Effective prediction model for preventing postoperative deep vein thrombosis during bladder cancer treatment

Objective To begin to understand how to prevent deep vein thrombosis (DVT) after an innovative operation termed intracorporeal laparoscopic reconstruction of detenial sigmoid neobladder, we explored the factors that influence DVT following surgery, with the aim of constructing a model for predicting DVT occurrence. Methods This retrospective study included 151 bladder cancer patients who underwent intracorporeal laparoscopic reconstruction of detenial sigmoid neobladder. Data describing general clinical characteristics and other common parameters were collected and analyzed. Thereafter, we generated model evaluation curves and finally cross-validated their extrapolations. Results Age and body mass index were risk factors for DVT, whereas postoperative use of hemostatic agents and postoperative passive muscle massage were significant protective factors. Model evaluation curves showed that the model had high accuracy and little bias. Cross-validation affirmed the accuracy of our model. Conclusion The prediction model constructed herein was highly accurate and had little bias; thus, it can be used to predict the likelihood of developing DVT after surgery.

Effectiveness of use of local hemostatic agents for external bleeding by visiting ambulance teams

The alternative use of local hemostatic agents based on chitosan is the gentlest method of stopping bleeding, with minimal damaging effect on tissues, in comparison with the imposition of a hemostatic tourniquet or a pressure bandage.Goal. To evaluate the effectiveness of temporary stopping of external bleeding with the help of local hemostatic agents based on chitosan in powder and bandage forms and to determine the expediency of their use by visiting ambulance teams.Materials and methods. Specialists of the field teams of Ambulance and Medical Emergency Care Station n. a. A. S. Puchkov (Moscow, Russia) used local hemostatic agents based on chitosan in the form of a powder, a bandage in comparison with traditional hemostatic agents (a hemostatic tourniquet to stop arterial bleeding and a pressure bandage). The criteria for hemostasis were the absence of wetting of the pressure bandage and the absence of the need for a hemostatic tourniquet.Results. 103 patients were included in the main group, and 106 patients with arterial and venous bleeding from wounds of various localization were included in the control group. The age of patients in the compared groups ranged from 18 to 94 years. When using hemostatic powder and bandage, primary hemostasis was achieved in 99 patients in 96.1 % of cases, compared with the control group in 76 patients in 67.9 % of cases.Conclusions. Simplicity and ease of use, the speed of stopping bleeding and achieving results, as well as the absence of the need for special skills among specialists in the use of hemostatic agents, improved the quality of emergency medical care for patients with bleeding and allowed them to be recommended as a dressing for emergency medical care.

Advances in the development of hemostatic biomaterials for medical application

Background Medical hemostatic biological materials are necessary for the development of the process of preventing and stopping damaged intravascular bleeding. In the process, some red blood cells and white blood cells are trapped in nets. The resulting plug is called a blood clot. This is often a good step in wound healing, but separation of blood clots from blood vessel walls can cause serious health problems. Main body The advance in the development of hemostatic biomaterials is necessary for biomedical application. Firstly, the historical background of artificial hemostasis has been included and the current research of hemostasis has been included in more detail. Secondly, the current research of hemostasis has been included on the oxidized cellulose-based hemostatic biomaterials such as starch based on composite cross-linking hemostatic networks, hemostatic materials on NHS-esters, hemostatic agent from local materials and biomaterials for hemostatic management. Thirdly, polysaccharide hemostatic materials, bio-inspired adhesive catechol-conjugated chitosan, mesoporous silica and bioactive glasses for improved hemostasis, minimally invasive hemostatic biomaterials and chitosan-base materials for hemostatic application have been included. Fourthly, the biological properties of natural hemostatic agent by plasma technology and the hemostatic agents based on gelatin-microbial transglutaminase mixes have been also included. Conclusion Current research on hemostasis includes hemostatic biomaterials such as cellulose-based hemostatic starch based on a complex cross-linked hemostatic network. It also includes polysaccharide hemostatic materials, biomimetic adhesive catechol-binding chitosan, mesoporous silica or physiologically active glass for hemostatic improvement, minimally invasive hemostatic chitosan-based materials, and gelatin-microbial transglutaminase-based hemostatic agents. Future studies should focus on modular combination of hemostatic imitation and reinforcement mechanisms of different materials and technologies to find the optimal system to promote and strengthen active platelet or platelet imitation aggregation in bleeding sites. The second optionally increases the production of thrombin and fiber formation at the site. Third, the formed fibrin biopolymer network has strengthened to reduce thrombosis and amplify hemostasis.

