Palliative effects of carnosol on lung-deposited pollutant particles-induced thrombogenicity and vascular injury in mice.

The toxicity of inhaled particulate air pollution perseveres even at lower concentrations than those of the existing air quality limit. Therefore, the identification of safe and effective measures against pollutant particles-induced vascular toxicity is warranted. Carnosol is a bioactive phenolic diterpene found in rosemary herb, with anti-inflammatory and antioxidant actions. However, its possible protective effect on the thrombotic and vascular injury induced by diesel exhaust particles (DEP) has not been studied before. We assessed here the potential alleviating effect of carnosol (20 mg/kg) administered intraperitoneally 1 h before intratracheal (i.t.) instillation of DEP (20 µg/mouse). Twenty-four hours after the administration of DEP, various parameters were assessed. Carnosol administration prevented the increase in the plasma concentrations of C-reactive protein, fibrinogen, and tissue factor induced by DEP exposure. Carnosol inhibited DEP-induced prothrombotic effects in pial microvessels in vivo and platelet aggregation in vitro. The shortening of activated partial thromboplastin time and prothrombin time induced by DEP was abated by carnosol administration. Carnosol inhibited the increase in pro-inflammatory cytokines (interleukin-6 and tumor necrosis factor α) and adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, and P-selectin) in aortic tissue. Moreover, it averted the effects of DEP-induced increase of thiobarbituric acid reactive substances, depletion of antioxidants and DNA damage in the aortic tissue. Likewise, carnosol prevented the decrease in the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) caused by DEP. We conclude that carnosol alleviates DEP-induced thrombogenicity and vascular inflammation, oxidative damage, and DNA injury through Nrf2 and HO-1 activation.

Histidine-Rich Glycoprotein Modulates the Toxic Effects of High-Dose Polyphosphate in Mice.

BACKGROUND: Polyphosphate (polyP), a procoagulant released from platelets, activates coagulation via the contact system and modulates cardiomyocyte viability. High-dose intravenous polyP is lethal in mice, presumably because of thrombosis. Previously, we showed that HRG (histidine-rich glycoprotein) binds polyP and attenuates its procoagulant effects. In this study, we investigated the mechanisms responsible for the lethality of intravenous polyP in mice and the impact of HRG on this process. METHODS: The survival of wild-type or HRG-deficient mice given intravenous synthetic or platelet-derived polyP in doses up to 50 mg/kg or saline was compared. To determine the contribution of thrombosis, the effect of FXII (factor XII) knockdown or enoxaparin on polyP-induced fibrin deposition in the lungs was examined. To assess cardiotoxicity, the ECG was continuously monitored, the levels of troponin I and the myocardial band of creatine kinase were quantified, and the viability of a cultured murine cardiomyocyte cell line exposed to polyP in the absence or presence of HRG was determined. RESULTS: In HRG-deficient mice, polyP was lethal at 30 mg/kg, whereas it was lethal in wild-type mice at 50 mg/kg. Although FXII knockdown or enoxaparin administration attenuated polyP-induced fibrin deposition in the lungs, neither affected mortality. PolyP induced dose-dependent ECG abnormalities, including heart block and ST-segment changes, and increased the levels of troponin and myocardial band of creatine kinase, effects that were more pronounced in HRG-deficient mice than in wild-type mice and were attenuated when HRG-deficient mice were given supplemental HRG. Consistent with its cardiotoxicity, polyP reduced the viability of cultured cardiomyocytes in a dose-dependent manner, an effect attenuated with supplemental HRG. CONCLUSIONS: High-dose intravenous polyP is cardiotoxic in mice, and HRG modulates this effect.

The proteasome inhibitor carfilzomib exerts anti-inflammatory and antithrombotic effects on the endothelium.

