Inhibited Adenosine Diphosphate Research Articles

Effects of water-soluble tomato concentrate on platelet aggregation

Objective: To investigate the antiplatelet aggregation effect of water-soluble tomato concentrate (WSTC) and explore the underlying molecular mechanisms. Materials and Methods: Platelet aggregometry was used to quantify rat platelet aggregation with the maximum aggregation rate in vitro and ex vivo. Then, the fibrinogen (FIB) binding assay was employed to detect the effect of WSTC on the activation of platelet integrin αIIβ3 (GP IIb/IIIa). Furthermore, Western blot was performed to assess the platelet protein levels of phosphoinositide 3-kinase 110 β (PI3K110 β), protein disulfide isomerase (PDI), platelet endothelial cell adhesion molecule 1 (PECAM-1), and β1-Tubulin. Results: WSTC inhibited adenosine diphosphate (ADP) and collagen-induced platelet aggregation in a concentration-dependent manner in vitro, at IC50values of 3.05 g/L and 8.03 g/L, respectively. Significantly reduced ex vivo ADP induced platelet aggregation was observed after oral consumption of WSTC for 4 weeks in rats; average inhibition rates were 24.42%, 21.48%, and 20.87% for 25 mg/Kg, 75 mg/Kg, and 150 mg/Kg WSTC, respectively. It appeared that WSTC had no influence on coagulation function in rats. Incubation with WSTC decreased FIB binding to GP IIb/IIIa by 17.47% and 32.29% at the concentrations of 0.6 and 6 g/L, respectively. WSTC at 0.6 and 6 g/L markedly downregulated PI3K110 β, PDI, and PECAM-1 in platelets, and upregulated β1-Tubulin, in a concentration-dependent manner. Conclusion: WSTC inhibits platelet activation through modulation of platelet skeletal stability and suppresses GP IIb/IIIa receptor-mediated platelet aggregation, likely via the PI3K signaling pathway and PDI inhibition.

Goal-directed platelet transfusions correct platelet dysfunction and may improve survival in patients with severe traumatic brain injury.

Platelet dysfunction, defined as adenosine diphosphate inhibition greater than 60% on thromboelastogram, is an independent predictor of increased mortality in patients with severe traumatic brain injury (TBI). We changed our practice to transfuse platelets for all patients with severe TBI and platelet dysfunction. We hypothesized that platelet transfusions would correct platelet dysfunction and improve mortality in patients with severe TBI. This retrospective review included adult trauma patients admitted to our Level I trauma center from July 2015 to October 2016 with severe TBI (head Abbreviated Injury Scale score ≥ 3) who presented with platelet dysfunction and subsequently received a platelet transfusion. Serial thromboelastograms were obtained to characterize the impact of platelet transfusion on clot strength. Subsequently, the platelet transfusion group was compared to a group of historical controls with severe TBI patients and platelet dysfunction who did not receive platelet transfusion. A total of 35 patients with severe TBI presented with platelet dysfunction. Following platelet transfusion clot strength improved as represented by decreased K time, increased α angle, maximum amplitude, and G-value, as well as correction of adenosine diphosphate inhibition. When comparing to 51 historic controls with severe TBI and platelet dysfunction, the 35 study patients who received a platelet transfusion had a lower mortality (9% vs. 35%; p = 0.005). In stepwise logistic regression, platelet transfusion was independently associated with decreased mortality (odds ratio, 0.23; 95% confidence interval, 0.06-0.92; p = 0.038). In patients with severe TBI and platelet dysfunction, platelet transfusions correct platelet inhibition and may be associated with decreased mortality. Therapeutic, level II.

