the underlying disease and elimination of the trigger mechanism are the cornerstone therapeutic approaches. Therapeutic strategies specific for DIC aim to control activation of blood coagulation and bleeding risk. The clinical trials using DIC as entry criterion are limited. Large randomized, phase III clinical trials have investigated the efficacy of antithrombin (AT), activated protein C (APC), tissue factor pathway inhibitor (TFPI), and thrombomodulin (TM) in patients with sepsis, but the diagnosis of DIC was not part of the inclusion criteria. Treatment with APC reduced 28-day mortality of patients with severe sepsis, including patients retrospectively assigned to a subgroup with sepsis-associated DIC. Treatment with APC did not have any positive effects in other patient groups. The APC treatment increased the bleeding risk in patients with sepsis, which led to the withdrawal of this drug from the market. Treatment with AT failed to reduce 28-day mortality in patients with severe sepsis, but a retrospective subgroup analysis suggested possible efficacy in patients with DIC. Clinical studies with recombinant TFPI or TM have been carried out showing promising results. The efficacy and safety of other anticoagulants (ie, unfractionated heparin, low-molecular-weight heparin) or transfusion of platelet concentrates or clotting factor concentrates have not been objectively assessed.

Keywords: activated protein C; antithrombin; disseminated intravascular coagulation; sepsis; thrombomodulin; tissue factor pathway inhibitor.

Figure 1.

Pathogenetic pathways in DIC. Activation of coagulation is driven by TF overexpression leading to explosive and disseminated thrombin generation, which results in consumption of natural coagulation inhibitors (mainly AT and PC) and in a hypercoagulable state. Thrombin, among other inducers, enhances platelet activation. Activated platelets amplify hypercoagulable state. Inhibition of fibrinolysis, through TAFI activation, increases fibrin formation and deposition in the microvasculature. This mechanism—among others—is implicated in the pathogenesis of organ dysfunction and multi-organ failure. Sustained thrombin generation has, as a consequence, the consumption of clotting factors, platelets, and fibrinogen. Severe clotting factor and fibrinogen deficiency together with severe thrombocytopenia are in the origin of the hemorrhagic syndrome in DIC. AT indicates antithrombin; DIC, disseminated intravascular coagulation; PC, protein C; TF, tissue factor.