In vitro effects of Gla-domainless factor Xa analog on procoagulant and fibrinolytic pathways in apixaban-treated plasma and whole blood.

BACKGROUND: Andexanet alfa is a Gla-domainless FXa (GDXa) analog used as an antidote to FXa inhibitors. Despite its clinical use, laboratory monitoring for anti-Xa reversal and the effect of andexanet on fibrinolysis has not been explored. We used a GDXa with a serine-to-alanine mutation at position 195 (chymotrypsin numbering) to model the interaction between andexanet and apixaban. METHODS: Six batches of pooled plasma, and whole blood from healthy volunteers were treated with increasing concentrations of apixaban with/without GDXa. Thrombin generation and plasmin generation (TG and PG) were tested in plasma, and whole blood thrombus formation was tested using thromboelastometry or a flow-chamber system. FXa was also tested in isolation for its ability to support plasmin activation with/without apixaban and GDXa. RESULTS: Apixaban (250-800 nM) concentration-dependently decreased the velocity and peak of TG in plasma. Apixaban prolonged the onset of thrombus formation in thromboelastometry and flow-chamber tests. GDXa normalized apixaban-induced delays in TG and whole blood thrombus formation. However, GDXa minimally affected the low PG velocity and peak caused by apixaban at higher concentrations (500-800 nM). FXa promoted plasmin generation independent of fibrin that was inhibited by apixaban at supratherapeutic concentrations. CONCLUSIONS: This study demonstrated the feasibility of assessing coagulation lag time recovery in plasma and whole blood following in vitro apixaban reversal using GDXa, a biosimilar to andexanet. In contrast, GDXa-induced changes in plasmin generation and fibrinolysis were limited in PG and tPA-added ROTEM assays, supporting the endogenous profibrinolytic activity of FXa and its inhibition at elevated apixaban concentrations.

Trends and Prediction of Surgical Site Infection After Elective Spine Surgery: An Analysis of the American College of Surgeons National Surgical Quality Improvement Project Database.

Background: Surgical site infection (SSI) is an infrequent but costly complication after elective spine surgery. Identification of important temporal changes and predictive factors may inform targeted prevention efforts. Patients and Methods: A retrospective study of elective spine surgery patients was performed using the National Surgical Quality Improvement Programs (NSQIP) database from 2011 and 2019. Temporal changes in SSI and related factors were examined descriptively. Recursive partitioning and bootstrap forest techniques were used to inform the development of predictive models for SSI. Results: A total of 6,038 (1.66%) of 363,754 patients had an SSI recorded. Peri-operative transfusion and preoperative anemia decreased over the nine-year period, however, obesity and diabetes mellitus increased, whereas the SSI rate remained essentially unchanged. A full model including 15 variables had an area under the curve (AUC) of 0.693 (95% confidence interval [CI], 0.686-0.700) whereas a reduced model with just nine variables had an AUC of 0.690 (95% CI, 0.683-0.697). Adjusted odd ratios (aOR) greater than two were noted for only three variables; a posterior approach (aOR, 2.32; 95% CI, 2.14-2.50), body mass index (BMI) >40 kg/m2 (aOR, 2.63; 95% CI, 2.39-2.90), and surgical duration longer than 350 minutes (aOR, 2.39; 95% CI, 2.14-2.67). Remaining retained variables included albumin <3.5 g/dL, inpatient procedure, peri-operative transfusion, diabetes mellitus (both insulin/non-insulin), anemia, and smoking. Conclusions: Surgical site infection rate remained unchanged over a nine-year period despite the lower rates of allogeneic blood transfusion. Class 3 obesity, long operative times, and a posterior approach mainly for thoracic/lumbar spine procedures seemed more pragmatic, but their predictive performance was only modest in our prediction models for SSI.

Factor VIII: A Dynamic Modulator of Hemostasis and Thrombosis in Trauma.

