Comparison of laser and traditional lancing devices for capillary blood sampling in patients with diabetes mellitus and high bleeding risk.

PURPOSE: Despite the importance of self-monitoring blood glucose (SMBG) for management of diabetes mellitus (DM), frequent blood sampling is discouraged by bleeding risk due to dual-antiplatelet agent therapy (DAPT) or thrombocytopenia. METHODS: We compared the bleeding time (BT) of sampling by using a laser-lancing-device (LMT-1000) and a conventional lancet in patients with DM and thrombocytopenia or patients undergoing DAPT. BT was measured using the Duke method, and pain and satisfaction scores were assessed using numeric rating scale (NRS) and visual analog scale (VAS). The consistency in the values of glucose and glycated-hemoglobin (HbA1c) sampled using the LMT-1000 or lancet were compared. RESULTS: The BT of sampling with the LMT-1000 was shorter than that with the lancet in patients with thrombocytopenia (60s vs. 85s, P = 0.024). The NRS was lower and the VAS was higher in laser-applied-sampling than lancet-applied sampling in the DAPT-user group (NRS: 1 vs. 2, P = 0.010; VAS: 7 vs. 6, P = 0.003), whereas the group with thrombocytopenia only showed improvement in the VAS score (8 vs. 7, P = 0.049). Glucose and HbA1c sampled by the LMT-1000 and lancet were significantly correlated in both the DAPT-user and the thrombocytopenia groups. CONCLUSION: The LMT-1000 can promote SMBG by shortening BT in subject with thrombocytopenia and by increasing satisfaction score, as well as by showing reliable glucose and HbA1c value.

Outcome and Prognostic Factors for Partial and Full Pulpotomy in the Management of Spontaneous Symptomatic Pulpitis in Carious Mature Permanent Teeth: A Randomized Clinical Trial.

INTRODUCTION: The aim of this study was to compare the outcome and prognostic factors for partial and full pulpotomy in the management of mature teeth with spontaneous symptomatic pulpitis. METHODS: The study was a parallel double-blind randomized clinical trial; 200 carious mature permanent teeth with spontaneous symptomatic pulpitis were randomized using a block randomization technique to either partial pulpotomy (n = 99) or full pulpotomy (n = 101). Intraoperative assessment of the pulp under magnification was performed, hemostasis was achieved with a 2.5% sodium hypochlorite moist pellet, and NeoPUTTY (Avalon Biomed, Bradenton, FL) was the pulpotomy material. Preoperative pain levels were recorded and re-evaluated after 1 week. Clinical and radiographic evaluation was performed after 6 and 12 months. Data were analyzed using the chi-square test, the Wilcoxon rank test, and regression analysis. RESULTS: At 1 week, immediate failure occurred in 4 cases in partial pulpotomy, and 196 of 200 subjects reported pain relief and were satisfied with the treatment with no significant difference. At 6 months, 6 teeth failed in the partial pulpotomy group and 1 tooth in the full pulpotomy group, with a higher success rate for full pulpotomy (98.96 vs 89.69, P = .003). At 12 months, the recall rate was 98% (96/200). Full pulpotomy was more successful than partial pulpotomy (98.98% [98/99] vs 84.53% [82/97], P < .001). Multivariate analysis revealed that the odds of success for full pulpotomy were 13.6 times higher than partial pulpotomy. Increased age and higher time to hemostasis were significantly associated with decreased odds of success. CONCLUSIONS: Full pulpotomy has a higher success rate than partial pulpotomy in the management of spontaneous symptomatic pulpitis. Hemostasis within 4 minutes in partial pulpotomy can be set as the cutoff point beyond which further tissue removal is indicated.

Relationships of apolipoprotein E genotypes with a cluster of seven in persons with type 2 diabetes.

