Safety and efficacy of desmopressin (DDAVP) in preventing hematoma expansion in intracranial hemorrhage associated with antiplatelet drugs use: A systematic review and metaanalysis.

INTRODUCTION: One of the most serious complications associated with antiplatelet agents is antiplatelet-associated intracranial hemorrhage (AA-ICH). Desmopressin is a synthetic antidiuretic hormone (ADH) analog. It has been linked to improving patient outcomes in antiplatelet-induced intracranial hemorrhage. The secondary outcomes included the incidence of thrombotic complications and neurological outcomes. METHODS: A systematic search was conducted on three databases (PubMed, Cochrane, and ClinicalTrials.gov) to find eligible literature that compares desmopressin (DDAVP) versus controls in patients with AA-ICH. The Mantel-Haenszel statistic was used to determine an overall effect estimate for each outcome by calculating the risk ratios and 95% confidence intervals (CI). Heterogeneity was measured using the I2 test. The risk of bias in studies was calculated using the New Castle Ottowa Scale. RESULTS: Five studies were included in the analysis with a total of 598 patients. DDAVP was associated with a nonsignificant decrease in the risk of hematoma expansion (RR = .8, 95% CI,.51-1.24; p = .31, I2 = 44%). It was also associated with a non-significant decrease in the risk of thrombotic events (RR,.83; 95% CI,.25-2.76; p = .76, I2 = 30%). However, patients in the DDAVP group demonstrated a significant increase in the risk of poor neurological outcomes (RR, 1.31; 95% CI, 1.07-1.61; p = .01, I2 = 0%). The risk of bias assessment showed a moderate to low level of risk. CONCLUSION: DDAVP was associated with a nonsignificant decrease in hematoma expansion and thrombotic events. However, it was also associated with a significantly poor neurological outcome in the patients. Thus, until more robust clinical trials are conducted, the use of DDAVP should be considered on a case-to-case basis.

Clinical Safety and Performance of GATT-Patch for Hemostasis in Minimal to Moderate Bleeding During Open Liver Surgery.

INTRODUCTION: Intraoperative blood loss and postoperative hemorrhage affect outcomes after liver resection. GATT-Patch is a new flexible, pliable hemostatic sealant patch comprising fibrous gelatin carrier impregnated with N-hydroxy-succinimide polyoxazoline. We evaluated safety and performance of the GATT-Patch for hemostasis at the liver resection plane. METHODS: Adult patients undergoing elective open liver surgery were recruited in three centers. GATT-Patch was used for minimal to moderate bleeding at the liver resection plane. The primary endpoint was hemostasis of the first-treated bleeding site at 3 min versus a prespecified performance goal of 65.4%. RESULTS: Two trial stages were performed: I (n = 8) for initial safety and II (n = 39) as the primary outcome cohort. GATT-Patch was applied in 47 patients on 63 bleeding sites. Median age was 60.0 (range 25-80) years and 70% were male. Most (66%) surgeries were for colorectal cancer metastases. The primary endpoint was met in 38 out of 39 patients (97.4%; 95% confidence interval: 84.6%-99.9%) versus 65.4% (P < 0.001). Of all the 63 bleeding sites, hemostasis was 82.7% at 30, 93.7% at 60, and 96.8% at 180 s. No reoperations for rebleeding or device-related issues occurred. CONCLUSIONS: When compared to a performance goal derived from state-of-the-art hemostatic agents, GATT-Patch for the treatment of minimal to moderate bleeding during liver surgery successfully and quickly achieved hemostasis with acceptable safety outcomes. (ClinicalTrials.gov Identifier: NCT04819945).

In Nordic countries 30-day mortality rate is half that estimated with EuroSCORE II in high-risk adult patients given aprotinin and undergoing mainly complex cardiac procedures.

