Treatment Of Thromboembolic Disease Research Articles

Peptide‐Based Organic‐Inorganic Hybrid Self‐Assemblies for Ultrasensitive and Visual Detection of Heparin

AbstractAccurate point‐of‐care testing (POC) of low molecular weight heparin (LMWH) can efficiently promote its rational use in the prevention and treatment of thromboembolic diseases but still remain a key challenge. Herein, a peptide‐derived supramolecular self‐assembly system is reported for ultrasensitive and visual detection of LMWH. Two different peptides are designed and modified by gold nanocluster (AuNC) and tetraphenylethene (TPE), respectively, to co‐assemble into nanoparticles, enabling the loading and co‐recognition of LMWH. Owing to two‐wavelength emission from the co‐assemblies at 624 and 460 nm that is highly sensitive to LMWH, such assemblies realize ratio‐type detection of LMWH. The sensitivity of the AuNC‐peptide to LMWH significantly increases when co‐assembling with TPE‐peptide, while that of TPE‐peptide maintains in a high level, enabling a balanced and ultrahigh sensitivity of both two fluorophores. Such self‐assemblies reach an extreme limit of detection of 0.0004 IU mL−1 and realize dramatic fluorescence color change when loading trace concentration of LMWH, which can be simply distinguished by naked‐eye. Thus, by preparing Pep2@AuNC/TPE‐Pep1 test strips the POC testing of LMWH in real thrombus patient samples has achieved. It provides a promising tool for on‐site and real‐time monitoring of anticoagulation therapy to guide LMWH titration into the therapeutic window.

Etiology, Treatment and Prevention Thromboembolic Diseases

The relevance of solving the issues of prevention and treatment of thromboembolic diseases is characterized not only by high mortality, but also by the lack of reliable methods for the early diagnosis of DVT and PATE. The problems of early diagnosis are associated with the polymorphism of clinical manifestations and the frequent asymptomatic course of the disease. In most cases, this is due to the non-specificity of the clinical manifestations of PE. The purpose of the article is to analyze the etiology, methods of treatment and prevention of thromboembolic diseases in surgical departments and non-surgical patients. The methodological basis of the research is a complex application of complementary approaches. The main approaches in this case were a retrospective statistical analysis of case histories with thromboembolic diseases. The article considers the results of foreign clinics, the National Surgical Center. MM. Mamakeev and clinics of the Department of Propaedeutic Surgery of the Kyrgyz State Medical Academy named after I.K. Akhunbaev. The article outlines the factors of occurrence, development of deep vein thrombosis and thromboembolic complications in surgical and non-surgical patients, as well as the use of fast-acting anticoagulating and thrombolytic agents. Particular emphasis in the article is given to the underestimation of individual predisposing genetically determined and acquired risk factors for the occurrence and development of DVT and PATE.

Research progress of nephrotic syndrome accompanied by thromboembolism.

Thromboembolism (TE) is a common and serious complication of nephrotic syndrome (NS). NS is associated with hypercoagulability, which may be induced by changes in coagulation, anticoagulant, and fibrinolytic factors. Moreover, accumulating evidence supports the hypothesis that the complex interactions between genetic and acquired risk factors in TE should be considered and that genetic susceptibility should not be ignored. Extracellular vesicles (EVs) also play unique roles. Further research on EVs may provide new insights into the discovery and treatment of TE associated with NS. The occurrence of NS accompanied by TE may be associated with various risk factors. Preventive anticoagulant therapy can not only reduce the risk of TE in patients but also aggravate the risk of bleeding. Heparin and vitamin K antagonists (VKAs), traditional anticoagulant drugs, have been extensively applied in the prevention and treatment of thromboembolic diseases, and emerging direct oral anticoagulants (DOACs) also provide an alternative choice. Owing to the particularity of NS, the safe application of DOACs still needs to be addressed. This review aimed to comprehensively describe the pathophysiology of TE in NS, as well as analyze the associated risk factors, the opportunity for preventive anticoagulation, and current anticoagulant information.

