Anticoagulant Potency Research Articles

Unveiling the bioactivity and bioaccessibility of phenolic compounds from organic coffee husks using an in vitro digestion model.

The large quantities of by-products generated in the coffee industry are a problem. Studies related to the biological potential of organic coffee husks are still limited. The aim of this work was to investigate the occurrence of phenolic compounds in organic coffee husks and to evaluate their potential as a source of bioactive dietary components. To achieve this objective, three extracts were prepared, namely extractable polyphenols (EPs), hydrolyzable non-extractable polyphenols (H-NEPs), and non-extractable polyphenols (NEPs). These extracts were characterized and evaluated for their bioactive properties after simulated gastrointestinal digestion. The results show that the extraction process affected the occurrence of phenols from coffee peels, especially for caffeic acid, gallic acid, and chlorogenic acid. The free and bound polyphenols found in the extracts and digests not only showed antioxidant properties against 2,2'-azino-bis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), ferric reducing antioxidant power (FRAP), and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals but were also strongly bioavailable and had good anticoagulant potential. These results highlight the potential health benefits of phytochemicals from coffee husks and open new perspectives for the use of such compounds in dietary supplements. © 2023 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

First-in-human trial of SAR107375E, a novel small molecule anticoagulant with dual inhibition of factor Xa and factor IIa

ABSTRACT Background SAR107375E is a direct dual inhibitor of both Factor Xa and Factor IIa and has shown potent anticoagulation activity in vitro and animals. This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending intravenous doses of SAR107375E in healthy Chinese adult subjects. Methods In this randomized, double-blind, placebo-controlled trial, 60 healthy Chinese adult subjects were administered intravenously single ascending doses (0.5, 1.5, 3.0, 5.0, 7.5, 10.0, 15.0, or 20.0 mg) of SAR107375E (N = 44) or placebo (N = 16). Plasma and urine concentrations of SAR107375E were measured and used to calculate pharmacokinetic parameters. Coagulation functions were measured and compared with baseline values. Treatment-emergent adverse events were recorded to evaluate safety. Results In plasma, from the 0.5 to 20.0 mg dose group, t1/2 is 1.51–4.00 h, Cmax is 59.05–1360 ug/L, and AUC0-t is 25.01–528.45 h*ug/L. And it shows dose proportionality in the 5.0–20.0 mg range. Activated partial thromboplastin time and Ecarin clotting time correlated linearly with drug plasma concentration. No serious adverse events were reported during the study. Conclusion SAR107375E exhibits good safety and tolerability, predictable pharmacokinetics and pharmacodynamics. Clinical trial registration www.chinadrugtrials.org.cn, identifier is CTR20211082.

Enantioselective Synthesis, Computational Molecular Docking and In Vitro Anticoagulant Activity of Warfarin-based Derivatives

Abstract: Warfarin containing a 4-hydroxycoumarin moiety possesses excellent anticoagulant activity, with the (S) enantiomer being the eutomer. The present work is designed to synthesize warfarin based derivatives enantioselectivity to explore their anticoagulant potential. The substituted chalcones were reacted with 4-hydroxycoumarin in the presence of the chiral organocatalyst 9-amino-9-deoxyepiquinine to afford warfarin-based analogues 5a- 5k. The structures of synthesized compounds 5a-5k were confirmed by Fourier transform infrared spectroscopy (FTIR), proton nuclear magnetic resonance spectroscopy (1H NMR), carbon-13 nuclear magnetic resonance spectroscopy (13C NMR) and electron ionization mass spectroscopy (EIMS) data. The enantiomeric excess (ee) has been found in the range of 16-99% as determined by chiral high-performance liquid chromatography (HPLC) analysis. The in vitro anticoagulant activity of the products 5a-5k was evaluated by plasma recalcification time (PRT) method, and it was found that most of the derivatives showed good anticoagulant activity, specifically compound 5b exhibited excellent results compared to that of warfarin. Compound 5b displayed an IC50 value of 249.88 μM, which is better than that of warfarin (IC50 408.70 μM). The molecular docking studies have been performed against vitamin K epoxide reductase with PDBID 3kp9. The synthesized compounds bind well in the active binding site of the target enzyme. The derivative 5b showed π-π stacking interactions with the amino acid phenylalanine (Phe 114). The antimicrobial activity of synthesized compounds has also been evaluated, and results showed moderate antimicrobial activity. Based on our results, it is proposed that derivative 5b may act as a lead compound to design more potent anticoagulant derivatives.

