The pathophysiology, diagnosis, and management of sepsis-associated disseminated intravascular coagulation

Abstract

Background: The International Society on Thrombosis and Haemostasis (ISTH) released overt disseminated intravascular coagulation (DIC) diagnostic criteria in 2001. Since then, DIC has been understood as the end-stage consumptive coagulopathy and not the therapeutic target. However, DIC is not merely a decompensated coagulation disorder, but also includes early stages with systemic activation in coagulation. Thus, the ISTH has recently released sepsis-induced coagulopathy (SIC) criteria that can diagnose compensated-phase of coagulopathy with readily available biomarkers.

Main body: DIC is a laboratory-based diagnosis due to various critical conditions, although sepsis is the most common underlying disease. The pathophysiology of sepsis-associated DIC is multifactorial, and in addition to coagulation activation with suppressed fibrinolysis, multiple inflammatory responses are initiated by activated leukocytes, platelets, and vascular endothelial cells as part of thromboinflammation. Although overt DIC diagnostic criteria were established by ISTH to diagnose the advanced stage of DIC, additional criteria that can detect an earlier stage of DIC were needed for potential therapeutic considerations. Accordingly, the ISTH introduced SIC criteria in 2019 that are easy to use and require only platelet count, prothrombin time-international normalized ratio, and Sequential Organ Failure Assessment Score. SIC score can be used to evaluate disease severity and determine the timing of potential therapeutic interventions. One of the major disadvantages in treating sepsis-associated DIC is the lack of availability of specific therapeutic approaches beyond treating the underlying infection. Clinical trials to date have failed because included patients who were not coagulopathic. Nevertheless, in addition to infection control, anticoagulant therapy will be the choice for sepsis-associated DIC. Therefore, the efficacy of heparin, antithrombin, and recombinant thrombomodulin has to be proven in future clinical studies.

Conclusion: It is necessary to develop a novel therapeutic strategy against sepsis-associated DIC and improve the outcomes. Consequently, we recommend screening and monitoring DIC using SIC scoring system.

Keywords: Antithrombin; Coagulopathy; Disseminated intravascular coagulation; Endothelial cell; Sepsis; Thrombomodulin.

Fig. 1

The initiation and progression of thromboinflammation in sepsis. The inflammation and host responses to infection induce coagulation disorder in sepsis. Although coagulation disorder is a part of host defense, excess coagulation disorder can be harmful to the host. Disseminated intravascular coagulation (DIC) is a systemic coagulation disorder that can cause the disturbance of tissue malcirculation and subsequent organ dysfunction. Sepsis-induced coagulopathy (SIC) is an early phase of DIC and a potential target of anticoagulant therapy. The advanced stage of DIC is defined as overt DIC and potentially the target of supplementation therapy

Fig. 2

Microthrombosis in the microcirculation in sepsis model of rat. Rat mesenteric microcirculation was observed under the intravital microscope after lipopolysaccharide injection. Round stiff leukocytes adhered to the unsmooth and swelled endothelial cells. Some leukocytes transmigrated to the extravascular space. Aggregated platelets stick to the leukocytes and endothelium and form leukocyte–platelet aggregation. Along with these changes, the blood flow gradually decreased

Fig. 3

Pathophysiology of sepsis-associated coagulation disorder. Monocytes, neutrophils, and platelets express various receptors such as Toll-like receptors (TLRs), Fcγ receptor (FcγR), and protease-activated receptor (PAR)-1, and induce inflammatory and procoagulant responses in these cells. Activated monocytes express tissue factor (TF) and phosphatidylserine (PS) on the surface, which initiate coagulation cascades. At the same time, monocytes release proinflammatory cytokines and stimulate neutrophils. Activated neutrophils release damage-associated molecular patterns (DAMPs) after cell death, and expel extracellular traps (NETs) that facilitate inflammation through binding to TLRs. Platelets release procoagulant microvesicles and prothrombotic substances such as von Willebrand factor (VWF) and platelet factor 4 (PF4). VWF helps platelet aggregation, and PF4 neutralizes heparan sulfate of the glycocalyx. Vascular endothelial cells lose anti-thrombogenicity by decreasing the production of nitric oxide (NO) and prostaglandin I₂ (PG I₂), and by increasing the production of plasminogen activator inhibitor 1 (PAI-1). Thrombomodulin which converts protein C (PC) to its activated form activated protein C (APC) is released from endothelial cells, and antithrombin is extravasated with increased vascular permeability. LPS lipopolysaccharide, Ig G immunoglobulin G, GP glycoprotein

Fig. 4

The therapeutic target of anticoagulant. The most popular anticoagulants worldwide are heparins, meanwhile, antithrombin and recombinant thrombomodulin are popularly used for disseminated intravascular coagulation (DIC) in Japan. For more than a decade, it has been reported that anticoagulant therapy is effective only for patients with coagulation disorder, and recent studies have shown that sepsis-associated DIC with high disease severity is the optimal target