OBJECTIVE.: The objective of the study was to determine if there would be statistically significant differences or trends among apolipoprotein E genotypes (2/2, 2/3, 2/4, 3/3, 3/4, and 4/4) for each member of the cluster of seven associated with type 2 diabetes (T2D). The cluster of seven includes abdominal obesity, hypertension, platelet hyperaggregability, hyperglycemia, dyslipidemia (decreased plasma levels of high-density lipoprotein cholesterol (HDL-C) and increased plasma levels of triglycerides)), increased low-density lipoprotein (LDL) oxidation, and increased inflammation. METHODS.: Forty-six patients with well-controlled T2D participated in the study. Abdominal obesity (assessed by waist circumference), hypertension (measured by manual sphygmomanometry), platelet hyperaggregability (measured by bleeding time), hyperglycemia (by enzymatic kit and spectrophotometry), decreased plasma levels of HDL-C and increased plasma levels of triglycerides (by enzymatic kit and spectrophotometry), increased LDL oxidation (measured by LDL conjugated dienes using spectrophotometry) and increased inflammation measured by C-reactive protein (CRP) (by EIA kit) were determined. RESULTS.: All genotypes, except 2/2 were found in the population studied. Abdominal obesity did not vary significantly across the five genotypes. However, glucose levels trended progressively higher going from 2/3 to 2/4 to 3/4 to 4/4. Systolic blood pressure was higher in 3/4 compared to 2/4 and trended higher in 3/4 compared to 3/3. Diastolic blood pressure trended higher in 3/3 vs 2/4 and significantly higher in 3/4 compared to 2/4. Triglycerides trended higher in 3/4 vs 3/3 while HDL-C came close to trending downward in 4/4 compared to 2/4. Bleeding time was unaffected by genotype. Plasma LDL conjugated dienes trended higher in 3/4 vs 2/4 and were significantly higher in 3/4 vs 3/3. CRP trended higher in 4/4 vs 2/3. CONCLUSION.: We can conclude that those with at least one 4 allele in the presence of another allele being 2, 3 or 4 is potentially (in the case of trends) deleterious or is deleterious in terms of hyperglycemia, hypertension (systolic and diastolic blood pressure), dyslipidemia, LDL conjugated dienes and CRP levels.

N-Acetyl Cysteine Prevents Arterial Thrombosis in a Dose-Dependent Manner In Vitro and in Mice.

BACKGROUND: Platelet-rich thrombi occlude arteries causing fatal infarcts like heart attacks and strokes. Prevention of thrombi by current antiplatelet agents can cause major bleeding. Instead, we propose using N-acetyl cysteine (NAC) to act against the protein VWF (von Willebrand factor), and not platelets, to prevent arterial thrombi from forming. METHODS: NAC was assessed for its ability to prevent arterial thrombosis by measuring platelet accumulation rate and occlusion time using a microfluidic model of arterial thrombosis with human blood. Acute clot formation, clot stability, and tail bleeding were measured in vivo with the murine modified Folts model. The effect of NAC in the murine model after 6 hours was also measured to determine any persistent effects of NAC after it has been cleared from the blood. RESULTS: We demonstrate reduction of thrombi formation following treatment with NAC in vitro and in vivo. Human whole blood treated with 3 or 5 mmol/L NAC showed delayed thrombus formation 2.0× and 3.7× longer than control, respectively (P<0.001). Blood treated with 10 mmol/L NAC did not form an occlusive clot, and no macroscopic platelet aggregation was visible (P<0.001). In vivo, a 400-mg/kg dose of NAC prevented occlusive clots from forming in mice without significantly affecting tail bleeding times. A lower dose of NAC significantly reduced clot stability. Mice given multiple injections showed that NAC has a lasting and cumulative effect on clot stability, even after being cleared from the blood (P<0.001). CONCLUSIONS: Both preclinical models demonstrate that NAC prevents thrombus formation in a dose-dependent manner without significantly affecting bleeding time. This work highlights a new pathway for preventing arterial thrombosis, different from antiplatelet agents, using an amino acid derivative as an antithrombotic therapeutic.

Biomedical properties and hemostatic efficacy of polyvinyl alcohol (PVA) based hydrogel in experimental rat liver injury model.