Effects of Bypassing Hemostatic Agents in the Co-Presence of NXT007, Emicizumab-Based Engineered Bispecific Antibody to Fixa/Fx, Using in Vitro Global Assays: Rough Indicators for Their Concomitant Use

Background: NXT007, emicizumab (Emi)-based engineered therapeutic bispecific antibody which increases tissue factor (TF)-triggered thrombin generation (TG) potential of factor(F) VIII-deficient plasma to non-hemophiliac ranges at around 5-30 μg/mL (Yamaguchi, ASH 2020), is currently in a phase 1/2 clinical study. In the clinical settings under NXT007-prophylaxis, bypassing hemostatic agents (BPAs), such as activated prothrombin complex concentrates (aPCC) and recombinant(r) FVIIa, may be concomitantly administered. Under Emi-prophylaxis, repeated doses of aPCC impose a thrombotic risk. Against the risk, NHF's Medical and Scientific Advisory Council (MASAC) recommends ≤50 U/kg and ≤100 U/kg of aPCC as initial dose and one day dosage, respectively. In case of NXT007-prophylaxis, concomitant-use with BPAs should be also carefully managed and thus basic non-clinical combination data are needed. Objectives: To examine in vitro effects of BPAs in the co-presence of NXT007 for providing rough indicators for determining their safe doses. Methods: First, TF-triggered TG assay was performed using commercial FVIII-deficient plasma. rFVIII, rFVIIa or aPCC was spiked in the co-presence of NXT007 or Emi (0.1-50 μg/mL). Second, the TG assay and whole blood clot viscosity test (ROTEM) using Ca 2+-trigger was performed using healthy volunteer's blood incubated with anti-FVIII antibodies (HA model), where aPCC or rFVIIa was spiked in the co-presence of NXT007. Third, ROTEM was performed as above using whole blood from persons with hemophilia A (PwHA) under Emi- or FVIII-prophylaxis. Results: Peak height of TF-triggered TG assay using FVIII-deficient plasma was increased by spiking each of the agents (rFVIII, rFVIIa or aPCC) in the co-presence of NXT007 (0.1-50 μg/mL). Peak height increase by rFVIII under NXT007 was roughly additive. Peak height increase by each BPA under NXT007 was synergistic. Synergistic effect by aPCC was more intensive than that by rFVIIa. The combination effect of 0.1 U/mL aPCC and 0.1-50 μg/mL NXT007 on peak height did not exceed that of 0.5 U/mL aPCC and 50 μg/mL Emi. Peak height at 2 μg/mL NXT007 alone was comparable to that at 50 μg/mL Emi alone. When adding BPAs to these two settings, similar synergistic effects were observed. It suggested that NXT007's combination actions with BPAs were qualitatively similar to Emi's. In the TG assay using the HA model plasma (n=2), the combined effect of aPCC and NXT007 was similarly confirmed. In ROTEM using the same HA model whole blood (n=2), clotting time (ROTEM-CT, 7380±605 sec) was shortened by spiking 5 μg/mL NXT007 (791±148 sec) to yield normal levels (1521±110 sec). Spiked aPCC (0.13, 0.65 U/mL in whole blood, equivalent to ~10, ~50 U/kg infusion) shortened ROTEM-CT (1228±549, 435±54 sec) and further shortened it in the co-presence of 5 or 15 μg/mL NXT007 (171±11, 113±1* or 143±4, 90±5* sec [* significantly ( p<0.05) shorter than that of the Emi-treated PwHA blood spiking 0.65 U/mL aPCC, 162±21 sec)]. In PwHA without Emi-prophylaxis (n=2), ROTEM-CT (5148±1290 sec) was shortened by spiking 5 or 15 μg/mL NXT007 (1598±482 or 1116±14 sec) to non-hemophiliac levels (20 IU/dL rFVIII, 1569±222 sec). Spiked aPCC (0.13, 0.65 U/mL) shortened ROTEM-CT (1383±322, 680±84 sec) and further shortened it in the co-presence of 5 or 15 μg/mL NXT007 (230±35, 144±4 or 193±11, 121±0* sec). Spiked rFVIIa also shortened ROTEM-CT in the co-presence of NXT007, but the intensity was less than spiked aPCC. ROTEM using blood from PwHA under Emi-prophylaxis (n=3) were also performed and demonstrated that the effects by co-spiking BPAs and NXT007 were roughly consistent with those using PwHA blood without Emi-prophylaxis. These ROTEM data indicated that the combined effect of 0.13 U/mL aPCC and 5-15 μg/mL NXT007 was less intensive than that of 0.65 U/mL aPCC spiked to the Emi-treated PwHA blood, while that of 0.65 U/mL aPCC and 5-15 μg/mL NXT007 had more intensive effect (Table). Conclusion: In considering concomitant use of BPA under NXT007-prophylaxis, dose of aPCC should be more carefully determined than that of rFVIIa. In this non-clinical study, the combined effect of ~0.13 U/mL aPCC (equivalent to ~10 U/kg infusion) and ~15 μg/mL NXT007 did not exceed that of 0.65 U/mL aPCC (50 U/kg infusion) under Emi-prophylaxis situation corresponding to the upper limit of initial concomitant dose recommended by MASAC, which might be rough indicators in future clinical settings. Figure 1 Figure 1. Disclosures Ogiwara: Chugai Pharmaceutical Co., Ltd.: Consultancy, Research Funding. Furukawa: Chugai Pharmaceutical Co., Ltd.: Research Funding. Sasai: Chugai Pharmaceutical Co., Ltd.: Research Funding. Inaba: Chugai Pharmaceutical Co., Ltd.: Current Employment. Kitazawa: Chugai Pharmaceutical Co., Ltd.: Current Employment, Current equity holder in publicly-traded company. Nogami: Chugai Pharmaceutical Co., Ltd.: Consultancy, Research Funding.