A trace amount of thrombin cleaves factor VIII (FVIII) into an active form (FVIIIa), which catalyzes FIXa-mediated activation of FX on the activated platelet surface. FVIII rapidly binds to von Willebrand factor (VWF) after secretion and becomes highly concentrated via VWF-platelet interaction at a site of endothelial inflammation or injury. Circulating levels of FVIII and VWF are influenced by age, blood type (nontype O > type O), and metabolic syndromes. In the latter, hypercoagulability is associated with chronic inflammation (known as thrombo-inflammation). In acute stress including trauma, releasable pools of FVIII/VWF are secreted from the Weibel-Palade bodies in the endothelium and then augment local platelet accumulation, thrombin generation, and leukocyte recruitment. Early systemic increases of FVIII/VWF (>200% of normal) levels in trauma result in a lower sensitivity of contact-activated clotting time (activated partial thromboplastin time [aPTT] or viscoelastic coagulation test [VCT]). However, in severely injured patients, multiple serine proteases (FXa plasmin and activated protein C [APC]) are locally activated and may be systemically released. Severity of traumatic injury correlates with prolonged aPTT and elevated activation markers of FXa, plasmin, and APC, culminating in a poor prognosis. In a subset of acute trauma patients, cryoprecipitate that contains fibrinogen, FVIII/VWF, and FXIII is theoretically advantageous over purified fibrinogen concentrate to promote stable clot formation, but comparative efficacy data are lacking. In chronic inflammation or subacute phase of trauma, elevated FVIII/VWF contributes to the pathogenesis of venous thrombosis by enhancing not only thrombin generation but also augmenting inflammatory functions. Future developments in coagulation monitoring specific to trauma patients, and targeted to enhancement or inhibition of FVIII/VWF, are likely to help clinicians gain better control of hemostasis and thromboprophylaxis. The main goal of this narrative is to review the physiological functions and regulations of FVIII and implications of FVIII in coagulation monitoring and thromboembolic complications in major trauma patients.

Temporal changes and predictors of perioperative blood transfusion in elective spine surgery: a retrospective analysis of a large surgical database.

BACKGROUND: Allogeneic blood transfusion used to be common in spine surgery. Patient blood management has been widely adopted, and it is important to reassess transfusion predictors in contemporary practice. METHODS: A retrospective study of inpatient spine surgery was performed using National Surgical Quality Improvement Program (NSQIP) data from 2011 to 2019. The primary outcome was perioperative transfusion within 72 h of surgery. Multivariable logistic regression and recursive partitioning were used to assess up to 15 variables including patient and surgical data, surgical specialty (orthopaedic surgery vs neurosurgery), and year of surgery. RESULTS: The study population included 251 971 US surgical patients; 6.9% of these patients received perioperative blood transfusion. Perioperative transfusions declined over time with the steepest decline from 2011 to 2015. The greatest reduction was seen among orthopaedic cases where the transfusion rate declined from 16.0% to 8.7% between 2011 and 2015. Eight variables were predictive factors in a reduced model: operative time, preoperative haemoglobin, vertebral level, number of vertebral levels, older age, surgeon specialty, arthrodesis, and year of surgery (area under the curve [AUC]=0.880; 95% confidence interval [CI], 0.878-0.883). Overall, longer operative time (>144 min) and greater numbers of vertebral levels had greater associations with transfusion than surgical specialty after adjustments. Prevalence of anaemia (15%) has not substantially declined. CONCLUSIONS: Perioperative blood transfusion rate in spine surgery has declined over the past decade. The extent and duration of surgery and preoperative haemoglobin level remain important factors associated with increased odds for perioperative blood transfusion.

High-dose intravenous iron supplementation after preoperative autologous blood donation is useful to prevent post-donation/preoperative anemia.