Effects of platelet dysfunction and platelet transfusion on outcomes in traumatic brain injury patients

ABSTRACTObjective: Platelet inhibition in traumatic brain injury (TBI) may be due to injury or antiplatelet medication use pre-injury. This study aims to identify factors associated with increased platelet arachidonic acid (AA) and adenosine diphosphate (ADP) inhibition and determine if platelet transfusion reduces platelet dysfunction and affects outcome.Methods: Prospective thromboelastography (TEG) assays were collected on adult patients with TBI with intracranial injuries detected by computed tomography (CT). Outcomes included in-hospital mortality, and CT lesion expansion.Results: Of 153 patients, ADP inhibition was increased in moderate and severe TBI compared to mild TBI (p = 0.0011). P2Y12 inhibiting medications had increased ADP inhibition (p = 0.0077). Admission ADP inhibition was not associated with in-hospital mortality (p = 0.24) or CT lesion expansion (p = 0.94). Mean reduction of ADP inhibition from platelet transfusion (−15.1%) relative to no transfusion (+ 11.7%) was not statistically different (p = 0.0472).Conclusions: Mild TBI results in less ADP inhibition compared to moderate and severe TBI, suggesting a dose response relationship between TBI severity and degree of platelet dysfunction. Further, study is warranted to determine efficacy and parameters for platelet transfusion in patients with TBI.

Thromboelastography With Platelet Mapping is Not an Effective Measure of Platelet Inhibition in Patients With Spontaneous Intracerebral Hemorrhage on Antiplatelet Therapy.

Thromboelastography with platelet mapping (TEG-PM) is a modality to measure platelet function, especially in patients taking antiplatelet medications. It consists of two components: arachidonic acid (AA), which is sensitive to aspirin, and adenosine diphosphate (ADP), which is sensitive to clopidogrel. In patients with spontaneous intracerebral hemorrhages (sICH), the clinical interpretation of platelet mapping is unclear. The objective of this study was to evaluate TEG-PM in patients with sICH on aspirin and/or clopidogrel who receive platelet transfusions. This study was an IRB-approved, retrospective case-control study over three years at an academic medical center. Adult patients with sICH were included if they had an admission computed tomography head (CTH) and platelet mapping followed by a repeat platelet mapping and CTH post platelet transfusion. A threshold of 50% inhibition was used as the benchmark for both ADP and AA inhibition. Around 248 subjects with sICH were identified, and 107 were excluded for incomplete documentation, leaving 141 for analysis. Of these, nine met our inclusion criteria. No statistical significance was found on the antithrombotic effects of aspirin or clopidogrel on TEG-PM (p=1.00 for both). Sensitivity and specificity of TEG-PM for clopidogrel was 100% and 42.9%, respectively, and 80% and 0%, respectively, for aspirin. Platelet transfusion did not significantly change AA or ADP inhibition (p=1.00). Hemorrhagic expansion on CTH was not associated with a decrease AA or ADP inhibition (p=1.00). TEG-PM is not an effective measure of platelet inhibition in sICH patients who were on antiplatelet medications and is not a reliable measurement following platelet transfusion.

Differential impact of diabetes mellitus on antiplatelet effects of prasugrel and clopidogrel

BackgroundAlthough prasugrel exerts stronger antiplatelet effects compared with clopidogrel, the factors affecting platelet reactivity under prasugrel have not been fully determined. This study aimed to find the novel mechanistic differences between two thienopyridines and identify the factor that influence platelet reactivity to each drug.MethodsForty patients with stable angina who underwent elective percutaneous coronary intervention were randomly assigned to receive either prasugrel (20 mg) or clopidogrel (300 mg) as a loading dose. Platelet function (light transmission, laser light scattering, and vasodilator-stimulated phosphoprotein phosphorylation) and plasma active metabolite levels were measured after the loading dose.ResultsPrasugrel consistently inhibited adenosine diphosphate receptor P2Y12 signalling to abolish amplification of platelet aggregation. Prasugrel abolished even small platelet aggregates composed of less than 100 platelets. On the other hand, clopidogrel inhibited large aggregates but increased small and medium platelet aggregates. Diabetes was the only independent variable for determining antiplatelet effects and active metabolite concentration of prasugrel, but not clopidogrel. Sleep-disordered breathing was significantly correlated with platelet reactivity in patients who had clopidogrel.ConclusionsPrasugrel efficiently abolishes residual P2Y12 signalling that causes small platelet aggregates, but these small aggregates are not inhibited by clopidogrel. Considering the differential effect of diabetes on antiplatelet effects between these two drugs, the pharmacokinetics of prasugrel, other than cytochrome P450 metabolism, might be affected by diabetes.Trial registrationUMIN-CTR UMIN000017624, retrospectively registered 21 May 2015.

