Candidates For Anticoagulation Research Articles

Improved risk prediction in patients with atrial fibrillation and clinical intermediate-risk CHA2DS2VASc-score utilizing high sensitive troponin T

Abstract Background Guidelines of the European Society of Cardiology recommend risk assessment to identify appropriate candidates for anticoagulation in patients with atrial fibrillation (AF). However, scores such as the CHA2DS2VASc-score show only a modest performance for prediction of adverse events. Methods This retrospective single-center all-comer sub-study from the Heidelberg Registry of Atrial Fibrillation (HERA-FIB) enrolled 9,995 consecutive patients with non-valvular AF, presenting to the emergency department (ED) from June 2009 until March 2020. We tested the performance of the CHA2DS2VASc-score with and without high sensitive cardiac troponin T (hs-cTnT) for prediction of a adverse events such as stroke or major bleedings. Per CHA2DS2VASc, stroke risk was classified as low (0 point in men, ≤1 point in females), intermediate, or high (≥2 points in men and ≥3 points in females). Results Performance of the CHA2DS2VASc-score for the prediction of the composite endpoint consisting of stroke and major bleeding was poor (AUC 0.600, 95%CI: 0.590-0.610) but improved after addition of hs-cTnT as a variable across all risk categories (AUC 0.618 95%CI: 0.608-0.628, ∆AUC 0.0182 95%CI: 0.0124-0.0240, p<0.0001), and particularly in patients at intermediate-risk (∆AUC 0.160 95%CI: 0.0653-0.254, p=0.0009). The absence of detectable hs-cTnT (< LoD) identified a cohort without incident events within patients with intermediate per CHA2DS2VASc. Conclusion Combination of hs-cTnT and clinical-based risk stratification in AF patients presenting to an ED with intermediate CHA2DS2VASc-score is simple and effective. Measurement of hs-cTnT improves prediction of stroke risk in patients with intermediate CHA2DS2VASc-score and may help guide decision for or against anticoagulation.

Mercaptopyrimidine-templated gold nanoclusters for antithrombotic therapy.

Here we report for the first time that mercaptopyrimidine-templated gold nanoclusters (DAMP-AuNCs) can be used as a novel anticoagulant candidate for the design of antithrombotic drugs. Anticoagulant mechanisms revealed that DAMP-AuNCs significantly inhibited thrombus formation by interacting with fibrinogen. Carrageenan-induced mice tail thrombosis model experiments showed that DAMP-AuNCs had antithrombotic efficacy comparable to heparin in vivo. More importantly, these ultrasmall AuNCs possess excellent blood compatibility and only induce negligible bleeding side effects. Our study is a successful attempt at developing novel antithrombotic agents with high biosafety.

Acute limb ischemia registry, the forgotten emergency

Abstract Background Although acute limb ischemia (ALI) is a leading cause of death and lower limb amputation, knowledge about its epidemiology, presentation, and treatment is limited. Aim The purpose of this study is to describe patient characteristics, diagnostic approaches taken, modes of presentation, and clinical developments in patients with ALI. Methods We prospectively included all ALI outpatients between 2016 and 2022. Patients who had ischemia due to trauma, iatrogenic causes, or those who developed it while in the hospital were excluded. We provide descriptive analysis for our registry, and performed a uni and multivariable regression model in order to identify clinical factors associated with the composite primary endpoint of intrahospital death and limb amputation. Results We included 89 consecutive patients with ALI. Table 1 describes the baseline characteristics. The median time from clinical presentation to first medical contact was 24 hours (IQR 4-72 hours). Time between clinical consultation and diagnosis was 1 hours (1.1–7 hours), and time between diagnosis and revascularization was 12 hours (4–36 hours). Although patients with a threatened limb sought treatment sooner than those without (12 hours vs 72 hours, p = 0.001), they had a higher rate of events. Peripheral thromboembolism was the main cause of ALI and the only etiology associated with death or amputation. Patients considered candidates for reperfusion therapy comprised 92% of the cohort, while 3 patients were considered candidates for direct amputation and 2 patients were considered candidates for anticoagulation due to the comorbidities they presented. Thirteen patients (21%) died or suffered limb amputations (three suprapatellar, two infrapatellar, and one in the forefoot). One third of the patients suffered a complication during hospitalization. Acute renal failure was the most frequent complication (27%). In a univariable regression analysis, age, embolic origin, higher levels of lactacidemia, and threatened limb were associated with the composite event of death and limb amputation, whereas in a multivariable regression model, serum lactic acid and have the vitality of the member threatened were independently associated with an increased odds of death or amputation (Tabla 2). Conclusions Acute limb ischemia is associated with an increased risk of intrahospital death and limb amputation. Serum lactacidemia and limb threatened at presentation were independently associated with an increased risk of clinical events. Risk of events is associated with the limb clinical condition and not with the delay in revascularization. Even those patients who do not die or are amputated have high morbidity and need for prolonged hospitalization. Increased awareness of the disease are critical for improving survival and limb preservation.