BACKGROUND: Carfilzomib (CFZ) is a second-generation proteasome inhibitor used to treat multiple myeloma. Potent inhibition of the proteasome results in chronic proteotoxic endoplasmic reticulum (ER) stress, leading to apoptosis. While CFZ has improved survival rates in multiple myeloma, it is associated with an increased risk of cardiovascular adverse effects. While this has been putatively linked to cardiotoxicity, CFZ could potentially also exhibit adverse effects on the endothelium. OBJECTIVES: To investigate the effects of CFZ on the endothelium. METHODS: Human umbilical vein endothelial cells (HUVECs) were treated with CFZ, and expression of relevant markers of ER stress, inflammation, and thrombosis was measured and functionally assessed. RESULTS: CFZ failed to induce ER stress in HUVECs but induced the expression of Kruppel-like factor 4, endothelial nitric oxide synthase, tissue plasminogen activator, and thrombomodulin and reduced tumor necrosis factor alpha (TNFα)-mediated intercellular adhesion molecule 1 and tissue factor expression, suggesting a potential protective effect on the endothelium. Consistent with these observations, CFZ reduced leukocyte adhesion under shear stress and reduced factor Xa generation and fibrin clot formation on the endothelium following TNFα treatment and inhibited von Willebrand factor (VWF) and angiopoietin-2 exocytosis from Weibel-Palade bodies. Subsequently, CFZ inhibited the formation of VWF-platelet strings, and moreover, media derived from myeloma cell lines induced VWF release, a process also inhibited by CFZ. CONCLUSION: These data demonstrate that CFZ is unable to induce ER stress in confluent resting endothelial cells and can conversely attenuate the prothrombotic effects of TNFα on the endothelium. This study suggests that CFZ does not negatively alter HUVECs, and proteasome inhibition of the endothelium may offer a potential way to prevent thrombosis.

Efficacy and safety of antiplatelet therapy in COVID-19: Insights from a meta-analysis of randomized controlled trials.

BACKGROUND: COVID-19 induces a pro-coagulant state with thrombotic events. This meta-analysis explores the efficacy and safety of antiplatelet-based therapy in COVID-19 patients through randomized controlled trials (RCTs). MATERIALS AND METHODS: A systematic literature search until March 10, 2023, identified 7 RCTs involving 23,415 inpatients. Of these, 11,891 received antiplatelet-based treatment, and 11,524 received placebo/other drugs. Statistical analysis was performed using Review Manager 5.4. RESULTS: The included trials involved patients with a mean age ranging from 54.3 to 62.0 years and a prevalence of hypertension ranging from 10.9 to 65.0% and coronary artery disease ranging from 3.2 to 32.7%. The pooled analysis showed no significant difference in overall mortality between groups (RR 1.0, 95% CI 0.99 - 1.01, p = 0.76). However, antiplatelet therapy significantly reduced major thrombotic events (RR 0.86, 95% CI 0.75 - 0.99, p = 0.04). Conversely, it increased major bleeding risks (RR 1.62, 95% CI 1.24 - 2.12, p = 0.0005). There was no significant difference in the incidence of invasive mechanical ventilation and respiratory death. CONCLUSION: Antiplatelet therapy does not confer mortality benefit in COVID-19 patients but lowers major thrombotic events while increasing major bleeding risks. Ongoing large RCTs will provide more information on the therapeutic value of this therapy.

[A case of aortic thrombus during chemotherapy for esophageal cancer].

A 59-year-old man presented to our hospital with a chief complaint of epigastric pain. Pertinent history included a distal gastrectomy for gastric cancer and alcohol dependence. He underwent contrast-enhanced computed tomography (CT) and esophagogastroduodenoscopy, which led to a diagnosis of esophageal cancer (cT2N2M1, stage IVb). Subsequently, he underwent chemotherapy using 5-fluorouracil and cis-diamminedichloroplatinum and radiotherapy. A total of 44 days after treatment initiation, the patient experienced nausea and hepatobiliary enzyme elevation. CT and abdominal ultrasonography were performed, and he was diagnosed with an abdominal aortic thrombus. Intravenous heparin was administered as an anticoagulant therapy. Twenty-two days after treatment initiation, the thrombus was no longer visible on abdominal ultrasonography. The patient was then treated with warfarin. It cannot be ruled out that the patient's hepatobiliary enzyme elevation was induced by the anticancer drugs. However, enzyme elevation improved with the disappearance of the abdominal aortic thrombus, suggesting that the aortic thrombus may have contributed to the hepatobiliary enzyme elevation. No thrombus recurrence was observed until the patient's death after an initial treatment with antithrombotic agents. This case indicates that malignant tumors and chemotherapy can cause aortic thrombi, and thus, care should be exercised in monitoring this potential complication.