PURPOSE: Bleeding is a leading cause of mortality and morbidity in the trauma and surgery field, using effective hemostatic agents can help us reduce bleeding especially in parenchymal hemorrhage. Nowadays polyvinyl alcohol (PVA) is known as a safe candidate for wound dressing and maybe a hemostatic agent. PVA-based hydrogel is a popular biocompatible material in the biomedical field especially when it has high water absorption. In this study, we investigated the PVA hydrogel's mechanical and biological properties as well as its hemostatic potential in parenchymal bleeding. METHODS: PVA hydrogel had made by the freeze-thawing approach, we used PVA hydrogel in comparison to standard treatment to investigate hemostatic potency. Also, we performed MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) tests to survey PVA cellular toxicity. After an acute liver injury, two groups of 12 rats were treated with PVA hydrogel or standard treatment with sterile gauze. The results including the time and volume of bleeding, and the time and survival rate of the rats were measured and compared. RESULTS: We saw that PVA hydrogel was safe with no cellular toxicity in the MTT assay. Regarding efficacy, PVA hydrogel increased rats' survival after bleeding from 75% to 91.7%, and decreased bleeding time (p: 0.015), and bleeding volume (p: 0.03) compared to the control group. CONCLUSION: Polyvinyl alcohol is safe. It has good biological properties with no cellular toxicity and has a significant hemostatic effect and can be regarded in control of parenchymal hemorrhage.

Application of Design of Experiment in the Optimization of Apixaban-Loaded Solid Lipid Nanoparticles: In Vitro and In Vivo Evaluation.

Solid lipid nanoparticles (SLnPs) are usually utilized as lipid-based formulations for enhancing oral bioavailability of BCS class IV drugs. Accordingly, the objective of this work was to investigate the effect of formulation and processing variables on the properties of the developed SLnPs for oral delivery of apixaban. Randomized full factorial design (24) was employed for optimization of SLnPs. With two levels for each independent variable, four factors comprising both formulations and processing factors were chosen: the GMS content (A), the Tween 80 content (B), the homogenization time (C), and the content of poloxamer 188 used (D). The modified hot homogenization and sonication method was employed in the formulation of solid lipid nanoparticles loaded with apixaban (APX-SLnPs). The size of APX-SLnPs formulations was measured to lie between 116.7 and 1866 nm, polydispersity index ranged from 0.385 to 1, and zeta potential was discovered to be in the range of - 12.6 to - 38.6 mV. The entrapping efficiency of APX-SLnPs formulations was found to be in the range of 22.8 to 96.7%. The optimized formulation was evaluated in vivo after oral administration to rats. Oral administration of APX-SLnPs resulted in significant prolongation in bleeding time compared with both positive and negative control. This indicates the ability of this system to enhance drug therapeutic effect either by increasing intestinal absorption or trans-lymphatic transport. So, this study highlighted the capability of SLnPs to boost the pharmacological effect of apixaban.

Over-expression of Dyrk1A affects bleeding by modulating plasma fibronectin and fibrinogen level in mice.

Down syndrome is the most common chromosomal abnormality in humans. Patients with Down syndrome have hematologic disorders, including mild to moderate thrombocytopenia. In case of Down syndrome, thrombocytopenia is not associated with bleeding, and it remains poorly characterized regarding molecular mechanisms. We investigated the effects of overexpression of Dyrk1A, an important factor contributing to some major Down syndrome phenotypes, on platelet number and bleeding in mice. Mice overexpressing Dyrk1A have a decrease in platelet number by 20%. However, bleeding time was found to be reduced by 50%. The thrombocytopenia and the decreased bleeding time observed were not associated to an abnormal platelet receptors expression, to a defect of platelet activation by ADP, thrombin or convulxin, to the presence of activated platelets in the circulation or to an abnormal half-life of the platelets. To propose molecular mechanisms explaining this discrepancy, we performed a network analysis of Dyrk1A interactome and demonstrated that Dyrk1A, fibronectin and fibrinogen interact indirectly through two distinct clusters of proteins. Moreover, in mice overexpressing Dyrk1A, increased plasma fibronectin and fibrinogen levels were found, linked to an increase of the hepatic fibrinogen production. Our results indicate that overexpression of Dyrk1A in mice induces decreased bleeding consistent with increased plasma fibronectin and fibrinogen levels, revealing a new role of Dyrk1A depending on its indirect interaction with these two proteins.

