Potent Antithrombotic Agents Research Articles

Discovery and Characterization of Panaxatriol as a Novel Thrombin Inhibitor from Panax notoginseng Using a Combination of Computational and Experimental Approaches.

Thrombin is a crucial enzyme in the coagulation cascade, and inhibitors of thrombin have been extensively studied as potential antithrombotic agents. The objective of this study was to identify natural inhibitors of thrombin from Panax notoginseng and evaluate their biological activity in vitro and binding characteristics. A combined approach involving molecular docking, thrombin inhibition assays, surface plasmon resonance, and molecular dynamics simulation was utilized to identify natural thrombin inhibitors. The results demonstrated that panaxatriol directly inhibits thrombin, with an IC50 of 10.3 µM. Binding studies using surface plasmon resonance revealed that panaxatriol interacts with thrombin, with a KD value of 7.8 µM. Molecular dynamics analysis indicated that the thrombin-panaxatriol system reached equilibrium rapidly with minimal fluctuations, and the calculated binding free energy was - 23.8 kcal/mol. The interaction between panaxatriol and thrombin involves the amino acid residues Glu146, Glu192, Gly216, Gly219, Tyr60A, and Trp60D. This interaction provides a mechanistic basis for further optimizing panaxatriol as a thrombin inhibitor. Our study has shown that panaxatriol serves as a direct thrombin inhibitor, laying the groundwork for further research and development of novel thrombin inhibitors.

BJTJ-1837, a novel FXI activation-blocking antibody

BackgroundFactor (F)XI contributes to thrombosis development while it plays a limited role in normal hemostasis. FXI targeting has the potential for preventing and treating thrombosis with little bleeding risk. ObjectivesThe aim of this study was to develop novel antibody therapeutics against FXI for the treatment of thrombosis-related diseases. MethodsMouse hybridoma technology was applied to screen for anti-FXI antibodies. Surface plasma resonance, enzyme inhibition, activated partial thromboplastin time, and prothrombin time assays were conducted to characterize the binding affinity and activity of antibodies. A cynomolgus monkey arterial venous shunt model was applied to validate the antithrombotic activities. ResultsA humanized antibody, BJTJ-1837, reported here bound to the protease domain of FXI and activated FXI with high affinity. BJTJ-1837 fully inhibited the activation of FXI by activated FXII and thrombin. BJTJ-1837 also demonstrated strong anticoagulant activity in human and cynomolgus monkey plasma as measured by activated partial thromboplastin time. Moreover, BJTJ-1837 showed favorable antithrombotic activity with a dose-dependent protection in an arterial venous shunt thrombosis model in cynomolgus monkeys without the bleeding adverse effect. Furthermore, BJTJ-1837 displayed favorable pharmacokinetic and pharmacodynamic properties and good developability. ConclusionAs a potential antithrombotic therapeutic agent with a safe profile, BJTJ-1837 is a very promising FXI activation-blocking antibody candidate.

An undefined cystatin CsCPI1 from tea plant Camellia sinensis harbors antithrombotic activity

Tea consumption has been linked to a decreased risk of cardiovascular disease (CVD) mortality, which imposes a heavy burden on the healthcare system; however, which components in tea cause this beneficial effect is not fully understood. Here we uncovered a cystatin (namely CsCPI1), which is a cysteine proteinase inhibitor (CPI) of the tea plant (Camellia sinensis) that promotes antithrombotic activity. Since thrombosis is a common pathogenesis of fatal CVDs, we investigated the effects of CsCPI1, which showed good therapeutic effects in mouse models of thrombotic disease and ischemic stroke. CsCPI1 significantly increases endothelial cell production of nitric oxide (NO) and inhibits platelet aggregation. Notably, CsCPI1 exhibited no cytotoxicity or resistance to pH and temperature changes, which indicates that CsCPI1 might be a potent antithrombotic agent that contributes to the therapeutic effects of tea consumption against CVD. Specifically, the antithrombotic effects of CsCPI1 are distinct from the classical function of plant cystatins against herbivorous insects. Therefore, our study proposes a new potential role of cystatins in CVD prevention and treatment, which requires further study.