Comparative Assessment of APTT Reagents for Evaluating Anticoagulant Sensitivity of Fucosylated Glycosaminoglycans (FGs) Derived from Sea Cucumbers.

Fucosylated glycosaminoglycans (FGs) derived from sea cucumbers exhibit potent intrinsic Xase (iXase) inhibition, anticoagulation, and antithrombosis. Plasma activated partial thromboplastin time (APTT), a widely used screening test worldwide, is crucial for evaluating anticoagulant efficacy. However, the applicability of these commercially available APTT reagents for assessing anticoagulation of FGs remains unreported. In this study, we investigated the disparity between ellagic acid and colloidal silica APTT reagents in evaluating anticoagulation of dHG-5 and dHLFG-4, two depolymerized FGs, and elucidated the underlying rationale. The results demonstrated that dHG-5 and dHLFG-4 exhibited heightened sensitivity to the ellagic acid APTT reagent both in vitro and in vivo, and did not significantly affect the activation of APTT reagents for plasma. In addition, both ellagic acid and colloidal silica APTT reagents inhibited the anti-iXase of dHG-5 and dHLFG-4, and the inhibition of the ellagic acid APTT reagent was less pronounced compared to the colloidal silica APTT reagent. These findings suggest that the reduced impact of the ellagic acid APTT reagent on the anti-iXase activity of dHG-5 and dHLFG-4 is responsible for the increased sensitivity in plasma APTT analysis. This study offers valuable insights into the characteristics of two APTT reagents applied for assessing the anticoagulant activity of FG-related compounds.

Composition and Anticoagulant Potential of Chondroitin Sulfate and Dermatan Sulfate from Inedible Parts of Garfish (Belone belone).

Glycosaminoglycans (GAGs) play a crucial role due to their significant biomedical functions. Chondroitin sulfate (CS) and dermatan sulfate (DS), the main representative family of GAGs, were extracted and purified from garfish (Belone belone) by-products, i.e., skin (GSB), bones (GCB), and heads (GHB), and their composition and anticoagulant activity were investigated. CS/DS were purified by ion-exchange chromatography with yields of 8.1% for heads, 3.7% for skin, and 1.4% for bones. Cellulose acetate electrophoresis was also explored for analyzing the extracted CS/DS. Interestingly, GHB, GSB, and GCB possessed sulfate contents of 21 ± 2%, 20 ± 1%, and 20 ± 1.5%, respectively. Physico-chemical analysis showed that there were no significant differences (p > 0.05) between the variances for sulfate, uronic acid, and total sugars in the GAGs extracted from the different parts of fish. Disaccharide analysis by SAX-HPLC showed that the GSB and GCB were predominately composed of ΔDi-4S [ΔUA-GalNAc 6S] (74.78% and 69.22%, respectively) and ΔDi-2,4S [ΔUA2S-GalNAc 4S] (10.92% and 6.55%, respectively). However, the GHB consisted of 25.55% ΔDi-6S [ΔUA-GalNAc 6S] and 6.28% ΔDi-2,6S [ΔUA2S-GalNAc 4S]. Moreover, classical anticoagulation tests were also used to measure their anticoagulant properties in vitro, which included the activated partial thromboplastin time, prothrombin time, and thrombin time. The CS/DS isolated from garfish by-products exhibited potent anticoagulant effects. The purified CS/DS showed exceptional anticoagulant properties according to this research and can be considered as a new agent with anticoagulant properties.

Molecular Docking and Dynamics Simulations of Ammi visnaga L. Constituents as Antimelanogenic, Anti-Inflammatory and Anticoagulant Agents.

