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Background: Screening for the risk of thromboembolism (TE) due to tranexamic acid (TXA) in patients with severe traumatic injury has not been performed in randomized clinical trials. Our objective was to determine if TXA dose was independently-associated with thromboembolism.Study Design and Methods: This is a secondary analysis of a single-center, double-blinded, randomized controlled trial comparing placebo to a 2-g or 4-g intravenous TXA bolus dose in trauma patients with severe injury. We used multivariable discrete-time Cox regression models to identify associations with risk for thromboembolic events within 30 days post-enrollment. Event curves were created using discrete-time Cox regression.Results: There were 50 patients in the placebo group, 49 in the 2-g, and 50 in the 4-g TXA group. In adjusted analyses for thromboembolism, a 2-g dose of TXA had an hazard ratio (HR, 95% confidence interval [CI]) of 3.20 (1.12-9.11) (p = .029), and a 4-g dose of TXA had an HR (95% CI) of 5.33 (1.94-14.63) (p = .001). Event curves demonstrated a higher probability of thromboembolism for both doses of TXA compared to placebo. Other parameters independently associated with thromboembolism include time from injury to TXA administration, body mass index, and total blood products transfused.Discussion: In patients with severe traumatic injury, there was a dose-dependent increase in the risk of at least one thromboembolic event with TXA. TXA should not be withheld, but thromboembolism screening should be considered for patients receiving a dose of at least 2-g TXA intravenously for traumatic hemorrhage. [ABSTRACT FROM AUTHOR]

Vascular endothelial injury is a hallmark of acute infection at both the microvascu- lar and macrovascular levels. The hallmark of SARS- CoV- 2 infection is the current COVID- 19 clinical sequelae of the pathophysiologic responses of hypercoagulabil- ity and thromboinflammation associated with acute infection. The acute lung injury that initially occurs in COVID- 19 results from vascular and endothelial damage from viral injury and pathophysiologic responses that produce the COVID- 19– associated coagulopathy. Clinicians should continue to focus on the vascular endothelial injury that occurs and evaluate potential therapeutic interventions that may benefit those with new infections during the current pandemic as they may also be of benefit for future pathogens that generate similar thromboinflammatory responses. The current Accelerating COVID- 19 Therapeutic Interventions and Vaccines (ACTIV) studies are important projects that will further define our management strategies. At the time of writing this report, two mRNA vaccines are now being distributed and will hopefully have a major impact on slowing the global spread and subsequent thromboinflamma- tory injury we see clinically in critically ill patients. [ABSTRACT FROM AUTHOR]

