Pharmacokinetic Parameter Driven Outcomes Model Predicts a Reduction in Bleeding Events Associated with BAY 81-8973 Versus Antihemophilic Factor (Recombinant) Plasma/Albumin- Free Method in a Chinese Healthcare Setting

Background: Long-term prophylactic therapy is considered the standard of care for hemophilia A patients. This study models the long-term clinical and cost outcomes of two factor VIII (FVIII) products using a pharmacokinetic (PK) simulation model in a Chinese population. Methods: Head-to-head PK profile data of BAY 81-8973 (KOVALTRY®) and antihemophilic factor (recombinant) plasma/albumin-free method (rAHF-PFM, ADVATE®) were applied to a two-state (alive and dead) Markov model to simulate blood FVIII concentrations at a steady state in prophylactically-treated patients with hemophilia A. Worsening of the Pettersson score was simulated and decline was associated with the probability of having orthopaedic surgery. The only difference between the compounds was FVIII concentration at a given time; each subject was treated with 25 IU/kg every 3 days. The model used a lifetime horizon, with cycle lengths of 1 year. Results: Cumulative bleeding events, joint bleeding events, and major bleeding events were reduced by 19.3%, 9.3% and 19.3%, respectively for BAY 81-8973 compared to rAHF-PFM. Hospitalizations and hospitalization days were also reduced by 19.3% for BAY 81-8973 compared to rAHF-PFM. BAY 81-8973 resulted in both cost savings and a gain in quality adjusted life years (QALYs) compared to rAHF-PFM. Conclusion: Based on modeled head-to-head comparisons, differences in PK-properties between BAY 81-8973 and rAHF-PFM result in a reduced number of bleeding events, leading to reduced costs and increased quality of life for BAY 81-8973. These results should be used to inform clinical practice in China when caring for patients with severe hemophilia A.

The Effect of Tranexamic Acid and Epsilon-Aminocaproic Acid on Bleeding During Hip and Knee Arthroplasty：A Retrospective Study

PurposeTo compare the hemostatic effect and risk of thrombosis between tranexamic acid and epsilon-aminocaproic acid.MethodsA retrospective study of 140 cases of joint replacement, including 93 cases in the tranexamic acid (TXA) group and 47 cases in the epsilon-aminocaproic acid (EACA) group. TXA or EACA was injected intravenously 30 minutes before surgery, and TXA or EACA was infused into the joint cavity after the wound was closed. The drainage, blood loss and plasma albumin loss were observed after operation.ResultsThe postoperative hemoglobin loss in the two groups was 19.1±11.4g/L, 20.3±13.6g/L, P>0.05. However, the drainage volume of the TXA group was less than that of the EACA group, which were 103.3±92.1ml and 117.4±120.9ml, respectively, P<0.05. The blood transfusion rate in the TXA group was higher than that in the EACA group, 14% and 34%, respectively, P<0.05. The postoperative plasma albumin loss of the two groups of patients was 7.4±8.0g/L and 7.3±5.5g/L respectively, P=0.05.ConclusionsThe hemostatic effect of TXA was slightly better than that of EACA, and the proportion of transfusion of TXA was lower.Level of Evidence: Level III