Non-vitamin K oral anticoagulants versus warfarin for the treatment of left ventricular thrombus.

INTRODUCTION: Left ventricular thrombus (LVT) is associated with significant morbidity and mortality. Conventional treatment comprises warfarin-mediated anticoagulation; it is unclear whether non-vitamin K oral anticoagulants (NOACs) exhibit comparable efficacy and safety. Limited data are available for Asian patients. This study compared NOACs with warfarin in terms of clinical efficacy and safety for managing LVT. METHODS: Clinical and echocardiographic records were retrieved for all adult patients with echocardiography-confirmed LVT at a major regional centre in Hong Kong from January 2011 to January 2020. Discontinuation of anticoagulation by 1 year was recorded. Outcomes were compared between patients receiving NOACs and those receiving warfarin. Primary outcomes were cumulative mortality and net adverse clinical events (NACEs). Secondary outcomes were complete LVT resolution and percentage reduction in LVT size at 3 months. RESULTS: Forty-three patients were included; 28 received warfarin and 15 received NOACs, with follow-up periods (mean ± standard deviation) of 20 ± 12 months and 22 ± 9 months, respectively (P=0.522). Use of NOACs was associated with significantly lower NACE risk (hazard ratio [HR]=0.111, 95% confidence interval [CI]=0.012-0.994; P=0.049) and a tendency towards lower cumulative mortality (HR=0.184, 95% CI=0.032-1.059; P=0.058). There were no significant differences in secondary outcomes. Considering LVT resolution, discontinuation of anticoagulation by 1 year was not significantly associated with different outcomes. CONCLUSION: Non-vitamin K oral anticoagulants may be an efficacious and safe alternative to warfarin for LVT management. Future studies should explore the safety and efficacy of anticoagulation discontinuation by 1 year as an overall strategy.

Anticoagulant and non-anticoagulant therapy in thrombotic antiphospholipid syndrome: old drugs and new treatment targets.

In this review, we discuss the current evidence on classic and newer oral anticoagulant therapy, older drugs such as HCQ and statins, and new potential treatment targets in APS. Vitamin K antagonists (VKAs) remain the cornerstone treatment for thrombotic events in APS. In patients fulfilling criteria for definite APS presenting with a first venous thrombosis, treatment with VKAs with a target international normalized ratio (INR) 2.0-3.0 is recommended. In patients with arterial thrombosis, treatment with VKA with target INR 2.0-3.0 or 3.0-4.0 is recommended by recent guidelines, considering the individual's bleeding and thrombosis recurrence risk. A combination of VKAs and low-dose aspirin (75-100 mg/daily) may also be considered. According to available evidence direct oral anticoagulants should be avoided in patients with arterial thrombosis and/or those with triple aPL positivity. Adjunctive treatment with HCQ and/or statins can be considered, especially in anticoagulation treatment-refractory APS. Potential targeted treatments in APS include B-cell targeting, complement inhibition, mammalian target of rapamycin inhibition, IFN targeting, adenosine receptors agonists, CD38 targeting or chimeric antigen receptor T-cell therapy. The safety and efficacy of these treatment targets needs to be examined in well-designed randomized controlled trials.

Comparison of thrombotic adverse events in patients treated with factor VIII products and emicizumab using the 2018-2022 US Food and Drug Administration Adverse Event Reporting System data.