Association of α2A-Adrenergic Receptor Genetic Variants with Platelet Reactivity in Chinese Patients on Dual Antiplatelet Therapy Undergoing Percutaneous Coronary Intervention

ObjectiveThe alpha 2A-adrenergic receptor gene (ADRA2A) polymorphism in individuals modifies the antiplatelet response to sympathetic stimulation. The aim of this study was to investigate the effect of ADRA2A variants on platelet reactivity in Chinese patients on dual antiplatelet therapy (DAPT) after undergoing percutaneous coronary intervention (PCI). MethodsFrom March 2011 to March 2013, 1,024 patients were enrolled in this prospective, single-center, observational study in China. Four single nucleotide polymorphisms (SNPs) of ADRA2A gene (rs11195419, rs3750625, rs13306146, and rs553668) and CYP2C19*2 were detected by ligase detection reaction (LDR), and adenosine diphosphate (ADP) inhibition was detected by thromboelastography (TEG®). ResultsThe minor allele frequencies of ADRA2A SNPs were common. Platelet ADP inhibition was significantly different among patients carrying rs11195419 (adjusted P = 0.022) and rs3750625 (adjusted P = 0.016). The homozygous allele carriers had the lowest ADP inhibition. However, ADP inhibition was not significantly different in rs553668 and rs13306146. At the multivariate analysis, rs11195419 (P = 0.033), rs3750625 (P = 0.020) and CYP2C19*2 (P = 0.002) were independent predictors of ADP inhibition. Subgroups analysis based on sex showed rs11195419 (P = 0.003) and rs3750625 (P = 0.002) were significantly associated with ADP inhibition in males, but not in females. ConclusionADRA2A genetic variations were associated with ADP-induced platelet aggregation during DAPT in Chinese patients undergoing PCI, and the effect was particularly more pronounced in males.

Platelet adenosine diphosphate receptor inhibition provides no advantage in predicting need for platelet transfusion or massive transfusion

Thrombelastography platelet mapping is a useful assay to assess antiplatelet therapy. Inhibited response to the adenosine diphosphate receptor on platelets occurs early after injury, but recent work suggests this alteration occurs even with minor trauma. However, the utility of thrombelastography platelet mapping, specifically the percent of adenosine diphosphate receptor inhibition, in predicting outcomes and guiding platelet transfusion in trauma-induced coagulopathy remains unknown We assessed the role of percent of adenosine diphosphate-inhibition in predicting survival, requirement for massive transfusion or platelet transfusion in patients at risk for trauma-induced coagulopathy. Thrombelastography platelet mapping was assessed in 303 trauma activation patients from 2014-2016 and in 89 healthy volunteers. Percent of adenosine diphosphate-inhibition is presented as median and interquartile range. We compared the area under the receiver operating characteristic curve of percent of adenosine diphosphate-inhibition, platelet count, and rapid thrombelastography maximum amplitude for in-hospital mortality, massive transfusion (>10 red blood cells or death/6hours), and platelet transfusion (>0 platelet units or death/6hour). Overall, 35 (11.5%) patient died, 27 (8.9%) required massive transfusion and 46, platelet transfusions (15.2%). Median percent of adenosine diphosphate-inhibition was 42.5% (interquartile range: 22.4-69.1%), compared with 4.3 % (interquartile range: 0-13.5%) in healthy volunteers (P<.0001). Patients that died, had a massive transfusion, or platelet transfusion had higher percent of adenosine diphosphate-inhibition than those that did not (P<.05 for all). However, percent of adenosine diphosphate-inhibition did not add significantly to the predictive performance of maximum amplitude or platelet count for any of the 3 outcomes, after adjustment for confounders. Subgroup analyses by severe traumatic brain injury, severe injury and requirement of red blood cells showed similar results. Adenosine diphosphate receptor inhibition did not add predictive value to predicting mortality, massive transfusion, or platelet transfusion. Thus, the role of thrombelastography platelet mapping as a solitary tool to guide platelet transfusions in trauma requires continued refinement.