Bleeding outcomes with ticagrelor versus clopidogrel in patients with acute coronary syndrome; a focused analysis from the multicenter CREA ARIAM Andalucia registry

Abstract Background/Introduction With the advent of more potent antithrombotic agents, bleeding has emerged as an important safety concern in patients with acute coronary syndrome (ACS). Moreover, hemorrhagic complications have been strongly linked with subsequent mortality in this clinical scenario. Purpose We sought to determine the incidence, types, timing and prognostic relevance of major bleeding events in ACS patients treated with ticagrelor or clopidogrel in contemporary practice. Methods Prospective, observational, multicentre all-comers registry of ACS patients who were intended to receive a 12-month DAPT course with ticagrelor or clopidogrel. Major bleeding was defined as a type 3 or 5 bleed using the Bleeding Academic Research Consortium (BARC) definition. Bleeding was further classified according to the anatomic location. All bleeding episodes were analysed accounting for death as a competing event, using competing risk regression models based on the on-treatment principle (i.e., according to the P2Y12 inhibitor actually received from date of index admission until either time of DAPT cessation plus 14 days or censoring, whichever occurred first). Results Among 2070 patients surviving to hospital discharge (mean age 63 years, 27% women, 62.5% STEMI), 106 (5.3%, 0.6%/year) experienced major bleeding event at a median time of 92 days (interquartile range, 6–187 days) after discharge. Most events (n=59, 55.7%) were BARC type 3a bleeds with 2 fatal bleeds (type 5b). In most cases (53%), the site of bleeding was gastrointestinal, followed by intracranial (n=13, 12%). After adjustments for baseline predictors, ticagrelor was associated with increased but not statistically significant risk of major bleeding compared with clopidogrel (5.6% vs 5.2%, adjusted hazard ratio [aHR] 1.40, 95% CI 0.96–2.05; P=0.075). Major bleeding was significantly associated with nearly 2-fold higher risk of mortality (aHR 1.94; 95% CI 1.32–2.86; P=0.001), irrespective of P2Y12 inhibitor treatment (P interaction = 0.159). Conclusion(s) Bleeding was not rare within 1 year after index ACS, with incidence rates peaked at 30 to 60 days post-index admission. The most common bleeding site was gastrointestinal followed by intracranial haemorrhage. Ticagrelor use was not associated with significantly increased risk of major bleeding compared with clopidogrel whereas bleeding led to a nearly 2-fold higher risk of major bleeding. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Astra-Zeneca

Current and Future Insights for Optimizing Antithrombotic Therapy to Reduce the Burden of Cardiovascular Ischemic Events in Patients with Acute Coronary Syndrome.

The pharmacological treatment strategies for acute coronary syndrome (ACS) in recent years are constantly evolving to develop more potent antithrombotic agents, as reflected by the introduction of more novel P2Y12 receptor inhibitors and anticoagulants to reduce the ischemic risk among ACS patients. Despite the substantial improvements in the current antithrombotic regimen, a noticeable number of ACS patients continue to experience ischemic events. Providing effective ischemic risk reduction while balancing bleeding risk remains a clinical challenge. This updated review discusses the currently approved and widely used antithrombotic agents and explores newer antithrombotic treatment strategies under development for the initial phase of ACS.

Current Status and Future Direction of Antithrombotic Therapy for Patients with STEMI Undergoing Primary PCI.

Since the introduction of the first pharmacological therapy for the treatment of patients with acute myocardial infarction in the early 20th century, treatment of myocardial infarction has evolved extensively throughout the years. Mechanical revascularization therapies such as the percutaneous transluminal coronary angioplasty, combined with the ongoing development of pharmacological therapies have successfully improved the survival of patients with acute myocardial infarction. To date, antiplatelet therapy (consisting of aspirin and an oral inhibitor) and anticoagulation therapy represent the main stay of pharmacological treatment in patients with ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI). The routine use of clopidogrel as antiplatelet agent has been largely replaced by the use of the more potent inhibitors ticagrelor and prasugrel. Unfractionated heparin remains the preferred anticoagulant therapy, despite the development of other anticoagulants, including enoxaparin and bivalirudin. To date, limited evidence exists supporting a pre-hospital initiation of antiplatelet and anticoagulant therapy in STEMI patients. The use of potent intravenous antiplatelet agents, including the glycoprotein IIb/IIIa inhibitors and the intravenous inhibitor cangrelor, is currently restricted to specific clinical settings. While several potent antithrombotic agents already exist, the search for novel potent antithrombotic agents continues, with a focus on balancing antithrombotic properties with an improved safety profile to reduce excess bleeding. This review provides an overview of currently available pharmacological therapies for the treatment of STEMI patients undergoing primary PCI, and an outlook for the ongoing development of novel agents in this field.