A Phase 3, Randomized, Double-Blinded Study of Four-Factor Prothrombin Complex Concentrate in Patients with Acute Major Bleeding on Direct Oral Anticoagulant Therapy with Factor Xa Inhibitor: The Lex-210 Study

Introduction: The benefit of direct oral anticoagulants (DOAC; Factor Xa Inhibitors [FXaI]) has been demonstrated in both clinical trials and real-world studies. However, 2% to 3.5% of DOAC-treated patients experience major bleeding annually, and this is associated with substantial morbidity, mortality, and the need for hospitalization. Therefore, reversal/hemostatic agents are used to control FXaI-related bleeding. The efficacy and safety profile of prothrombin complex concentrates (PCCs) as hemostatic agents in patients with FXaI-related bleeding requires further investigation. Methods: The pivotal LEX-210 study (NCT04867837) is a Phase 3, multicenter, prospective, randomized, double-blinded, group-sequential, parallel-group, adaptive design study to demonstrate the hemostatic efficacy and safety of four-factor PCC (Octaplex®, Octapharma) in patients with acute major bleeding on DOAC therapy with FXaI. LEX-210 will include patients aged ≥18 years who have received or are believed to have received a dose of oral FXaI. Patients must have a baseline anti-factor Xa activity equivalent to at least 100 ng/mL according to the available test (e.g., chromogenic assay) and have acute major bleeding. Key exclusion criteria are bleeding that is immediately life-threatening and acute trauma for which reversal of DOAC therapy with FXaI alone would not be expected to control the bleeding event. The study will enroll approximately 200 patients, with the aim to include at least 91 evaluable patients in each group. Patients will be randomized 1:1 to either of two study groups: low-dose 15 IU/kg body weight vs. high-dose 50 IU/kg body weight PCC. The primary objective of this study is to demonstrate superior hemostatic effectiveness of PCC dosed at 50 IU/kg vs. 15 IU/kg for emergency reversal of the anticoagulant effect of DOACs in patients with major bleeding associated with FXaI. The primary endpoint of LEX-210 is the proportion of patients in whom PCC demonstrates hemostatic effectiveness, i.e., binary outcome of effective (rating of excellent or good) or non-effective (rating of poor or none) in management of major bleeding events within 24 hours after the start of initial management, as assessed by an Independent Data Monitoring and Endpoint Adjudication Committee according to predefined criteria modified from those used by Sarode et al., (see Table 1). Secondary endpoints are the change in endogenous thrombin potential as measured by thrombin generation assay from baseline to 1 hour after PCC administration, the 30-day event rate of thromboembolic events and all-cause mortality, the occurrence of adverse events, and vital signs and laboratory parameters. Results: LEX-210 is planned to start in Q3 2021 and will be performed at approximately 60 sites in North America and Europe. Completion is expected by Q1 2024. Conclusions: The LEX-210 study is designed to confirm the safety and hemostatic efficacy of PCC in the management of FXaI-related major bleeding, offering an effective alternative for the management of major bleeding events in these patients. Figure 1 Figure 1. Disclosures Sarode: Portola: Consultancy; CSL Behring: Consultancy; Octapharma: Consultancy; Cerus: Research Funding; Siemens: Research Funding. Maack: Octapharma: Current Employment. Solomon: Octapharma: Current Employment. Knaub: Octapharma: Current Employment. Schulman: Octapharma: Research Funding; Boehringer-Ingelheim: Research Funding.

Hemostatic agents in periapical surgery: The systematic review

Several agents have been used to secure hemostasis during periapical surgery. Their efficacy, biological response and side effects differ from each other.Aim. Of this review article is to assess systematically the available scientific evidence about the clinical response after using hemostatic agents during apical surgery.Materials and methods. The study of publications was produced in the electronic databases such as Google Scholar, PubMed during a systematic review of the literature. Included articles contain information about using hemostatic agents during periapical surgery and their adverse effects. The publication date criterion was selected from January 2006 to September 2021.Results. 55 articles were viewed during the review. After analyzing the literature for inclusion criteria, the total number of publications has become 10.Conclusions. According to literature data, different hemostatic agents are used during periapical surgery, but there weren’t any inflammatory reactions while using calcium sulfate.