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Predicting the likelihood vascular events in patients with BCR/ABL1-negative myeloproliferative neoplasms (MPN) is essential for the treatment of the disease. However, effective assessment methods are lacking. Thrombin-antithrombin complex (TAT), plasmin-α2- plasmininhibitor complex (PIC), thrombomodulin (TM), and tissue plasminogen activator-inhibitor complex (t-PAIC) are the new direct indicators for coagulation and fibrinolysis. The aim of this study was to investigate the changes of these four new indicators in thrombotic and hemorrhagic events in BCR/ABL1-negative MPN. The study cohort of 74 patients with BCR/ABL negative myeloproliferative disorders included essential thrombocythemia, polycythemia vera, and primary myelofibrosis (PMF). A panel of 4 biomarkers, including TAT, PIC, TM, and t-PAIC were determined using Sysmex HISCL5000 automated analyzers, whereas fibrin/fibrinogen degradation products (FDP), D-dimer and Antithrombin III (ATIII) were analyzed using Sysmex CS5100 coagulation analyzer. A total of 24 (32.4%) patients experienced thrombotic events and hemorrhagic events occurred in 8 patients (10.8%). Compared to patients without hemorrhagic-thrombotic events, patients with thrombotic events had higher fibrinogen (FIB) level, FDP level and lower ATIII activity, while patients with hemorrhagic events had lower white blood cell count and hemoglobin level, higher FDP level (P < 0.05). Patients with a JAK2V617F mutation were more likely to experience thrombotic events (P < 0.05). In addtion, patients with thrombotic events had higher TAT, PIC, TM, and t-PAIC levels than patients without hemorrhagic-thrombotic events (P < 0.05), whereas patients with hemorrhagic events had a lower median value in TAT and TM (no statistical difference, P > 0.05). Patients with higher TAT, TM and t-PAIC were more likely to experience thrombotic events (P < 0.05), and only TAT was positively correlated with thrombotic events (Spearman r =0.287, P = 0.019). TAT, PIC, TM, and t-PAIC combined with ATIII and FDP have a certain value for predicting thrombosis in patients with BCR/ABL1-negative MPN. These 6 parameters are worth further exploration as predictive factors and prognostic markers for early thrombotic events. [ABSTRACT FROM AUTHOR]

Twig-like middle cerebral artery (MCA) is a rare intracranial vascular pathology that was hypothesized to be an arrest on the evolutionary fusion of the plexiform arterial network in the forebrain into a single MCA artery. This anomaly predisposes affected individuals to worse outcomes such as intracranial hemorrhages due to its association with aneurysms and primitive plexiform arterial systems that are prone to rupture. In this case report, a 30-year-old male had a loss of consciousness after serving as a ceremonial guard for four straight days. The patient did not have any neurologic localizing signs but presented with occasional generalized headaches relieved by pain medications. Cranial MRA showed suspicious stenosis of the left MCA. A cranial computed tomography angiogram showed complete stenosis of the M1 segment of the left MCA. Digital subtraction angiography was also done, which confirmed the complete occlusion of the said segment with collaterals from the A1 of the anterior cerebral artery supplying the distal portions of the left MCA. These findings, hence, suggested the presence of a twig-like MCA. In this article, the prevalence, pathogenesis, arrival to the diagnosis, and clinical relevance shall be discussed. [ABSTRACT FROM AUTHOR]

Aim and background: This study attempted to identify similarities and differences in adverse events (AEs) between human epidermal growth factor receptor 2 (HER2) inhibitors, especially those related to hemorrhagic events and nervous system disorders. Methods: This study summarized the types, frequencies, and system organ classes (SOCs) of AEs of HER2 inhibitors. The US Food and Drug Administration Adverse Event Reporting System (FAERS) data from January 2004 through March 2022 was collected and analyzed. Disproportionality analyses were conducted to detect AEs signals for every HER2 inhibitor. The chi-square test, Wilcoxon test, and descriptive analysis were used to compare the differences of AEs for specific SOCs or drugs. Results: A total of 47,899 AE reports were obtained for eight HER2 inhibitors. Trastuzumab-related AEs were reported in the highest number and combination of regimens. In monotherapy, trastuzumab had the highest reported rate of cardiac disorders-related AEs (24.0%). However, small-molecule drugs exceeded other drugs in the reported rates of AEs related to gastrointestinal disorders, metabolism and nutrition disorders. The highest reported rates of respiratory disorders (47.3%) and hematologic disorders (22.4%) were associated with treatment with trastuzumab deruxtecan (T-DXd). Patients treated with trastuzumab emtansine (TDM-1) had the highest reported rate (7.28%) of hemorrhagic events, especially intracranial haemorrhage events. In addition, patients treated with TDM-1 with concomitant thrombocytopenia were likely to experience hemorrhagic events compared to other HER2 inhibitors (p < 0.001). The median time to onset of intracranial haemorrhage associated with trastuzumab (0.5 months) and TDM-1 (0.75 months) was short. However, there was no significant difference in median time to onset intracranial haemorrhage between patients in different age groups or with different outcomes. Disproportionality analysis results reveal that cerebral haemorrhage is a positive signal associated with T-DXd and TDM-1. In addition, tucatinib was the drug with the highest rate of reported nervous system disorders (31.38%). Memory impairment (83 cases) is a positive signal for tucatinib. Conclusion: The types and reporting rates of AEs associated with different HER2 inhibitors vary across multiple systems. In addition, hemorrhagic events concomitant with TDM-1 treatment and nervous system disorders concomitant with tucatinib treatment may be worthy of attention. [ABSTRACT FROM AUTHOR]