Objectives. To describe current on- (isolated coronary arterty bypass grafting, iCABG) and off-label (non-iCABG) use of aprotinin and associated safety endpoints in adult patients undergoing high-risk cardiac surgery in Nordic countries. Design. Data come from 10 cardiac surgery centres in Finland, Norway and Sweden participating in the European Nordic aprotinin patient registry (NAPaR). Results. 486 patients were given aprotinin between 2016 and 2020. 59 patients (12.1%) underwent iCABG and 427 (87.9%) non-iCABG, including surgery for aortic dissection (16.7%) and endocarditis (36.0%). 89.9% were administered a full aprotinin dosage and 37.0% were re-sternotomies. Dual antiplatelet treatment affected 72.9% of iCABG and 7.0% of non-iCABG patients. 0.6% of patients had anaphylactic reactions associated with aprotinin. 6.4% (95 CI% 4.2%-8.6%) of patients were reoperated for bleeding. Rate of postoperative thromboembolic events, day 1 rise in creatinine >44µmol/L and new dialysis for any reason was 4.7% (95%CI 2.8%-6.6%), 16.7% (95%CI 13.4%-20.0%) and 14.0% (95%CI 10.9%-17.1%), respectively. In-hospital mortality and 30-day mortality was 4.9% (95%CI 2.8%-6.9%) and 6.3% (95%CI 3.7%-7.8%) in all patients versus mean EuroSCORE II 11.4% (95%CI 8.4%-14.0%, p < .01). 30-day mortality in patients undergoing surgery for aortic dissection and endocarditis was 6.2% (95%CI 0.9%-11.4%) and 6.3% (95%CI 2.7%-9.9%) versus mean EuroSCORE II 13.2% (95%CI 6.1%-21.0%, p = .11) and 14.5% (95%CI 12.1%-16.8%, p = .01), respectively. Conclusions. NAPaR data from Nordic countries suggest a favourable safety profile of aprotinin in adult cardiac surgery.

Comparison of hemostatic ability between spray coagulation and forced coagulation modes in endoscopic submucosal dissection in patients with early gastric neoplasms: a study protocol for multicenter randomized controlled trial (Spray-G trial).

BACKGROUND: Endoscopic submucosal dissection (ESD) is the standard treatment for early gastric neoplasms (EGN). Controlling intraoperative bleeding is crucial for ensuring safe and reliable procedures. ESD using the spray coagulation mode (SCM-ESD) has been developed to control bleeding more effectively than ESD using the conventional forced coagulation mode (FCM-ESD). This study aims to compare the hemostatic efficacies of SCM-ESD and FCM-ESD. METHODS: This multicenter, prospective, parallel, randomized, open-label superiority trial will be conducted in five Japanese institutions. Patients with a preoperative diagnosis of intramucosal EGC will be randomized to undergo either SCM-ESD or FCM-ESD. The primary outcome measure is the completion of ESD with an electrosurgical knife alone, without the use of hemostatic forceps. Secondary outcomes include the number and duration of hemostasis using hemostatic forceps, procedure time, curability, and safety. A total of 130 patients will be enrolled in this study. DISCUSSION: This trial will provide evidence on the hemostatic efficacy of SCM-ESD compared with FCM-ESD in patients with intramucosal EGN, potentially improving the safety and reliability of ESD procedures. TRIAL REGISTRATION: The trial has been registered at the University Hospital Medical Information Network Clinical Trials Registration (UMIN-CTR) as UMIN000040518. The reception number is R000054009.

Topical hemostatic agents in spinal surgery.

Spinal surgery can be associated with significant intraoperative blood loss which may lead to various complications. As the number of patients undergoing spinal surgery increases over time, accurate and effective hemostasis becomes critically important. Despite various surgical hemostatic techniques, conventional interventions such as compression, suture, ligation, and heat-generating cautery, are not suitable for osseous and epidural venous plexus bleeding during spinal procedures. Therefore, a variety of hemostatic agents have been developed to promote hemostasis. As they differ in terms of mechanism, form, application and potential adverse reactions, it is important to understand the natural features of existing agents. Here we comprehensively review currently available topical hemostatic agents from different sources and summarize their mechanisms of action, applications, and current or potential utilization in spinal surgery. We found hemostatic agents from different sources exert hemostatic actions through different mechanisms. In addition, topical hemostatic agents play various roles in spinal surgery including as hemostatic agent, dura mater repair, drug-carrier, skin closure, and fibrosis prevention. Compressive neurological complications are the most common complications of these hemostatic agents. Therefore, optimal use in spinal environments should match their features, indications, and efficacy with clinical conditions.