Hemostatic efficacy of a flowable collagen-thrombin matrix during coronary artery bypass grafting: a double-blind randomized controlled trial.

BACKGROUND: Flowable hemostatic agents have the advantage of being able to be applied to irregular wound surfaces and difficult to reach areas. We sought to compare the effectiveness and safety of the flowable hemostatic sealants Collastat® (collagen hemostatic matrix, [CHM]) and Floseal® (gelatin hemostatic matrix, [GHM]) during off-pump coronary artery bypass (OPCAB). METHODS: In this prospective, double-blind, randomized controlled trial, 160 patients undergoing elective OPCAB surgery were enrolled between March 2018 and February 2020. After primary suture of the aortocoronary anastomosis, an area of hemorrhage was identified, and patients received either CHM or GHM (n = 80, each). Study endpoints were the following: proportion of successful intraoperative hemostasis and time required for hemostasis overall postoperative bleeding, proportion of transfusion of blood products, and surgical revision for bleeding. RESULTS: Of the total patients, 23% were female, and the mean age was 63 years (range 42-81 years). Successful hemostasis proportion within 5 min was achieved for 78 patients (97.5%) in the GHM group, compared to 80 patients (100%) in the CHM group (non-inferiority p = 0.006). Two patients receiving GHM required surgical revision to achieve hemostasis. There were no differences in the mean time required to obtain hemostasis [GHM vs. CHM, mean 1.49 (SD 0.94) vs. 1.35 (0.60) min, p = 0.272], as confirmed by time-to-event analysis (p = 0.605). The two groups had similar amounts of mediastinal drainage for 24 h postoperatively [538.5 (229.1) vs. 494.7 (190.0) ml, p = 0.298]. The CHM group required less packed red blood cells, fresh frozen plasma, and platelets for transfusion than the GHM group (0.5 vs. 0.7 units per patient, p = 0.047; 17.5% vs. 25.0%, p = 0.034; 7.5% vs. 15.0%, p = 0.032; respectively). CONCLUSIONS: CHM was associated with a lower need for FFP and platelet transfusions. Thus, CHM is a safe and effective alternative to GHM. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04310150.

The role of hemostatic agents after tooth extractions: A systematic review and meta-analysis.

BACKGROUND: Hemostatic agents are used to control bleeding after tooth extraction and have been compared with conventional measures (that is, sutures or gauze pressure) in several studies. The objective of this systematic review was to evaluate the benefits of topical hemostatic agents for controlling bleeding after tooth extractions, especially in patients receiving antithrombotic therapy. TYPES OF STUDIES REVIEWED: The authors conducted a literature search in MEDLINE (PubMed), Scopus, and the Cochrane Central Register of Controlled Trials, including prospective human randomized clinical trials in which researchers compared hemostatic agents with conventional methods and reported the time to achieve hemostasis and postoperative bleeding events. RESULTS: Seventeen articles were eligible for inclusion. Hemostatic agents resulted in a significantly shorter time to achieve hemostasis in both healthy patients and patients taking antithrombotic drugs (standardized mean difference, -1.02; 95% CI, -1.70 to -0.35; P = .003 and standardized mean difference, -2.30; 95% CI, -3.20 to -1.39; P < .00001, respectively). Significantly fewer bleeding events were noted when hemostatic agents were used (risk ratio, 0.62; 95% CI, 0.44 to 0.88; P = .007). All forms of hemostatic agents (that is, mouthrinse, gel, hemostatic plug, and gauze soaked with the agent) had better efficacy in reducing the number of postoperative bleeding events than conventional hemostasis measures, except for hemostatic sponges. However, this was based on a small number of studies in each subgroup. CONCLUSIONS: The use of hemostatic agents seemed to offer better bleeding control after tooth extractions in patients on antithrombotic drugs than conventional measures. PRACTICAL IMPLICATIONS: Findings of this systematic review may help clinicians attain more efficient hemostasis in patients requiring tooth extraction. This systematic review is registered in the PROSPERO database. The registration number is CRD42021256145.

Comparison of the effects of tranexamic acid, nitroglycerin, and remifentanil on the prevention of bleeding during herniated lumbar intervertebral disc surgery: A randomized clinical trial.