BACKGROUND: Relatively little is known about thrombotic adverse events (AEs) of emicizumab in postmarketing real-world settings, particularly in comparison with factor VIII (FVIII) products. A recent European study reported a potentially greater thrombotic risk of emicizumab compared with FVIII products. OBJECTIVES: This drug safety study aims to investigate whether thrombotic AEs are more frequently reported for emicizumab than for FVIII products and if so, whether it is independent of bypassing agents as coreporting drugs using the United States Food and Drug Administration Adverse Event Reporting System data. METHODS: Disproportionality analyses for thrombotic AEs of emicizumab vs FVIII products were conducted. Three signal detection indicators were used: proportional reporting ratio (PRR), reporting odds ratio (ROR), and informational component (IC). RESULTS: During 2018-2022, the proportions of thrombotic AEs among all AEs were 4.07% (97 out of 2383) and 1.44% (134 out of 9324) for emicizumab and FVIII products, respectively: PRR = 2.83 (2.19-3.66), ROR = 2.91 (2.23-3.79), and IC = 1.04 (0.70-1.28). Bypassing agents as coreporting drugs were identified in 36% and 15% of the total thrombotic AE reports associated with emicizumab and FVIII products, respectively. Even after thrombotic AE reports with bypassing agents were excluded, the reporting proportion of thrombotic AEs was still greater for emicizumab than for FVIII products: PRR = 2.19 (1.60-2.99). CONCLUSION: Thrombotic AEs in the United States Food and Drug Administration Adverse Event Reporting System data were about 3 times more frequently reported for emicizumab than for FVIII products. More research and efforts in the future are warranted for monitoring, elucidating, and preventing the potential risk of thrombotic AEs in hemophilia therapy, including emicizumab.

Thrombosis with thrombocytopenia syndrome (TTS) and vaccine-induced immune thrombocytopenia and thrombosis (VITT): Brighton Collaboration case definitions and guidelines for data collection, analysis, and presentation of immunisation safety data.

This is a revision of the online November 2021 Brighton thrombosis with thrombocytopenia syndrome (TTS) case definition and a new Brighton Collaboration case definition for vaccine-induced immune thrombocytopenia and thrombosis (VITT). These case definitions are intended for use in clinical trials and post-licensure pharmacovigilance activities to facilitate safety data comparability across multiple settings. They are not intended to guide clinical management. The case definitions were developed by a group of subject matter and Brighton Collaboration process experts as part of the Coalition for Epidemic Preparedness Innovations (CEPI)-funded Safety Platform for Evaluation of vACcines (SPEAC). The case definitions, each with defined levels of diagnostic certainty, are based on relevant published evidence and expert consensus and are accompanied by specific guidelines for TTS and VITT data collection and analysis. The document underwent peer review by a reference group of vaccine safety stakeholders and haematology experts to ensure case definition useability, applicability and scientific integrity.

Infographics on risks associated with COVID-19 and the willingness to get the AstraZeneca vaccine: two randomized online experiments.

BACKGROUND: Germans hesitated to get vaccinated with AstraZeneca in the COVID-19 pandemic after reports of blood clots. METHODS: In two preregistered online experiments with stratified randomization (Study 1 N = 824, Study 2: N = 1,056), we tested whether providing evidence-based benefit-risk information reduces the perceived risk of the AstraZeneca vaccine and the perceived probability of blood clots due to the AstraZeneca vaccine and increases the vaccination intention. In Study 1, participants saw no infographic (control) or one of two infographics (low vs. high exposure risk varied by the underlying incidence rates). Study 2 additionally varied the infographic design displaying the risk information (presented as table, circle icons, or manikin-like icons). RESULTS: The infographic decreased the risk perception of the vaccine compared to no infographic (Study 1: Cohens d = 0.31, 95% CI [0.14, 0.48]; Study 2: Cohens d = 0.34, 95% CI [0.06, 0.62]), but it did not influence the perceived probability of blood clots due to the AstraZeneca vaccine (Study 2: Cohens d = 0.05, 95% CI [-0.23, 0.33]). Also, the infographic design did not affect the perceived probability of blood clots (Study 2). The vaccination intention was not affected by viewing the infographic (Study 1: Cohens d = 0.04, 95% CI [-0.13, 0.21]; Study 2: Cohens d = 0.04, 95% CI [-0.24, 0.32]) nor the presented infection rate (Study 1: Cohens d = 0.07, 95% CI [-0.09, 0.24], Study 2: Cohens d = 0.01, 95% CI [-0.12, 0.15]) but by risk perceptions, sociodemographic characteristics, confidence in the AstraZeneca vaccine, and preference for alternative vaccines. CONCLUSIONS: The evidence-based benefit-risk information helped putting the risk of vaccinations into perspective. Nevertheless, objective risk information alone did not affect vaccination intention that was low due to the preexisting lacking vaccine confidence.