In this study, anti-melanogenic, anti-inflammatory and anti-coagulant potentials of eighteen selected constituents of Ammi visnaga L. were investigated by Induced Fit Docking (IFD) and molecular dynamic simulation with Schrödinger software. The binding free energies of the selected natural compounds were computed by means of ΔG MM-GBSA studies. Anti-melanogetic activity of the constituent against agaricus bisporus tyrosinase, Priestia megaterium tyrosinase and Homo sapiens tyrosinase were evaluated. The result showed that apiumetin had more negative binding free energy against three tyrosinase enzymes than cognate ligands, tropolone and kojic acid. Docking analysis was also performed to predict the constituents with anti-inflammatory activity against human Tumor necrosis factor, Cyclooxygenase-2, Prostaglandin D2 11-ketoreductase AKR1C3 and Prostaglandin reductase PTGR2. The results showed that pyranocoumarins (visnadin, dihydrosamidin, samidin) have more negative binding free energy against Cyclooxygenase-2 and Prostaglandin D2 11-ketoreductase receptors than cognate drugs, rofecoxib and indomethacin. In addition, docking analysis shows that pyranocoumarins, apiumetin and cimifugin have more negative binding free energy against Vitamin K epoxide reductase than S-warfarin drug, predicting that they have anticoagulant activity. Furthermore, the constituents and their cognate drugs were subjected to 100 ns MD Simulation to predict their stability at the active sites of the enzymes.

Exploiting Chemical Protein Synthesis to Study the Role of Tyrosine Sulfation on Anticoagulants from Hematophagous Organisms.

ConspectusTyrosine sulfation is a post-translational modification (PTM) that modulates function by mediating key protein-protein interactions. One of the early proteins shown to possess this PTM was hirudin, produced in the salivary glands of the medicinal leech Hirudo medicinalis, whereby tyrosine sulfation led to a ∼10-fold improvement in α-thrombin inhibitory activity. Outside of this pioneering discovery, the involvement of tyrosine sulfation in modulating the activity of salivary proteins from other hematophagous organisms was unknown. We hypothesized that the intrinsic instability of the tyrosine sulfate functionality, particularly under the acidic conditions used to isolate and analyze peptides and proteins, has led to poor detection during the isolation and/or expression of these molecules.Herein, we summarize our efforts to interrogate the functional role of tyrosine sulfation in the thrombin inhibitory and anticoagulant activity of salivary peptides and proteins from a range of different blood feeding organisms, including leeches, ticks, mosquitoes, and flies. Specifically, we have harnessed synthetic chemistry to efficiently generate homogeneously sulfated peptides and proteins for detailed structure-function studies both in vitro and in vivo.Our studies began with the leech protein hirudin P6 (from Hirudinaria manillensis), which is both sulfated on tyrosine and O-glycosylated at a nearby threonine residue. Synthetically, this was achieved through solid-phase peptide synthesis (SPPS) with a late-stage on-resin sulfation, followed by native chemical ligation and a folding step to generate six differentially modified variants of hirudin P6 to assess the functional interplay between O-glycosylation and tyrosine sulfation. A one-pot, kinetically controlled ligation of three peptide fragments was used to assemble homogeneously sulfoforms of madanin-1 and chimadanin from the tick Haemaphysalis longicornis. Dual tyrosine sulfation at two distinct sites was shown to increase the thrombin inhibitory activity by up to 3 orders of magnitude through a novel interaction with exosite II of thrombin. The diselenide-selenoester ligation developed by our lab provided us with a means to rapidly assemble a library of different sulfated tick anticoagulant proteins: the andersonins, hyalomins, madanin-like proteins, and hemeathrins, thus enabling the generation of key structure-activity data on this family of proteins. We have also confirmed the presence of tyrosine sulfation in the anticoagulant proteins of Anopheles mosquitoes (anophelins) and the Tsetse fly (TTI) via insect expression and mass spectrometric analysis. These molecules were subsequently synthesized and assessed for thrombin inhibitory and anticoagulant activity. Activity was significantly improved by the addition of tyrosine sulfate modifications and led to molecules with potent antithrombotic activity in an in vivo murine thrombosis model.The Account concludes with our most recent work on the design of trivalent hybrids that tandemly occupy the active site and both exosites (I and II) of α-thrombin, with a TTI-anophelin hybrid (Ki = 20 fM against α-thrombin) being one of the most potent protease inhibitors and anticoagulants ever generated. Taken together, this Account highlights the importance of the tyrosine sulfate post-translational modification within salivary proteins from blood feeding organisms for enhancing anticoagulant activity. This work lays the foundation for exploiting native or engineered variants as therapeutic leads for thrombotic disorders in the future.