Impact of a modified anti-thrombotic guideline on stroke in children supported with a pediatric ventricular assist device

Stroke is the most feared complication associated with the Berlin Heart EXCOR pediatric ventricular assist device (VAD), the most commonly used VAD in children, and affects 1 in 3 children. We sought to determine whether a modified anti-thrombotic guideline, involving more intense platelet inhibition and less reliance on platelet function testing, is associated with a lower incidence of stroke. All children supported with the EXCOR at Stanford from 2009 to 2014 were divided into 2 cohorts based on the primary anti-thrombotic guideline used to prevent pump thrombosis: (1) the Edmonton Anti-thrombotic Guideline (EG) cohort, which included children implanted before September 2012 when dual anti-platelet therapy was used with doses titrated to Thromboelastrography/PlateletMapping (TEG/PM); and (2) the Stanford Modified Anti-thrombotic Guideline (SG) cohort, which included children implanted on or after September 2012 when triple anti-platelet therapy was used routinely and where doses were uptitrated to high, weight-based dosing targets, with low-dose steroids administered as needed for inflammation. At baseline, the EG (N = 16) and SG (N = 11) cohorts were similar. The incidence rate of stroke in the SG cohort was 84% lower than in the EG cohort (0.8 vs 4.9 events per 1,000 days of support, p = 0.031), and 86% lower than in the previous Investigational Device Exemption trial (p = 0.006). The bleeding rate was also lower in the SG cohort (p = 0.015). Target doses of aspirin, clopidogrel and dipyridamole were higher (all p < 0.003), with less dosing variability in the SG cohort than in the EG cohort. There was no difference in adenosine diphosphate inhibition by TEG/PM, but arachidonic acid inhibition was higher in the SG cohort (median 75% vs 39%, p = 0.008). Stroke was significantly less common in pediatric patients supported with the Berlin Heart EXCOR VAD using a triple anti-platelet regimen uptitrated to high, weight-based dosing targets as compared with the dual anti-platelet regimen titrated to PM, and without a higher risk of bleeding. Larger studies are needed to confirm these findings.

Antiplatelet and anti-proliferative action of disintegrin from Echis multisquamatis snake venom.

AimTo purify the platelet aggregation inhibitor from Echis multisquamatis snake venom (PAIEM) and characterize its effect on platelet aggregation and HeLa cell proliferation.MethodsSodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and matrix assisted laser desorption/ionization time-of-flight (MALDI-TOF) were used for PAIEM identification. Platelet aggregation in the presence of PAIEM was studied on aggregometer Solar-AP2110. The changes of shape and granularity of platelets in the presence of PAIEM were studied on flow cytometer COULTER EPICS XL, and degranulation of platelets was estimated using spectrofluorimetry. Indirect enzyme-linked immunosorbent assay was used for the determination of target of PAIEM on platelet surface. An assay based on 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide was used to evaluate the effect of PAIEM on the proliferation of HeLa cells in cell culture.ResultsThe molecular weight of the protein purified from Echis multisquamatis venom was 14.9 kDa. Half-maximal inhibitory concentration (IC50) of PAIEM needed to inhibit adenosine diphosphate (ADP)-induced platelet aggregation was 7 μM. PAIEM did not affect thrombin- or ADP-induced platelet activation, but it did prevent binding of the anti-IIb antibody to glycoprotein IIb/IIIa (GPIIbIIIa)-receptor of adhered platelets and inhibited the viability of HeLa cells by 54%.ConclusionAs a member of the disintegrin family, PAIEM inhibited platelet aggregation and cell proliferation possibly by blocking integrin-mediated interactions. However, it did not impair cellular signaling causing any changes in platelet shape and granularity and did not affect ADP-induced platelet degranulation. This disintegrin was shown to be a potent inhibitor of integrin-mediated cellular interactions including platelet aggregation or cancer cell proliferation.