Anticoagulation Regimens in Pregnancy.

This article explores current recommendations for anticoagulation therapy in pregnancy, including antepartum, intrapartum, and postpartum guidelines. The authors review various screening strategies used to assess whether a patient is an appropriate candidate for anticoagulation during pregnancy and the postpartum period. The article includes dosing regimens, optimal surveillance, and medication reversal. The authors also address the challenges of transitioning between low-molecular-weight heparin and unfractionated heparin. Finally, there is a discussion of intrapartum anticoagulation management, especially as it relates to the administration of regional anesthesia, and the indications for and timing of thromboprophylaxis following delivery.

Prevalence of silent atrial fibrillation and cardiovascular disease in patients with obstructive sleep apnea

ObjectivePatients with silent and undiagnosed atrial fibrillation (AF) have increased risk of ischemic stroke. Patients with obstructive sleep apnea (OSA) have an increased risk of both AF and ischemic stroke. Our aim was to investigate the prevalence of silent AF and associated risk factors in patients investigated for OSA or with known OSA. MethodsThis prospective observational study was performed in two sites; one outpatient sleep-clinic at Zealand University Hospital and one private Ear-Nose- and Throat clinic. Patients were investigated with a type-3 portable sleep-monitoring device, while heart rhythm was home-monitored for 7 days with an event-triggered loop recorder. Patients were stratified in groups of mild, moderate and severe OSA based on Apnea-Hypopnea-Index (AHI). ResultsIn a cohort of 303 patients, 238 (78.5%) were diagnosed with moderate/or severe OSA and 65 (21.5%) with no/mild OSA who constituted the control group. In 238 patients with moderate and severe OSA, AF was detected in 21 patients (8.8%) vs. 1 patient (1.5%,[p=0.045]) with mild OSA. Candidates for anticoagulation therapy were referred for further cardiovascular treatment. The majority of patients had known hypertension (n = 200,66%) and dyslipidemia (n = 235,[77.6%]) In patients with moderate/or severe OSA (AHI≥15), hypertension was more dysregulated (p=0.005) and more patients suffered from unknown prediabetes (n = 36, 3.1% vs. 14.3%[p<0.001]). ConclusionUndiagnosed AF and undertreated cardiovascular modifiable risk factors are common in a cohort of patients with OSA. With this study we propose that long-period home-monitoring in these patients is useful for identifying candidates for preventive anticoagulation, cardiovascular treatment and possibly prevent future ischemic stroke.

Critical Quality Control Methods for a Novel Anticoagulant Candidate LFG-Na by HPSEC-MALLS-RID and Bioactivity Assays.

A low molecular weight fucosylated glycosaminoglycan sodium (LFG-Na) is a novel anticoagulant candidate from the sea cucumber Holothuria fuscopunctata that selectively inhibits intrinsic tenase (iXase). The molecular weight, molecular weight distribution and bioactivities are the critical quality attributes of LFG-Na. The determination of these quality attributes of such an oligosaccharides mixture drug is challenging but critical for the quality control process to ensure its safety and efficacy in clinical use. Herein, the molecular weight and molecular weight distribution of LFG-Na were successfully determined using high performance size exclusion chromatography coupled with multi angle laser light scattering and refractive index detector (HPSEC-MALLS-RID). Comparing to the conventional method, HPSEC-MALLS-RID based on the refractive index increment (dn/dc) did not require the reference substances to establish the calibration curve. The acceptance criteria of LFG-Na were established, the weight-average molecular weight () should be 4000 to 6000 Da, the polydispersity (/) < 1.40, and the fraction with molecular weights of 1500 to 8000 Da should be no less than 80% of the total. HPSEC-MALLS-RID was also utilized for the determination of the starting material native fucosylated glycosaminoglycan (NFG) to choose a better manufacturing process. Furthermore, APTT assay was selected and the potency of anti-iXase, referring to the parallel line assay (PLA) method, was established to clarify the consistency of its biological activities. The results suggest that HPSEC-MALLS-RID and bioactivity assays are critical quality control methods for multi-component glycosaminoglycan LFG-Na. The methods also provide a feasible strategy to control the quality of other polysaccharide medicines.