Factor XI/XIa Inhibition: The Arsenal in Development for a New Therapeutic Target in Cardio- and Cerebrovascular Disease.

Despite major advancements in the development of safer and more effective anticoagulant agents, bleeding complications remain a significant concern in the treatment of thromboembolic diseases. Improvements in our understanding of the coagulation pathways highlights the notion that the contact pathway-specifically factor XI (FXI)-has a greater role in the etiopathogenesis of thrombosis than in physiological hemostasis. As a result, a number of drugs targeting FXI are currently in different stages of testing and development. This article aims to review the different strategies directed towards FXI-inhibition with a brief summation of the agents in clinical development, and to comment on the therapeutic areas that could be explored for potential indications. Therapeutics targeting FXI/FXIa inhibition have the potential to usher in a new era of anticoagulation therapy.

Thromboembolic Disease and Cardiac Thrombotic Complication in COVID-19: A Systematic Review.

The coronavirus 2019 pandemic has affected many healthcare systems worldwide. While acute respiratory distress syndrome (ARDS) has been well-documented in COVID-19, there are several cardiovascular complications, such as myocardial infarction, ischaemic stroke, and pulmonary embolism, leading to disability and death. The link between COVID-19 and increasing thrombogenicity potentially occurs due to numerous different metabolic mechanisms, ranging from endothelial damage for direct virus infection, associated excessive formation of neutrophil extracellular traps (NETs), pathogenic activation of the renin-angiotensin-aldosterone system (RAAS), direct myocardial injury, and ischemia induced by respiratory failure, all of which have measurable biomarkers. A search was performed by interrogating three databases (MEDLINE; MEDLINE In-Process and Other Non-Indexed Citations, and EMBASE). Evidence from randomized controlled trials (RCT), prospective series, meta-analyses, and unmatched observational studies were evaluated for the processing of the algorithm and treatment of thromboembolic disease and cardiac thrombotic complications related to COVID-19 during SARS-CoV-2 infection. Studies out with the SARS-Cov-2 infection period and case reports were excluded. A total of 58 studies were included in this analysis. The role of the acute inflammatory response in the propagation of the systemic inflammatory sequelae of the disease plays a major part in determining thromboembolic disease and cardiac thrombotic complication in COVID-19. Some of the mechanisms of activation of these pathways, alongside the involved biomarkers noted in previous studies, are highlighted. Inflammatory response led to thromboembolic disease and cardiac thrombotic complications in COVID-19. NETs play a pivotal role in the pathogenesis of the inflammatory response. Despite moving into the endemic phase of the disease in most countries, thromboembolic complications in COVID-19 remain an entity that substantially impacts the health care system, with long-term effects that remain uncertain. Continuous monitoring and research are required.

Bleeding Outcomes Using Novel Oral Anticoagulants (NOACs) in End-Stage Renal Disease (ESRD) Versus Coumadin