Background: Surgery is a well-known and effective method of treating lumbar intervertebral disc herniation. The present study aimed to compare the effects of administering tranexamic acid (TXA), nitroglycerin (NTG), and remifentanil (REF) on hemorrhage prevention during herniated lumbar intervertebral disc surgery. Methods: A double-blind clinical trial was conducted on 135 participants undergoing lumbar intervertebral disc surgery. A randomized block design was used for subject assignment to three groups including TXA, NTG, and REF. The hemodynamic parameters, bleeding rate, hemoglobin level, and the amount of infused propofol were measured and recorded after surgery. Data were then analyzed in SPSS software using Chi-square test and analysis of variance. Results: The mean age of participants in the study was 42.12 ± 7.93 years, and all three groups were equal in terms of demographic characteristics (P > 0.05). The mean arterial pressure (MAP) of the TXA and NTG groups was notably higher than the REF group (P < 0.008). The mean heart rate (HR) of the TXA and NTG groups was notably higher than the REF group (P < 0.05). The propofol dosage used in the TXA group was higher than the two groups of NTG and REF (P < 0.001). Conclusion: Among participants undergoing lumbar intervertebral disc surgery, the greatest MAP variability was observed in the NTG group. Higher mean HR and propofol consumption was observed in the NTG and TXA groups when compared to REF. No statistically significant differences were noted between groups in oxygen saturation or bleeding risk. Based on these findings, REF may be considered a preferred surgical adjunct over TXA and NTG during lumbar intervertebral disc surgery.

Circadian rhythm and aneurysmal subarachnoid hemorrhage: Is there an alarm clock for the rupture timing?

BACKGROUND AND PURPOSE: Data on the temporal distribution of the bleeding time of intracranial aneurysms are limited to a few small studies. With this study, the aim was to analyze time patterns of the occurrence of aneurysmal subarachnoid hemorrhage (SAH), particularly focusing on the impact of patients' socio-demographic and clinical characteristics on the ictus timing. METHODS: The study is based on an institutional SAH cohort with 782 consecutive cases treated between January 2003 and June 2016. Data were collected on the ictus time, patients' socio-demographic and clinical characteristics, as well as the initial severity and outcome. Univariate and multivariate analyses were performed on the bleeding timeline. RESULTS: There were two peaks in the circadian rhythm of SAH, one in the morning (7-9 a.m.) and the other in the evening (7-9 p.m.). The strongest alterations in the bleeding time patterns were observed for weekdays, patients' age, sex and ethnicity. Individuals with chronic alcohol and painkiller consumption showed a higher bleeding peak between 1 and 3 p.m. Finally, the bleeding time showed no impact on the severity, clinically relevant complications and the outcome of SAH patients. CONCLUSIONS: This study is one of the very few detailed analyses of the impact of specific socio-demographic, ethnic, behavioral and clinical characteristics on the rupture timing of aneurysms. Our results point to the possible relevance of the circadian rhythm for the rupture event, and therefore might be useful in the elaboration of preventive measures against aneurysm rupture.

Towards 50 years of platelet function analyser (PFA) testing.

The platelet function analyser (PFA) is a prevalent platelet function screening instrument, and comes in two models-the original PFA-100 and the contemporary PFA-200. The instruments have 'identical' output, being a 'closure time' (CT). Moreover, normal reference ranges provided by the manufacturer, for the specific test cartridges, are the same for both models. There are three different types of test cartridge: collagen/epinephrine (C/Epi), collagen/adenosine diphosphate (C/ADP), and "Innovance PFA P2Y" (only available in certain geographical locations). The PFA-100 was released in the mid 1990s, and so is approaching 50 years of age. The PFA-200, released in some locations in the mid 2010s, is destined to eventually replace the PFA-100, but is not yet available in the USA. The test system is highly sensitive to von Willebrand disease (VWD; C/Epi and C/ADP) and to aspirin therapy (C/Epi only), but only has moderate sensitivity to defects in platelet function and/or deficiencies in platelet number. Accordingly, recommendations for use for screening platelet function vary according to user experience. Some workers have alternatively used the PFA to assess thrombosis risk or pre-operative bleeding risk. In this review, we provide an overview of the history of PFA, and summarise its current clinical utility.

