This paper will review the involvement of disseminated intravascular coagulation-induced microvascular thrombosis in the pathogenesis of multiple organ dysfunction syndrome and the interaction ...between disseminated intravascular coagulation and systemic inflammatory response syndrome in critically ill patients. The published literature on clinical and experimental studies are the data sources of the study. Histologic evidence of microvascular thrombosis and tissue injury in disseminated intravascular coagulation has been reported in clinical, experimental, and autopsy findings. Proinflammatory cytokine-evoked neutrophil–endothelial activation and interplay between inflammation and coagulation through protease-activated receptors contribute to enhanced microvascular fibrin deposition in organs. In a clinical setting, systemic inflammatory response syndrome and disseminated intravascular coagulation synergistically play pivotal roles in the development of multiple organ dysfunction syndrome and in the poor prognosis of critical illness. Disseminated intravascular coagulation contributes to microvascular thrombosis and subsequent multiple organ dysfunction syndrome. Recent knowledge on the relationship between disseminated intravascular coagulation and systemic inflammatory response syndrome gives further insight into the pathogenic mechanisms of multiple organ dysfunction syndrome in critically ill patients.
Hemostasis and thrombosis in trauma patients consist of physiological hemostasis for wound healing and the pathological reaction of disseminated intravascular coagulation (DIC). Whole body trauma, ...isolated brain injury, and fat embolism syndrome, if extremely severe, can cause DIC and affect a patient's prognosis. Shock-induced hyperfibrinolysis causes DIC with the fibrinolytic phenotype, contributing to oozing-type severe bleeding. If uncontrolled, this phenotype progresses to thrombotic phenotype at the late stage of trauma, followed by microvascular thrombosis, leading to organ dysfunction. Another type of pathological hemostatic change is acute coagulopathy of trauma shock (ACOTS), which gives rise to activated protein C-mediated systemic hypocoagulation, resulting in bleeding. ACOTS occurs only in trauma associated with shock-induced hypoperfusion and there is nothing to suggest DIC in this phenomenon. This review will provide information about the recent advances in hemostasis and thrombosis in trauma and will clarify the pathogeneses of the pathological processes observed in trauma patients.
Knowing the pathophysiology of trauma-induced coagulopathy is important for the management of severely injured trauma patients. The aims of this review are to provide a summary of the recent advances ...in our understanding of thrombosis and hemostasis following trauma and to discuss the pathogenesis of disseminated intravascular coagulation (DIC) at an early stage of trauma. Local hemostasis and thrombosis respectively act to induce physiological wound healing of injuries and innate immune responses to damaged-self following trauma. However, if overwhelmed by systemic inflammation caused by extensive tissue damage and tissue hypoperfusion, both of these processes foster systemic DIC associated with pathological fibrin(ogen)olysis. This is called DIC with the fibrinolytic phenotype, which is characterized by the activation of coagulation, consumption coagulopathy, insufficient control of coagulation, and increased fibrin(ogen)olysis. Irrespective of microvascular thrombosis, the condition shows systemic thrombin generation as well as its activation in the circulation and extensive damage to the microvasculature endothelium. DIC with the fibrinolytic phenotype gives rise to oozing-type non-surgical bleeding and greatly affects the prognosis of trauma patients. The coexistences of hypothermia, acidosis, and dilution aggravate DIC and lead to so-called trauma-induced coagulopathy. He that would know what shall be must consider what has been. The Analects of Confucius.
The aims of this review are to demonstrate that the changes in coagulation and fibrinolysis observed in cardiac arrest and resuscitation can be recognized as disseminated intravascular coagulation ...(DIC), and to discuss the probability of DIC being a therapeutic target. The appearance of triggers of DIC, such as damage‐associated molecular patterns, inflammatory cytokines, and adrenaline, is associated with platelet activation, marked thrombin generation and fibrin formation, insufficient anticoagulation pathways, and increased fibrinolysis by tissue‐type plasminogen activator, followed by the suppression of fibrinolysis by plasminogen activator inhibitor‐1, in patients with cardiac arrest and resuscitation. Simultaneous neutrophil activation and endothelial injury associated with glycocalyx perturbation have been observed in these patients. The degree of these changes is more severe in patients with prolonged precardiac arrest hypoxia and long no‐flow and low‐flow times, patients without return of spontaneous circulation, and non‐survivors. Animal and clinical studies have confirmed decreased cerebral blood flow and microvascular fibrin thrombosis in vital organs, including the brain. The clinical diagnosis of DIC in patients with cardiac arrest and resuscitation is associated with multiple organ dysfunction, as assessed with the sequential organ failure assessment score, and increased mortality. This review confirms that the coagulofibrinolytic changes in cardiac arrest and resuscitation meet the definition of DIC proposed by the ISTH, and that DIC is associated with organ dysfunction and poor patient outcomes. This evidence implies that established DIC should be considered to be one of the main therapeutic targets in post–cardiac arrest syndrome.