Background: Although isolated calf muscular vein thrombosis (ICMVT) is commonly seen after hip and knee arthroplasty, no treatment guidelines for ICMVT after joint replacement are available. The purpose of this study was to evaluate the outcomes of patients with ICMVT for anticoagulant therapy at different time points after primary hip and knee arthroplasty. Methods: Patients with ICMVT after primary hip and knee arthroplasty were included in the study. Diagnosis was established with Doppler ultrasound. Patients were followed up clinically and with Doppler ultrasound at 1, 2, and 3 months. The outcomes were efficacy (complete resolution) and acceptability (hemorrhagic events). Anticoagulant therapy at curative dosage was prescribed for 1 month and was extended for 2 additional months in case of incomplete resolution at 1 month or if propagation was present. The chi-square test was used to compare the outcomes at different time points. Results: 302 patients were taken hip and knee arthroplasty from January 2021 to May 2022, in which 51 patients presented with 51 ICMVTs postoperatively. The incidence of ICMVT was about 16.89%. Resolution of ICMVT was considered complete at 1, 2, and 3 months at 36.73%, 61.22%, and 91.84%, respectively, with significant differences among the time points (P < 0.05). All patients with ICMVT receiving anticoagulant therapy remained free of propagations and hemorrhagic events within 3 months. Conclusion: Our findings provide new insights into the anticoagulant therapy for ICMVT after primary hip and knee arthroplasty, taking oral Rivaroxaban for 3 months is effective and safe, which contributes to provide the reference for clinical practice. [ABSTRACT FROM AUTHOR]

Purpose: Laparoscopic sleeve gastrectomy (LSG) is currently the most common bariatric surgery in the world. Although it appears to be a safe treatment for obesity, it is still at risk of complications. The latest literature shows that postoperative bleeding occurs in 2–4% of cases, and up to 3% of cases requires reoperation for hemostasis. The aim of the study is to assess the effect of tranexamic acid (TXA) on hemorrhagic events and the reoperation rate in patients undergoing LSG. Methods: The study was designed as a retrospective analysis of patients undergoing LSG. We investigate the patients 6 months before and 6 months after introducing the prophylaxis doses of TXA into our bariatric protocol (non-TXA group vs TXA group). Results: Three hundred fourteen patients underwent LSG in a high-volume center from 2016 to 2017. After introducing TXA, a statistically significant reduction in the incidence of hemorrhage during surgery was observed (22.3% vs 10.8%, p = 0.006). There was a statistically significant reduction in the need for the staple line oversewing (10.2% vs 1.9%, p = 0.002). The mean operating time and the mean length of hospital stay were significantly higher in the non-TXA group than TXA group (63.1 vs 53.7 min, p < 000.1; 2.3 vs 2.1, p = 0.02). In both groups of patients, no venous thromboembolism or other complications occurred within 6 months after the surgery. Conclusions: The prophylactic doses of TXA may be useful in reducing the hemorrhagic events during LSG. It may also shorten the length of hospital stay and the operating time. [ABSTRACT FROM AUTHOR]

Computed tomography for coronavirus infection (COVID-19) is effective not only in making a diagnosis, but also in timely and accurately detecting some complications of this disease in different organs and systems. The paper shows various complications of coronavirus infection that a radiologist may face in practice, which develop both in the natural course and due to therapy for COVID-19, including hemorrhagic and thrombotic events in coagulopathy, pneumothorax, and pneumomediastinum as a result of the direct cytotoxic effect of SARS-CoV-2 on pneumocytes, and barotrauma during mechanical ventilation, as well as pathological fractures due to osteoporosis, including steroid osteoporosis that has developed during therapy with glucocorticosteroids. It considers the main causes and pathogenesis of various complications of coronavirus infection.

Abstract Background Dual antiplatelet therapy (DAPT) is necessary for stent assisted coiling. However, long term use of DAPT has a potential risk of hemorrhagic events. We aimed to examine the relationship between clopidogrel reactivity and complications. Methods Patients who underwent stent assisted coiling for unruptured aneurysms or previously treated aneurysms and received periprocedural DAPT in our institution between August 2011 to March 2020 were included. Platelet reactivity for clopidogrel was measured by VerifyNow assay system, and we defined the cut off value of P2Y12 Reaction Units (PRU) at 208 and classified patients as hypo-responders (PRU≧208) or responders (PRU