Design of a structure-activity relationship model of vitamin K epoxide reductase (VKORC1) inhibitors combining chemical synthesis of new compounds, enzymatic assays and molecular modelling

Vitamin K antagonists (VKAs) anticoagulants have been used since the 1950s as medicines and rodenticides. These molecules are mainly 4-hydroxycoumarin derivatives and act by inhibiting the vitamin K epoxide reductase (VKORC1), an endoplasmic reticulum membrane resident enzyme. However, many VKORC1 mutations have been reported over the last decade, inducing VKAs resistances and thus treatments failures. Although studies have reported experimental and computational investigations of VKAs based on VKORC1 structural homology models, the development of new effective anticoagulants has been quite complex due to the lack of structural data and reliable structure–activity relationships. However, the recent publication of VKORC1 crystal structure provides new information for further studies. Based on these findings, we combined chemical synthesis, enzymatic assays and molecular modelling methods to design a structure–activity relationship (SAR) model. Our results proved that the lipophilicity, the membrane permeability of inhibitors and their affinity towards human VKORC1 enzyme are the main characteristics for potent anticoagulants. Our SAR model managed to rank compounds according to their ability to inhibit the human VKORC1. Such a tool might constitute an alternative to evaluate new molecules potency before their chemical synthesis and biological assessment and might assist the development of new VKAs.

Dynamics of acute-phase and endothelial reactions and immune complex formation during bone replacement with germanium-doped calcium-phosphate ceramics of bone fragment fractures in dogs

Bone defects that occur with fragment fractures lead to an increase in the number of postoperative complications. Therefore, to restore the structure and function of the bone, there is a need for bone replacement, in particular doped calcium-phosphate ceramics. The purpose of the work is the biochemical assessment of acute-phase and endothelial reactions and immune complex formation during bone replacement with germanium-doped calcium-phosphate ceramics of bone fragment fractures in dogs. Dogs with fragment fractures of long tubular bones and plate osteosynthesis were included in the study. In the experimental group (n = 10), bone defects were replaced with germanium-doped calcium-phosphate ceramics (HА/β-TCP/l-Gе-700), in the control group (n = 10) – unalloyed (HА/β-TCP-700). Blood samples were taken after the injury and on the 3rd, 7th, 14th, 30th, and 60th days after osteosynthesis. Partial recovery of limb function in the experimental group was faster by 1.3 times (P < 0.001) and full by 1.2 times (P < 0.01) compared to the control. On the 60th day, in experimental animals, the defect was filled with a regenerate of high X-ray density without a periosteal reaction, while in the control animals, the bone regenerate did not have sufficient density with a significant periosteal reaction. In both groups, total protein and albumin content varied within the normal range. The activity of protein C on the 3rd day in the experimental group was 1.3 times higher (Р ˂ 0.001), and on the 7th day, it was twice as high (P ˂ 0.001) compared to the control group with normalization by the 14th day. The concentration of ceruloplasmin from the 7th day in the control animals was 1.1 times higher (Р ˂ 0.001) than in the experimental animals, with normalization in the latter by the 60th day. The level of small molecular circulating immune complexes (CIC) after the injury increased by 1.1 times (Р ˂ 0.001) and reached a peak in the control and experimental groups on the 14th day, with an increase in indicators by 2.1 and 1.4 times (Р ˂ 0.001), respectively, with normalization in the experimental group on the 60th day. The level of nitric oxide (NO) in the control group increased from the 7th to the 60th day, with a peak on the 30th day, and in the experimental group – from the 3rd to the 30th, with a peak on the seventh day. Osteoreplacement of fragment fractures of long tubular bones in dogs with calcium-phosphate ceramics doped with germanium is accompanied by a moderate level of the acute phase reaction and immune complex formation, an increase in the endothelial reaction and the anticoagulant potential of the blood, which contributes to a decrease in the intensity of the inflammatory-resorptive stage of reparative osteogenesis and an increase in its proliferative phase, which, respectively, accelerates the consolidation of fractures.