N-Stearoylethanolamine Inhibits Integrin-Mediated Activation, Aggregation, and Adhesion of Human Platelets.

N-stearoylethanolamine (NSE), a lipid mediator that belongs to the N-acylethanolamine (NAE) family, has anti-inflammatory, antioxidant, and membranoprotective actions. In contrast to other NAEs, NSE does not interact with cannabinoid receptors. The exact mechanism of its action remains unclear. The aim of this study is to evaluate the action of NSE on activation, aggregation, and adhesion of platelets that were chosen as a model of cellular response. Aggregation of platelets was measured to analyze the action of NSE (10^-6-10^-10 M) on platelet reactivity. Changes in granularity and shape of resting platelets and platelets stimulated with ADP in the presence of NSE were monitored by flow cytometry, and platelet deganulation was monitored by spectrofluorimetry. In vivo studies were performed using obese insulin-resistant rats. Binding of fibrinogen to the GPIIb/IIIa receptor was estimated using indirect ELISA and a scanning electron microscopy (SEM). It was found that NSE inhibits the activation and aggregation of human platelets. Our results suggest that NSE may decrease the activation and subsequent aggregation of platelets induced by ristocetin, epinephrine, and low doses of ADP. NSE also reduced the binding of fibrinogen to GPIIb/IIIa on activated platelets. These effects could be explained by the inhibition of platelet activation mediated by integrin receptors: the GPIb-IX-V complex for ristocetin-induced activation and GPIIb/IIIa when epinephrine and low doses of ADP were applied. The anti-platelet effect of NSE complements its anti-inflammatory effect and allows us to prioritize studies of NSE as a potent anti-thrombotic agent. SIGNIFICANCE STATEMENT: N-stearoylethanolamine (NSE) was shown to possess inhibitory action on platelet activation, adhesion, and aggregation. The mechanism of inhibition possibly involves integrin receptors. This finding complements the known anti-inflammatory effects of NSE.

Synthesis, structural characterization, and evaluation of new peptidomimetic Schiff bases as potential antithrombotic agents.

New Schiff bases functionalized with amide and phenolic groups synthesized by the condensation of 2-hydroxybenzaldehyde and 2-hydroxyacetophenone with amino acid amides which in turn were prepared in two steps from N-Boc-amino acids and homoveraltrylamine through intermediate compounds N-Boc-amino acids amides. The compounds were characterized by elemental analysis, FT-IR, UV–Vis, and NMR spectroscopy. The crystal structures of three Schiff bases were determined by single crystal X-ray diffraction. There exists O–Hcdots N, N–Hcdots O, and C–Hcdots O types of hydrogen bonds and C–Hcdotsuppi secondary bonding interactions in these crystalline solids. The Schiff bases have been screened for anticoagulant and antiplatelet aggregation activities. All the compounds showed procoagulant activity which shortens the clotting time of citrated human plasma in both platelet-rich plasma and platelet-poor plasma except the derivatives of L-methionine which showed anticoagulant activity by prolonging the clotting time. In addition, the compounds derived from benzyl cysteine and phenylalanine showed adenosine diphosphate induced antiplatelet aggregation activity, whereas others did not show any role. Moreover, all these compounds revealed non-hemolytic activity with red blood cells.Graphical abstract Supplementary InformationThe online version contains supplementary material available at 10.1007/s00706-022-02936-6.

Bleeding outcomes with ticagrelor versus clopidogrel in patients with acute coronary syndrome. A focused analysis from the multicenter CREA-ARIAM Andalucia registry