Anthocyanin supplementation in alleviating thrombogenesis in overweight and obese population: A randomized, double-blind, placebo-controlled study

The aim was to evaluate the effect of anthocyanin (ACN) supplementation in reducing thrombogenesis and maintaining hemostasis in pro-thrombotic overweight and obese individuals. Twenty-six (M=9, F=17) overweight/obese (BMI>25) individuals participated in this randomized, double-blind, placebo-controlled, crossover design dietary intervention trial. Volunteers consumed ACN (320mg/day) or placebo capsules for 28-days followed by a two-week wash-out period. ACN supplementation inhibited adenosine diphosphate (ADP)-induced platelet activation-related conformational change and degranulation by reducing PAC-1 expression by 12% and P-selectin expression by 9% respectively. ACN supplementation also alleviated thrombogenic progression by reducing monocyte-platelet aggregate formation by 29% and platelet endothelial cell adhesion molecule-1 (PECAM-1) expression by 21%. Platelet aggregation induced by ADP, collagen and arachidonic acid was reduced by 36%, 17%, and 24% respectively. ACN supplementation has the potential to reduce the risk of thrombosis in overweight/obese population by targeting specific pathways of platelet activation/aggregation and endothelial dysfunction associated leucocyte migration.

The Effect of Combined Aspirin and Clopidogrel Treatment on Cancer Incidence

BackgroundMultiple studies have shown an association between aspirin treatment and a reduction in newly diagnosed cancer. Conversely, there are conflicting clinical and laboratory data on the effect of combined clopidogrel and aspirin therapy on cancer incidence, including analyses suggesting an increased cancer risk. No large-scale cohort study has been performed to address this issue in a heterogeneous real-world scenario. We investigated the effect of clopidogrel and aspirin on cancer incidence compared with aspirin alone and no antiplatelet therapy. MethodsA population-based historical cohort study of subjects aged ≥50 years covered by Clalit Health Services, an Israeli health maintenance organization, was performed. Patients treated with the newer antiplatelet drugs, prasugrel or ticagrelor, which, like clopidogrel, inhibit adenosine diphosphate receptors, and those with prior cancer were excluded. Prescription records of antiplatelet medication were retrieved. ResultsThe cohort included 183,912 subjects diagnosed with 21,974 cancer cases based upon the International Classification of Diseases, Ninth Revision. Dual aspirin and clopidogrel was prescribed in 9.6%, while 49% received aspirin alone and 41% used neither. Compared with nonusers, there was a lower risk of cancer in subjects exposed to aspirin with (hazard ratio [HR] 0.46; 95% confidence interval [CI], 0.44-0.49) or without clopidogrel (HR 0.54; 95% CI, 0.52-0.56), on long-term follow-up. Combined treatment was associated with a lower cancer risk than the aspirin-only group (HR 0.92; 95% CI, 0.86-0.97). ConclusionsDual clopidogrel and aspirin treatment is safe regarding the cancer risk. This study generates the hypothesis that clopidogrel may reduce cancer incidence.

Synthetic polyphosphate inhibits endogenous coagulation and platelet aggregation in vitro

Platelet-derived polyphosphate has previously been indicated to induce coagulation. However, industrially synthesized polyphosphate has been found to have different effects from those of the platelet-derived form. The present study investigated whether synthetic sodium polyphosphate inhibits coagulation using routine coagulation tests and thromboelastography. Synthetic polyphosphate was found to inhibit adenosine diphosphate-, epinephrine-, arachidonic acid-, ristocetin-, thrombin-, oxytocin- and pituitrin-induced platelet aggregation. The effects of synthetic polyphosphate in clotting inhibition were revealed by the analysis of clotting factor activity and platelet aggregation tests. Synthetic polyphosphate may inhibit platelet aggregation by reducing platelet calcium levels, as indicated by the results of flow cytometric analysis and high-throughput fluorescent screening. Furthermore, analysis of thromboxane (TX)B2 by ELISA indicated that synthetic polyphosphate reduces platelet aggregation by inhibiting the TXA2 signaling pathway. In conclusion, synthetic polyphosphate inhibits clotting factor activity and endogenous coagulation by reducing the levels of calcium ions and TXA2 to curb platelet aggregation.