Beer-gut microbiome alliance: a discussion of beer-mediated immunomodulation via the gut microbiome.

As a long-established fermented beverage, beer is rich in many essential amino acids, vitamins, trace elements, and bioactive substances that are involved in the regulation of many human physiological functions. The polyphenols in the malt and hops of beer are also important active compounds that interact in both directions with the gut microbiome. This review summarizes the mechanisms by which polyphenols, fiber, and other beneficial components of beer are fermentatively broken down by the intestinal microbiome to initiate the mucosal immune barrier and thus participate in immune regulation. Beer degradation products have anti-inflammatory, anticoagulant, antioxidant, and glucolipid metabolism-modulating potential. We have categorized and summarized reported data on changes in disease indicators and in vivo gut microbiota abundance following alcoholic and non-alcoholic beer consumption. The positive effects of bioactive substances in beer in cancer prevention, reduction of cardiovascular events, and modulation of metabolic syndrome make it one of the candidates for microecological modulators.

Biofabrication of silver nanoparticles using Spirulina platensis: In vitro anti-coagulant, thrombolytic and catalytic dye degradation activity.

Green synthesis of nanoparticles is an emerging field due to it's biosafety and promising results. Biological systems due to their biodiversity are employed in different production processes. In this study Spirulina platensis mediated silver nanoparticles (S-AgNPs) production was done. The Uv spectra, FTIR and SEM analysis was performed for the characterization of biosynthesized S-AgNPs. The biocompatibility evaluation of S-AgNPs was done through hemolysis analysis. S-AgNPs were also evaluated for anticoagulant and thrombolytic potential. In addition to the medical applications of S-AgNPs, silver nanoparticles have been known to show potential industrial applications among which one application is the utilization of silver nanoparticles in the degradation of toxic industrial dyes. Therefore, degradation assay of Eosin Y and Methylene Blue dyes was estimated. The SEM analysis of S-AgNPs showed the particle size of 50-65 nm, whereas the biocompatibility analysis showed that these S-AgNPs are biocompatible at ≤400 μM concentration. The S-AgNPs showed good anticoagulant potential and thrombolytic potential and were able to degrade 44% of the thrombus. The S-AgNPs significantly degraded 76% of Eosin Y within 30 min, whereas Methylene Blue was 80% degraded within 20 min (P-value ≤ .001). To the best of our knowledge, the dye degradation of Eosin Y, thrombolytic activity and anticoagulant activity of S-AgNPs produced from the biomass of Spirulina platensis has been reported for the first time. In the current study, we conclude that our biosynthesized S-AgNPs showed promising medical and industrial applications and these nanoparticles can be further evaluated and upscaled for large scale applications.

Cloning, characterization, and heterologous expression of a candidate Hirudin gene from the salivary gland transcriptome of Hirudo nipponia

Hirudin is a pharmacologically active substance in leeches with potent blood anticoagulation properties. Although recombinant hirudin production isolated from Hirudo medicinalis Linnaeus and Hirudinaria manillensis Lesson is known, to our knowledge, this study is the first to report recombinant hirudin expression and production from Hirudo nipponia Whitman. Thus, the present study aimed to clone and characterize the full-length cDNA of a candidate hirudin gene (c16237_g1), which is localized on the salivary gland transcriptome of H. nipponia, and further evaluate its recombinant production using a eukaryotic expression system. The 489-bp cDNA possessed several properties of the hirudin “core” motifs associated with binding to the thrombin catalytic pocket. A fusion expression vector (pPIC9K-hirudin) was constructed and successfully transformed into Pichia pastoris strain GS115 via electroporation. Sodium dodecyl sulphate–polyacrylamide gel electrophoresis and western blot analysis confirmed hirudin expression. The recombinant protein was expressed with a yield of 6.68 mg/L culture. Mass spectrometry analysis further confirmed target protein expression. The concentration and antithrombin activity of purified hirudin were 1.67 mg/mL and 14,000 ATU/mL, respectively. These findings provide a basis for further elucidating the molecular anticoagulation mechanism of hirudin, and address China’s growing market demand for engineered H. nipponia-derived hirudin and hirudin-based drugs.

