Viral-Induced Inflammatory Coagulation Disorders: Preparing for Another Epidemic

Abstract

Several viral infectious diseases have emerged or re-emerged from wildlife vectors that have generated serious threats to global health. Increased international travel and commerce increase the risk of transmission of viral or other infectious diseases. In addition, recent climate changes accelerate the potential spread of domestic disease. The coronavirus disease 2019 (COVID-19) pandemic is an important example of the worldwide spread, and the current epidemic will unlikely be the last. Viral hemorrhagic fevers, such as dengue and Lassa fevers, may also have the potential to spread worldwide with a significant impact on public health with unpredictable timing. Based on the important lessons learned from COVID-19, it would be prudent to prepare for future pandemics of life-threatening viral diseases. The key concept that connect COVID-19 and viral hemorrhagic fever is the coagulation disorder. This review focuses on the coagulopathy of acute viral infections since hypercoagulability has been a major challenge in COVID-19, but represents a different presentation compared with viral hemorrhagic fever. However, both thrombosis and hemorrhage are understood as the result of thromboinflammation due to viral infections, and the role of anticoagulation is important to consider.

Fig. 1

Comparison of coagulopathy evoked by viral hemorrhagic fever and COVID-19. In the typical course of severe viral hemorrhagic fever, the significant suppression in adaptive immune system along with the abrupt activation in the coagulation system is induced initially which immediately turns to the consumptive coagulopathy phase. As a result, hemorrhage is the main phenotype in the late phase. In contrast, the activation in coagulation is mainly localized in the lung in COVID-19, and the systemic thrombotic phase lasts longer. The consumptive coagulation disorder is seen in limited cases even in a late phase.

Fig. 2

Pathogenesis of COVID-19-associated coagulopathy. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly infects macrophages/monocytes, which provoke inflammation and thrombosis by releasing proinflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL) 1β and IL6, and expressing tissue factor (TF). Activated neutrophils eject neutrophil extracellular traps (NETs) and disrupt the antithrombogenicity by damaging glycocalyx. Thrombin is the central mediator that activates endothelial cells, elicits a proinflammatory reaction, prothrombotic change, and activates platelet aggregation. SARS-CoV-2 also infects endothelial cell through binding to angiotensin converting enzyme 2 (ACE2) and stimulates the release of factor VIII, VWF, and angiopoietin 2 (Ang2). EC, endothelial cell; MPO, myeloperoxidase; PAI-1, plasminogen activator inhibitor 1; VWF, von Willebrand factor.

Fig. 3

Pathogenesis of viral hemorrhagic fever. Infected dendritic cells and macrophages lose their ability to produce type I interferon (IFN) sufficiently and lymphocytes fall into cell death. Inappropriate dendritic cell function causes a perturbation in the innate immune system that leads to increased vascular permeability. Furthermore, the replicated viruses disseminate throughout the body and induce a variety of systemic reactions, such as dysfunction of the visceral parenchymal cells, platelet disability, and coagulopathy which lead to disseminated intravascular coagulation leading to uncontrolled hemorrhage. EC, endothelial cell; IFN, interferon; IL, interleukin; MCP-1, monocyte chemoattractant protein 1; NETs, neutrophil extracellular traps; PAR-1, protease activated receptor 1; TF, tissue factor.