Thromboplasminflammation in coronavirus disease 2019 (COVID-19) coagulopathy consists of angiotensin II (Ang II)-induced coagulopathy, activated factor XII (FXIIa)- and kallikrein, kinin ...system-enhanced fibrinolysis, and disseminated intravascular coagulation (DIC). All three conditions induce systemic inflammation
each pathomechanism-developed production of inflammatory cytokines. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) downregulates angiotensin-converting enzyme 2, leading to an increase in Ang II levels. Ang II-induced coagulopathy comprising platelet activation, thrombin generation, plasminogen activator inhibitor-1 expression and endothelial injury causes thrombosis
the angiotensin II type 1 receptor. SARS-CoV-2 RNA and neutrophil extracellular trap (NET) DNA activate FXII, resulting in plasmin generation through FXIIa- and kallikrein-mediated plasminogen conversion to plasmin and bradykinin-induced tissue-type plasminogen activator release from the endothelium
the kinin B2 receptor. NETs induce immunothrombosis at the site of infection (lungs), through histone- and DNA-mediated thrombin generation, insufficient anticoagulation control, and inhibition of fibrinolysis. However, if the infection is sufficiently severe, immunothrombosis disseminates into the systemic circulation, and DIC, which is associated with the endothelial injury, occurs. Inflammation, and serine protease networks of coagulation and fibrinolysis, militate each other through complement pathways, which exacerbates three pathologies of COVID-19 coagulopathy. COVID-19 coagulopathy causes microvascular thrombosis and bleeding, resulting in multiple organ dysfunction and death in critically ill patients. Treatment targets for improving the prognosis of COVID-19 coagulopathy include thrombin, plasmin, and inflammation, and SARS-CoV-2 infection. Several drugs are candidates for controlling these conditions; however, further advances are required to establish robust treatments based on a clear understanding of molecular mechanisms of COVID-19 coagulopathy.
This study aimed to investigate the incidence and significance of disseminated intravascular coagulation (DIC) in coronavirus disease 2019 (COVID-19). A multicenter cohort study was conducted using ...large-scale COVID-19 registry data. The patients were classified into DIC and non-DIC groups based on the diagnosis on admission (day 1) and on any of the days 1, 4, 8, and 15. In total, 23,054 patients were divided into DIC (n = 264) and non-DIC (n = 22,790) groups on admission. Thereafter, 1654 patients were divided into 181 patients with DIC and 1473 non-DIC patients based on the DIC diagnosis on any of the days from 1 to 15. DIC incidence was 1.1% on admission, increasing to 10.9% by day 15. DIC diagnosis on admission had moderate predictive performance for developing multiple organ dysfunction syndrome (MODS) on day 4 and in-hospital death and was independently associated with MODS and in-hospital death. DIC diagnosis on any of the days from 1 to 15, especially days 8 and 15, was associated with lower survival probability than those without DIC and showed significant association with in-hospital death. In conclusion, despite its low incidence, DIC, particularly late-onset DIC, plays a significant role in the pathogenesis of poor prognosis in patients with COVID-19.
The pathomechanisms of hypoxemia and treatment strategies for type H and type L acute respiratory distress syndrome (ARDS) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced ...coronavirus disease 2019 (COVID-19) have not been elucidated.