Sulfated modification, basic characterization, antioxidant and anticoagulant potentials of polysaccharide from Sagittaria trifolia

To discover novel antioxidants and anticoagulants for the prevention and treatment of cardiovascular diseases remains ongoing concern. Sagittaria trifolia is a commonly consumed aquatic vegetable with highly nutritious value and wideplantingarea in China. Polysaccharides are the major bioactive constituents, but little information is available on anticoagulant potential. In this work, a polysaccharide from S. trifolia (PST) was modified by sulfation to produce four sulfated derivatives (SPST-1 ∼ 4), and their antioxidant and anticoagulant potentials were evaluated. Various means of analysis confirmed the success of sulfation on PST. The unmodified PST possessed notable antioxidant and pro-coagulant activities. To some extent, sulfated modification reduced the antioxidant capacity of PST with the increase of degree of substitution (DS), but for the derivative SPST-4 with moderate DS and smallest molecular weight (MW) exerted better antioxidant activity, in particular of scavenging nitrogen-containing radicals. Interestingly, sulfation reversed the innate activity of PST from pro-coagulation to anticoagulation, which highlydependedon DS. The derivative SPST-3 with highest DS and moderate MW elicited promising anticoagulant potential, particularly at concentration of 5.00 mg/mL, which was superior to that of heparin (positive control) in the aspect of prolonging thrombin time and prothrombin time. Herein, the present contribution would give evidence that PST and sulfated derivatives SPST-3 and SPST-4 own potentials to be developed as hemostatic, anticoagulant, and antioxidant candidates, respectively.

MarioHeart: Novel In-Vitro Flow Model for Testing Heart Valve Prostheses and Anticoagulant Therapies.

Mechanical heart valve (MHV) prostheses present a risk of thromboembolic complications despite antithrombotic therapy. Further steps in the development of more hemocompatible MHVs and new anticoagulants are impeded due to the lack of adequate in-vitro models. With the development of a novel in-vitro model (MarioHeart), a pulsatile flow similar to the arterial circulation is emulated. The MarioHeart design owns unique features as 1) a single MHV within a torus with low surface/volume ratio, 2) a closed loop system, and 3) a dedicated external control system driving the oscillating rotational motion of the torus. For verification purposes, a blood analog fluid seeded with particles was used to assess fluid velocity and flow rate using a speckle tracking method on high-speed video recordings of the rotating model. The flow rate resembled the physiological flow rate in the aortic root, in both shape and amplitude. Additional in-vitro runs with porcine blood showed thrombi on the MHV associated with the suture ring, which is similar to the in-vivo situation. MarioHeart is a simple design which induces well-defined fluid dynamics resulting in physiologically nonturbulent flow without stasis of the blood. MarioHeart seems suitable for testing the thrombogenicity of MHVs and the potential of new anticoagulants.

Amine-functionalized biochar: Highly re-useable and green alternative for heparin recovery from porcine intestinal mucosa

Heparin is an invaluable pharmaceutical ingredient typically recovered from bovine lung or porcine intestinal mucosa by a complex and costly multi-step process. The design of an efficient environmentally improved adsorbent that has high adsorption capacity and high thermal and chemical stability to withstand the harsh steps of the heparin recovery process is essential. In addition, the importance of having the right functional groups on the surface of the material when designing an adsorbent is highlighted. Herein we describe the use of APTES-functionalized biochar (N-Char) as an efficient and sustainable adsorbent to recover heparin from a porcine intestinal mucosa sample. Results demonstrate that the N-Char can recover as much as 60% (∼31 mg g−1) of heparin from a real sample solution (Porcine intestinal mucosa) under optimized conditions with anticoagulant potency of 59 ± 3 U per gram of mucosa, compared to 51 ± 2 U per gram for the heparin recovered via the commercial resin Amberlite FPA98 Cl. Functionalized biochar demonstrates high stability throughout five recycling adsorption/desorption rounds, indicating excellent re-usability.