Objectives: Hyperglycemia induces vascular dysfunction that is thought to be initiated by neutrophils. Neutrophil activation produces endothelial injury by pathways that include NETosis, a type of specific cell death. In this study, we investigated the effects of hyperglycemia on neutrophil activation, cell death, NETosis, and endothelial glycocalyx damage using a mouse diabetes model. Methods: We used db/db mice as a type 2 diabetes model, and C57BL/6 mice were the controls. At 5, 8, and 12 weeks of age, the proportion of CD11b+ granulocytes/monocytes, neutrophil extracellular trap (NET)‐forming granulocytes/monocytes, and damaged and nonviable granulocytes/monocytes was analyzed. In addition, serum levels of high mobility group box 1, histone H3, and glycocalyx components that included syndecan‐1 and hyaluronan were measured. Results: In diabetic mice, we observed an increased proportion of CD11b+ granulocytes/monocytes. The proportion of NET‐forming granulocytes/monocytes increased from the early stages of the experiments. The proportions of damaged and nonviable granulocytes/monocytes increased over time. In the 12‐week‐old diabetic mice, serum histone H3 levels increased. Circulating levels of syndecan‐1 and hyaluronan decreased over time and were lower in diabetic mice. Conclusion: Neutrophil activation and cell death induce endothelial glycocalyx damage, and NET formation also participates in the mechanisms of vascular injury in type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background/Objectives: Prothrombin complex concentrates (PCC) are increasingly administered off‐label in the United States to treat bleeding in cardiovascular surgical patients and carry the potential risk for acquired thromboembolic side‐effects after surgery. Therefore, we hypothesized that the use of low‐dose 3‐factor (3F) PCC (20‐30 IU/kg), as part of a transfusion algorithm, reduces bleeding without increasing postoperative thrombotic/thromboembolic complications. Materials/Methods: After IRB approval, we retrospectively analysed 114 consecutive, complex cardiovascular surgical patients (age > 18 years), between February 2014 and June 2015, that received low‐dose 3F‐PCC (Profilnine®), of which seven patients met established exclusion criteria. PCC was dosed according to an institutional perioperative algorithm. Allogeneic transfusions were recorded before and after PCC administration (n = 107). The incidence of postoperative thromboembolic events was determined within 30 days of surgery, and Factor II levels were measured in a subset of patients (n = 20) as a quality control measure to avoid excessive PCC dosing. Results: Total allogeneic blood product transfusion reached a mean of 12·4 ± 9·9 units before PCC and 5·0 ± 6·3 units after PCC administration (P < 0·001). The mean PCC dose was 15·8 ± 7·1 IU/kg. Four patients (3·8%) each experienced an ischaemic stroke on postoperative day 1, 2, 4 and 27. Seven patients (6·5%) had acquired venous thromboembolic disease within 10 days of surgery. Median factor II level after transfusion algorithm adherence and PCC administration was 87%. Conclusions: 3F‐PCC use for refractory bleeding after cardiovascular surgery resulted in reduced transfusion of allogeneic blood and blood products. Adherence to this algorithmic approach was associated with an acceptable incidence of postoperative thrombotic/thromboembolic complications. [ABSTRACT FROM AUTHOR]

Background: Retrospective studies suggested that storage age of RBCs is associated with inflammation and thromboembolism. The Red Cell Storage Duration Study (RECESS) trial randomized subjects undergoing complex cardiac surgery to receive RBCs stored for shorter versus longer periods, and no difference was seen in the primary outcome of change in multiple organ dysfunction score.Study Design and Methods: In the current study, 90 subjects from the RECESS trial were studied intensively using a range of hemostasis, immunologic, and nitric oxide parameters. Samples were collected before transfusion and on Days 2, 6, 28, and 180 after transfusion.Results: Of 71 parameters tested, only 4 showed a significant difference after transfusion between study arms: CD8+ T-cell interferon-γ secretion and the concentration of extracellular vesicles bearing the B-cell marker CD19 were higher, and plasma endothelial growth factor levels were lower in recipients of fresh versus aged RBCs. Plasma interleukin-6 was higher at Day 2 and lower at Days 6 and 28 in recipients of fresh versus aged RBCs. Multiple parameters showed significant modulation after surgery and transfusion. Most analytes that changed after surgery did not differ based on transfusion status. Several extracellular vesicle markers, including two associated with platelets (CD41a and CD62P), decreased in transfused patients more than in those who underwent surgery without transfusion.Conclusions: Transfusion of fresh versus aged RBCs does not result in substantial changes in hemostasis, immune, or nitric oxide parameters. It is possible that transfusion modulates the level of platelet-derived extracellular vesicles, which will require study of patients randomly assigned to receipt of transfusion to define. [ABSTRACT FROM AUTHOR]

Background Total thrombus formation velocity calculated using amplitude parameters obtained at different times could be used to estimate the amplification and the propagation phases observed during coagulation processes, and therefore might be useful to predict postoperative hemostatic products administration in pediatric patients. Methods We retrospectively analyzed data from 49 children <3 months of age who underwent cardiac surgery. Children ≤1 month of age routinely received fresh frozen plasma during bypass while children >1 month of age did not. The EXTEM parameters were used to calculate velocity curves using amplitudes obtained at different times, the area under the curve called total thrombus formation and the maximum rate of thrombus formation. These parameters were compared between children who received fresh frozen plasma and those who did not. Receiver operating characteristics curves were used to define variables that could be used to predict postoperative fresh frozen plasma transfusion. Results Total thrombus formation and maximum rate of thrombus formation significantly increased in children who received fresh frozen plasma compared to those who did not. Both total thrombus formation and maximum rate of thrombus formation have a better specificity to predict postoperative fresh frozen plasma transfusion compared to clotting time or maximal clot firmness. Conclusion Based on this descriptive study, dynamic ROTEM® parameters of total thrombus formation could be used to estimate the amplification and the propagation phases of coagulation in children. These parameters might be used in further well-designed study to predict the need for hemostatic products in children undergoing cardiac surgery with cardiopulmonary bypass. [ABSTRACT FROM AUTHOR]