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): The study project was financially supported by a no conditional grant (AstraZeneca) Background/Introduction With the advent of more potent antithrombotic agents, bleeding has emerged as an important safety concern in patients with acute coronary syndrome (ACS). Moreover, hemorrhagic complications have been strongly linked with subsequent mortality in this clinical scenario. Purpose We sought to determine the incidence, types, timing and prognostic relevance of major bleeding events in ACS patients treated with ticagrelor or clopidogrel in contemporary practice. Methods Prospective, observational, multicentre all-comers registry of ACS patients who were intended to receive a 12-month DAPT course with ticagrelor or clopidogrel. Major bleeding was defined as a type 3 or 5 bleed using the Bleeding Academic Research Consortium (BARC) definition. Bleeding was further classified according to the anatomic location. All bleeding episodes were analysed accounting for death as a competing event, using competing risk regression models based on the on-treatment principle (i.e., according to the P2Y12 inhibitor actually received from date of index admission until either time of DAPT cessation plus 14 days or censoring, whichever occurred first). Results Among 2070 patients surviving to hospital discharge (mean age 63 years, 27% women, 62.5% STEMI), 106 (5.3%, 0.6%/year) experienced major bleeding event at a median time of 92 days (interquartile range, 6–187 days) after discharge. Most events (n=59, 55.7%) were BARC type 3a bleeds with 2 fatal bleeds (type 5b). In most cases (53%), the site of bleeding was gastrointestinal, followed by intracranial (n=13, 12%). After adjustments for baseline predictors, ticagrelor was associated with increased but not statistically significant risk of major bleeding compared with clopidogrel (5.6% vs 5.2%, adjusted hazard ratio [aHR] 1.40, 95% CI 0.96 – 2.05; P = .075). Major bleeding was significantly associated with nearly 2-fold higher risk of mortality (aHR 1.94; 95% CI 1.32– 2.86; P = .001), irrespective of P2Y12 inhibitor treatment (P interaction = .159). Conclusion(s) Bleeding was not rare within 1 year after index ACS, with incidence rates peaked at 30 to 60 days post-index admission. The most common bleeding site was gastrointestinal followed by intracranial haemorrhage. Ticagrelor use was not associated with significantly increased risk of major bleeding compared with clopidogrel whereas bleeding led to a nearly 2-fold higher risk of major bleeding.

Pathways of prevention and treatment of ischemic‐reperfusion injury as consequence of myocardial infarction

Myocardial infarction and the phenomenon of ischemic‐reperfusion injury (IRI) which happens as adverse unwanted effect of the restoration of blood flow in the affected area in the post infarction period is one of the main causes of patient’s death all over the world, what makes the prevention and treatment of this condition a frequent issue for clinicians. For treatment patient undergoes mechanical reperfusion of the affected area of the heart and often uses potent antithrombotic agents. Ischemic‐reperfusion injury can happen consequently because of cellular mechanisms (like calcium overload in cardiomyocytes, excessive generation of reactive oxygen species, mitochondrial damage and others). It was discovered that cardiomyocytes can resist ischemic‐reperfusion injury because of specific mechanisms inherent to these cells; ability was named ‘cardio protection’. For future use for prevention and treatment of this health issue, research has been carried out on experimental heart conditioning and pre‐conditioning (it has low possibility of application in clinical practice), new pharmacological preparations are being searched for and their effectiveness is being verified in terms of their ability to induce a cardio protective effect.

Taurine and Its Derivatives: Analysis of the Inhibitory Effect on Platelet Function and Their Antithrombotic Potential.

Taurine is a semi-essential, the most abundant free amino acid in the human body, with a six times higher concentration in platelets than any other amino acid. It is highly beneficial for the organism, has many therapeutic actions, and is currently approved for heart failure treatment in Japan. Taurine has been repeatedly reported to elicit an inhibitory action on platelet activation and aggregation, sustained by in vivo, ex vivo, and in vitro animal and human studies. Taurine showed effectiveness in several pathologies involving thrombotic diathesis, such as diabetes, traumatic brain injury, acute ischemic stroke, and others. As human prospective studies on thrombosis outcome are very difficult to carry out, there is an obvious need to validate existing findings, and bring new compelling data about the mechanisms underlying taurine and derivatives antiplatelet action and their antithrombotic potential. Chloramine derivatives of taurine proved a higher stability and pronounced selectivity for platelet receptors, raising the assumption that they could represent future potential antithrombotic agents. Considering that taurine and its analogues display permissible side effects, along with the need of finding new, alternative antithrombotic drugs with minimal side effects and long-term action, the potential clinical relevance of this fascinating nutrient and its derivatives requires further consideration.