Use of Aprotinin versus Tranexamic Acid in Cardiac Surgery Patients with High-Risk for Excessive Bleeding (APACHE) trial: a multicentre retrospective comparative non-randomized historical study.

OBJECTIVES: Following the reintroduction of aprotinin into the European market, the French Society of Cardiovascular and Thoracic Anaesthesiologists recommended its prophylactic use at half-dose for high-risk cardiac surgery patients. We examined whether the use of aprotinin instead of tranexamic acid could significantly reduce severe perioperative bleeding. METHODS: This multicentre, retrospective, historical study included cardiac surgery patients treated with aprotinin or tranexamic acid between December 2017 and September 2020. The primary efficacy end point was the severe or massive perioperative bleeding (class 3-4 of the universal definition of perioperative bleeding). The safety secondary end points included the occurrence of thromboembolic events and all-cause mortality within 30 days after surgery. RESULTS: Among the 693 patients included in the study, 347 received aprotinin and 346 took tranexamic acid. The percentage of patients with severe or massive bleeding was similar in the 2 groups (42.1% vs 43.6%, Adjusted odds ratio [ORadj] = 0.87, 95% confidence interval: 0.62-1.23, P = 0.44), as was the perioperative need for blood products (81.0% vs 83.2%, ORadj = 0.75, 95% confidence interval: 0.48-1.17, P = 0.20). However, the median (Interquartile range) 12 h postoperative blood loss was significantly lower in the aprotinin group (383 ml [241-625] vs 450 ml [290-730], P < 0.01). Compared to tranexamic acid, the intraoperative use of aprotinin was associated with increased risk for thromboembolic events (adjusted Hazard ratio 2.30 [95% Cl: 1.06-5.30]; P = 0.04). CONCLUSIONS: Given the modest reduction in blood loss at the expense of a significant increase in thromboembolic adverse events, aprotinin use in high-risk cardiac surgery patients should be based on a carefully considered benefit-risk assessment.

Skin Perfusion After Hemostatic Net: An Anatomic and Radiologic Study in a Cadaver Model.

BACKGROUND: The hemostatic net is a recent technique initially developed to reduce the occurrence of postoperative hematomas following facelift procedures. Its applications have expanded to include skin redraping, deep plane fixation, and other areas beyond the face. However, no experimental study has investigated its effect on skin blood supply. OBJECTIVES: The aim of this study was to analyze facial skin vascularization after applying a hemostatic net to fresh cadavers. METHODS: Fourteen hemifaces from fresh adult cadavers were examined. The study model involved a deep plane facelift procedure with the use of a hemostatic net. The first step, involving 4 hemifaces, included dissections and two-/three-dimensional angiographies by digital microangiography and computed tomography scan, respectively. The purpose was to evaluate the influence of the hemostatic net on vascular perfusion. The second step involved a sequential dye perfusion study performed on 10 other hemifaces that underwent facelift procedures with the hemostatic net to determine its impact on skin perfusion. RESULTS: The anatomic and radiologic techniques enabled visualization of skin, and showed the arterial system reaching the subdermal vascular plexus and branching between the vascular territories, without interference from the net. The sequential dye perfusion study showed staining after injection in each facelift flap, with comparable coloration distributions before and after the application of the net. CONCLUSIONS: The hemostatic net did not affect the skin blood supply, correlating with no clinical increases in ischemia and necrosis rates in the facelift flap. This study provides additional evidence supporting the safety of the hemostatic net in clinical practice.

Four-factor prothrombin complex concentrate versus andexanet alfa for direct oral anticoagulant reversal.