Albumin and fibrinogen kinetics in sepsis: a prospective observational study

Background The measurement of circulating substrate concentrations does not provide information about substrate kinetics. It, therefore, remains unclear if a decrease in plasma concentration of albumin, as seen during critical illness, is a consequence of suppressed production in the liver or increased peripheral clearance. In this study, using stable isotope tracer infusions, we measured albumin and fibrinogen kinetics in septic patients and in a control group of non-septic subjects. Methods With the approval from the institutional Research Ethics Board and after obtaining written informed consent from patients or their substitute decision maker, mechanically ventilated patients with sepsis and patients scheduled for elective coronary artery bypass grafting were enrolled. Patients in the non-sepsis group were studied on the day before surgery. The stable isotope L-[ring-2H5]phenylalanine was used to measure absolute synthesis rates (ASR) of albumin and fibrinogen. A priming dose of L-[ring-2H5]phenylalanine (4 µmol/kg) was given followed by a six-hour infusion at a rate of 0.15 µmol/kg/min. At baseline and hourly thereafter, blood was drawn to measure isotope enrichments by gas chromatography/mass spectrometry. Very low density lipoprotein apolipoprotein-B 100 isotopic enrichment was used to represent the isotopic enrichment of the phenylalanine precursor pool from which the liver synthesizes proteins. Plasma albumin and fibrinogen concentrations were also measured. Results Mean plasma albumin in septic patients was decreased when compared to non-septic patients, while synthesis rates were comparable. Mean plasma fibrinogen and ASR in septic patients was increased when compared to non-septic patients. In non-septic patients, no statistically significant correlation between plasma albumin and ASR was observed but plasma fibrinogen significantly correlated with ASR. In septic patients, plasma albumin and fibrinogen significantly correlated with ASR. Conclusions While septic patients showed lower plasma albumin levels than non-septic patients, albumin synthesis was similar in the two groups suggesting that hypoalbuminemia during sepsis was not caused by suppressed hepatic production but a result of enhanced clearance from the circulation. Hyperfibrinogenemia in septic patients was a consequence of increased fibrinogen production. Trial registration: ClinicalTrials.gov: NCT02865408 (registered on August 12, 2016) and ClinicalTrials.gov: NCT02549443 (registered on September 15, 2015).

Limited Role of Antithrombin Deficiency in Hypercoagulopathy Associated with Nephrotic Syndrome

Background: Nephrotic syndrome (NS) is associated with an acquired hypercoagulopathy that drives venous thromboembolic comorbidities. The molecular mechanisms underlying NS-associated hypercoagulopathy are incompletely understood, however previous studies proposed marked urinary loss of antithrombin (AT) as a primary etiology. We have previously demonstrated, in rodent NS models, that there is no correlation between AT antigen and thrombin generation, which we have previously used to characterize the hypercoagulopathy. The objective of this study is to examine the association between AT antigen, AT activity, and hypercoagulopathy along with NS disease severity markers (proteinuria and plasma albumin) in 2 cohorts that include both pediatric and adult NS patients. Methods: Plasma samples were obtained from both cohorts as follows: (1) Samples were obtained on presentation from 147 adult and pediatric patients participating in the NEPTUNE prospective observational cohort study (2) Samples were obtained on presentation and after 7 weeks of glucocorticoid therapy (GC) in steroid sensitive and steroid resistant pediatric patients participating in the PNRC study. AT antigen and activity assays were performed using ELISA and chromogenic assays, respectively. Thrombin generation assay, plasma albumin, and urine protein-to-creatinine ratio were determined as previously described. Results: There was no significant relationship between AT antigen or AT activity and thrombin generation parameters. AT antigen and activity also did not correlate with NS severity markers (plasma albumin and proteinuria) in the NEPTUNE cohort (Figure1). In PNRC pediatric cohort, no significant correlation was found between AT antigen and thrombin generation or other disease severity markers. However, AT activity was significantly associated with both plasma albumin and endogenous thrombin potential at presentation (Figure 2) and at follow-up. Interestingly, GC therapy significantly improved AT activity in steroid-sensitive but not steroid-resistant NS patients (Figure 3). A comprehensive literature review and meta-analysis was also performed which revealed that clinically significant AT deficiency (&lt;0.7 IU/mL) is uncommon in both pediatric and adult NS patients. Conclusion: AT antigen does not correlate with thrombin generation-defined hypercoagulopathy in adult or pediatric NS patients. AT activity does correlate with hypercoagulopathy in pediatric NS patients and improves significantly with successful remission inducing therapy. These data suggest that pediatric NS patients may have a qualitative, but not quantitative, AT deficiency that is responsive to therapy. The mechanism underlying this qualitative deficiency should be characterized in future studies. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Correlation of Intravenous Vitamin C Injection and Plasma Albumin Level in Burnt Rats (Experimental Animal Study)