Extracellular fibrinogen-binding protein (Efb), a key immune evasion protein of Staphylococcus aureus and a potential therapeutic target

Due to the continued growth of antibiotic-resistant Staphylococcus aureus strains, it is necessary to explore alternative targets for future therapeutic applications. For this reason, is important to understand the staphylococcal immune evasion mechanisms with a special focus on extracellular fibrinogen-binding protein (Efb) and Efb related proteins. Therefore, it was conducted a literature review to compile relevant information on this protein. It was found that Efb has three binding sites with biological relevance that could be used as therapeutic targets with specificity for fibrinogen, platelets, and complements. First, the fibrinogen-binding motifs also found in coagulase block neutrophil αMβ2 adherence to fibrinogen and attract fibrinogen to the bacterial surface, forming capsule-like structures that block phagocytosis. Second, Efb is a potent anti-thrombotic agent, probably related to its P-selectin binding capacity. Efb P-selectin binding blocks the interaction of P-selectin with the PSGL-1 receptor, thereby impairs the mechanisms of platelet-mediated leukocyte recruitment to the site of vascular injury. Third, the Efb complement binding domain, also found in other staphylococcal complement inhibitory proteins like Ecb, Sbi, and SCIN, is responsible for the evasion of the complement-mediated immune response. Efb reduces the formation of C3 convertase and the interaction with neutrophils, affect B-cells activation, and maturation. Efb binding sites have a clear implication on the virulence of Staphylococcus aureus in mastitis, wound infection, staphylococcal pneumonia, and infections related to implanted devices, and contributes to staphylococcal persistence in host tissues and abscess formation in the kidneys. Given the biological relevance of Efb binding sites in staphylococcal infections, they are promising vaccine targets. Additionally, due to the inhibitory effect of Efb on platelets and complements, Efb can be a potential therapeutic agent to treat diseases associated with thrombosis and abnormal complement activity.

Percutaneous Coronary Intervention in Patients With a History of Gastrointestinal Bleeding (From the Blue Cross Blue Shield of Michigan Cardiovascular Consortium)

Potent antithrombotic agents are routinely prescribed after percutaneous coronary intervention (PCI) to reduce ischemic complications. However, in patients who are at an increased bleeding risk, this may pose significant risks. We sought to evaluate the association between a history of gastrointestinal bleeding (GIB) and outcomes after PCI. We linked clinical registry data from PCIs performed at 48 Michigan hospitals between 1/2013 and 3/2018 to Medicare claims. We used 1:5 propensity score matching to adjust for patient characteristics. In-hospital outcomes included bleeding, transfusion, stroke or death. Post-discharge outcomes included 90-day all-cause readmission and long-term mortality. Of 30,206 patients, 1.1% had a history of GIB. Patients with a history of GIB were more likely to be older, female, and have more cardiovascular comorbidities. After matching, those with a history of GIB (n=312) had increased post-procedural transfusions (15.7% vs 8.4%; p < 0.001), bleeding (11.9% vs 5.2%; p < 0.001), and major bleeding (2.8% vs 0.6%; p=0.004). Ninety-day readmission rates were similar among those with and without a history of GIB (34.3% vs 31.3%; p=0.318). There was no significant difference in post-discharge survival (1 year: 78% vs 80%; p=0.217; 5 years: 54% vs 51%; p=0.189). In conclusion, after adjusting for baseline characteristics, patients with a history of GIB had increased risk of post-PCI in-hospital bleeding complications. However, a history of GIB was not significantly associated with 90-day readmission or long-term survival.

Agonist-Induced Signaling and Integrin-Mediated Function in Murine Platelets Is Distinctly Regulated By the α Isoform of the Catalytic Subunit of Protein Phosphatase 1