Background:Patients with end-stage renal disease (ESRD) have been excluded from pivotal clinical trials with novel oral anticoagulants (NOACs). These patients are both at increased risk of venous and arterial thromboembolism and the risk of bleeding is also elevated, thus making treating such patients a challenge. Patients with ESRD and atrial fibrillation (AF) additionally have an increased risk of stroke, compared with less severe renal impairment. The risk of venous thromboembolism (VTE) is also positively correlated with CKD, suggesting ESRD is a hypercoagulable stage.Vitamin K antagonists (VKAs) such as warfarin are the mainstay of treatment as prevention or treatment of thromboembolic disease in ESRD, although the use is highly debated. Randomized controlled trials (RCTs) evaluating DOACs in AF all demonstrated non-inferiority for stroke or side effects, however these studies excluded patients on hemodialysis (HD) and those with creatinine clearance less than 25-30. There appears to be a dearth of high-quality evidence regarding use of DOACs in patients with ESRD. This retrospective analysis aims to evaluate whether use of NOACS causes increased bleeding rates compared to warfarin in the specific population of ESRD patients.Methods:Our study was a retrospective analysis of data using chart review of patients from an urban community medical center between the years 2017-2020. Retrospective data was entered into an electronic data form. Patients required a documented diagnosis of ESRD on hemodialysis and must have received at least one dose of anticoagulation to be included in analysis. Retrospective data pertaining to bleeding events were extracted for this analysis, including GI bleeding, intracranial bleeding, or any other major bleeding. Major bleeding events were defined as those requiring hospitalization or blood transfusion, or any other specific medical intervention. Demographics and clinical variables were presented using frequency and percentages. Patients were stratified into two groups, NOAC use and warfarin use. Continuous variables were analyzed using independent T test while chi square test was used for categorical variables. A p value <0.05 was considered statistically significant.Results:A total sample of 208 patients with ESRD on dialysis who had received anticoagulation were included in this analysis. 51% of patients were male and the majority were African American (79%). The mean age was 67. 43% of patients were on NOACs while 57% were on warfarin. Several other clinical factors were also recorded, with 38% of patients being obese, 92% with hypertension, 58% with diabetes, 45% with coronary artery disease, and 67% with atrial fibrillation. Bleeding outcomes were recorded for both patients who had received a NOAC or warfarin. 24 bleeding events were noted in NOAC group versus 44 events in the warfarin group. There was a higher rate of any major bleeding in the warfarin group versus NOAC group (37% vs 27%), however this not statistically significant (p=0.138)Limitations:More data will need to be collected to gain statistical significance of primary endpoint findings, and we have estimated that a total of approximately 680 patient outcomes would need to be analyzed to gain statistical significance. This data collection is currently underway. Other limitations include the retrospective nature of this study, with heavy reliance on review of patient charts for proper documentation of clinically relevant bleeding while on anticoagulation. Ideally, a prospective study would be better able to standardize data.Conclusions:Based on current data analysis, there is a trend towards warfarin having higher rates of bleeding compared to DOACs in ESRD patients on dialysis, 37% versus 27%, although this is only approaching statistical significance. These findings may shift current lines of thought that warfarin is a more acceptable choice of anticoagulation in ESRD patients given long term experience with this drug. Further studies are needed to make more definite conclusions. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Antithrombotic Drugs in Cirrhosis

Abstract In patients with liver cirrhosis treated for portal vein thrombosis, there was no increase in the risk of bleeding, but there was a decrease in the incidence of liver decompensation and an increase in the survival of treated patients when compared to the untreated ones(1). Current guidelines(2) do not provide specific recommendations for the prophylaxis or treatment of thromboembolic diseases in patients with liver cirrhosis(3). In order to determine the influence of anti-thrombotic treatment on the prognosis of liver cirrhosis, 85 patients with liver cirrhosis were followed clinically, by laboratory and ultrasound parameters, for 6 months. Microsoft Excel and IBM SPSS Statistics 20 were used to analyse the data of patients, divided into two groups according to the presence or absence of anti-thrombotic treatment initiated for cardiovascular pathology. The obtained results showed that the mortality rate between the two groups was similar: 11.54% untreated, 12.12% treated, the decompensation rate of untreated patients was higher than that of the treated ones (36.54% vs. 24.24%) with antithrombotic drugs and that no patient among those treated with antithrombotic drugs showed upper digestive haemorrhage (p =0.038). The conclusions drawn from this study were that patients with liver cirrhosis in antithrombotic treatment have a better prognosis than untreated ones, in the absence of major bleeding complications, but for a change in guidelines and current practice, studies are needed on a larger number of patients in order to validate these observations.