Bioactive chemical constituents from the root bark of Morus australis

Two new pyranoflavonoids, morustralins A (1) and B (2), a new natural benzene derivative, one benzenoid (Z)-1-hydroxy-4-(2-nitroethenyl)benzene (3), and thirty known compounds were isolated and characterized from the root bark of Morus australis. The structures of the new compounds were established from spectroscopic and spectrometric analyses. Ten isolates (1–10) were examined for inhibitory effects on adenosine diphosphate (ADP)-, arachidonic acid (AA)-, and platelet-aggregating factor (PAF)-induced platelet aggregation. Among the tested compounds, compound 3 displayed the most significant inhibition of ADP- and AA-induced platelet aggregation with IC50 values of 9.76±5.54 and 9.81±2.7μM, respectively. In addition, eight purified compounds (3–10) were examined for inhibition of nitric oxide (NO) production in RAW 264.7 cells and six compounds (3–8) displayed significant inhibitory effects with IC50 values ranging from 2.1±0.3 to 6.3±0.6μM.

Bromelain has paradoxical effects on blood coagulability: a study using thromboelastography.

Bromelain is a crude extract from pineapple that is known for a wide array of pharmacological effects including protein digestion, fibrinolytic and anti-immune inflammatory effects and has been popularly used as a phytotherapeutic drug. However, its clinical values and applications remain understudied. The aim of this study was to investigate the effect of bromelain on the coagulability of blood using thromboelastography (TEG). We identified 0.4 U/ml as the minimum concentration of bromelain that results in modification of a normal TEG tracing. We studied the effects of this dose on whole blood samples obtained from normal and hypercoagulable individuals using TEG and evaluated their plasma using conventional tests including prothrombin time (PT) and activated partial thromboplastin time (APTT). We extended this analysis to investigate the effect of bromelain on platelet aggregation in normal blood and on the coagulability of mice blood in vivo in response to a clinically relevant dose injected intraperitoenally. The addition of bromelain ex vivo reduced coagulability of both normal and hypercoagulable blood significantly and resulted in 47 and 22% prolongation of PT and 20 and 10% prolongation of APTT in normal and hypercoagulable samples, respectively and inhibited adenosine di-phosphate (ADP)-induced platelet aggregation by 19%. In vivo, there was a considerable variation in TEG parameters in blood obtained from mice and unexpectedly a paradoxical effect toward hypercoagulability was shown in response to 1.5 mg/kg bromelain injected intraperitoneally into seven different animals. However, these results were not statistically significant when compared with the saline-injected animals. Although the in-vitro findings in this small study indicate a potential anticoagulant effect for bromelain, this needs to be interpreted with caution as neither an oral nor intravenous routes were evaluated. The paradoxical in-vivo data following intraperitoneal administration show the complexity of the effects of bromelain beyond platelets and indicate possible effects on other cells or proteins that require further investigations.

Platelet adenosine diphosphate inhibition in trauma patients by thromboelastography correlates with paradoxical increase in platelet dense granule content by flow cytometry

The mechanism of platelet dysfunction in acute traumatic coagulopathy is unknown. Traumatic brain injury is hypothesized as a cause, while some investigators presume platelets become "exhausted." We hypothesized that platelet hyperstimulation and consumption resulting from trauma leads to decreased platelet function secondary to depletion of platelet granules. Twenty-five trauma patients were divided into traumatic brain injury and no traumatic brain injury groups. Healthy volunteers served as controls. All had thromboelastography with platelet mapping and flow cytometric assays of mepacrine performed. Mepacrine uptake in unstimulated platelets was used for quantification of platelet content of dense granules. Twelve patients with traumatic brain injury and 13 patients without traumatic brain injury were enrolled. Twenty-one trauma patients showed adenosine diphosphate inhibition (>30%) on thromboelastography with platelet mapping compared with the healthy volunteers who served as controls (P<.01). Mepacrine assay showed a difference in mean fluorescent intensity for all trauma patients of 4,259±1,341 compared with controls of 3,143±709 (P=.044), correlating with greater quantities of dense granules. Neither adenosine diphosphate inhibition nor average difference in mean fluorescent intensity between traumatic brain injury and no traumatic brain injury groups were significant (P=.2). Trauma patients maintain their dense granule, contradicting the theory of platelet granule exhaustion as the etiology for platelet dysfunction in traumatic brain injury.