Platelet activation at the site of injury is promoted by agonist-induced inside-out and integrin αIIbβ3-initiated outside-in signaling. Our understanding of the agonist and integrin mediated signaling pathways has largely been driven by studies that have examined the role of protein kinases. As models of signal transduction have been refined to include protein phosphorylation and protein dephosphorylation events, the contribution of the protein phosphatases to platelet signaling and function have garnered fresh attention. This is particularly evident for the catalytic subunit of serine/threonine protein phosphatase 1 (PP1c), wherein, its role in platelet biology has been previously assessed with pharmacological agents like calyculin A and okadaic acid. Although such chemical inhibitors represent a useful tool, it lacks specificity to discriminate the different isoforms of PP1c. PP1cα represents a major platelet expressed isoform and its contribution to platelet function is not known. To explore the potential role of PP1cα isoform in platelet signaling, we generated a platelet specific PP1cα -/- mice by crossing the PP1cα floxed mice with a platelet factor 4 (PF4) cre mice. Immunoblotting studies from PP1cα -/- mice confirmed that PP1cα was lost in platelets but not in lymphocytes. A compensatory upregulation of the PP1cβ but not PP1cγ1 isoform was noticed in PP1cα -/- platelets. Loss of PP1cα decreased platelet aggregation and soluble fibrinogen binding to low dose thrombin, thromboxane analog and convulxin, suggesting that PP1cα promotes agonist-induced inside-out signaling. In contrast, PP1cα -/- platelets displayed enhanced adhesiveness to immobilized fibrinogen and increased fibrin clot retraction, processes that are dependent on integrin-mediated outside-in signaling. In a microfluidic perfusion system, whole blood from PP1cα -/- mice displayed increased thrombus formation on collagen. p38 mitogen activated protein kinase (MAPK) was activated in PP1cα -/- platelets, and p38 inhibitor blocked the increased integrin-mediated PP1cα -/- platelet functions. These observations suggest that PP1cα suppress integrin-mediated function in part by decreasing the activation of p38 MAPK. Thus, unlike the conclusion gathered from generic phosphatase inhibitors that PP1c promotes platelet function, our studies using a genetic approach indicate that PP1cα contributes to platelet signaling in a fashion that is specific to the mode of signaling. Specifically, PP1cα promotes platelet agonist-induced inside-out signaling and suppress integrin-mediated outside-in signaling. This observation suggests that chemical activators of PP1cα isoform could serve as a potential antithrombotic agent. DisclosuresNo relevant conflicts of interest to declare.

Antithrombotic Therapy in Acute Coronary Syndromes: Current Evidence and Ongoing Issues Regarding Early and Late Management.

A few decades ago, the understanding of the pathophysiological processes involved in the coronary artery thrombus formation has placed anticoagulant and antiplatelet agents at the core of the management of acute coronary syndrome (ACS). Increasingly potent antithrombotic agents have since been evaluated, in various association, timing, or dosage, in numerous randomized controlled trials to interrupt the initial thrombus formation, prevent ischemic complications, and ultimately improve survival. Primary percutaneous coronary intervention, initial parenteral anticoagulation, and dual antiplatelet therapy with potent P2Y12 inhibitors have become the hallmark of ACS management revolutionizing its prognosis. Despite these many improvements, much more remains to be done to optimize the onset of action of the various antithrombotic therapies, for further treating and preventing thrombotic events without exposing the patients to an unbearable hemorrhagic risk. The availability of various potent P2Y12 inhibitors has opened the door for individualized therapeutic strategies based on the clinical setting as well as the ischemic and bleeding risk of the patients, while the added value of aspirin has been recently challenged. The strategy of dual-pathway inhibition with P2Y12 inhibitors and low-dose non-vitamin K antagonist oral anticoagulant has brought promising results for the early and late management of patients presenting with ACS with and without indication for oral anticoagulation. In this updated review, we aimed at describing the evidence supporting the current gold standard of antithrombotic management of ACS. More importantly, we provide an overview of some of the ongoing issues and promising therapeutic strategies of this ever-evolving topic.

Abstract 14588: Post-discharge Readmission and Survival After Percutaneous Coronary Intervention Among Patients With a History of Recent Gastrointestinal Bleeding: Insights From the Blue Cross Blue Shield of Michigan Cardiovascular Consortium

Introduction: Given the use of potent antithrombotic agents during and after PCI, patients (pts) are at an increased risk of gastrointestinal bleeding (GIB). Hypothesis: We hypothesize that pts with a history of recent GIB have a higher risk of post-discharge readmission and mortality compared with those without a history of GIB. Methods: We linked clinical registry data from PCIs performed between 1/1/2013 and 3/31/2018 at 48 Michigan hospitals to Medicare claims. A recent history of GIB prior to PCI was defined in the clinical PCI registry as any occurrence of melena or hematemesis in the last 30 days or any history of GIB including peptic ulcer disease that may influence clinical management during this hospitalization. Primary outcomes of interest were 90-day readmission after PCI and long-term mortality. We used 1:5 propensity-matching to adjust for differences in characteristics between pts with and without a history of recent GIB. Log-rank testing was used to evaluate survival at 1 and 5 years. Fisher's exact testing was used to compare the rates of 90-day readmission after PCI. Results: Of 30,206 pts, 1.1% had a history of GIB. Pts with a history of GIB were more likely to be older, female, black, and have more cardiovascular comorbidities. After matching 1896 pts, those with a history of GIB (n=316) appeared to have decreased survival early after PCI (Fig); however, the differences in survival were not statistically significant at 1 yr (76.%3 vs. 80.1%; p=0.11) or 5 yrs (52.5% vs. 52.2%; p=0.50) (Fig). There was no significant difference in readmission rates among those with and without a history of GIB (33.5% vs. 30.2%; p=0.26). Conclusions: Pts with and without a history of recent GIB had similar risks of readmission and long-term mortality after PCI. Although a history of GIB has previously been shown to be associated with increased post-PCI bleeding complications, a recent history of GIB was not associated with long-term post-PCI outcomes.