Effects of Anticoagulant Therapy and Frailty in the Elderly Patients with Atrial Fibrillation.

Objective: This study explored whether anticoagulation is safe for frail and non-frail elderly patients who have nonvalvular atrial fibrillation (NVAF). Methods: At hospital discharge, the anticoagulant regimen and frailty status were recorded for 361 elderly patients (aged ≥75 y) with NVAF. The patients were followed for 12 months. The endpoints included occurrence of thrombosis; bleeding; all-cause death; and cardiovascular events. Results: At hospital discharge, frailty affected 50.42% of the population and the anticoagulation rate was 44.04%. At discharge, age (OR 0.948, P = 0.006), paroxysmal NVAF (OR 0.384, P < 0.001), and bleeding history (OR 0.396, P = 0.001) were associated with a decrease in rate of receiving anticoagulation, while thrombotic events during hospitalization (OR 2.281, P = 0.021) were associated with an increase. Relative to non-frail patients, those with frailty showed a higher rate of ischemic stroke (5.33% cf. 3.01%), bleeding (P = 0.006) events, and all-cause mortality (P = 0.001). Relative to the group without anticoagulation, in those with anticoagulation the rate of thrombotic events was lower (6.99 cf. 10.98%) and bleeding events were higher (20.98 cf. 12.72%), but the risk of major bleeding was comparable. Conclusion: In the elderly patients with NVAF, the decision toward anticoagulation therapy at hospital discharge was influenced by age, bleeding history, paroxysmal atrial fibrillation diagnosis, and absence of thrombosis. Frail patients were at greater risk of bleeding and all-cause mortality. Anticoagulation tended to reduce the risk of thrombotic events.

Thrombotic events associated with low baseline direct oral anticoagulant levels in atrial fibrillation: the MAS study.

ABSTRACT: Although effective and safe, treatment with direct oral anticoagulants (DOAC) in atrial fibrillation (AF) is still associated with thrombotic complications. Whether the measurement of DOAC levels may improve treatment efficacy is an open issue. We carried out the observational, prospective, multicenter Measure and See (MAS) study. Blood was collected 15 to 30 days after starting DOAC treatment in patients with AF who were followed-up for 1 year. Plasma samples were centralized for DOAC level measurement. Patients' DOAC levels were converted into drug/dosage standardized values to allow a pooled analysis in a time-dependent, competitive-risk model. The measured values were transformed into standardized values (representing the distance of each value from the overall mean) by subtracting the DOAC-specific mean value from the original values and dividing by the standard deviation. Trough and peak DOAC levels were assessed in 1657 and 1303 patients, respectively. In total, 21 thrombotic complications were recorded during 1606 years of follow-up (incidence of 1.31% of patients per year). Of 21 thrombotic events, 17 occurred in patients whose standardized activity levels were below the mean of each DOAC (0); the incidence was the highest (4.82% of patients per year) in patients whose standardized values were in the lowest class (-1.00 or less). Early measurement of DOAC levels in patients with AF allowed us to identify most of the patients who, having low baseline DOAC levels, subsequently developed thrombotic complications. Further studies are warranted to assess whether thrombotic complications may be reduced by measuring baseline DOAC levels and modifying treatment when indicated. This trial was registered at www.ClinicalTrials.gov as #NCT03803579.

High platelet reactivity strongly predicts early stent thrombosis in patients with drug-eluting stent implantation.

