Disseminated intravascular coagulation immediately after trauma predicts a poor prognosis in severely injured patients

Wada, Takeshi; Shiraishi, Atsushi; Gando, Satoshi; Fujishima, Seitaro; Saitoh, Daizoh; Kushimoto, Shigeki; Ogura, Hiroshi; Abe, Toshikazu; Mayumi, Toshihiko; Sasaki, Junichi; Kotani, Joji; Takeyama, Naoshi; Tsuruta, Ryosuke; Takuma, Kiyotsugu; Yamashita, Norio; Shiraishi, Shin Ichiro; Ikeda, Hiroto; Shiino, Yasukazu; Tarui, Takehiko; Nakada, Taka‐aki; Hifumi, Toru; Okamoto, Kohji; Sakamoto, Yuichiro; Hagiwara, Akiyoshi; Masuno, Tomohiko; Ueyama, Masashi; Fujimi, Satoshi; Umemura, Yutaka; Otomo, Yasuhiro

doi:10.1038/s41598-021-90492-0

Cited by 14 publications

(13 citation statements)

References 40 publications

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“…Table 1 shows that the low AT group had a higher proportion of elderly individuals and women. Previous studies have suggested that hypercoagulability in women after injury may be caused by the effects of estrogen (7,26,27). In addition, increased tissue factor expression, which activates extrinsic The SF levels on hospital arrival based on the general coagulofibrinolytic markers, including antithrombin.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, DAMPs induce neutrophil activation, followed by the release of neutrophil extracellular traps (NETs) that mainly comprise histones and promote further thrombin generation. These processes constitute the pathophysiology of disseminated intravascular coagulation (DIC), which is defined on the basis of dysregulated inflammatory coagulofibrinolytic responses to a traumatic insult (5,6) and can induce poor outcomes through the development of consumption coagulopathy and multiple organ dysfunction syndrome (MODS) (7). Another important factor in the pathophysiology of DIC is impaired anticoagulant mechanisms (2).…”

Section: Introductionmentioning

confidence: 99%

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Association of antithrombin with development of trauma-induced disseminated intravascular coagulation and outcomes

et al. 2022

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IntroductionTrauma activates the innate immune system to modulate hemostasis and minimize the damage caused by physiological bodily responses, including the activation of coagulation. Sufficiently severe trauma overwhelms physiological responses and elicits the systemic inflammatory response syndrome, which leads to the onset of disseminated intravascular coagulation (DIC), characterized by dysregulated inflammatory coagulofibrinolytic responses. Impaired anticoagulant mechanisms, including antithrombin, constitutes the pathology of DIC, while the dynamics of antithrombin and relevance to outcomes in trauma-induced coagulopathy have not been fully elucidated. This study investigated the associations of antithrombin activity with DIC onset and outcomes in severely injured patients.MethodsThis retrospective sub-analysis of a multicenter, prospective study included patients with an injury severity score ≥16. We characterized trauma patients with low antithrombin activity (antithrombin <80% on hospital arrival, n = 75) in comparison with those who had normal antithrombin activity (antithrombin ≥80%, n = 200). Global markers of coagulation and fibrinolysis, molecular biomarkers for thrombin generation (soluble fibrin [SF]), and markers of anticoagulation (antithrombin) were evaluated to confirm the associations of antithrombin with DIC development and outcomes, including in-hospital mortality and the multiple organ dysfunction syndrome (MODS).ResultsPatients with low antithrombin activity had higher prevalence of shock, transfusion requirements, and in-hospital mortality. Higher DIC scores and more severe organ dysfunction were observed in the low AT group compared to that in the normal AT group. Antithrombin activity on arrival at the hospital was an independent predictor of the development of DIC in trauma patients, and levels of SF increased with lower antithrombin values (antithrombin activity > 85%). Antithrombin activity at 3 h showed good predictive performance for in-hospital mortality, and a multivariable Cox proportional-hazard regression model with a cross-product term between the antithrombin and DIC showed that the in-hospital mortality in patients with DIC increased with decreased antithrombin activity. A multivariable logistic regression model showed that the odds for the development of MODS in patients with DIC increased with lower antithrombin values.ConclusionDecreased antithrombin activity in trauma-induced coagulopathy is associated with poor outcomes through worsening of DIC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Association of antithrombin with development of trauma-induced disseminated intravascular coagulation and outcomes

et al. 2022

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“…Third, medical students and medical staff from our hospital were recruited as healthy volunteers using a selection method employed in our previous studies: however, they were not age- or sex-matched to the patients. Fourth, we centrifuged collected blood samples at 4°C to avoid false high value of measurements in accordance with our previous studies ( 19 – 21 ). However, one-time centrifugation of blood samples at low temperature without checking platelet counts can lead to residual platelets in the processed samples, which could have affected the measurements, especially PAI-1 values.…”

Section: Discussionmentioning

confidence: 81%

“…The tPA ELISA kit does not detect t-PA associated with PAI-1; it only detects free t-PA as supported by the protocol provided along with this kit specifying that functionally active tPA will form a covalent complex with biotinylated human PAI-1, which is bound to the avidin coated on the microtiter plate, and that complexed tPA will not bind to the PAI-1 and will not be detected by the assay. The reliability of these assay reagents has been verified, and the studies quantifying soluble fibrin measured using these reagents have been published ( 19 – 21 ).…”

Section: Methodsmentioning

confidence: 95%

Association of Histones With Coagulofibrinolytic Responses and Organ Dysfunction in Adult Post-cardiac Arrest Syndrome

Mizugaki

Wada²,

Tsuchida³

et al. 2022

Front. Cardiovasc. Med.