Swimming improves platelet dysfunction in mice fed with a high-fat diet.

BACKGROUND: We investigated the effects and mechanism of swimming on platelet function in mice fed with a high-fat diet. MATERIAL AND METHODS: Mice were randomly divided into the control group (NC), high-fat group (HF), and high-fat diet combined with swimming group (FE). The FE group swam for 60 min a day, 5 days a week, for 8 weeks. RESULTS: Compared with the NC group, the HF group had significant weight gain, dyslipidemia, abbreviated bleeding time after tail breakage, increased clot retraction, increased platelet aggregation rate, increased spread of platelets on fibrinogen, and increased pAKT level in platelets. Compared with the HF group, the FE group had lower body weight, improved dyslipidemia, prolonged bleeding time, reduced clot retraction, reduced platelet aggregation rate, decreased spread of platelets on fibrinogen, and decreased pAKT level in platelets. CONCLUSIONS: By inhibiting the level of pAKT in platelets, swimming improves platelet dysfunction in mice fed with a high-fat diet.

Hemostatic function of cold-stored platelets in a thrombocytopenic rabbit bleeding model.

BACKGROUND: Transfusion of cold-stored platelet concentrates (CS-PCs) appears effective in massively bleeding patients. However, few studies have evaluated their in vivo hemostatic function in severe thrombocytopenia. STUDY DESIGN AND METHODS: The in vivo function of plasma-depleted human PCs was evaluated in rabbits with a blocked reticuloendothelial system and busulfan-induced thrombocytopenia. On day 1, a human apheresis PC was processed in a platelet additive solution (PAS-PC) and split evenly for cold or room temperature storage (RTS). On days 3, 6, or 9, RTS- or CS-PAS-PCs were transfused (4.0 × 109 platelets/kg) after plasma depletion into two to four rabbits that developed adequate thrombocytopenia (<25 × 109 /L). Ear bleeding time was measured by two incisions in small veins. The hemostatic rate was defined as the percentage of rabbits achieving bleeding cessation within 600 s at either incision. The experiment was repeated using five different PCs on each storage day. RESULTS: The mean pre-transfusion rabbit platelet count was 8.6 ± 5.2 × 109 /L. The hemostatic rates with RTS- and CS-PAS-PCs were both 100% on day 3, 93 ± 15% and 73 ± 15% on day 6 (p = .07), and 65 ± 36% and 73 ± 37% on day 9 (p = .27), respectively, with no statistical differences. Total platelet counts were significantly lower after CS-PAS-PC than RTS-PAS-PC transfusion on all days (e.g., 58.7 ± 5.7 vs. 42.4 ± 14.7 × 109 /L, p = .0007, day 9), and did not reach 50 × 109 /L in several experiments. Platelet count increments correlated significantly with hemostatic efficacy for CS-PAS-PC transfusion only. DISCUSSION: CS-PAS-PCs might achieve similar hemostasis as RTS-PAS-PCs in thrombocytopenic patients with mild bleeding. Hemostatic efficacy could be improved by transfusing more CS-PAS-PCs.

Naoxintong capsule limits myocardial infarct expansion by inhibiting platelet activation through the ERK5 pathway.

BACKGROUND: In the clinic, Naoxintong capsule (NXT) has been applied in two level prevention of ischemic disease. However, its mechanism of action requires further study. PURPOSE: This study investigated whether NXT could affect platelet function and activation under ischemic pathological conditions. MATERIALS AND METHODS: Wistar rats were divided into six groups, sham, saline, NXT (250, 500, 1000 mg/kg), and aspirin group (10 mg/kg). For the pre-treatment assays, MI model was established after pre-administration of saline, NXT-L, NXT-M, NXT-H, and aspirin respectively for 14 days, and after surgery, there were no continuous treatments. For the post-treatment assay, rats were orally administered for 3 days after MI. FeCl3-induced thrombosis model was applied to determine the thrombus wet weight. Bleeding time was used to assess the ability of the platelets to develop a hemostatic plug. RESULTS: NXT decreased infarct size, decreased LDH, CK, and CK-MB values, and improved cardiac function. NXT inhibited platelets activation through reducing CD62P-positive platelets and inhibited infarct expansion by decreasing the number of CD45-positive cells and the amount of MMP9 secreted into the heart tissue. Mechanistically, NXT inhibited platelets activation through decreasing ROS levels, decreasing ERK5 phosphorylation, and increasing RAC1 phosphorylation in MI rats. Pre-treatment with NXT decreased thrombus formation and had normal bleeding times. CONCLUSION: NXT showed obviously preventive effects, which was associated with negative control of platelet activation. The above results provide a basis for clinically expanding application of NXT.