Stent thrombosis (ST) is a fatal complication after percutaneous coronary intervention (PCI). The association between P2Y12 reaction unit (PRU) level and stent thrombosis occurrence remains unclear. Based on the multicenter, observational PTRG-DES (Platelet function and genoType-Related long-term proGnosis in DES-treated patients) registry of patients with drug-eluting stents (DES) implantation, a total of 11,714 patients with PRU values were analyzed. We sought to identify the predictors of early stent thrombosis (EST) and compared the primary outcome, a composite of cardiac death, myocardial infarction, and revascularization, between EST and non-EST groups. EST, defined as definite ST within 1 month after index PCI, occurred in 51 patients. PRU values were significantly higher in the EST group (263.5 ± 70.8 vs. 217.5 ± 78.7, p < 0.001). In multivariable analysis, PRU ≥ 252 (OR, 5.10; 95% CI 1.58-16.46; p = 0.006) and aspirin reaction unit ≥ 414 (OR 4.85; 95% CI 1.07-21.97; p = 0.040) were independent predictors of EST. The cumulative incidence of primary composite outcome at one year was significantly higher in the EST group (38.2% vs. 3.9%, Log-rank p < 0.001). In patients treated with clopidogrel after successful DES implantation, EST was associated with higher platelet reactivities, and a greater risk of cardiovascular events.Trial Registration: clinicaltrials.gov Identifier: NCT04734028.

Thrombosis of acute superior mesenteric artery in a patient with breast cancer receiving toremifene therapy: a case report and literature review.

It is widely recognized that cancer itself is related to increased risk of thromembolism. Venous thromboembolism is relatively common in breast cancer patients, but arterial thrombosis, especially acute superior mesenteric artery thrombosis (SMAT) associated with chemotherapy or endocrinotherapy, rarely occurs in breast cancer patients. There were few reports about acute SMAT in cancer patients who underwent chemotherapy, but no reports of acute SMAT caused by endocrine-therapy. We reported a 54-year-old patient with acute SMAT during toremifene treatment after breast cancer surgery. She underwent 4 cycles chemotherapy of TC regimen, then accepted toremifen endocrinotherapy because of positive estrogen receptor. She suffered from acute SMAT after 2 months toremifen treatment. Therefore, we consider that this case of acute SMAT may be a rare adverse event of toremifen. In view of the high risk and rarity of acute SMAT caused by toremifene, we suggest that except for venous thrombosis, arterial thrombosis in special position (ATSP) should be kept in mind during use of toremifene. Once a thrombotic event occurs, toremifene should be stopped immediately.

Trends in the Use of Recombinant Activated Factor VII and Prothrombin Complex Concentrate in Heart Transplant Patients in Virginia.

OBJECTIVES: To explore trends in intraoperative procoagulant factor concentrate use in patients undergoing heart transplantation (HTx) in Virginia. Secondarily, to evaluate their association with postoperative thrombosis. DESIGN: Patients who underwent HTx were identified using a statewide database. Trends in off-label recombinant activated factor VII (rFVIIa) use and on-label and off-label prothrombin complex concentrate (PCC) use were tested using the Mantel-Haenszel test. Multivariate logistic regression was used to test for an association between procoagulant factor concentrate administration and thrombosis. SETTING: Virginia hospitals performing HTx. PARTICIPANTS: Adults undergoing HTx between 2012 and 2022. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 899 patients who required HTx, 100 (11.1%) received off-label rFVIIa, 69 (7.7%) received on-label PCC, and 80 (8.9%) received off-label PCC. There was a downward trend in the use of rFVIIa over the 10-year period (p = 0.04). There was no trend in on-label PCC use (p = 0.12); however, there was an increase in off-label PCC use (p < 0.001). Patients who received rFVIIa were transfused more and had longer cardiopulmonary bypass time (p < 0.001). Receipt of rFVIIa was associated with increased thrombotic risk (odds ratio [OR] 1.92; 95% CI 1.12-3.29; p = 0.02), whereas on-label and off-label PCC use had no association with thrombosis (OR 0.98, 95% CI 0.49-1.96, p = 0.96 for on-label use; and OR 0.61, 95% CI 0.29-1.30, p = 0.20 for off-label use). CONCLUSIONS: Use of rFVIIa in HTx decreased over the past decade, whereas off-label PCC use increased. Receipt of rFVIIa was associated with thrombosis; however, patients who received rFVIIa were more severely ill, and risk adjustment may have been incomplete.

