Efficacy and safety of recombinant human soluble thrombomodulin (ART-123) in disseminated intravascular coagulation: results of a phase III, randomized, double-blind clinical trial

BACKGROUND: Soluble thrombomodulin is a promising therapeutic natural anticoagulant that is comparable to antithrombin, tissue factor pathway inhibitor and activated protein C. OBJECTIVES: We conducted a multicenter, double-blind, randomized, parallel-group trial to compare the efficacy and safety of recombinant human soluble thrombomodulin (ART-123) to those of low-dose heparin for the treatment of disseminated intravascular coagulation (DIC) associated with hematologic malignancy or infection. METHODS: DIC patients (n = 234) were assigned to receive ART-123 (0.06 mg kg(-1) for 30 min, once daily) or heparin sodium (8 U kg(-1) h(-1) for 24 h) for 6 days, using a double-dummy method. The primary efficacy endpoint was DIC resolution rate. The secondary endpoints included clinical course of bleeding symptoms and mortality rate at 28 days. RESULTS: DIC was resolved in 66.1% of the ART-123 group, as compared with 49.9% of the heparin group [difference 16.2%; 95% confidence interval (CI) 3.3-29.1]. Patients in the ART-123 group also showed more marked improvement in clinical course of bleeding symptoms (P = 0.0271). The incidence of bleeding-related adverse events up to 7 days after the start of infusion was lower in the ART-123 group than in the heparin group (43.1% vs. 56.5%, P = 0.0487). CONCLUSIONS: When compared with heparin therapy, ART-123 therapy more significantly improves DIC and alleviates bleeding symptoms in DIC patients.     

Treatment effects of high-dose antithrombin without concomitant heparin in patients with severe sepsis with or without disseminated intravascular coagulation

BACKGROUND: Disseminated intravascular coagulation (DIC) is a serious complication of sepsis that is associated with a high mortality. OBJECTIVES: Using the adapted International Society on Thrombosis and Haemostasis (ISTH) diagnostic scoring algorithm for DIC, we evaluated the treatment effects of high-dose antithrombin (AT) in patients with severe sepsis with or without DIC. PATIENTS AND METHODS: From the phase III clinical trial in severe sepsis (KyberSept), 563 patients were identified (placebo, 277; AT, 286) who did not receive concomitant heparin and had sufficient data for DIC determination. RESULTS: At baseline, 40.7% of patients (229 of 563) had DIC. DIC in the placebo-treated patients was associated with an excess risk of mortality (28-day mortality: 40.0% vs. 22.2%, P < 0.01). AT-treated patients with DIC had an absolute reduction in 28-day mortality of 14.6% compared with placebo (P = 0.02) whereas in patients without DIC no effect on 28-day mortality was seen (0.1% reduction in mortality; P = 1.0). Bleeding complications in AT-treated patients with and without DIC were higher compared with placebo (major bleeding rates: 7.0% vs. 5.2% for patients with DIC, P = 0.6; 9.8% vs. 3.1% for patients without DIC, P = 0.02). CONCLUSIONS: High-dose AT without concomitant heparin in septic patients with DIC may result in a significant mortality reduction. The adapted ISTH DIC score may identify patients with severe sepsis who potentially benefit from high-dose AT treatment.     

Trauma‐induced coagulopathy: The past,present, and future

Trauma remains a leading cause of death worldwide, and most early preventable deaths in both the civilian and military settings are due to uncontrolled hemorrhage, despite paradigm advances in modern trauma care. Combined tissue injury and shock result in hemostatic failure, which has been identified as a multidimensional molecular, physiologic and clinical disorder termed trauma‐induced coagulopathy (TIC). Understanding the biology of TIC is of utmost importance, as it is often responsible for uncontrolled bleeding, organ failure, thromboembolic complications, and death. Investigations have shown that TIC is characterized by multiple phenotypes of impaired hemostasis due to altered biology in clot formation and breakdown. These coagulopathies are attributable to tissue injury and shock, and encompass underlying endothelial, immune and inflammatory perturbations. Despite the recognition and identification of multiple mechanisms and mediators of TIC, and the development of targeted treatments, the mortality rates and associated morbidities due to hemorrhage after injury remain high. The purpose of this review is to examine the past and present understanding of the multiple distinct but highly integrated pathways implicated in TIC, in order to highlight the current knowledge gaps and future needs in this evolving field, with the aim of reducing morbidity and mortality after injury.     