Molecular docking-assisted screening reveals tannic acid as a natural protein disulphide isomerase inhibitor with antiplatelet and antithrombotic activities.

Protein disulphide isomerase (PDI) promotes platelet activation and constitutes a novel antithrombotic target. In this study, we reported that a PDI‐binding plant polyphenol, tannic acid (TA), inhibits PDI activity, platelet activation and thrombus formation. Molecular docking using plant polyphenols from dietary sources with cardiovascular benefits revealed TA as the most potent binding molecule with PDI active centre. Surface plasmon resonance demonstrated that TA bound PDI with high affinity. Using Di‐eosin‐glutathione disulphide fluorescence assay and PDI assay kit, we showed that TA inhibited PDI activity. In isolated platelets, TA inhibited platelet aggregation stimulated by either GPVI or ITAM pathway agonists. Flow cytometry showed that TA inhibited thrombin‐ or CRP‐stimulated platelet activation, as reflected by reduced granule secretion and integrin activation. TA also reduced platelet spreading on immobilized fibrinogen and platelet adhesion under flow conditions. In a laser‐induced vascular injury mouse model, intraperitoneal injection of TA significantly decreased the size of cremaster arteriole thrombi. No prolongation of mouse jugular vein and tail‐bleeding time was observed after TA administration. Therefore, we identified TA from natural polyphenols as a novel inhibitor of PDI function. TA inhibits platelet activation and thrombus formation, suggesting it as a potential antithrombotic agent.

Postoperative Venous Thromboembolism Prophylaxis: Changes in the Daily Clinical Practice, Modified Guidelines.

With current clinical practice, postoperative venous thromboembolism (VTE) risk is not only well controlled, but it is steadily decreasing, especially in orthopaedic surgery, thanks to fast-track and day case procedures, new surgical techniques, and potent antithrombotic agents. Thromboprophylaxis is becoming increasingly adapted to these patients. Aspirin is also extensively prescribed in total hip replacement and total knee replacement procedures in the United States and Australia. Mechanical prophylaxis is sometimes applied alone but most often combined with anticoagulant agents. However, large evidence-based studies are still needed to confirm these optimistic tendencies. In the meantime, physicians have to keep strong control over the VTE risk to prevent the reappearance of pulmonary embolism after admission to the surgical wards.

Postoperative Thromboprophylaxis With New Oral Anticoagulants is Superior to LMWH in Hip Arthroplasty Surgery: Findings from the Swedish Registry.