BACKGROUND: Optimal reversal agent for direct oral anticoagulant (DOAC)-associated major bleeding has not been described. Before the approval of andexanet alfa (AA) in 2018, 4-factor prothrombin complex concentrate (4F-PCC) was recommended by major guidelines. Currently, AA is recommended as the first-line agent by most guidelines. With a paucity of literature comparing the 2 agents, there is clinical value in assessing hemostatic efficacy and safety of the 2 agents. OBJECTIVE: This study aimed to evaluate hemostatic efficacy and safety of AA and 4F-PCC in all DOAC-associated major bleedings. METHODS: A multicenter, retrospective chart review was performed of adult subjects who were admitted for a DOAC-associated major bleeding and received 4F-PCC from February 2018 to May 2019 or AA from May 2019 to September 2021. Some of the exclusion criteria included not receiving a DOAC, receiving multiple reversal agents during the same hospitalization, receiving reversal for any nonmajor bleeding indication, and not receiving the full dose of a reversal agent. The primary outcome was hemostatic efficacy 24 hours after the end of the reversal agent administration. Secondary outcomes included time to administration, hospital mortality, length of stay, need for surgery, and need for additional blood product. Safety outcome was incidence of thrombotic events. RESULTS: There were 99 subjects included in the 4F-PCC group and 84 subjects in the AA group. Hemostatic efficacy was achieved in 69 subjects (69.7%) in the 4F-PCC group and 63 subjects (75%) in the AA group (P = 0.927). In-hospital mortality was seen in 20 subjects (20.2%) in the 4F-PCC group and 10 subjects (11.9%) in the AA group. Thrombotic events were seen in 7 subjects (7.1%) in the 4F-PCC group and 6 subjects (7.1%) in the AA group. CONCLUSIONS: There were no significant differences in hemostatic efficacy, in-hospital mortality, and number of thrombotic events between 4F-PCC and AA.

Desmopressin to prevent and treat bleeding in pregnant women with an inherited bleeding disorder: a systematic literature review.

BACKGROUND: Although desmopressin (DDAVP) is an accessible and inexpensive hemostatic drug, its use in pregnancy is still debated due to safety uncertainties. OBJECTIVES: We aimed to review the safety and effectiveness of DDAVP in women with an inherited bleeding disorder during pregnancy and delivery. METHODS: Databases were searched for articles up to July 25, 2022, reporting maternal and/or neonatal outcomes. PRISMA methodology for systematic reviews and meta-analyses was followed (PROSPERO CRD42022316490). RESULTS: Fifty-three studies were included, comprising 273 pregnancies. Regarding maternal outcomes, DDAVP was administered in 73 women during pregnancy and in 232 during delivery. Safety outcome was reported in 245 pregnancies, with severe adverse events reported in 2 (1%, hyponatremia with neurologic symptoms). Overall, DDAVP was used as monotherapy in 234 pregnancies, with effectiveness reported in 153 pregnancies (82% effective; 18% ineffective). Regarding neonatal outcomes, out of 60 pregnancies with reported neonatal outcomes after DDAVP use during pregnancy, 2 children (3%) had a severe adverse event (preterm delivery n = 1; fetal growth restriction n = 1). Of the 232 deliveries, 169 neonates were exposed to DDAVP during delivery, and in 114 neonates, safety outcome was reported. Two children (2%) experienced a moderate adverse event (low Apgar score n = 1; transient hyperbilirubinemia not associated with DDAVP n = 1). CONCLUSION: DDAVP use during pregnancy and delivery seems safe for the mother, with special attention to the occurrence of hyponatremia and for the child, especially during delivery. However, due to poor study designs and limited documentation of outcomes, a well-designed prospective study is warranted.

Analysis of Reported Adverse Events Related to Hemospray: An FDA MAUDE Database Study.

BACKGROUND: Topical hemostatic powder is a mineral powder that forms an adherent barrier and coagulates active bleeding in the gastrointestinal (GI) tract. Hemospray is the first hemostatic powder approved by the Food and Drug Administration (FDA) in the United States. Hemospray has been increasingly used to manage GI bleeding. However, data on the adverse events of hemostatic powders are lacking. Therefore, we aim to report and analyze adverse events associated with Hemospray using the FDA's "Manufacturer and User Facility Device Experience" database. METHODS: We analyzed the postmarketing surveillance data from the FDA's Manufacturer and User Facility Device Experience database for Hemospray, initially known as TC-325, from June 2018 through April 2022. Results of the search were classified into device-related technical issues, patient-related adverse events and health care staff-related adverse events. RESULTS: Five hundred two medical device reporting claims were identified from June 2018 through April 2022. Seven duplicate claims were identified, and some claims included more than one event type. Therefore, there were 558 device-related problems, 28 patient-related adverse events, and 2 adverse events in health care staff members. The most common device-related problems were activation failure or failure to fire (n = 385, 70.0%) and obstruction of carbon dioxide flow (n = 121, 21.7). The most common patient-related adverse events included tissue injury or bleeding (n = 21) and perforation (n = 5). CONCLUSION: Although Hemospray is a valuable tool in the armamentarium for endoscopists in managing GI bleeding, endoscopists must be mindful of deice-related problems and potential patient-related adverse events.