Study of INR Profile in Patients on Vitamin K Antagonists in Tanta University Hospital Egypt

Background: Oral vitamin K antagonists are highly effective in the prevention and treatment of thromboembolic disease. Optimal use of these agents in clinical practice is challenged by their narrow therapeutic window. We aimed to Study the international normalized ratio values in patients on vitamin K antagonists to find out which patient characteristics that are associated with good INR control. &#x0D; Methods: From June 2019 till May 2020 we studied 502 patients receiving vitamin K antagonists (VKAs) as an oral anticoagulant treatment for thromboembolic prevention for at least more than 1 month. The cases were classified into two groups according to time to therapeutic range (TTR); group I included 289 patients with TTR &lt; 65 and group II that included 213 patients with TTR ≥ 65. We included patients with atrial fibrillation, prosthetic valve replacement or deep venous thrombosis.&#x0D; Results: In univariate regression analysis, increasing age, male gender, lower level of education, diabetes mellitus, hypertension, smoking, chronic kidney disease, coronary artery disease and higher CHADS-VASC were revealed as risk factors for poor response (time to therapeutic range (TTR) &lt; 65). With multivariate logistic regression analysis, lower level of education, HTN, smoking, CKD and higher CHADS-VASC were revealed as independent risk factors for poor response (TTR &lt; 65).&#x0D; Conclusion: This study indicated that, poor education, hypertension, smoking, chronic kidney disease, and high CHADS VSAC score were independent predictors of poor time to therapeutic range (TTC) control.

Intracranial Hemorrhage In Patients Receiving Direct Oral Anticoagulant Therapy: Clinical Assessment, Management And Related Laboratory Studies

Abstract Introduction/Objective Direct oral anticoagulants (DOACs) have gained wide use in prevention and treatment of thromboembolic diseases. Although relatively rare with DOAC therapy, intracranial hemorrhage may become a medical emergency and needs to be managed with caution to avoid adverse consequences. Methods During the review of 94 patients with DOAC therapy related bleeding complications at William Beaumont hospital – Troy, Michigan, 3 patients were identified with intracranial hemorrhage. Information on DOAC therapy, the cause related to intracranial hemorrhage, and clinical assessment and management of these patients were collected from electronic medical charts with concurrent laboratory studies. Results There were 1 male and 2 female patients, ages 63, 67 and 86. Two patients were taking rivaroxaban 20 mg daily and 1 patient apixaban 5 mg bid for atrial fibrillation and DVT. Patients were clinically stable with no prior significant bleeding events, except for minor skin rashes. All patients experienced a minor trauma to the head and showed signs of brain injury. They were brought to the emergency department immediately. DOAC therapy was discontinued during the emergency evaluation. CT studies revealed 1 patient with subdural hematoma and 2 patients with focal intraparenchymal hemorrhage without mass effects. Both clinical and laboratory assessment revealed stable medical conditions. Patients received conservative care without surgical intervention and repeat CT studies demonstrated resolution of hemorrhage. One patient discontinued DOAC therapy permanently and the others resumed DOAC therapy with antidotes available. Clinical follow up showed no additional bleeding events. Conclusion Intracranial hemorrhage can occur in patients received DOAC therapy, even in clinically stable patients, and most likely happens after head injury. In this small group of patients, both clinical and laboratory evaluations showed stable medical conditions, with no need for surgery intervention. However, the decision of continuing DOAC therapy should be made with caution and it is reasonable to have antidote available for these patients.

Characterization of thrombin/factor Xa inhibitors in Rhizoma Chuanxiong through UPLC-MS-based multivariate statistical analysis