Background Rivaroxaban, apixaban and dabigatran are non-vitamin K antagonist oral anticoagulants (NOACs) that are widely used for treatment or prevention of venous thromboembolism and stroke in patients with atrial fibrillation. Objective To estimate and compare hemorrhagic events report of rivaroxaban, apixaban and dabigatran. Setting FDA Adverse Event Reporting System (FAERS) database. Methods The reporting odds ratio (ROR) was used to assess the signal of hemorrhagic events of different NOACs. Main outcome measure The overall hemorrhagic events and hemorrhagic events in different physiological systems. Results From January 1, 2014 to December 31, 2019, the total number of reports of hemorrhage related to rivaroxaban was 53,085, and the numbers of apixaban and dabigatran were 13,151 and 14,100 respectively. The overall ROR (95% CI) of hemorrhagic events reporting for rivaroxaban versus dabigatran and apixaban versus dabigatran were 1.58 (1.54–1.62) and 0.47 (0.46–0.48) respectively. The ROR (95% CI) for rivaroxaban versus dabigatran in gastrointestinal system, nervous system, renal and urinary system, skin and subcutaneous tissue, and eye system was 1.38 (1.34–1.42), 0.94 (0.90–0.98), 1.07 (1.01–1.13), 0.80 (0.70–0.90), and 1.38 (1.19–1.60) respectively. The RORs (95% CI) for apixaban versus dabigatran in gastrointestinal system, nervous system, renal and urinary system, skin and subcutaneous tissue, and eye system were 0.28 (0.27–0.29), 0.69 (0.66–0.73), 0.31 (0.29–0.34), 0.98 (0.86–1.12), and 1.18 (1.00–1.39), respectively. Conclusions Overall, we found a moderate signal of higher frequency of reporting hemorrhage in rivaroxban compared with dabigatran and decreased hemorrhagic event reporting in apixaban compared with dabigatran. While this potential signal has not been confirmed in clinical trials or observational studies, in clinical practice, attention should be paid to the risk of potential hemorrhage when the patients switch from apixaban to dabigatran or rivaroxban. [ABSTRACT FROM AUTHOR]

Background: despite well-studied safety profile of dabigatran its interactions with genetic polymorphism parameters are poorly understood, especially in patients with moderate chronic kidney disease (CKD). This study was aimed to evaluate relationships between CES1 and ABCB1 polymorphism, dabigatran trough plasma concentration (DTPC) and bleeding events in patients with AF and CKD.Methods: patients with atrial fibrillation (AF) and stage 3 CKD treated with dabigatran 110mg or 150 mg have been included in the study. Real-time PCR was used to evaluate single nucleotide polymorphisms (SNPs) of the ABCB1 gene (rs1045642, rs4148738) and CES1 gene (rs2244613). A plasma trough concentration/dose (C/D) ratio was used as a pharmacokinetic index.Results: a total of 60 patients, aged 51–89 years (median age 76 years) were evaluated. Compared with patients given 150 mg twice a day, those given 110 mg twice a day were older (79 vs 67.5, p < 0.0001) and had lower creatinine clearance (CrCl) (50.5 vs 60.5 mL/min/1.73 m2, p = 0.015). We found C/D values to have high interindividual variability (mean 365.9 ± 290.4 μg/ml: mg/day, range 23.64-1452.73). Individuals with CKD 3B had higher concentration of dabigatran compared with those with 3A stage (488.7 ± 232.3 vs 332 ± 297.8 μg/ml : mg/day, p = 0.02). Consequently, there also was negative correlation of C/D with CrCl (r = -0.4, p = 0.0015). Evaluated SNPs (rs1045642, rs4148738, and rs2244613) did not affect C/D values (H test p > 0.05).Conclusions: C/D values were significantly higher in patients with CKD 3B stage and those treated with dabigatran 110 mg. There was no influence of aforementioned SNPs on dabigatran trough concentrations and clinical outcomes.

Background: Dual antiplatelet therapy (DAPT) is necessary for stent assisted coiling. However, long term use of DAPT has a potential risk of hemorrhagic events. We aimed to examine the relationship between clopidogrel reactivity and complications.Methods: Patients who underwent stent assisted coiling for unruptured aneurysms or previously treated aneurysms and received periprocedural DAPT in our institution between August 2011 to March 2020 were included. Platelet reactivity for clopidogrel was measured by VerifyNow assay system, and we defined the cut off value of P2Y12 Reaction Units (PRU) at 208 and classified patients as hypo-responders (PRU≧208) or responders (PRU<208). The rates of hemorrhagic and thrombotic events within 30 days (acute phase) and 30 days after the procedure (delayed phase) were compared between the two groups. Furthermore, changes in hemoglobin levels were measured before and after the procedure and at chronic stages (1 to 6 months thereafter).Results: From 61 patients included in this study, 36 patients were hypo-responders and 25 patients were responders. Hemorrhagic events occurred 8.0% only in responders in the acute phase (p = 0.16), and 2.78% in hypo-responders and 20.0% in responders in the delayed phase (p = 0.037). Changes in hemoglobin levels before and after the procedure were 1.22 g/dl in hypo-responders and 1.74 g/dl in responders (p = 0.032) while before the procedure and chronic stages they were 0.39 g/dl in hypo-responders and 1.39 g/dl in responders (p <  0.01). Thrombotic events were not significantly different between the two groups.Conclusion: Long term use of DAPT after stent assisted coiling is related to hemorrhagic events in the delayed phase. Preventing for hemorrhagic events, the duration of DAPT should be carefully considered in clopidogrel responders. [ABSTRACT FROM AUTHOR]