A multitrait genetic study of hemostatic factors and hemorrhagic transformation after stroke treatment.

BACKGROUND: Thrombolytic recombinant tissue plasminogen activator (r-tPA) treatment is the only pharmacologic intervention available in the ischemic stroke acute phase. This treatment is associated with an increased risk of intracerebral hemorrhages, known as hemorrhagic transformations (HTs), which worsen the patient's prognosis. OBJECTIVES: To investigate the association between genetically determined natural hemostatic factors' levels and increased risk of HT after r-tPA treatment. METHODS: Using data from genome-wide association studies on the risk of HT after r-tPA treatment and data on 7 hemostatic factors (factor [F]VII, FVIII, von Willebrand factor [VWF], FXI, fibrinogen, plasminogen activator inhibitor-1, and tissue plasminogen activator), we performed local and global genetic correlation estimation multitrait analyses and colocalization and 2-sample Mendelian randomization analyses between hemostatic factors and HT. RESULTS: Local correlations identified a genomic region on chromosome 16 with shared covariance: fibrinogen-HT, P = 2.45 × 10-11. Multitrait analysis between fibrinogen-HT revealed 3 loci that simultaneously regulate circulating levels of fibrinogen and risk of HT: rs56026866 (PLXND1), P = 8.80 × 10-10; rs1421067 (CHD9), P = 1.81 × 10-14; and rs34780449, near ROBO1 gene, P = 1.64 × 10-8. Multitrait analysis between VWF-HT showed a novel common association regulating VWF and risk of HT after r-tPA at rs10942300 (ZNF366), P = 1.81 × 10-14. Mendelian randomization analysis did not find significant causal associations, although a nominal association was observed for FXI-HT (inverse-variance weighted estimate [SE], 0.07 [-0.29 to 0.00]; odds ratio, 0.87; 95% CI, 0.75-1.00; raw P = .05). CONCLUSION: We identified 4 shared loci between hemostatic factors and HT after r-tPA treatment, suggesting common regulatory mechanisms between fibrinogen and VWF levels and HT. Further research to determine a possible mediating effect of fibrinogen on HT risk is needed.

Iatrogenic Carotid Artery Pseudoaneurym: Successful Treatment With Percutaneous Thrombin Injection.

This report demonstrates the successful treatment of a carotid artery pseudoaneurysm using percutaneous thrombin injection. The patient, a 62-year-old woman with multiple comorbidities, experienced a pseudoaneurysm following an unintentional carotid artery puncture during a failed attempt to place a triple lumen catheter in the right jugular vein. Percutaneous thrombin injection was chosen as the treatment method, with Doppler ultrasound monitoring. Follow-up examinations showed no signs of recurrence, and the patient was discharged after nine days without complications.

FRONTIER1: a partially randomized phase 2 study assessing the safety, pharmacokinetics, and pharmacodynamics of Mim8, a factor VIIIa mimetic.