BackgroundThe dry root and rhizome of Ligusticum chuanxiong Hort., or Chuanxiong, has been used as a blood-activating and stasis-removing traditional Chinese medicine for 1000 years. Our previous studies have shown the inhibitory activity on platelet and thrombin (THR) of Chuanxiong. THR and factor Xa (FXa) play significant roles in the coagulation cascade and their inhibitors are of valuable in the treatment of thromboembolic diseases. The aim of the present study is to screen THR and FXa inhibitors from Chuanxiong.MethodsFour extracts [ethyl acetate (EA), butanol (BA) and remained extract (RE) from 75% ethanol extract, and water extract (WE)] of Chuanxiong were prepared, and their THR/FXa inhibitory activities were assessed in vitro. Following silica-gel column chromatography (SC), the active EA extract and BA extract was further partitioned, respectively. Their active fractions (EA-SC1 to EA-SC5; BA-SC1 to BA-SC5) were obtained and analyzed by LC–MS. After modeling by the principal component analysis (PCA) and orthogonal partial least squares discriminate analysis (OPLS-DA), the specific marker compounds were predicted and identified. Their enzyme inhibitory was assessed in vitro and interactions with THR/FXa were investigated by molecular docking analysis.ResultsChuanxiong EA extract showed strong activity against THR and BA extract was more effective in inhibiting FXa activity, and their fractions exhibited obvious difference in enzyme inhibitory activity. Furthermore, marker compounds a–h were predicted by PCA and OPLS-DA, and their chemical structures were identified. Among them, senkyunolide A, Z-ligustilide, ferulic acid and senkyunolide I (IC50 was determined as 0.77 mM) with potential THR inhibitory activity, as well as isochlorogenic acid A with FXa inhibitory activity were screened out. It was found that the four components could interact with the active site of THR, and the binding energy was lower than − 5 kcal/mol. Isochlorogenic acid A were bound to the active site of FXa, and the binding energy was − 9.39 kcal/mol. The IC50 was determined as 0.56 mM.ConclusionsTHR/FXa inhibitory components in different extracts of Chuanxiong were successfully characterized by the method of enzyme inhibition activity assays with ultra performance liquid chromatography-quadrupole time of flight mass spectrometry-based multivariate statistical analysis.

Oral treatment with a chemically characterized parsley (Petroselinum crispum var. neapolitanum Danert) aqueous extract reduces thrombi formation in rats

Petroselinum crispum var. neapolitanum Danert (Apiaceae) (PC), popularly known as parsley, is an herb native to the Mediterranean region widely cultivated around the world for culinary and ethnomedicinal purposes. The herb is traditionally used in various parts of the world to treat arterial hypertension, hemorrhoid, nose bleeding, hyperlipidemia, and pain, among other indications. The aim of this study was to evaluate the antithrombotic activity of an aqueous extract PC in rats. Aerial parts of a flat-leaf variety of parsley were extracted by decoction. In vivo thrombosis in rat models as well as ex vivo assays were used in the evaluation of PC antithrombotic effects. Intravenous administration of PC (25 mg/kg.b.w), 5 min before thrombosis induction, reduced the venous thrombus formation by 98.2%, while oral administration (125 mg/kg.b.w) impaired it by 76.2%. In the arterial thrombosis model, the oral administration of PC at 15 or 25 mg/kg.b.w, 60 min before thrombosis induction, increased the carotid artery occlusion time by 150% (37.0 ± 6.44 min) and 240% (more than 60 min), respectively. A HPLC-DAD-MS/MS profile of PC extract used in this study was provided. Apiin showed to be the most abundant phenolic compound in the extract. It also revealed the presence of many coumaric acid derivatives. Our results indicate that PC is a potential candidate for the development of a phytotherapeutic drug in the treatment of thromboembolic diseases and provide a detailed chemical profile useful for controlling PC extract production in view of phytotherapy.

Antithrombotics in intracerebral hemorrhage in the era of novel agents and antidotes: A review.

Intracerebral hemorrhage (ICH)1 is characterized by the pathological accumulation of blood within the brain parenchyma, most commonly associated with hypertension, arteriovenous malformations, or trauma. However, it can also present in patients receiving antithrombotic drugs, either anticoagulants such as acenocoumarol/warfarin-novel oral anticoagulants or antiplatelets, for the prevention and treatment of thromboembolic disease. The purpose of this review is to present current bibliographic data regarding ICH irrespective of the cause, as well as post-hemorrhage use of antithrombotic agents. Moreover, this review attempts to provide guidelines concerning the termination, inversion, and of course resumption of antithrombotic therapy. We reviewed the most recently presented available data for patients who dealt with intracerebral hemorrhagic events while on antithrombotic agents (due to atrial fibrillation, prosthetic mechanical valves or recent/recurrent deep vein thrombosis). Furthermore, we examined and compared the thromboembolic risk, the bleeding risk, as well as the re-bleeding risk in two groups: patients receiving antithrombotic therapy versus patients not on antithrombotic therapy. Antithrombotic therapy is of great importance when indicated, though it does not come without crucial side-effects, such as ICH. Optimal timing of withdrawal, reversal, and resumption of antithrombotic treatment should be determined by a multidisciplinary team consisting of a stroke specialist, a cardiologist, and a neurosurgeon, who will individually approach the needs and risks of each patient.