Effectiveness of prothrombin complex concentrate for the treatment of bleeding: A systematic review and meta‐analysis

Prothrombin complex concentrate (PCC) is increasingly being used as a treatment for major bleeding in patients who are not taking anticoagulants. The aim of this systematic review and meta‐analysis is to evaluate the effectiveness of PCC administration for the treatment of bleeding in patients not taking anticoagulants. Studies investigating the effectivity of PCC to treat bleeding in adult patients and providing data on either mortality or blood loss were eligible. Data were pooled using Mantel‐Haenszel random effects meta‐analysis or inverse variance random effects meta‐analysis. From 4668 identified studies, 17 observational studies were included. In all patient groups combined, PCC administration was not associated with mortality (odds ratio = 0.83; 95% confidence interval [CI], 0.66‐1.06; P = .13; I² = 0%). However, in trauma patients, PCC administration, in addition to fresh frozen plasma, was associated with reduced mortality (odds ratio = 0.64; CI, 0.46‐0.88; P = .007; I² = 0%). PCC administration was associated with a reduction in blood loss in cardiac surgery patients (mean difference: ?384; CI, ?640 to ?128, P = .003, I² = 81%) and a decreased need for red blood cell transfusions when compared with standard care across a wide range of bleeding patients not taking anticoagulants (mean difference: ?1.80; CI, ?3.22 to ?0.38; P = .01; I² = 92%). In conclusion, PCC administration was not associated with reduced mortality in the whole cohort but did reduce mortality in trauma patients. In bleeding patients, PCC reduced the need for red blood cell transfusions when compared with treatment strategies not involving PCC. In bleeding cardiac surgery patients, PCC administration reduced blood loss.     

A retrospective comparative study of recombinant human thrombomodulin and gabexate mesilate in sepsis-induced disseminated intravascular coagulation patients

The novel biological agent recombinant human thrombomodulin (rhTM) has been used clinically in Japan to treat disseminated intravascular coagulation (DIC) since 2008. Previous studies have shown the efficacy of rhTM versus heparin therapy or non-rhTM therapy. We retrospectively evaluated and compared the efficacies of rhTM and gabexate mesilate (GM) in patients diagnosed with sepsis-induced DIC. From September 2010 to October 2012, patients with sepsis-induced DIC who were treated with rhTM (n = 13) or GM (n = 10) at Nagasaki Municipal Hospital were extracted. Patients receiving other anticoagulants in combination were excluded. Clinical information, laboratory data, Sequential Organ Failure Assessment (SOFA) scores, and DIC scores were obtained from the medical records. Mortality at days 7 and 30 after DIC diagnosis and changes in laboratory data and SOFA scores from days 1–7 were evaluated. The groups' clinical characteristics did not differ, except for the relatively higher C-reactive protein (CRP) levels in the rhTM group (P = 0.0508). The survival rates of the rhTM and GM groups on days 7 and 30 were 92.3%, 69.2% and 80%, 70%, respectively, both group indicated similar mortality. However, on day 7, the platelet counts, SOFA scores, and CRP levels significantly improved in the rhTM group; the platelet counts and SOFA scores did not improve significantly in the GM group. The platelet counts of the rhTM group significantly improved compared to the GM group (P = 0.004). Recombinant human thrombomodulin might be more effective for sepsis-induced DIC than GM.     

Differentiating disseminated intravascular coagulation (DIC) with the fibrinolytic phenotype from coagulopathy of trauma and acute coagulopathy of trauma‐shock (COT/ACOTS)

Two concepts have been proposed for the hemostatic changes occurring early after trauma. Disseminated intravascular coagulation (DIC) with the fibrinolytic phenotype is characterized by activation of the coagulation pathways, insufficient anticoagulant mechanisms and increased fibrinolysis. Coagulopathy of trauma and acute coagulopathy of trauma‐shock (COT/ACOTS) occurs as a result of increased activation of the thrombomodulin and protein C pathways, leading to the suppression of coagulation and activation of fibrinolysis. Despite the differences between these two conditions, independent consideration of COT/ACOTS from DIC with the fibrinolytic phenotype is probably incorrect. Robust diagnostic criteria based on its pathophysiology are required to establish COT/ACOTS as a new independent disease concept. In addition, the independency of its characteristics, laboratory data, time courses and prognosis from DIC should be confirmed. Confusion between two concepts may be based on studies of trauma lacking the following: (i) a clear distinction of the properties of blood between the inside and outside of vessels, (ii) a clear distinction between physiologic and pathologic hemostatic changes, (iii) attention to the time courses of the changes in hemostatic parameters, (iv) unification of the study population, and (v) recognition that massive bleeding is not synonymous with coagulation disorders. More information is needed to elucidate the pathogenesis of these two entities, DIC with the fibrinolytic phenotype and COT/ACOTS after trauma. However, available data suggest that COT/ACOTS is not a new concept but a disease entity similar to or the same as DIC with the fibrinolytic phenotype.     