Fibrinogen plays a critical role in achieving and maintaining hemostasis and is fundamental to effective clot formation. There is increasing awareness of the important role of fibrinogen as a key target for the treatment and prevention of acquired bleeding. Fibrinogen is the first coagulation factor to fall to critically low levels (<1.0 g/L) during major hemorrhage (normal plasma fibrinogen levels range from 2.0 to 4.5 g/L), and current guidelines recommend maintaining the plasma fibrinogen level above 1.5 g/L. Fibrinogen supplementation can be achieved using plasma or cryoprecipitate; however, there are a number of safety concerns associated with these allogeneic blood products and there is a lack of high-quality evidence to support their use. Additionally, there is sometimes a long delay associated with the preparation of frozen products for infusion. Fibrinogen concentrate provides a promising alternative to allogeneic blood products and has a number of advantages: it allows a standardized dose of fibrinogen to be rapidly administered in a small volume, has a very good safety profile, and is virally inactivated as standard. Administration of fibrinogen concentrate, often guided by point-of-care viscoelastic testing to allow individualized dosing, has been successfully used as hemostatic therapy in a range of clinical settings, including cardiovascular surgery, postpartum hemorrhage, and trauma. Results show that fibrinogen concentrate is associated with a reduction or even total avoidance of allogeneic blood product transfusion. Fibrinogen concentrate represents an important option for the treatment of coagulopathic bleeding; further studies are needed to determine precise dosing strategies and thresholds for fibrinogen supplementation. [ABSTRACT FROM AUTHOR]

Factor XIII (FXIII) is activated by thrombin to form a transglutaminase (FXIIIa) that stabilizes clot formation by the cross-linking of fibrin monomers and antifibrinolytic proteins. Although rare, FXIII deficiency is characterized by variable bleeding manifestations depending on the magnitude of the deficiency. A congenital FXIII deficiency with levels less than 1% can be detected in children who present with prolonged bleeding from the umbilical stump as well as protracted bleeding after trauma. An acquired FXIII deficiency may occur in a number of diseases or clinical situations where FXIII levels and/or its activity are decreased. Patients may also develop a relative deficiency in FXIII as a result of hemorrhage or dilutional changes from transfusions during surgery or trauma and are at increased risk for postoperative bleeding. Genetic studies have identified a wide range of mutations that affect the activity of the FXIII protein but in lieu of molecular genetic analyses, FXIII deficiency can be identified by specific diagnostic assays that measure either the transglutaminase activity of the protein or the levels of the protein and its individual subunits. Replacement therapy has also been shown to increase FXIII levels and reduce bleeding symptoms in patients with congenital FXIII deficiency. This review presents recent findings on the biology of FXIII and the clinical manifestations observed among patients with congenital and acquired FXIII deficiencies. [ABSTRACT FROM AUTHOR]