Comparison of 90-Day Adverse Events Associated With Aspirin and Potent Anticoagulation Use for Venous Thromboembolism Prophylaxis: A Cohort Study of 72,288 Total Knee and 35,142 Total Hip Arthroplasty Patients

BackgroundWhile aspirin is acceptable for venous thromboembolism (VTE) prophylaxis following total joint arthroplasty in most patients, more potent agents are used in patients considered higher risk for VTE. We evaluated the efficacy and safety of aspirin versus potent anticoagulation agents following total knee arthroplasty (TKA) and total hip arthroplasty (THA). MethodsA cohort study of 72,288 TKA and 35,142 THA from the Kaiser Permanente Total Joint Replacement Registry was performed (2009 to 2019). Identified medications were aspirin, factor Xa inhibitors, low-molecular-weight heparin (LMWH), and warfarin. A validated VTE risk score was assigned to each patient. Propensity score-weighted logistic regressions were used to evaluate 90-day VTEs. Noninferiority testing was performed with a margin of 1.25 using the upper bound (UB) of the 1-sided 95% CI. ResultsFor TKA, aspirin was not inferior to LMWH (odds ratio [OR] = 0.77, UB = 1.09) and warfarin (OR = 0.64, UB = 0.90); there was no evidence to support noninferiority of aspirin compared to factor Xa inhibitors. Findings were consistent for THA (LMWH: OR = 0.59, UB = 0.75; warfarin: OR = 0.69, UB = 0.89). TKA was considered higher risk for VTE, whereas aspirin use demonstrated noninferiority compared to warfarin (OR = 0.54, UB = 0.81), we lacked evidence of noninferiority when compared to LMWH and factor Xa inhibitors. We lacked evidence of noninferiority of aspirin versus any potent anticoagulation in higher-risk THA. ConclusionAspirin was found to be effective and safe for VTE prevention in primary total joint arthroplasty, including in patients considered higher risk for VTE. Level of EvidenceIII

Heparin, Heparan Sulphate and Sepsis: Potential New Options for Treatment.

Sepsis is a life-threatening hyperreaction to infection in which excessive inflammatory and immune responses cause damage to host tissues and organs. The glycosaminoglycan heparan sulphate (HS) is a major component of the cell surface glycocalyx. Cell surface HS modulates several of the mechanisms involved in sepsis such as pathogen interactions with the host cell and neutrophil recruitment and is a target for the pro-inflammatory enzyme heparanase. Heparin, a close structural relative of HS, is used in medicine as a powerful anticoagulant and antithrombotic. Many studies have shown that heparin can influence the course of sepsis-related processes as a result of its structural similarity to HS, including its strong negative charge. The anticoagulant activity of heparin, however, limits its potential in treatment of inflammatory conditions by introducing the risk of bleeding and other adverse side-effects. As the anticoagulant potency of heparin is largely determined by a single well-defined structural feature, it has been possible to develop heparin derivatives and mimetic compounds with reduced anticoagulant activity. Such heparin mimetics may have potential for use as therapeutic agents in the context of sepsis.

Testosterone therapy increases the anticoagulant potential in men with opioid-induced hypogonadism: a randomized, placebo-controlled study.

Hypogonadism is prevalent during opioid treatment, and low testosterone concentrations are associated with cardiovascular disease. The effect of testosterone replacement therapy (TRT) on the coagulation system in men with hypogonadism is not clarified. We investigate the effects of TRT on the tissue factor (TF) and contact activation pathways of coagulation in opioid-treated men. This was a double-blinded, placebo-controlled study in 37 men with total testosterone < 12 nmol/L randomized to 24 weeks of testosterone injections (n = 17) or placebo (n = 20). Variables of the coagulation system were analysed at baseline and after 24 weeks. Measurements included the TF pathway (endogenous thrombin potential (ETP) and peak thrombin), the contact activation pathway (endogenous kallikrein potential (EKP) and peak kallikrein), coagulation factors (FVII, FX, prothrombin, and FXII), and inhibitors (tissue factor pathway inhibitor (TFPI), protein C, protein S, antithrombin, and C1 esterase inhibitor (C1inh)). Between-group differences at 24 weeks were determined with analysis of covariance. Within-group changes in TRT and placebo were analysed with paired t-test. Between-group differences at 24 weeks were observed for ETP (P = 0.036), FVII (P = 0.044), FX (P = 0.015), prothrombin (P = 0.003), protein C (P = 0.004), and protein S (P = 0.038). Within the TRT group, ETP, peak thrombin, FVII, FX, prothrombin, TFPI, protein C, FXII, and C1inh decreased and protein S increased (all P < 0.05). Within the placebo group, coagulation outcomes were unchanged. TRT affects the coagulation system in an anticoagulant direction through suppressed TF pathway in men with opioid-induced hypogonadism.