To estimate the effectiveness of high-dose intravenous (IV) iron supplementation for iron deficiency anemia after preoperative autologous blood donation (PAD), 155 donors who visited the donation office of the University of Tokyo Hospital from December 2020 to June 2021 and showed suspected post-donation anemia were analyzed. The participants were treated with high-dose intravenous (IV) iron supplementation (high-dose group, n = 30) or a combination of low-dose IV iron and oral iron supplementation (low-dose group, n = 125). The preoperative hemoglobin (Hb) and Hb decreasing ratios during PAD (ΔHb) were compared between the two groups. Multivariate linear regression analyses were also performed to identify the confounding factors associated with preoperative Hb and ΔHb as well as high-dose IV iron supplementation. Preoperative Hb level was slightly higher in the high-dose group than in the low-dose group (12.1 ±â€¯1.1 vs. 11.9 ±â€¯1.1 g/dL, p = 0.27). ΔHb was significantly higher in the high-dose group than in the low-dose group (3.7 % ± 8.8 % vs. 7.7 % ± 6.5 %, p = 0.011). On the multivariate linear regression analyses, high-dose IV iron supplementation was significantly associated with higher preoperative Hb and lower ΔHb levels (p = 0.021 and 0.017, respectively) as well as the donation available period (period from the first visit to the donation office to the operation) and administration of erythropoiesis-stimulating agents. High-dose IV iron supplementation after PAD will be useful in the treatment of post-donation anemia.

Cardiac Variation of Internal Jugular Vein as a Marker of Volume Change in Hemorrhagic Shock.

BACKGROUND: Fluid resuscitation, which is critical to counter acute hemorrhagic shock, requires prompt and accurate intravascular volume estimation for optimal fluid administration. This study aimed to evaluate whether cardiac variation of internal jugular vein (IJV), evaluated by ultrasonography, could detect hypovolemic status and predict response to fluid resuscitation. METHODS: Patients undergoing autologous blood transfusion for elective surgery who were prospectively enrolled at the study blood donation center between August 2014 and January 2015. Vertical B-mode ultrasonography movies of IJV were recorded at five timepoints during blood donation: before donation, during donation, end of donation, end of fluid replacement, and after hemostasis. Cardiac variation of the IJV area and circumference were objectively measured using an automated extraction program together with blood pressure and heart rate. RESULTS: A total of 140 patients were screened, and data from 104 patients were included in the final analyses. Among the variables analyzed, only collapse index area and collapse index circumference could detect both intravascular volume loss and response to fluid administration. CONCLUSIONS: Cardiac variation of IJV may be a reliable indicator of intravascular volume loss and response to fluid administration in hemorrhagic shock.

Comparison of two point of care whole blood coagulation analysis devices and conventional coagulation tests as a predicting tool of perioperative bleeding in adult cardiac surgery-a pilot prospective observational study in Japan.

BACKGROUND: It is widely accepted that Point-of Care Test (PoCT) devices are useful in the detection of coagulopathies in situations of massive bleeding such as major cardiac surgery. These devices contribute to the reduction of blood transfusion. However, their implementation remains limited in Japan because of their cost and lack of health insurance support. STUDY DESIGN AND METHODS: Conventional coagulation tests and thromboelastography (TEG)/Sonoclot values were measured in 50 consecutive cardiac surgery cases. Clinical background information such as operative procedures was obtained from electronic medical records, and the theoretical perioperative total blood loss was calculated by measuring the hemoglobin content and total red blood cell transfusion volume. The correlation between perioperative total blood loss and the measured laboratory values or clinical parameters was evaluated by a multivariate linear regression analysis. The risk factors of the total amount of platelet transfusion and postoperative drain bleeding volume were similarly evaluated. RESULTS: No significant association between the estimated perioperative total blood loss (eTBL) and the laboratory measurements including conventional coagulation tests, TEG and Sonoclot was observed. On the other hand, postoperative drain bleeding volume was significantly associated with postoperative Sonoclot CR (p = 0.039) as well as preoperative use of oral anticoagulants and cell saver treated blood volume. Platelet transfusion amount was significantly associated with post-CBP PF and time to peak value of Sonoclot (p = 0.014 and 0.001, respectively). CONCLUSION: Sonoclot measurements may be useful to estimate the risks of postoperative bleeding and platelet transfusion in cardiac surgeries in Japan.