Coagulation parameters in lung cancer patients: A systematic review and meta‐analysis

BackgroundHypercoagulability in lung cancer patients is associated with a high incidence of mortality and morbidity in the world. Therefore, this meta‐analysis aimed to explore the correlation of the basic coagulation abnormalities in lung cancer patients compared with the control.MethodPubMed, Scopus, and other sources were employed to identify eligible studies. The outcome variable was expressed using mean ± standard deviation (SD). Heterogeneity among studies and publication bias were evaluated. The quality of included studies was also assessed based on Newcastle–Ottawa Scale checklist.ResultFinally, through a total of eight studies, prolonged prothrombin time (PT; standard mean difference [SMD]: 1.29; 95% CI: 0.47–2.11), plasma D‐dimer value (SMD 3.10; 95% CI 2.08–4.12), fibrinogen (SMD 2.18; 95% CI:1.30–3.06), and platelet (PLT) count (SMD 1.00; 95% CI 0.84–1.16) were significantly higher in lung cancer patients when compared with the control group. The single‐arm meta‐analysis also showed that compared with control, lung cancer patients had high pooled PT 13.7 (95% CI:12.2–15.58) versus 11.79 (95% CI = 10.56–13.02), high D‐dimer 275.99 (95% CI:172.9–11735.9) versus 0.2 (95% CI:0.20–0.37), high plasma fibrinogen 5.50 (95% CI:4.21–6.79) versus 2.5 (95% CI:2.04–2.91), and high PLT count 342.3 (95% CI:236.1–448.5) versus 206.6 (95% CI:176.4–236.7).ConclusionIn conclusion, almost all the coagulation abnormalities were closely associated with lung cancer, and hence coagulation indexes provide an urgent clue for early diagnosis and timely management.     

Serum concentration of chromogranin A at admission: An early biomarker of severity in critically ill patients

Background. Chromogranin A (CGA), a stress marker released with catecholamines by the adrenal medulla, has never been associated with acute inflammation in critically ill patients.

Aim. To determine evidence for a link between serum concentration of CGA, biomarkers of inflammation, and outcome in patients admitted with or without the systemic inflammatory response syndrome (SIRS).

Methods. At admission, we measured in 53 patients and 14 healthy controls the serum concentrations of CGA, procalcitonin, and C-reactive protein. We also assessed the Simplified Acute Physiological Score (SAPS) in the patients.

Results. Serum CGA concentrations were significantly increased in SIRS patients with a median value of 115 µg/L (68.0–202.8), when compared to healthy controls (P<0.001). In cases where infection was associated with SIRS, patients had the highest increase in CGA with a median value of 138.5 µg/L (65–222.3) (P<0.001). CGA concentrations positively correlated with inflammation markers (procalcitonin, C-reactive protein), but also with SAPS. Receiver operating characteristic (ROC) analysis showed that CGA is equivalent to SAPS as an indicator for 28-day mortality (area under curve (AUC) for both: 0.810).

Conclusions. Patients with CGA concentration superior to 71 µg/L have a significantly shorter survival. A Cox model confirmed that CGA and SAPS were independent predictors of outcome.     

Efficacy and safety of intralymphatic immunotherapy in allergic rhinitis: A systematic review and meta‐analysis

BackgroundIntralymphatic immunotherapy (ILIT) is a potential treatment option for allergic rhinitis (AR). We aimed to determine the efficacy (primary outcomes) and safety (secondary outcomes) of ILIT in treating patients with AR.MethodsAn electronic literature search was performed using MEDLINE and Cochrane Central Register of Controlled Trials CENTRAL (from their inception to December 2020). A random‐effects model was used to estimate the pooled prevalence with 95% confidence intervals. This study is registered with PROSPERO (CRD42019126271).ResultsWe retrieved a total of 285 articles, of which 11 satisfied our inclusion criteria. There were 452 participants with age ranged from 15 to 58 years old. Intralymphatic immunotherapy was given in three doses with intervals of four weeks between doses in 10 trials. One trial gave three and six doses with an interval of two weeks. Both primary and secondary outcomes showed no difference between ILIT and placebo for all trials. There was no difference in the combined symptoms and medication score (SMD ‐0.51, 95% CI −1.31 to 0.28), symptoms score (SMD −0.27, 95% CI −0.91 to 0.38), medication score (SMD −6.56, 95% CI −21.48 to 8.37), rescue medication (RR 12.32, 95% CI 0.72–211.79) and the overall improvement score (MD −0.07, 95% CI −2.28 to 2.14) between ILIT and placebo. No major adverse events noted.ConclusionsIntralymphatic immunotherapy possibly has a role in the treatment of AR patients. This review found it is safe but not effective, which could be contributed by the high variation amongst the trials. Future trials should involve larger numbers of participants and report standardized administration of ILIT and outcome measures.