BACKGROUND: Coagulopathy after cardiopulmonary bypass (CPB) is caused by multiple perturbations in cellular and humoral elements of coagulation. A timely and comprehensive method to evaluate hemostasis would be helpful in the management of bleeding patients after CPB. The assessment of whole blood coagulation using rotation thromboelastometry (ROTEM) was compared to coagulation tests routinely performed during cardiac surgery. STUDY DESIGN AND METHODS: Blood was obtained from 26 patients undergoing CPB surgery at baseline, at 60 minutes on CPB, at the end of CPB, and on admission to intensive care unit. ROTEM tests (extrinsically activated [EXTEM], intrinsically activated [INTEM], specific clot formation [FIBTEM]), prothrombin time, activated partial thromboplastin time, platelet (PLT) count, fibrinogen, prothrombin level, antithrombin level, and thrombin generation (TG) measurement were performed. RESULTS: We observed strong correlations between FIBTEM-amplitude at 10 minutes (A10) and fibrinogen level (r = 0.87; p < 0.001) and between EXTEM/ INTEM-A10 variables and PLT count (r = 0.72 and 0.67, respectively; p < 0.001). Receiver operating characteristic analysis demonstrated that EXTEM-A10 and INTEM-A10 are predictive of thrombocytopenia below 80 × 109/L (area under the curve [AUC], 0.83 and 0.82, respectively), and FIBTEM-A10 was highly predictive of fibrinogen level below 200 mg/dL (AUC, 0.96). There were only weak correlations found between TG peak and clot formation time of EXTEM or INTEM (r = 0.30 and 0.29, respectively; p < 0.05). CONCLUSION: ROTEM variables demonstrated clinically relevant correlations with PLT counts and fibrinogen levels. In particular, decreasing levels of fibrinogen can be quickly determined (<15-20 min) using FIBTEM. [ABSTRACT FROM AUTHOR]

The article examines several methods in pharmacology that can be used to reduce perioperative bleeding. It reviews data obtained regarding aprotinin, including current perspectives and communications from the Food and Drug Administration. The reduction of bleeding and transfusion needs in cardiac and orthopedic surgery is discussed.

Thrombin plays a central role in coagulation and haemostasis. Binding of thrombin to thrombomodulin generates activated protein C (APC), which exerts a negative feedback on thrombin formation. Aprotinin, a natural proteinase inhibitor is used extensively during cardiac surgery because this procedure is often associated with profound activation of coagulation and inflammatory pathways. Some in vitro evidences suggest that aprotinin inhibits APC, but the clinical relevance is unclear. The recombinant human soluble thrombomodulin (rhsTM)-modified thrombin generation (TG) assay was used to investigate the effects of aprotinin on APC in plasma samples obtained from healthy volunteers, aprotinin-treated cardiac surgical patients and in protein C (PC)-depleted plasma. Based on the results of in vitro TG assay, addition of rhsTM (0·75–3·0 μg/ml) to volunteer or patient platelet-poor plasma significantly reduced (70·8 ± 21·9 and 95·3% ± 4·6%, respectively) thrombin formation when compared with PC-depleted plasma (8·3% ± 5·2%). Aprotinin (100–200 KIU) caused a small, statistically insignificant decrease in the peak thrombin formation in normal and PC-deficient plasma (12·0 ± 6·1%). In cardiac surgical patients, levels of functional PC, factor II, antithrombin and platelet significantly decreased after cardiopulmonary bypass (CPB). Soluble thrombomodulin concentrations were increased after CPB (3·5 ± 2·2 to 5·0 ± 2·2 ng/ml), but they were still within the normal range for human plasma. Our results showed that, even though endogenous PC level is decreased after CPB, it retains its activity in the presence of thrombomodulin, and aprotinin has limited inhibitory effect on APC generation. [ABSTRACT FROM AUTHOR]

BACKGROUND: In recent years, the hemostatic agent recombinant factor VIIa (rFVIIa) has emerged as a potentially new therapeutic agent for management of coagulopathy in patients with cirrhosis or following severe traumatic injury, a complex problem for clinicians in which standard treatment strategies are not always effective. As with other hemostatic agents, a primary safety concern of rFVIIa therapy is the theoretical possibility that systemic administration could confer an increased risk of thrombotic complications. So far, clinical experience indicates rFVIIa to be a safe treatment for currently approved indications within hemophilia. Little information is available, however, for patient populations outside this clinical setting. STUDY DESIGN AND METHODS: This article reviews critical safety data obtained from 13 Novo Nordisk–sponsored clinical trials of rFVIIa in patients with coagulopathy secondary to anticoagulant therapy, cirrhosis, or severe traumatic injury. RESULTS: Thrombotic adverse events were reported for 5.3 percent (23/430) of placebo-treated patients and 6.0 percent (45/748) of patients on active treatment. No significant difference was found between placebo-treated and rFVIIa-treated patients with respect to the incidence of thrombotic AEs, either on an individual trial basis or for these trial populations combined (p = 0.57). CONCLUSION: An important determinant for the safety profile reported here is likely to be the specific mechanism of action of rFVIIa, shown in experimental studies to be localized to the site of vascular injury where tissue factor is exposed. [ABSTRACT FROM AUTHOR]

Discusses the role of hemostatic agents in improving hemostasis by improving stimulating fibrin formation or inhibiting fibrinolysis. Importance of pharmacologic agents as adjuncts to blood products; Details on the increasing use of drugs in cardiovascular medicine; Potential application of recombinant activated factor as a therapy for refractory bleeding.