Combined effect of a direct oral anticoagulant edoxaban and an inhibitor of activated thrombin-activatable fibrinolysis inhibitor on clot lysis.

Fibrinolysis is regulated by the thrombin/thrombin-activatable fibrinolysis inhibitor (TAFI) system. Thus, anticoagulants and inhibitors of TAFI are expected to accelerate fibrinolysis. The combined effects of an anticoagulant and a TAFIa inhibitor on fibrinolysis remain unknown. The aim of this study was to evaluate the combined effect of edoxaban, an oral direct factor Xa (FXa) inhibitor, and a TAFIa inhibitor, potato tuber carboxypeptidase inhibitor (PCI) on tissue-type plasminogen activator (t-PA)-induced clot lysis in human plasma in vitro. Pooled human plasma (containing 180ng/mL t-PA and 0.1nM thrombomodulin) was mixed with edoxaban and/or PCI. Clot formation was induced by 2.5pM tissue factor and 4µM phospholipids and clot lysis time was examined. Plasma plasmin-α2 antiplasmin complex (PAP) concentration was measured as a marker of plasmin generation. Edoxaban or PCI alone significantly shortened the t-PA-induced clot lysis time and plasma PAP concentration. The combination of these compounds significantly accelerated the clot lysis compared with the inhibitors alone. Addition of PCI (0.3, 1, and 3μg/mL) to 75ng/mL edoxaban increased plasma PAP concentration compared with edoxaban alone; however, compared with PCI alone only the combination of 0.3μg/mL PCI + 75ng/mL edoxaban showed the significant increase in PAP concentration. Concomitant use of an oral direct FXa inhibitor, edoxaban, and a TAFIa inhibitor, PCI, significantly accelerate fibrinolysis via enhancement of plasmin generation. These results suggest that the combination of edoxaban and a TAFIa inhibitor might be beneficial for the treatment of thromboembolic diseases.

Antiplatelet Therapy Monitoring in Neonates and Children.

Antiplatelet agents are used for the prevention and treatment of thromboembolic disease in an increasingly complex population of pediatric patients. Despite their importance for clinical outcome, there is no consensus on the most effective monitoring strategies. This review describes the current state of knowledge focusing on antiplatelet therapy monitoring in children. The authors searched five databases (PubMed-NCBI, MEDLINE-OVID, SCOPUS-Elsevier, ScienceDirect, and Cochrane) from January 2000 to October 2017 using keywords selected a priori. Identified articles were sorted according to the antiplatelet agents administered, methods of antiplatelet monitoring, and outcome measures. Twenty studies were included, with 14 cohort studies, 3 randomized controlled trials, and 3 cross-sectional studies. Eleven different antiplatelet monitoring tools were used, with the most common being Light Transmission Aggregometry, Urinary Thromboxane, Thromboelastography with Platelet Mapping, and VerifyNow. In the majority of studies, antiplatelet therapy monitoring was used to describe adequacy or responsiveness to treatment based on laboratory cut-off values, which were not uniform and sourced from adult studies or extrapolated from test manuals. Several studies evaluated monitoring related to clinical outcome or adjusted therapy to reach predefined therapeutic targets. There was no single laboratory method found to be distinctly better for monitoring antiplatelet treatment. Associations between laboratory assays and clinical outcomes or assays and gold standard measurements were highly inconsistent. The current literature lacks consensus on clinical benefits and measurable effects of monitoring antiplatelet therapy in pediatric patients. This review highlights important areas for research required to determine the value of antiplatelet therapy monitoring in children.