Aspirin should be used for the prevention of cardiovascular (CV) events by the risk–benefit balance. This study was conducted to clarify CV and bleeding events in Japanese aspirin users with a history of CV diseases. This study was a prospective, nationwide, multicenter cooperative registry of Japanese patients with CV diseases at risk of thromboembolism who were taking aspirin (75–325 mg) for at least 1 year. We observed major CV and bleeding events during follow-up. Patients with history of ischemic stroke (IS), transient ischemic attack (TIA), coronary artery disease (CAD), atrial fibrillation (AF), and venous thromboembolism (VTE) were included and analyzed in this sutdy. CV events included IS, TIA, CAD, CV death, angioplasty or stenting, and hospitalization because of CV disease. Bleeding events included major bleeding requiring hospitalization and/or blood transfusion. A total of 1506 patients were categorized into IS/TIA (N = 540), CAD (N = 632), and AF/VTE (N = 232). Among them, 101 patients had two or more categories. CV and bleeding events occurred in 61 (3.82%/year) and 15 patients (0.93%/year), respectively. The annual rates of CV and bleeding events were 2.81% and 0.93% in IS/TIA, 5.32% and 0.75% in CAD, 1.15% and 1.15% in AF/VTE, and 6.44% and 0.91% in two or more disease categories, respectively. The Management of Aspirin-induced Gastrointestinal Complications (MAGIC) study clarified the rates of major CV and bleeding events with long-term use of aspirin in patients with prior CV diseases in real-world clinical practice. The risk–benefit balance of aspirin was acceptable in patients with IS/TIA, CAD, and multiple CV diseases but not in those with AF/VTE. Trial Registration: The MAGIC Study is registered at UMIN Clinical Trial Registry (www.umin.ac.jp/ctr/index-j.htm), number UMIN000000750. [ABSTRACT FROM AUTHOR]

Aim. To study the initial disorders in the coagulation system, as factors influencing the development of bleeding during anticoagulant therapy with direct oral anticoagulants (DOAC).Material and methods. 117 patients receiving DOAC (direct thrombin inhibitors – dabigatran, and Xa factor inhibitors – rivaroxaban and apixaban) were included into the cohort study in parallel groups. In addition to evaluate the efficacy and safety of therapy, an extensive analysis of the blood hemostasis system was performed in patients before the start of anticoagulant therapy.Results. No thromboembolic events and major bleedings were registered in patients receiving DOAC during 24 month observation. No significant correlations were observed between minor bleeding frequency in both groups (16.33% in dabigatran group and 22.39% in Xa factor inhibitors group) and troponin I and hemoglobin levels, as well as HAS-BLED and ATRIA risk scores. Among patients receiving dabigatran initial decrease in von Willebrand factor plasma level (p=0.02) and increase in fibrinogen blood concentration (p=0.02) were predictors of minor bleedings. These predictors of bleeding events were not found in Xa inhibitor groups.Conclusions. DOAC in patients with atrial fibrillation showed their efficacy and safety without any differences between classes of direct thrombin inhibitors and Xa factor inhibitors. Among the possible predictors of spontaneous minor hemorrhagic events on the dabigatran therapy, a reduced level of von Willebrand factor and elevated fibrinogen level may be considered when choosing a dose of the drug. Markers of hemorrhagic complications development were not determined for the Xa factor inhibitors. Limitation of this study was the absence of randomization, that is why the results should be interpreted with caution.

Aim and background: This study attempted to identify similarities and differences in adverse events (AEs) between human epidermal growth factor receptor 2 (HER2) inhibitors, especially those related to hemorrhagic events and nervous system disorders. Methods: This study summarized the types, frequencies, and system organ classes (SOCs) of AEs of HER2 inhibitors. The US Food and Drug Administration Adverse Event Reporting System (FAERS) data from January 2004 through March 2022 was collected and analyzed. Disproportionality analyses were conducted to detect AEs signals for every HER2 inhibitor. The chi-square test, Wilcoxon test, and descriptive analysis were used to compare the differences of AEs for specific SOCs or drugs. Results: A total of 47,899 AE reports were obtained for eight HER2 inhibitors. Trastuzumab-related AEs were reported in the highest number and combination of regimens. In monotherapy, trastuzumab had the highest reported rate of cardiac disorders-related AEs (24.0%). However, small-molecule drugs exceeded other drugs in the reported rates of AEs related to gastrointestinal disorders, metabolism and nutrition disorders. The highest reported rates of respiratory disorders (47.3%) and hematologic disorders (22.4%) were associated with treatment with trastuzumab deruxtecan (T-DXd). Patients treated with trastuzumab emtansine (TDM-1) had the highest reported rate (7.28%) of hemorrhagic events, especially intracranial haemorrhage events. In addition, patients treated with TDM-1 with concomitant thrombocytopenia were likely to experience hemorrhagic events compared to other HER2 inhibitors ( p < 0.001). The median time to onset of intracranial haemorrhage associated with trastuzumab (0.5 months) and TDM-1 (0.75 months) was short. However, there was no significant difference in median time to onset intracranial haemorrhage between patients in different age groups or with different outcomes. Disproportionality analysis results reveal that cerebral haemorrhage is a positive signal associated with T-DXd and TDM-1. In addition, tucatinib was the drug with the highest rate of reported nervous system disorders (31.38%). Memory impairment (83 cases) is a positive signal for tucatinib. Conclusion: The types and reporting rates of AEs associated with different HER2 inhibitors vary across multiple systems. In addition, hemorrhagic events concomitant with TDM-1 treatment and nervous system disorders concomitant with tucatinib treatment may be worthy of attention., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer LZ declared a shared parent affiliation with the author ZM to the handling editor at the time of review., (Copyright © 2024 Bao, Chen, Duan, Wang, Lai, Mo and Zhu.)