Murine Models in the Evaluation of Heparan Sulfate-Based Anticoagulants.

Evaluating prospective anticoagulant therapies in animal thrombosis and bleeding models are standard pre-clinical approaches. Mice are frequently used for initial evaluations because a variety of models have been developed in this well-characterized species, and mice are relatively inexpensive to maintain. Because mice seem to be resistant to forming "spontaneous" thrombosis, vessel injury is used to induce intravascular clot formation. For the purpose of testing heparin-based drugs, we adapted a well-established model in which thrombus formation in the carotid artery is induced by exposing the vessel to ferric chloride. For studying anticoagulant effects on venous thrombosis, we use a model in which the inferior vena cava is ligated and the size of the resulting clots are measured. The most common adverse effect of anticoagulation therapy is bleeding. We describe a simple tail bleeding time that has been used for many years to study the effects of anticoagulants on hemostasis. We also describe a more reproducible, but more technically challenging, saphenous vein bleeding model that is also used for this purpose.

EGb 761® Does Not Affect Blood Coagulation and Bleeding Time in Patients with Probable Alzheimer's Dementia-Secondary Analysis of a Randomized, Double-Blind Placebo-Controlled Trial.

Following reports of bleeding upon Ginkgo intake, we assessed whether Ginkgo extract EGb 761® affects coagulation or platelet function or increases the risk of bleeding. In a double-blind, placebo-controlled trial, prothrombin time, activated partial thromboplastin time, international normalized ratio and bleeding time were measured in patients with Alzheimer's dementia at baseline, weeks 6 and 26. A total of 513 patients were randomized to 120 mg (n = 169) or 240 mg EGb 761® (n = 170) or placebo (n = 174). No relevant changes were found for coagulation parameters and bleeding time. Numbers of bleeding-related adverse events were similar in all groups. Concomitant intake of acetylsalicylic acid was documented for 68 patients in the placebo group and 105 in the EGb 761® groups. Within these groups, the means at baseline and week 26 differed by less than 1 unit for prothrombin time and bleeding time and less than 0.1 unit for international normalized ratio. Data on warfarin treatment in nine patients each taking placebo or EGb 761® did not indicate enhancement of warfarin effects by EGb 761®. No evidence was found that EGb 761® affects hemostasis or increases the bleeding risk. No pharmacodynamic interactions with warfarin or acetylsalicylic acid were found.

Hemostasia en fístulas arteriovenosas: comparación de la presión manual con la ejercida por un dispositivo regulable / Hemostasis of arteriovenous fistula: Comparison of direct two-finger pressure to an adjustable device

Antecedentes y objetivo: Valorar la presión generada por una pinza ajustable en fístulas arteriovenosas (FAV) durante el proceso de hemostasia y compararla con la generada por la compresión manual. Evaluar las variaciones de la compresión manual durante el proceso de hemostasia. Métodos: Se analizaron los datos de 51 sesiones de hemodiálisis de 15 pacientes. Se utilizó la presión intraacceso como indicador indirecto de la presión generada por ambos métodos sobre la FAV. La misma se registró antes de retirar la aguja venosa (PBasal), tras retirar la aguja y colocar la pinza (P1), tras ajustar la pinza (P2), al comenzar el paciente a ejercer compresión manual (M0), a los 3min del inicio de la presión manual (M3) y a los 6min del inicio de la presión manual (M6). Resultados: La presión intraacceso fue menor al aplicar la pinza y ajustarla (P2) que al aplicar presión manual (M0), con una diferencia media de −9,43mmHg (variación −18,57%, IC95%: −14,09 a −4,77mmHg, p<0,001). La presión manual mostró una tendencia descendente durante el proceso de hemostasia (M3-M0: −8,82mmHg, p<0,001; M6-M0: −12,55mmHg, p<0,001). Conclusión: La compresión ejercida por una pinza ajustable es inferior o similar a la ejercida de forma manual por el paciente. Esta última muestra una intensidad decreciente durante el proceso de hemostasia. Estos datos sugieren que algunas de las premisas sobre las que se basan algunas de las recomendaciones presentes en las guías clínicas podrían ser imprecisas. (AU)