Management of Patients with Acute Subdural Hemorrhage During Treatment with Direct Oral Anticoagulants.

Anticoagulation therapy is a major risk factor for unfavorable patient outcomes following (traumatic) intracranial hemorrhage. Direct oral anticoagulants (DOAC) are increasingly used for the prevention and treatment of thromboembolic diseases. Data on patients treated for acute subdural hemorrhage (SDH) during anticoagulation therapy with DOAC are limited. We analyzed the medical records of consecutive patients treated at our institution for acute SDH during anticoagulation therapy with DOAC or vitamin K antagonists (VKA) during a period of 30months. Patient characteristics such as results of imaging and laboratory studies, treatment modalities and short-term patient outcomes were included. A total of 128 patients with preadmission DOAC (n = 65) or VKA (n = 63) intake were compared. The overall 30-day mortality rate of this patient cohort was 27%, and it did not differ between patients with DOAC or VKA intake (26% vs. 27%; p = 1.000). Similarly, the rates of neurosurgical intervention (65%) and intracranial re-hemorrhage (18%) were comparable. Prothrombin complex concentrates were administered more frequently in patients with VKA intake than in patients with DOAC intake (90% vs. 58%; p < 0.0001). DOAC treatment in patients with acute SDH did not increase in-hospital and 30-day mortality rates compared to VKA treatment. These findings support the favorable safety profile of DOAC in patients, even in the setting of intracranial hemorrhage. However, the availability of specific antidotes to DOAC may further improve the management of these patients.

Pre-clinical pharmacodynamic study of a novel oral factor Xa inhibitor zifaxaban

Zifaxaban is an orally active, direct Factor Xa (FXa) inhibitor that is in development for the prevention and treatment of arterial and venous thrombosis. This study was conducted to investigate the biochemical and pharmacological activity of zifaxaban. In vitro activity was evaluated by enzyme, platelet aggregation, and clotting assays. In vivo effects were examined in venous thrombosis, arteriovenous-shunt thrombosis, carotid thrombosis, and bleeding models in rats. Zifaxaban competitively inhibits human FXa (IC50 = 11.1 nM) with > 10,000-fold greater selectivity than other serine proteases. It did not impair platelet aggregation induced by collagen, adenosine diphosphate (ADP) or arachidonic acid. It significantly prolonged clotting time, prothrombin time (PT), and activated partial thromboplastin time (APTT) in the plasma of humans, rabbits, and rats, with a relatively weak effect on thrombin time (TT). In venous thrombosis models in rats, zifaxaban strongly suppressed thrombus formation with ED50 values of 3.09 mg/kg, and its best efficacy time occurred at 2 h after administration. In arteriovenous-shunt thrombosis and carotid thrombosis models in rats, it inhibited thrombus formation in a dose-dependent manner. And in the rat tail bleeding assay, it showed a trend of less bleeding than rivaroxaban at doses that achieved the same antithrombotic effect. In conclusion, zifaxaban is a selective and direct FXa inhibitor and a promising oral anticoagulant for the prophylaxis and treatment of thromboembolic diseases.

Medicare part D prescribing for direct oral anticoagulants in the United States: Cost, use and the "rubber effect".