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BackgroundPatients successfully resuscitated from cardiac arrest often develop organ dysfunction caused by systemic inflammation and increased coagulation, leading to disseminated intravascular coagulation (DIC). The involvement of histones in DIC and organ dysfunction in patients with sepsis and trauma has been previously reported, raising the probability that histones may also be associated with pathophysiology in patients after cardiac arrest and resuscitation. This study evaluated the relationship between histones and organ dysfunction related to coagulofibrinolytic changes in patients with post-cardiac arrest syndrome (PCAS).MethodsThis prospective single-center observational study assessed 35 adult patients with PCAS who were divided into two groups, i.e., 15 patients with multiple organ dysfunction syndrome (MODS) and 20 patients without MODS. MODS was defined as a sequential organ failure assessment score of ≥12. The plasma levels of histones and coagulofibrinolytic markers, including soluble fibrin, tissue-type plasminogen activator, plasminogen activator inhibitor-1, plasmin-alpha 2-plasmin inhibitor complex (PIC), and soluble thrombomodulin, were measured in patients with PCAS immediately after admission to the emergency department, and 3 and 24 h after arriving at the hospital.ResultsPCAS patients with MODS had higher DIC scores [4 (3.0–5.0) vs. 1 (0.0–3.0), p = 0.012] and higher mortality rates (66.7% vs. 20.0%, p = 0.013) than those without MODS. Moreover, patients with MODS exhibited higher histone levels than those without MODS during the early phase of the post-resuscitation period. Severe endothelial injury and higher thrombin and plasmin generation were observed in the MODS group. Plasma levels of histones were positively correlated with those of soluble fibrin immediately after resuscitation (rho = 0.367, p = 0.030) and PIC 3 h after arriving at the hospital (rho = 0.480, p = 0.005). This correlation was prominent in the patient population with MODS (soluble fibrin: rho = 0.681, p = 0.005, PIC: rho = 0.742, p = 0.002).ConclusionsThis study demonstrated that elevated histone levels were associated with increased levels of thrombin, and subsequent plasmin generation in PCAS patients, especially those with MODS. Further studies are required to elucidate the causal relationship between histones and organ dysfunction related to DIC in PCAS.

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“…They activate innate immune responses, leading to inflammation and coagulation activation, which are essentially physiological responses for hemostasis and tissue repair. However, if the trauma is sufficiently severe, these responses change from physiological to pathological conditions, resulting in DIC development (12). Antithrombin (AT), a natural anticoagulant, plays an important role in the coagulation pathway by showing 80% inhibitory activity against thrombin (13).…”

Section: Introductionmentioning

confidence: 99%

Antithrombin activity levels for predicting long-term outcomes in the early phase of isolated traumatic brain injury

Takahashi

Wada²,

Nakae³

et al. 2022

Front. Immunol.

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Coagulopathy management is an important strategy for preventing secondary brain damage in patients with traumatic brain injury (TBI). Antithrombin (AT) is a natural anticoagulant that controls coagulation and inflammation pathways. However, the significance of AT activity levels for outcomes in patients with trauma remains unclear. This study aimed to investigate the relationship between AT activity levels and long-term outcomes in patients with TBI; this was a sub-analysis of a prior study that collected blood samples of trauma patients prospectively in a tertiary care center in Kawaguchi City, Japan. We included patients with isolated TBI (iTBI) aged ≥16 years admitted directly to our hospital within 1 h after injury between April 2018 and March 2021. General coagulofibrinolytic and specific molecular biomarkers, including AT, were measured at 1, 3, 6, 12, and 24 h after injury. We analyzed changes in the AT activity levels during the study period and the impact of the AT activity levels on long-term outcomes, the Glasgow Outcome Scale-Extended (GOSE), 6 months after injury. 49 patients were included in this study; 24 had good neurological outcomes (GOSE 6–8), and 25 had poor neurological outcomes (GOSE 1–5). Low AT activity levels were shown within 1 h after injury in patients in the poor GOSE group; this was associated with poor outcomes. Furthermore, AT activity levels 1 h after injury had a strong predictive value for long-term outcomes (area under the receiver operating characteristic curve of 0.871; 95% CI: 0.747–0.994). Multivariate logistic regression analysis with various biomarkers showed that AT was an independent factor of long-term outcome (adjusted odds ratio: 0.873; 95% CI: 0.765–0.996; p=0.043). Another multivariate analysis with severity scores showed that low AT activity levels were associated with poor outcomes (adjusted odds ratio: 0.909; 95% CI: 0.822–1.010; p=0.063). We demonstrated that the AT activity level soon after injury could be a predictor of long-term neurological prognosis in patients with iTBI.

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Disseminated intravascular coagulation immediately after trauma predicts a poor prognosis in severely injured patients

Cited by 14 publications

References 40 publications

Association of antithrombin with development of trauma-induced disseminated intravascular coagulation and outcomes

Association of antithrombin with development of trauma-induced disseminated intravascular coagulation and outcomes

Association of Histones With Coagulofibrinolytic Responses and Organ Dysfunction in Adult Post-cardiac Arrest Syndrome

Antithrombin activity levels for predicting long-term outcomes in the early phase of isolated traumatic brain injury

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