SUMMARY Aprotinin has been studied extensively in cardiac surgery and is the only FDA approved pharmacological treatment to reduce blood transfusion in coronary artery bypass grafting (CABG) associated with cardiopulmonary bypass (CPB). Aprotinin has been evaluated in multiple double blind, placebo-controlled, multicenter studies in cardiac surgery. In US studies, aprotinin has not been associated with an increased risk of post-CPB myocardial infarction, graft closure, or increased risk of renal dysfunction, and may in fact be associated with a decreased risk of stroke. The mechanism of action is complex, but aprotinin displays antiinflammatory properties due to its complex array of protease inhibition. As with any polypeptide, there is a risk of anaphylaxis that is influenced by prior exposure. Cardiac surgery can be associated with significant bleeding and the need for allogeneic blood products. Although multiple approaches have been reported to reduce bleeding and transfusions, aprotinin represents an important pharmacologic strategy to reduce bleeding. [ABSTRACT FROM AUTHOR]

Platelet (PLT) transfusions are administered in cardiac surgery to prevent or treat bleeding, despite appreciation of the risks of blood component transfusion. The current analysis investigates the hypothesis that PLT transfusion is associated with adverse outcomes associated with coronary artery bypass graft surgery (CABG). Data originally collected during double-blind placebo-controlled phase III trials for licensure of Trasylol (aprotinin injection) were retrospectively analyzed. Adverse outcome data of patients (n = 1720) that received, and did not receive, perioperative PLT transfusion were compared. Logistic regression analysis was used to assess the association of perioperative adverse events with PLT transfusion. Propensity scoring analysis was used to verify results of the logistic regression. Patients receiving PLTs were more likely to have prolonged hospital stays, longer surgeries, more bleeding, re-operation for bleeding, and more RBC transfusions, and less likely to have full-dose aprotinin administration. Adverse events were statistically more frequent in patients that received one or more PLT transfusion. Logistic regression analysis showed that PLT transfusion was associated with infection, vasopressor use, respiratory medication use, stroke, and death. Propensity scoring analysis confirmed the risk of PLT transfusion. PLT transfusion in the perioperative period of CABG was associated with increased risk for serious adverse events. PLT transfusion may be a surrogate marker for sicker patients and have no causal role in the outcomes observed. However, a direct contribution to outcomes remains possible. [ABSTRACT FROM AUTHOR]

A response from the authors of the article "Fibrinogen as a therapeutic target for bleeding: a review of critical levels and replacement therapy" in a 2014 issue of the journal is presented.

A letter to the editor is presented in response to the article that discussed whether preoperative fibrinogen concentrations provide information about postoperative bleeding volume and transfusion requirements after on-pump coronary artery bypass grafting (CABG) surgery by M. Karlsson and colleagues in a previous issue.

The article focuses on issues of hemostatic effectiveness and safety of aprotinin and tranexamic acid in high-transfusion-risk cardiac surgery. The authors of the study used propensity analysis to match patients who received aprotinin for high-transfusion-risk cardiac surgery to patients who receive tranexamic acid. They reported patients treated with aprotinin represented a small percentage of all the patients they evaluated.

Presents an abstract of the research paper 'Anaphylactic Reactions in Anesthesia and Intensive care,' by Jerrold H. Levy presented during The Scandinavian Society of Anesthesiologists 25th Congress in Aarhus, Denmark.

The article reflects on issues relating to hemostasis and blood transfusion in cardiac surgery. It discusses the relation of excessive bleeding after cardiac surgery to the hemostatic system and the role of pharmacologic intervention in reducing the alterations in hemostatic system during cardiopulomonary bypass (CPB).