Introduction: Brainstem cavernous malformations (BSCMs) are clusters of dilated sinusoidal channels. Clinical presentation is characterized by focal neurological deficits and/or hemorrhage. The goal of this study is to analyze surgical indications and approaches in a series of patients with BSCM and review pertinent literature and suggest prognostic factors related to the anatomical, clinical, and surgical data collected. Methods: We retrospectively reviewed the clinical data of 55 patients with BSCM, treated at three centers, from January 2006 to March 2016. We collected anagraphic data, pre and postoperative neurological status, pre and postradiological images, surgical procedures, and follow-up results. We summarized the anatomical, clinical, and surgical aspects of the lesions and identified two large groups based on the chosen approach: lateral and medial. Clinical and radiological results were then compared. Results: The series comprised 55 patients. Hemorrhagic onset was observed in all patients. Suboccipital, retrosigmoid, anterior, subtentorial, subtemporal, transvermian, telovelar, far lateral and trans, and infratentorial approaches were performed. Neurological status improved postoperatively in 34 cases at last follow-up. Five patients showed clinical neurological worsening. Total resection was achieved in 46 cases and, during a mean follow-up of 63.4 months, no recurrence or re-bleeding occurred in those patients. The mean follow-up was 63.9 months. The mean modified Rankin Scale at final follow-up was used to analyze the results and draw our conclusions. Conclusions: A reasonable surgical approach, selection, and gentle handling of the surrounding structures are required to prevent impairment of neurologic function and avoid partial resection. [ABSTRACT FROM AUTHOR]

Aim. To evaluate platelet activity changes in patients with coronary artery disease (CAD) treated with aspirin, clopidogrel and combination of these drugs; to estimate the rate of resistance of CAD patients to antiplatelet treatment. Material and methods. 199 patients with stable CAD were included in the study. Of them, 83 were given aspirin, 46 received clopidogrel, 34 - double antiplatelet therapy (both aspirin and clopidogrel). The trial also studied an additional group of 18 CAD patients on double antiplatelet therapy who had hemorrhages. The control group consisted of 25 healthy volunteers. Platelet aggregation was measured both by a mean size of aggregates (MSA) and light transmission (LTM, Born method) using BIOLA platelet aggregation analyzer. A platelet shape, leukocyte-platelet aggregates (LPA) and erythrocyte-platelet aggregates (EPA) in the whole blood were studied using scanning electron microscopy. The levels of IL-6 and sVCAM were also measured. Results. It was found that 59.8% patients with CAD had high platelet reactivity revealed in 94.9% of cases by measuring spontaneous and induced by 0.1 mcM ADP platelet aggregation. LTM revealed increased platelet reactivity only in 10.7% patients. Resistance to aspirin correlated with the presence of LTA (r = 0.629, p = 0.0001) and the number of large "reticulated" platelets (r = 0.334, p = 0.001). Low platelet reactivity was associated with the presence of circulating EPA (r = -0.362, p = 0.008). Administration of clopidogrel did not decrease platelet reactivity to normal levels in 34.7% patients which correlated with the presence of LPA and EPA. In 83.3% patients with hemorrhages platelet aggregation, induced by 5.0 mcM, ADP was dramatically decreased. Conclusion. Resistance to antiplatelet therapy is related to platelet heterogeneity, the presence of inflammation and state of erythrocytes. LT is capable to reveal only a part of patients resistant to antiplatelet drugs. To fully identify these patients, it is necessary to register spontaneous platelet aggregation and aggregation induced by low doses of ADP. Redundant inhibition of platelet reactivity could be the cause of hemorrhagic events.