IntroductionDirect oral anticoagulants (DOAC) have gained an increased share over warfarin for prevention and treatment of thromboembolic disease. We studied DOAC adoption across providers and medical specialties.MethodsRetrospective, cross-sectional analysis of Medicare Part D public use files (PUF), 2013 to 2015. We summarized prescription data for claims and drug payment, stratified by drug class, specialty and calendar year. We treated DOAC claims as a count outcome and explored patterns of expansion across prescribers via a truncated negative binomial regression. We described dispersion and spread in DOAC prescribing, across hospital referral regions (HRRs), including the p90/p10 ratios, and the median absolute deviation from the median.ResultsIn 2015 part D PUF, oral anticoagulant claims have climbed to approximately 24.4 million with a payment cost of approximately $3.3 billion. DOAC claims comprised 31.0% of oral anticoagulant claims, showing a relative increase of approximately 127% compared to 2013. The upper decile of prescribers accounted for half of the oral anticoagulant prescriptions and the resulting cost. The median cost per DOAC claim in 2015 was $367.4 (interquartile range 323.9 to 445.9), as opposed to $12.3 (interquartile range 9.2 to 16.5) for warfarin. The median cost per standardized (30-day supply) prescription was $317.0 (interquartile range 303.8 to 324.3) and $8.0 (6.7 to 9.8) for DOACs and warfarin, respectively. DOAC adoption differs by specialty. Cardiologists, cardiac electrophysiologists and orthopedics had the highest predicted DOAC share per 100 claims (53.8, 72.9 and 71.5, respectively in 2015); nephrologists, family practitioners and geriatricians the lowest (22.3, 21.5 and 20.7, respectively in 2015). The p90/p10 ratio and the median absolute deviation from the median varied across HRRs and correlated positively with the prevalence of stroke and atrial fibrillation in the Medicare population.ConclusionsDOACs have been increasing their share year-over-year, but adoption varies across specialties. In prevalent areas for stroke and atrial fibrillation, prescription dispersion magnifies, and this may signify a rapid adoption by top providers.

Fine structural characterization of sulodexide

Sulodexide is a heparinoid which combines the properties of its components heparin and dermatan sulfate and is used not only for the prophylaxis and treatment of thromboembolic diseases but also for the treatment of diabetic nephropathy. Despite many clinical studies have been conducted to investigate its activity and safety, no data are available on the fine chemical characterization of its components. In this work, the in-depth investigation on the structural features of both the whole mixture and the isolated components was accomplished, involving the analysis of molecular weight distribution and of their mono, di and oligosaccharide composition by HP-SEC/TDA, 2D-NMR and HPLC–MS techniques. Moreover, also the separation of fractions endowed of graded affinity to antithrombin was achieved followed again by detailed structural analysis. The combination of different techniques permits to profile in depth the structural features of such a drug and offers a useful tool for possible analysis of batch production.

Heparin-induced Thrombocytopenia

Abstract Heparin products are commonly used in the hospitalized patient for prophylaxis or treatment of thromboembolic disease. One adverse effect of using heparin products with potential devastating consequences is heparin-induced thrombocytopenia (HIT). It is crucial the health care providers, including nurse practitioners (NPs), consider HIT in the differential diagnosis for this patient population when they present with thrombocytopenia. This article provides NPs with the latest evidence-based guidelines for diagnosing and managing the patient with HIT.

Anticoagulant-Related Hemorrhagic Complication: A Rare Presentation

An anticoagulant is a drug (blood thinner) that treats, prevents, and reduces the risk of blood clots-breaking off and traveling to vital organs of the body, which can lead to life threatening situations. Anticoagulants are commonly used medications in the prevention and treatment of thromboembolic disease. Vitamin K antagonists (VKAs), primarily warfarin, have been the most frequently used agents for patients requiring chronic anticoagulation. More recently, newer oral anticoagulants including the direct thrombin inhibitors and factor Xa inhibitors have become available. Bleeding is the major complication of anticoagulant and fibrinolytic therapy. The criteria for defining the severity of bleeding vary considerably between studies, accounting in part for the variation in the rates of bleeding reported. The major determinants of vitamin K antagonist (VKA)-induced bleeding are the intensity of the anticoagulant effect, underlying patient characteristics, and the length of therapy. Iliopsoas hematoma is a rare complication that occurs in patients receiving anticoagulant therapy. The clinical manifestation of iliopsoas hematoma is non-specific. It can mimic orthopedic or neurological disorders, including paraesthesia or paresis of the thigh and leg due to compression of the nerve plexus.