Direct Oral Anticoagulants: Laboratory Challenges and Antidotes.

The use of direct oral anticoagulants (DOACs) is increasing in patients needing treatment of venous thromboembolism (VTE) and stroke prevention in atrial fibrillation (SPAF). This is due to the net clinical benefit in comparison to vitamin K antagonists (VKAs). The rise in DOAC use is accompanied by a remarkable reduction in heparin and VKA prescriptions. However, this rapid change in anticoagulation patterns brought new challenges to patients, prescribers, laboratories, and emergency physicians. Patients have new liberties concerning nutritional habits and comedication and no longer need frequent monitoring or dose adjustments. Still, they have to comprehend that DOACs are potent anticoagulants that may cause or contribute to bleeding. Challenges for the prescriber include decision pathways for choosing the right anticoagulant and dosage for a specific patient and to change bridging practice in case of invasive procedures. Laboratory personnel are challenged by DOAC due to limited 24/7 availability of specific DOAC quantification tests and by the impact of DOAC on routine coagulation assays and thrombophilia tests. Challenges for the emergency physician result from the increasing age of DOAC anticoagulated patients, the difficulties to establish last intake of DOAC type and dosage, to interpret coagulation test results in emergency situations, and to make decisions for or against DOAC reversal strategies in acute bleeding or urgent surgery. In conclusion, although DOACs make long-term anticoagulation safer and more convenient for patients, DOACs pose challenge to all healthcare providers involved in anticoagulation decisions. The key to correct patient management and optimal outcome therefore lies in education.

Extract from Sea Buckthorn Seeds-A Phytochemical, Antioxidant, and Hemostasis Study; Effect of Thermal Processing on Its Chemical Content and Biological Activity In Vitro.

Sea buckthorn (Hippophae rhamnoides L.) is a small tree, valued for its medicinal properties throughout the ages. Sea buckthorn berries and leaves are a known source of phytochemicals and have been used in the treatment of inflammation, oedema, hypertension, ulcers, and wounds in folk medicine. Sea buckthorn seeds are natural dietary sources of various bioactive compounds as well, but the number of studies on their content and biological properties is still insufficient. For the first time, we examined the phytochemical content and biological activity of sea buckthorn seeds in vitro. We have studied the effect of two extracts-from regular (no thermal processing) and roasted (thermally processed) sea buckthorn seeds-on the levels of oxidative stress induced by H2O2/Fe2+ in plasma, coagulation times, and white thrombus formation (measured by Total Thrombus-formation Analysis System-T-TAS). We observed that sea buckthorn seeds contain diverse flavonoids, mostly glycosides of isorhamnetin, kaempferol, and quercetin, as well as smaller amounts of proanthocyanidins and catechin, triterpenoid saponins, and a number of unidentified polar and hydrophobic compounds. Both extracts inhibited lipid peroxidation and protein carbonylation, but only the extract from roasted seeds decreased oxidation of thiol groups in plasma treated with H2O2/Fe2+. They did not alter coagulation times, but the extract from roasted seeds at the highest concentration (50 µg/mL) prolonged the time needed for white thrombus formation. The results indicate that sea buckthorn seeds have antioxidant activity that is not impaired by thermal processing and possess anticoagulant potential, but more research is needed in order to ascertain which compounds are responsible for these effects, especially in in vivo models.