Aflibercept (Ziv-aflibercept, VEGF Trap, AVE005) is an engineered protein that functions as a decoy receptor to bind vascular endothelial growth factor A (VEGF-A). Hemorrhagic events, including epistaxis, gastrointestinal bleeding, and pulmonary bleeding, is one of its major adverse effects, but the incidence rate and overall risk has not been systematically studied. Therefore, we conducted a meta-analysis of published clinical trials to investigate the incidence and relative risk of hemorrhagic events in cancer patients treated with aflibercept. Electronic databases including PubMed, Embase, Cochrane databases, and American Society of Clinical Oncology abstracts were searched. Eligible studies were phase II and III prospective clinical trials of cancer patients treated with aflibercept with toxicity profile on hemorrhagic events. Overall incidence rates, relative risk (RR), and 95 % confidence intervals (CI) were calculated using fixed or random effects models depending on the heterogeneity of the included studies. A total of 4,538 patients with a variety of solid tumors from 13 prospective clinical trials were included for the meta-analysis. The overall incidences of all-grade and high-grade hemorrhagic events in cancer patients were 22.1 % (95 % CI, 16.5-29.7 %) and 4.2 % (95 % CI, 3.9-4.6 %), respectively. The relative risks of hemorrhagic events of aflibercept compared to control were increased for all-grade (RR = 2.63; 95 % CI, 2.07-3.34) and high-grade (RR = 2.45, 95 % CI, 1.62-3.72) hemorrhagic events. The risk of developing high-grade hemorrhagic events with aflibercept was comparable to that of bevacizumab (RR = 1.26; 95 % CI, 0.89-1.79). Aflibercept is associated with an increased risk of developing hemorrhagic events in patients with solid tumors. Close monitoring and management of hemorrhagic events are recommended. [ABSTRACT FROM AUTHOR]

Background We aimed at determining the overall incidence and risk of hemorrhagic events associated with vascular endothelial growth factor receptor-tyrosine-kinase inhibitors (VEGFR-TKIs). Methods We searched PubMed, EMBASE and Cochrane library databases for relevant prospective, randomized controlled trials (RCTs). Statistical analyses were conducted to calculate the summary incidence, relative risks (RRs) and 95% confidence intervals (CIs) by using either random-effects or fixed-effects models according to the heterogeneity of included studies. Results The overall incidence of all-grade and high-grade hemorrhagic events was 9.1% (95% CI: 6.8–12.1%) and 1.3% (95% CI 0.8% to 2.1%), respectively. And the use of VEGFR-TKIs was associated with an increased risk of hemorrhagic events, with a relative risk (RR) of 1.67 (95% CI 1.19–2.33, P = 0.003), but not for high-grade hemorrhagic events (RR 1.23, 95% CI 0.86–1.77, P = 0.25). The risk of developing all-grade hemorrhagic events varied significantly with tumor types (P < 0.001) and different VEGFR-TKIs (P < 0.001). Additionally, the most common causes of all-grade hemorrhagic events were hemoptysis (48.6%) and epistaxis (20.7%), while hemoptysis (41.8%) and CNS hemorrhage (13.4%) was the most common cause of high-grade hemorrhagic events. Conclusions While the use of VEGFR-TKIs is associated with a significantly increased risk of developing hemorrhagic events in cancer patients, this is primarily for lower grade events. [ABSTRACT FROM PUBLISHER]

Abstract: Objective: To compare hemorrhagic events between clopidogrel and ticagrelor in the Platelet Inhibition and Patient Outcomes (PLATO) trial. Methods: We examined the FDA Medical Review. Results: Compared to clopidogrel, ticagrelor significantly increased spontaneous bleeds, major bleeds, major plus minor bleeds, and major plus minor plus minimal bleeds. Ticagrelor also increased both major and fatal/life-threatening bleeds versus clopidogrel when CABG was performed between 24 and 96h after stopping medication, which was also accompanied by a larger volume of chest tube drainage and transfusions. Moreover, ticagrelor increased CABG-related bleeding versus clopidogrel in those patients who did not wait until day 5 after stopping treatment to have CABG. Additionally, compared to clopidogrel, ticagrelor increased the risk of hematuria (RR=1.91; 95% CI: 0.95–3.83), intracranial hemorrhage or subdural or other hematoma (RR 1.87; 95% CI: 1.02–3.42), subcutaneous hemorrhage, ecchymosis, hematoma (RR=1.63; 95% CI: 0.84–3.17), epistaxis (RR=1.49; 95% CI: 0.67–3.32), retroperitoneal hematoma or hemorrhage (RR=1.49; 95% CI: 0.53–4.19), gastrointestinal/anal bleed (RR=1.23; 95% CI: 0.93–1.64) and bleed/hematoma (RR=1.21, 95% CI: 1.02–1.43). Conclusions: Clopidogrel is safer than ticagrelor in regard to bleeding. Additionally, ticagrelor's purported faster antiplatelet ‘offset’ is substantially longer than its pharmacokinetics indicate. Considering the fact that the mortality, stent thrombosis and myocardial infarction ‘benefit’ of ticagrelor have recently been challenged, and that the increase in stroke on ticagrelor has recently been shown to be worse than originally published, the decision to use ticagrelor over clopidogrel in the face of a higher risk for bleeds is not advised. [Copyright &y& Elsevier]