SARS-CoV-2 mainly targets the lungs and blood, leading to ARDS, and systemic thrombosis or bleeding. Angiotensin II-induced coagulopathy, SARS-CoV-2-induced hyperfibrin(ogen)olysis, and pulmonary and/or disseminated intravascular coagulation due to immunothrombosis contribute to COVID-19-associated coagulopathy. Type H ARDS is associated with hypoxemia due to diffuse alveolar damage-induced high right-to-left shunts. Immunothrombosis occurs at the site of infection due to innate immune inflammatory and coagulofibrinolytic responses to SARS-CoV-2, resulting in microvascular occlusion with hypoperfusion of the lungs. Lung immunothrombosis in type L ARDS results from neutrophil extracellular traps containing platelets and fibrin in the lung microvasculature, leading to hypoxemia due to impaired blood flow and a high ventilation/perfusion (VA/Q) ratio. COVID-19-associated ARDS is more vascular centric than the other types of ARDS. D-dimer levels have been monitored for the progression of microvascular thrombosis in COVID-19 patients. Early anticoagulation therapy in critical patients with high D-dimer levels may improve prognosis, including the prevention and/or alleviation of ARDS.
Right-to-left shunts and high VA/Q ratios caused by lung microvascular thrombosis contribute to hypoxemia in type H and L ARDS, respectively. D-dimer monitoring-based anticoagulation therapy may prevent the progression to and/or worsening of ARDS in COVID-19 patients.
Trauma-induced coagulopathy is caused by multiple factors, such as anemia, hemodilution, hypothermia, acidosis, shock, and serious trauma itself, which affects patient outcomes due to critical ...bleeding requiring massive transfusion. Disseminated intravascular coagulation (DIC) with the fibrinolytic phenotype directly caused by trauma and/or traumatic shock has been considered to be the primary pathophysiology of trauma-induced coagulopathy. The key to controlling DIC is vigorous treatment of the underlying disorder, that is, trauma itself and hemorrhagic shock. Damage control resuscitation, consisting of damage control surgery, permissive hypotension, and hemostatic resuscitation, aims to control severe trauma and critical bleeding, which is equivalent to managing the underlying disorder of DIC. At present, however, evidence-based practices for damage control resuscitation are lacking. A robust prospective outcome study for damage control resuscitation that considers DIC with the fibrinolytic phenotype as the main pathological condition of trauma-induced coagulopathy affecting patient outcome is essential for improving therapeutic strategies.
Dysregulated innate immunity participates in the pathomechanisms of disseminated intravascular coagulation (DIC) in trauma-induced coagulopathy. Accidental and regulated cell deaths and neutrophil ...extracellular traps release damage-associated molecular patterns (DAMPs), such as histones, nuclear and mitochondrial DNA, and high-mobility group box 1, into circulation immediately after trauma. DAMP-induced inflammation activation releases tissue factor-bearing procoagulant extracellular vesicles through gasdermin D-mediated pore formation and plasma membrane rupture by regulated cell death. DAMPs also evoke systemic inflammation, platelet, coagulation activation, and impaired fibrinolysis associated with endothelial injury, leading to the dysfunction of anticoagulation systems, which are the main pathophysiological mechanisms of DIC. All these processes induce systemic thrombin generation in vivo, not restricted to the injury sites immediately after trauma. Thrombin generation at the site of injury stops bleeding and maintains homeostasis. However, DIC associated with endothelial injury generates massive thrombin, enhancing protease-activated, receptor-mediated bidirectional interplays between inflammation and coagulation, aggravating the diverse actions of thrombin and disturbing homeostasis. Insufficiently regulated thrombin causes disseminated microvascular thrombosis, resulting in tissue hypoxia due to reduced oxygen delivery, and mitochondrial dysfunction due to DAMPs causes tissue dysoxia. In addition, DAMP-induced calcium influx and overload, as well as neutrophil activation, play a role in endothelial cell injury. Tissue hypoxia and cytotoxicity result in multiple organ dysfunction in DIC after trauma. Controls against dysregulated innate immunity evoking systemic inflammation, thrombin generation, and cytotoxicity are key issues in improving the prognosis of DIC in trauma-induced coagulopathy.
•Trauma is one of the leading causes of disseminated intravascular coagulation (DIC).•Innate immune activation interlinks with inflammatory and coagulofibrinolytic responses.•DIC is defined as dysregulated inflammatory and coagulofibrinolytic responses to insults.•Dysregulated innate immunity is essential in the pathomechanisms of trauma-induced DIC.
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