An ethanol extract of Ramulus mori improves blood circulation by inhibiting platelet aggregation.

Inappropriate platelet aggregation can cause blood coagulation and thrombosis. In this study, the effect of an ethanol extract of Ramulus mori (ERM) on blood circulation was investigated. The antithrombotic activity of ERM on rat carotid arterial thrombosis was evaluated in vivo, and the effect of ERM on platelet aggregation and blood coagulation time was evaluated ex vivo. To evaluate the safety of ERM, its cytotoxicity to platelets and its effect on tail bleeding time were assessed; ERM was not toxic to rat platelets and did not prolong bleeding time. Moreover, administering ERM to rats had a significant preventive effect on carotid arterial thrombosis in vivo, and significantly inhibited adenosine diphosphate- and collagen-induced platelet aggregation ex vivo, whereas it did not prolong coagulation periods, such as prothrombin time and activated partial thromboplastin time. The results suggest that ERM is effective in improving blood circulation via antiplatelet activity rather than anticoagulation activity.

Antithrombotic activity of Vitis labrusca extract on rat platelet aggregation.

Vitis labrusca is a grapevine that has antioxidant, neuroprotective, hepatoprotective, and anticarcinogenic activity. However, the antithrombotic effect of Vitis labrusca leaves on platelets is yet to be ascertained. We investigated the inhibitory effect of V. labrusca leaf extract (VLE) on platelet aggregation in vitro and ex vivo. The thromboxane B2 (TXB2) and serotonin concentrations were measured by ELISA. The flavonoids content was measured by ultraperformance liquid chromatography (UPLC). The antithrombotic activity of VLE was evaluated using various agonists in vitro. VLE strongly inhibited adenosine diphosphate (ADP)-induced platelet aggregation. In rats, VLE treatment (100 mg/kg) reduced ADP-stimulated platelet aggregation, without affecting tail bleeding and coagulation time. Moreover, VLE significantly suppressed TXB2 and serotonin secretion. UPLC analysis indicated that VLE contains quercetin, isorhamnetin, and rutin. Our results indicate that VLE possesses antiplatelet activity via the suppression of TXB2 and serotonin, without affecting bleeding. Further, we identified the flavonoids present in VLE. Thus, VLE may be a potential agent for the prevention of cardiovascular diseases.

Adenosine diphosphate platelet dysfunction on thromboelastogram is independently associated with increased morality in traumatic brain injury.

The purpose of this study is to determine if adenosine diphosphate (ADP) platelet dysfunction on thromboelastogram (TEG) is associated with increased in-hospital mortality in patients with head trauma. The hypothesis is that ADP dysfunction is associated with increased mortality. This retrospective review evaluated trauma patients admitted to a level 1 trauma center from February 2011 to October 2013 who received a TEG. Patients were included if the TEG was drawn within the first 24h of admission and the head abbreviated injury score was greater than or equal to three. Patients were categorized as severe ADP dysfunction if the degree of ADP inhibition on TEG exceeded 60%. A total of 90 patients were included (no ADP dysfunction n=37; ADP dysfunction n=53). Initial Glasgow Coma Scale [GCS (12±4 vs. 11±5; p=0.26)] and use of pre-injury antiplatelet agents (30 vs. 28%; p=0.88) were similar. Patients with ADP dysfunction on TEG had a higher in-hospital mortality rate (8 vs. 32%; p<0.01). ADP dysfunction was independently associated with in-hospital mortality upon fixed logistic regression (OR 6.2; 95% CI 1.2-33) while controlling for age, gender, hypotension, pre-injury antiplatelet agents, GCS and Injury Severity Score. ADP dysfunction on TEG is associated with increased mortality in patients with traumatic brain injury.