Current guidelines offer a choice of P2Y12 receptor antagonist among clopidogrel, prasugrel or ticagrelor on top of aspirin (ASA) for dual antiplatelet therapy (DAPT) in patients after acute coronary syndromes (ACS). However, the comparative risks of gastrointestinal (GI) adverse events during DAPT are not clear. Two large ACS trials (TRITON and PLATO) provide a valuable opportunity to directly match the risks of GI complications among current antiplatelet regimens. We compared the rates of GI adverse events after prasugrel and ticagrelor versus clopidogrel based on the Food and Drug Administration (FDA) clinical safety reviews. When compared with ticagrelor, clopidogrel is safer with regard to GI-related risks including fewer overall GI/anal bleeding events and spontaneous GI hemorrhagic episodes, less nausea, vomiting, dyspepsia and diarrhea, and a lower rate of presence of Helicobacter pylori. Among GI symptoms, only constipation was more common after clopidogrel than following ticagrelor. There were extrahepatic risks observed with ticagrelor but not with prasugrel when compared to clopidogrel. Prasugrel unquestionably caused more bleeding from the GI tract and GI malignancies than clopidogrel. However, the entire spectrum of GI effects of prasugrel is much less well known and mostly based on sponsor analysis rather than FDA-verified numbers. Among 3 DAPT options on top of ASA, clopidogrel seems to represent the safest alternative, although comprehensive data on direct prasugrel-associated GI effects are lacking or inconclusive. Copyright © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Anticoagulation is an effective therapeutic means of reducing thrombotic risk in patients with various conditions, including atrial fibrillation, mechanical heart valves, and major surgery. By its nature, anticoagulation increases the risk of bleeding; this risk is particularly high during transitions of care. Established anticoagulants are not ideal, due to requirements for parenteral administration, narrow therapeutic indices, and/or a need for frequent therapeutic monitoring. The development of effective oral anticoagulants that are administered as a fixed dose, have low potential for drug-drug and drug-food interactions, do not require regular anticoagulation monitoring, and are suitable for both inpatient and outpatient use is to be welcomed. Three new oral anticoagulants, the direct thrombin inhibitor, dabigatran etexilate, and the factor Xa inhibitors, rivaroxaban and apixaban, have been approved in the US for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation; rivaroxaban is also approved for prophylaxis and treatment of deep vein thrombosis, which may lead to pulmonary embolism in patients undergoing knee or hip replacement surgery. This review examines current options for anticoagulant therapy, with a focus on maintaining efficacy and safety during transitions of care. The characteristics of dabigatran etexilate, rivaroxaban, and apixaban are discussed in the context of traditional anticoagulant therapy. [ABSTRACT FROM AUTHOR]

Disseminated intravascular coagulation (DIC) is a life-threatening complication, and its control is essential for therapeutic success. Recombinant human soluble thrombomodulin alfa (rTM) is a novel therapeutic agent for DIC. The efficacy of rTM in the treatment of DIC is reportedly superior to that of conventional anti-DIC treatments, such as unfractionated heparin or low molecular weight heparin, but hemorrhagic events occasionally interfere with the therapeutic benefits of rTM. We assessed the clinical features of 20 consecutive patients who were given rTM for DIC associated with various hematologic disorders. Eight patients achieved remission of both primary disease and DIC, eight died due to progression of the primary disease, and four died of various hemorrhagic complications. Assessment of 16 biomarkers for coagulation showed that the four patients who died of hemorrhagic complications despite remission of their primary disease showed lower ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin Type 1 motif, member 13) plasma activity than other patients ( P = 0.016). The optimal cut-off level of ADAMTS-13 for predicting risk of hemorrhagic complications was 42 % ( P = 0.007). Plasma ADAMTS-13 activity determined at diagnosis of DIC may help predict the risk of hemorrhagic events during and/or following DIC treatment with hematologic disorders. [ABSTRACT FROM AUTHOR]

Objective: To explore the relationship between clinical features, peripheral blood cell count, coagulation function, gene mutation and hemorrhagic events and thrombotic events in essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis(PMF) patients., Methods: Clinical data of 78 patients with ET, PV, and PMF who were admitted to the Second Affiliated Hospital of Chongqing Medical University between September 2019 and August 2020 were retrospectively analyzed. Information about sex, age, gene mutation, peripheral blood cell count, coagulation function, and hemorrhagic and thrombotic events was included, and the influence of these data on the occurrence of hemorrhagic and thrombotic events was estimated., Results: Among the 78 patients with myeloproliferative neoplasms, there were 47 cases of ET, 15 cases of PV, and 16 cases of PMF.A total of 10 patients (12.82%) experienced hemorrhagic events and 27 (34.62%) experienced thrombotic events. Male,patients aged ≥ 60 years, and patients with a JAK2V617F mutation were more likely to experience thrombotic events (P<0.05). Patients with thrombotic events had higher platelet (PLT) counts and fibrinogen (FIB) levels than patients without hemorrhagic-thrombotic events (P<0.05).White blood cell (WBC) count, red blood cell (RBC) count, hemoglobin (HGB) level, prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT) and international normalized ratio (INR) showed no statistical difference between patients with thrombotic events and patients without hemorrhagic-thrombotic events (P>0.05). There was also no significant difference in the above-mentioned indexes between patients with hemorrhagic events and patients without hemorrhagic-thrombotic events (P>0.05). Among JAK2V617F positive myeloproliferative neoplasm patients, male patients were more likely to have thrombotic events (P<0.05), and patients with thrombotic events had higher platelet counts than those without hemorrhagic-thrombotic events (P<0.05). There was no significant difference in age, white blood cell count, red blood cell count, hemoglobin level, PT, APTT, FIB, TT or INR between patients with thrombotic events and patients without hemorrhagic-thrombotic events (P>0.05)., Conclusion: Sex, age, JAK2V617F mutation and platelet count have a certain value for predicting thrombosis in patients with myeloproliferative neoplasms.