Background Burn is tissue injury caused by heat, radiation, electricity, contact with hot objects or chemicals. It’s a global public health problem accounting for an estimated 180000 death annually according to WHO. Aim of the Work To detect the efficacy of intravenous vitamin C and plasma albumin level in burnt rats. Materials and Methods This study was an experimental study on 14 rats only not including any human and they were divided into two groups: Group A that represented burnt rats that won’t be injected with parenteral vitamin C and Group B represented burnt rats that will be injected with parenteral vitamin C. Results There was no statistically significant difference found between two groups regarding albumin level and total proteins level before burn and Post burn 8h. There was highly statistically significant difference between Albumin level and total proteins level before Burn, Post Burn 8h level and Post Burn 24h level. Conclusion It is concluded that vitamin C holds potential as a powerful adjunct in burn resuscitation and it may be safe and decreases fluid requirement in the acute phase after burn injury.

Causes of The Nephrotic Syndrome In Sweden 2014-2019 Depending On Clinical Presentation And Demographics

Background: Many different pathological processes can affect the integrity of the glomerular capillary wall and cause massive leakage of protein resulting in the Nephrotic Syndrome (NS). The prognosis and response to therapy differs depending on diagnosis, but renal biopsy cannot always be performed promptly. These is insufficient knowledge to which extent clinical parameters can predict the diagnosis. Methods: Age, gender, haematuria, proteinuria, plasma creatinine, plasma albumin and final diagnosis were retrieved for all adult patients with NS as indication for biopsy or massive albuminuria in conjunction with a low plasma albumin from the biopsy module of the Swedish Renal Registry (SRR) between 2014 and 2019. A basic calculator was developed to demonstrate the importance of clinical presentations in relation to the likelihood of having a specific diagnosis.Results: 913 unique patients were included in the study. Overall membranous nephropathy (17%) was the most common diagnoses, but when studying those <50 years old or women minimal change nephropathy (21 and 17 %) was the most frequent diagnosis. When examining those between 50 and 70 years-old, those with chronic kidney disease (CKD) 4 and those with negative dipstick tests for hematuria diabetic nephropathy (23, 30 and 21 %) was the most common underlying disease. Among those with high grade hematuria (grade 3-4 on dipsticks) Membranoproliferative glomerulonephritis was most common (14%), closely followed by IgA nephropathy (13%). Focal segmental glomerulosclerosis (9.7%) was less common than in many comparable studies. Conclusions: Clinical parameters have a profound impact on the likelihood of different diagnoses in adult patients with NS. Differences in clinical practice, inclusion criteria in studies and probably genetic background are important to account for when comparing data from different parts of the world.

Physiological condition reflects polymorphism at the toll-like receptors in a colonial waterbird

Toll-like receptors (TLRs) are a crucial component of vertebrate innate immune response. Despite their importance, associations of TLR diversity with fitness-related traits have rarely been examined in wild animal populations. Here, we tested for associations of TLR polymorphism with physiological condition in a colonial waterbird, the Black-headed Gull (Chroicocephalus ridibundus). Physiological condition and polymorphism at 4 TLR loci were assessed in 60 gulls from a breeding colony in northern Poland. We found that blood hemoglobin and plasma albumin concentrations were positively associated with TLR diversity across all genotyped loci. Plasma concentrations of albumin and triglycerides were also associated with the presence of specific TLR variants and locus-specific diversity. All significant associations between physiological condition and TLRs were primarily apparent at the level of nucleotide, rather than amino acid allelic variants. Although the exact molecular mechanisms responsible for these associations require further investigation, our study provides strong correlational support for links between TLR diversity and physiological condition in a wild avian population, and it adds to the growing, but still modest, body of evidence for the fitness-related consequences of individual TLR repertoire in wild birds.