Thromboelastography Does Not Detect Preinjury Antiplatelet Therapy in Acute Trauma Patients

Thromboelastography (TEG) with platelet mapping has been proposed as an assay to detect the presence of antiplatelet agents (APA), yet no study has evaluated TEG markers of platelet dysfunction in acute trauma patients stratified by the use of preinjury APA. We hypothesized that patients on preinjury APA would demonstrate prolonged TEG markers of platelet dysfunction compared with those not on preinjury APA. This retrospective review evaluated all trauma patients admitted to a Level I trauma center from February 2011 to April 2013 who received a TEG within the first 24 hours of admission. Patients were classified as receiving preinjury APA or no APA if their documented medications included either aspirin or adenosine diphosphate (ADP) antagonists, including clopidogrel, prasugrel, and ticagrelor. A total of 129 patients were included (APA, n = 35; no APA n = 94) in the study. The time from admission to the first TEG was similar (APA 175 ± 289 minutes versus no APA 216 ± 321 minutes, P = 0.5). There was no significant difference in TEG markers of platelet dysfunction, including per cent ADP inhibition (APA 61.7 ± 25.8% versus no APA 62.3 ± 28.8%; P = 0.91) or per cent arachidonic acid inhibition (APA 58.2 ± 31% versus no APA 53.8 ± 34%; P = 0.54). Both groups had similar proportion of severe platelet dysfunction, defined as ADP inhibition greater than 70 per cent (APA 40% versus no APA 40%; P = 0.8) and arachidonic acid inhibition greater than 70 per cent (APA 40% versus no APA 39%; P = 0.89). In conclusion, platelet dysfunction after major trauma is common. Therefore, TEG alone should not be used to evaluate for the presence of APA due to apparent lack of specificity.

Insufficient platelet inhibition and thromboembolic complications in patients with intracranial aneurysms after stent placement.

OBJECT Insufficient platelet inhibition has been associated with an increased incidence of thromboembolic complications in cardiology patients undergoing percutaneous coronary intervention. Data regarding the relationship between insufficient platelet inhibition and thromboembolic complications in patients undergoing neurovascular procedures remain controversial. The purpose of this study was to assess the relationship of insufficient platelet inhibition and thromboembolic complications in patients with intracranial aneurysm undergoing stent treatment. METHODS The authors prospectively recruited patients with intracranial aneurysms undergoing stent treatment and maintained the data in a database. MRI with diffusion-weighted sequences was performed within 24 hours of stent insertion to identify acute ischemic lesions. The authors used thromboelastography to assess the degree of platelet inhibition in response to clopidogrel and aspirin. Univariate and multivariate logistic regression analysis was used to identify potential risk factors of thromboembolic complications. RESULTS One hundred sixty-eight patients with 193 aneurysms were enrolled in this study. Ninety-one of 168 (54.2%) patients with acute cerebral ischemic lesions were identified by diffusion-weighted MRI. In 9 (5.4%) patients with ischemic lesions, transient ischemic attack or stroke was found at discharge, and these complications were found in 11 (6.5%) patients during the follow-up period. The incidence of periprocedural thromboembolic complications increased with resistance to antiplatelet agents, hypertension, hyperlipidemia, complete occlusion, and aneurysm of the anterior circulation. The multivariate regression analysis demonstrated that the anterior circulation and adenosine diphosphate (ADP) inhibition percentage were independent risk factors of perioperative thromboembolic complications. The maximum amplitude and ADP inhibition percentage were independent risk factors for thromboembolic complications during the follow-up period. CONCLUSIONS The ADP inhibition percentage is related to thromboembolic complications after stent placement for intracranial aneurysms. The increase of the ADP inhibition may decrease the risk of thromboembolic complications.