Background and objectives: To evaluate the pressure generated by an adjustable hemostasis clamp on arteriovenous fistulas (AVF) during the hemostasis proccess, and compare it with the direct two-finger pressure applied by the patient. To evaluate the variations of the direct two-finger pressure along the hemostasis process. Methods: We analyzed data obtained in 51 hemodialysis procedures from 15 patients. AVF intra-access pressure was used as indirect indicator of the pressure generated by both methods. It was recorded before venous needle removal (PBasal), at clamp application (P1), after clamp adjustement by a nurse (P2), at the beginning of the direct two-finger pressure by the patient (M0), after 3min of two-finger pressure (M3) and after 6min of two-finger pressure (M6). Results: Intra-access pressure was lower with the adjusted clamp (P2) than with the direct two-finger pressure by the patient (M0) (variation of −18.57%, 95%CI: −14.09 to −4.77mmHg, P<.001). Intra-access pressure generated by the direct two-finger pressure method showed a decreasing trend along the hemostasis process (M3-M0: −8.82mmHg, P<.001; M6-M0: −12.55mmHg, P<.001). Conclusion: An adjustable fistula arm clamp generates a lower pressure in AVF than the direct two-finger pressure applied by the patient. The latter showed a decreasing trend along the hemostasis process. These data suggest that some of the recommendations from clinical guidelines could be based on inaccurate premises. (AU)

Bleeding and Subsequent Cardiovascular Events and Death in Atrial Fibrillation With Stable Coronary Artery Disease: Insights From the AFIRE Trial.

BACKGROUND: Early bleeding after percutaneous coronary intervention is associated with increased risk of death and myocardial infarction; however, the association between bleeding and subsequent major adverse cardiac and cerebrovascular events (MACCE) remains unclear in patients with atrial fibrillation and stable coronary artery disease. We thus aimed to investigate this association. METHODS: The AFIRE trial (Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease) was a multicenter, open-label trial conducted in Japan. This post hoc analysis included 2215 patients with atrial fibrillation and stable coronary artery disease treated with rivaroxaban or rivaroxaban plus an antiplatelet agent. MACCE was defined as a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, or death from any cause. The association of bleeding with subsequent MACCE risk was investigated using time-adjusted Cox multivariate analysis after adjusting for baseline characteristics and time from bleeding. Bleeding events were classified according to the International Society on Thrombosis and Haemostasis criteria. RESULTS: Among the 2215 patients, 386 (17.4%) had bleeding during follow-up, of whom 63 (16.3%) also experienced MACCE; MACCE incidence was higher in patients with bleeding than in those without (8.38% versus 4.20% per patient-year; hazard ratio, 2.01 [95% CI, 1.49-2.70]; P<0.001). The proportion of patients with both bleeding and MACCE (developed after bleeding) was 73.0% (46 of 63); 27.0% (17 of 63) experienced MACCE before bleeding. Time-adjusted Cox multivariate analysis revealed a temporal association between major bleeding and subsequent MACCE, with particularly high MACCE risks within 30 days after major bleeding (hazard ratio, 7.81 [95% CI, 4.20-14.54]). CONCLUSIONS: In patients with atrial fibrillation and stable coronary artery disease, major bleeding was strongly associated with subsequent MACCE. Thus, it is important to prevent major bleeding to avoid cardiovascular events and death. Registration: URL: https://www.umin.ac.jp/ctr; Unique identifier: UMIN000016612. URL: https://www.clinicaltrials.gov; Unique identifier: NCT02642419. Graphic Abstract: A graphic abstract is available for this article.