Systemic Arterial and Venous Thrombotic Events Associated With Anti-Vascular Endothelial Growth Factor Injections: A Meta-Analysis.

PURPOSE: To compare the risk of systemic arteriovenous thrombotic events between intravitreal anti-vascular endothelial growth factor (anti-VEGF) and sham injections. DESIGN: Random-effects meta-analysis. METHODS: A systematic search was performed on OVID MEDLINE, Embase, and Cochrane Library from January 2005 to August 2023. Our inclusion criteria were randomized controlled trials (RCTs) reporting on systemic arteriovenous events for standard dose intravitreal anti-VEGF agents for any indication. RESULTS: A total of 20 RCTs reporting on 12,833 eyes were included. There was no significant difference in the risk of any thrombotic event between bevacizumab 1.25 mg and ranibizumab 0.5 mg (Risk ratio (RR) = 0.96, 95% CI = 0.52-1.75, P = .89). There was no significant difference between bevacizumab and ranibizumab when restricting to arterial thrombotic events (RR= 0.88, 95% CI = 0.60-1.30, P = .53) or venous thrombotic events (RR = 1.99, 95% CI =86 0.68-5.82], P = .21). The risk of arterial thrombotic events was similar between aflibercept and bevacizumab (RR = 1.11, 95% CI = 0.60-2.07, P = .74), between aflibercept and ranibizumab (RR= 0.77, 95% CI = 0.49-1.21, P = .26), between brolucizumab and aflibercept (RR= 0.67, 95% CI = 0.32-1.38, P = .27), and between aflibercept and faricimab (RR = 0.96, 95% CI = 0.43-2.17, P = .93). Compared to sham, neither dose of ranibizumab (0.5 mg or 0.3 mg) showed a higher risk of arterial thrombotic events. CONCLUSIONS: There was a similar risk of systemic arteriovenous thrombotic adverse events between anti-VEGF agents and between ranibizumab and sham injections.

Life-Threatening Subglottic Thrombus Formation after Administration of Nebulized Tranexamic Acid.

We present a case of subglottic thrombus formation after administration of nebulized tranexamic acid (TXA) for postoperative hemoptysis following CO2 laser wedge excision of subglottic stenosis. Although other factors certainly could have resulted in postoperative bleeding and subsequent thrombus formation, the patient's rapid decompensation following administration of nebulized TXA suggests a direct effect. We recommend implementing an airway action plan regarding TXA use for patients presenting to the emergency department with postoperative hemorrhage following otolaryngology procedures. Laryngoscope, 134:1356-1358, 2024.

Contraceptives and Thrombosis: An Intertwined Revolutionary Road.

The development of oral contraceptives (OCs) began in 1921 and continued in the following years until the first regulatory approval from the Food and Drug Administration was granted in 1960. However, it took several years to realize that OCs presented an important but not frequent risk of venous thrombosis. Several reports ignored this dangerous effect and only in 1967 the Medical Research Council clearly stated this as an important risk. Later, research led to the formulation of second-generation OCs containing progestins, which nevertheless presented an increased thrombotic risk. In early 1980s, OCs containing third-generation progestins were introduced into the market. Only in 1995, it became clear that these new compounds induced a higher thrombotic risk than that related to the second-generation progestins. It appeared clear that the modulating action of progestins was against the procoagulant activity of estrogens. Lastly, at the end of the 2000s, OCs containing natural estrogens and a fourth-generation progestin (dienogest) became available. The prothrombotic effect of those natural products was not different from that of preparations containing second-generation progestins. Moreover, research over the years has produced much data on risk factors associated with OCs use such as age, obesity, cigarette smoking, and thrombophilia. These findings allowed us to better assess the individual thrombotic risk (both arterial and thrombotic) of each woman before offering an OC. Furthermore, research has shown that in high-risk people the use of single progestin is not dangerous as far as thrombosis is concerned. In conclusion, the OCs road has been long and difficult but has led to a great and unthinkable scientific and social enrichment since the 1960s.