The article presents abstracts of papers presented at the 39th European Society of Clinical Pharmacy (ESCP) European Symposium on Clinical Pharmacy and the 3th Société Française de Pharmacie Clinique (SFPC) Congress: Clinical Pharmacy at the Front Line of Innovations in Lyon, France, including "Hallucinations Due to Therapeutic Doses of Ertapenem," "Carboplatin Dosage in Overweight Patient: Case Report" and "Severe Hypokalemia Associated With Flucloxacillin."

Background and Purpose: Intracranial hemorrhage (ICH) is one of the major adverse events related to the endovascular management of acute ischemic stroke. It is important to evaluate the risk of ICH as it may result in clinical deterioration of the patients. Development of tools which can predict the risk of ICH after thrombectomy can reduce the procedure-related morbidity and mortality. 2D parenchymal blood flow could potentially act as an indicator for ICH., Methods: 2D parenchymal blood flow was used to evaluate pre- and postthrombectomy digital subtraction angiography series of patients with acute ischemic stroke in the anterior circulation. A recently developed software allows the separation of the vascular filling and parenchymal blush signals using band-pass and band-reject filtering to allow for greater visibility of the parenchyma offering a better visual indicator of the effect of treatment. The "wash-in rate" was selected as the parameter of interest to predict ICH., Results: According to the presence or absence of signs of intracranial parenchymal hemorrhage in the follow-up dual-energy CT brain scans, the patients were classified into a hemorrhagic and nonhemorrhagic group (15 patients each). The only significant difference between the groups is the calculated wash-in rate after thrombectomy ( p = 0.024). The cutoff value of the wash-in rate after thrombectomy was suggested to be 11,925.0, with 60% sensitivity to predict the hemorrhage and 93.3% specificity., Conclusions: Elevated parametric parenchymal blood flow wash-in rates after thrombectomy may be associated with increased risk of hemorrhagic events.

The purpose of this study was to investigate the overall incidence and relative risk (RR) of hemorrhagic events in cancer patients treated with ramucirumab. 298 potentially relevant citations on ramucirumab from Pubmed, Web of Science and the Cochrane Database, as well as abstracts presented at conferences (all up to March 2016) were identified through our initial search. Only phase II and III prospective clinical trials of ramucirumab among cancer patients with toxicity records on hemorrhagic events were selected for final analysis. Data was extracted from the original studies by two independent reviewers. The overall incidence, RR, and 95% confidence intervals (CI) were calculated using fixed or random effects models according to the heterogeneity of the enrolled studies. The statistical analysis was performed by STATA version 11.0 (Stata Corporation, College Station, TX). 4963 patients with a variety of solid tumors from eleven eligible studies were selected into our analysis. The results demonstrated that the overall incidences of all-grade and high-grade hemorrhagic events in cancer patients were 27.6% (95% CI, 18.7-36.5%) and 2.3% (95% CI, 1.3-3.2%), respectively. The RR of hemorrhagic events of ramucirumab compared to control was significantly increased for low-grade (RR, 2.06; 95% CI, 1.85-2.29, p < 0.001), but not for high-grade (RR, 1.19, 95% CI, 0.80-1.76, p=0.39) hemorrhagic events. Hemorrhagic events associated with ramucirumab are modest and manageable while patients could continue to receive ramucizumab treatment to achieve their maximum clinical benefits.

Dabigatran and warfarin are oral anticoagulant drugs widely used for the prevention of stroke in patients with atrial fibrillation. The objective of this study was to evaluate the interaction between aging and dabigatran- and warfarin-induced gastrointestinal (GI) and nervous system hemorrhage using data available in the FDA Adverse Event Reporting System (FAERS) database. We analyzed reports of hemorrhagic events in the GI and nervous system recorded in the FAERS database between 2004 and 2014 using an adjusted reporting odds ratio (ROR). We demonstrated that dabigatran-associated GI hemorrhage was significantly increased in patients over the age of 80 years. The RORs of dabigatran increased with increasing age, although aging had little effect on warfarin-associated GI hemorrhage. The ROR for anticoagulant-associated nervous system hemorrhage was not significantly affected by aging, as compared to GI hemorrhage. Our results indicate that the excretion of dabigatran may be affected by aging, as compared to warfarin, likely due to renal function decline. Our results emphasize the need for physicians to closely monitor GI bleeding in aging patients, because it is closely related to renal function deterioration.