Although the use of thromboprophylaxis is well established, there is no consensus on the preferred thromboprophylaxis regimen after THA; large, population-based studies offer an opportunity to examine this problem in a robust way that can complement results from randomized trials. Using data from a large national registry, we asked: (1) Is there any difference between low-molecular weight heparin (LMWH) and new oral anticoagulants in preventing symptomatic deep vein thrombosis (DVT) and pulmonary embolism (PE), after THA? (2) Are there any differences in safety parameters, such as bleeding, reoperations and mortality, between LMWH and new oral anticoagulants? Between 2008 and 2012, 78,066 THAs were performed in Sweden. This study evaluated 32,663 (42%) of them, selected through the merger of several national registries. These patients underwent unilateral THA due to primary osteoarthritis. They had not experienced any venous thromboembolic events 5 years before the index operation and were not prescribed potent antithrombotic agents, of any type, in the 6 months before the index operation. Additionally, their postoperative thromboprophylaxis was confirmed in a national registry by purchase of prescribed medications. We divided the cohort into two groups: those patients who received new oral anticoagulants (5752, 18%) and those who received LMWH (26,881, 82%) as postoperative thromboprophylaxis. Our primary endpoints were the frequencies of symptomatic DVT and symptomatic PE within 3 months of surgery. Our secondary comparison was a between-group comparison of bleeding (by way of diagnostic coding), reoperation, and mortality within 3 months of surgery. Odds ratios (OR) are presented with 95% confidence intervals (CIs) as pooled results for the two groups after adjustment for duration of thromboprophylaxis (short or extended for at least 28 days), year of the index operation, Elixhauser comorbidity index, sex, age and previous treatment with platelet aggregation inhibitors. The risk of symptomatic DVT was lower in the group that received new oral anticoagulants than the group that received LMWH (0.3% versus 0.6%, OR, 0.47; 95% CI, 0.27-0.76; p = 0.026). The risk of symptomatic PE was lower in the group that received new oral anticoagulants than the group that received LMWH (0.1% versus 0.4%, OR, 0.36; 95% CI, 0.16-0.69; p = 0.005). There was no difference in the risk of bleeding (by way of diagnostic coding) (OR, 1.03; 95% CI, 0.82-1.28; p = 0.688), reoperation (OR, 1.02; 95% CI, 0.71-1.44; p = 0.860) or mortality (OR, 0.83; 95% CI, 0.31-1.88; p = 0.883) between groups. New oral anticoagulants were associated with a lower risk of symptomatic DVT and symptomatic PE in this large, registry study, and we observed no differences in the risk of bleeding, reoperation, or death between the groups. Although we were able to control for a number of potential confounding variables, we cannot ascertain the indications that drove the prescription decisions in this setting, and there were important between-group differences in terms of duration of thromboprophylaxis (new oral anticoagulants generally were used for a longer period of time after surgery). Future studies, preferably large randomized trials with pragmatic inclusion criteria, to analyze symptomatic DVT, symptomatic PE and death are needed to confirm or refute our findings. Level III, therapeutic study.

Comparison of Effects of Anti-thrombin Aptamers HD1 and HD22 on Aggregation of Human Platelets, Thrombin Generation, Fibrin Formation, and Thrombus Formation Under Flow Conditions.

HD1 and HD22 are two of the most-studied aptamers binding to thrombin exosite I and exosite, respectively. To complete of their pharmacological profiles, the effects of HD1 and HD22 on thrombin-, ristocetin-, and collagen-induced human platelet aggregation, on thrombin generation and fibrin formation in human plasma, as well as on thrombus formation in human whole blood under flow conditions were assessed. The dissociation constants for HD1 and HD22 complexes with thrombin in simulated plasma ionic buffer were also evaluated. HD1 was more potent than HD22 in terms of inhibiting thrombin-induced platelet aggregation in platelet-rich plasma (PRP; 0.05–3 μM) and in washed platelets (WPs; 0.005–3 μM): approximately 8.31% (±6.99% SD) and 89.53% (±11.38% SD) for HD1 (0.5 μM) and HD22 (0.5 μM), respectively. Neither HD1 nor HD22 (3 μM) did influence platelets aggregation induced by collagen. Both of them inhibited ristocetin-induced aggregation in PRP. Surprisingly, HD1 and HD22 aptamers (3 μM) potentiated ristocetin-induced platelet aggregation in WP. HD1 reduced thrombin generation in a concentration-dependent manner [ETP at 3 μM: 1677.53 ± 55.77 (nM⋅min) vs. control 2271.71 ± 423.66 (nM⋅min)], inhibited fibrin formation (lag time at 3 μM: 33.70 min ± 8.01 min vs. control 7.91 min ± 0.91 min) and reduced thrombus formation under flow conditions [AUC30 at 3 μM: 758.30 ± 344.23 (kPa⋅min) vs. control 1553.84 ± 118.03 (kPa⋅min)]. HD22 (3 μM) also delayed thrombin generation but increased the thrombin peak. HD22 (3 μM) shortened the lag time of fibrin generation (5.40 min ± 0.26 min vs. control 7.58 min ± 1.14 min) but did not modify thrombus formation (3, 15 μM). Kd values for the HD1 complex with thrombin was higher (257.8 ± 15.0 nM) than the Kd for HD22 (97.6 ± 2.2 nM). In conclusion, HD1 but not HD22 represents a potent anti-thrombotic agent, confirming the major role of exosite I in the action of thrombin. HD22 aptamer blocking exosite II displays weaker anti-platelet and anti-coagulant activity, with surprising activating effects on thrombin and fibrin generation most likely induced by HD22-induced allosteric changes in thrombin dynamic structure.