BACKGROUND: Mim8 (denecimig) is a factor VIII (FVIII) mimetic bispecific antibody in development for the treatment of hemophilia. Data from the phase 1 part of FRONTIER1 (EudraCT: 2019-000465-20, NCT04204408, and NN7769-4513) suggested that Mim8 was well tolerated in healthy participants and exhibited pharmacokinetic (PK) properties consistent with dose proportionality. OBJECTIVES: The partially randomized, phase 2, multiple ascending dose (MAD) part of FRONTIER1 aimed to evaluate the safety, PK, pharmacodynamics (PD), and exploratory efficacy of Mim8 in participants with hemophilia A with or without FVIII inhibitors. METHODS: The MAD part of FRONTIER1 consisted of 42 participants, assigned to 5 cohorts, with participants in cohorts 3 and 4 randomized 1:1 to dosing weekly or every 4 weeks, respectively. Four of the 42 participants (9.5%) had FVIII inhibitors prior to study enrolment. The primary endpoint was treatment-emergent adverse events (TEAEs). PK and PD were evaluated by Mim8 plasma concentration and thrombin generation, respectively. Exploratory efficacy was assessed via the number of treated bleeds. Safety and PD parameters were also evaluated from an exploratory cohort treated with emicizumab. RESULTS: Mim8 was well tolerated, with 1 serious TEAE (anxiety-related chest pain) deemed unrelated to Mim8. There was no dose dependency on the number, causality, type, or severity of TEAEs. PK/PD properties supported weekly to monthly dosing approaches, and few participants experienced treated bleeds beyond the lowest dose cohort (1 in cohorts 2 and 3, and 3 in cohort 5). CONCLUSION: These data support the continued clinical development of Mim8, and FRONTIER1 has proceeded onto an extension phase.

[Effect of recombinant human thrombin for hemostasis in liver resection: a randomized controlled phase â ¢ clinical trial].

Objective: To evaluate the hemostatic efficacy, safety and immunogenicity of recombinant human thrombin in the treatment of liver wounds that still ooze after conventional surgical hemostasis. Methods: A multicenter, stratified randomized, double-blind, placebo-controlled phase Ⅲ trial with a planned enrollment of 510 subjects at 33 centers, with a 2∶1 randomization to the thrombin group versus the placebo group. An interim analysis will be conducted after approximately 70% of the subjects have completed the observation period. The primary efficacy endpoint was the rate of hemostasis within 6 minutes at the point of bleeding that could be evaluated. Safety analysis was performed one month after surgery, and the positive rates of anti-drug antibody (ADA) and neutralizing antibody were evaluated. Results: At the interim analysis, a total of 348 subjects had been randomized and received the study drug (215 were male and 133 were female). They were aged 19-69 (52.9±10.9)years. Among them, 232 were in the thrombin group and 116 were in the placebo group, with balanced and comparable demographics and baseline characteristics between the two groups. The hemostasis rate at 6 minutes was 71.6% (95%CI:65.75%-77.36%) in the thrombin group and 44.0% (95%CI: 34.93%-53.00%) in the placebo group, respectively (P<0.001). No grade≥3 drug-related adverse events and no drug-related deaths were reported from the study.No recombinant human thrombin-induced immunologically-enhanced ADA or immunologically-induced ADA was detected after topical use in subjects. Conclusion: Recombinant human thrombin has shown significant hemostatic efficacy and good safety in controlling bleeding during liver resection surgery, while also demonstrating low immunogenicity characteristics.

Hemostatic Spray TC-325 (Hemospray®) and Unexpected Esophageal Entrapment of Gastroscope With Airway Management Considerations: A Case Report.

Bleeding from the upper gastrointestinal tract is responsible for approximately 2% of all hospital admissions annually, with an up to 17% mortality rate. Therapeutic endoscopic interventions are often indicated for establishing hemostasis. These interventions include but are not limited to thermal coagulation with cautery, mechanical methods using band ligation or hemostatic clips, and hemostatic spray. Anesthesia providers are frequently involved in providing sedation for those endoscopic procedures. In 2018, the United States Food and Drug Administration approved a hemostatic spray, Hemospray® TC-325 (Cook Medical, Winston- Salem, NC, USA) for controlling nonvariceal upper gastrointestinal bleeding. The inorganic, mineral-based powder forms a mechanical tamponade by absorbing water and attracting clotting factors to the bleeding site. Adverse events associated with using the product are reported as rare but have included perforation and difficulty in removing the gastroscope. This case presents unexpected entrapment of the gastroscope in a patient's esophagus after the bleeding site was treated with Hemospray. Potential difficulties with airway management strategies are discussed.