Left atrial appendage closure using WATCHMAN device in chronic kidney disease and end-stage renal disease patients.

Chronic kidney disease (CKD) and end-stage renal disease are considered independent risk factors for developing atrial fibrillation (AF). Percutaneous occlusion of left atrial appendage (LAAC) using WATCHMAN device is a widely accepted alternative to anticoagulation therapy to prevent ischemic stroke in AF in patients who are not candidates for anticoagulation. There is limited data regarding the utilization and periprocedural safety of this intervention in patients with CKD/ESRD. We retrospectively reviewed all hospitalizations from 2016 to 2017 with (ICD-10) procedure diagnosis code of LAA closure using WATCHMAN procedure with and without a secondary diagnosis of CKD/ESRD in acute-care hospitals across the United States using the national inpatient sample. Demographic variables (gender, race, income, hospital characteristics, medical comorbidities) were collected and compared. The primary outcomes were inpatient mortality, hospital length, and cost of stay. There were over 71 million discharges included in the combined 2016 and 2017 NIS database. Sixteen thousand five hundred five hospitalizations were for adult patients with a procedure code for LAA closure via watchman procedure. Of 16,505 patients, 3245 (19.66%) had CKD and ESRD. There was no statistically significant difference in mortality, length, and cost of stay in patients with and without CKD/ESRD. There were no statistically significant differences in periprocedural cerebrovascular accidents in both groups. Patients with and without ESRD/CKD who undergo LAA occlusion with Watchman have similar procedure related, in-hospital mortality, and complications.

Apixaban in a porcine model of mechanical valve thrombosis in pulmonary position-a pilot study.

OBJECTIVESThe newest mechanical valves have low thrombogenicity, making them candidates for anticoagulation with a direct oral anticoagulant. While these drugs hold great promise to replace warfarin, clinical trials have been disappointing so far. We aimed to evaluate apixaban in a porcine model of mechanical valve thrombosis with On-X® (CryoLife) aortic valves implanted in pulmonary position.METHODSOn-X® valves were implanted in pulmonary valve position in 9 Yucatan pigs. Animals received prophylactic enoxaparin 40 mg for 1 week. Pigs in the low-dose group received 5 mg apixaban twice daily for 10 weeks. The intermediary-dose group received 5 mg twice daily for 6 weeks and then 10 mg twice daily afterwards. The high-dose group received 15 mg twice daily for 10 weeks. After sacrifice, valves were macroscopically evaluated and thrombus weight was documented.RESULTSThe median weight of the 9 animals was 64.3 kg, range 52.5–70.9. In the low-dose group (2 animals), both valves showed manifest, chronic thrombosis with blocked hinges. In the intermediary-dose group, a normal functioning valve without thrombosis was seen in 2/4 animals. In the high-dose group (3 pigs), there was no valve thrombosis. No bleeding events occurred. In all animals, apixaban plasma levels were low compared to clinical target levels.CONCLUSIONSThe pulmonary position seems to be an aggressive model for mechanical valve thrombosis in pigs. Apixaban has the potential to prevent valve thrombosis, even in these thrombogenic conditions. Detailed pharmacokinetic studies are needed to determine the ideal apixaban dosage for future experiments and to enable extrapolation to the clinical situation.

Intracranial Hemorrhage Associated with Therapeutic Anticoagulation in Three Critically Ill COVID-19 Patients: A Case Series

Introduction: The COVID-19 pandemic has challenged global health with novel pathogenesis that is both severe and poorly understood. Several mechanisms have been proposed to explain the severity and complexity of the clinical illness including cytokine storm release, thromboembolic microangiopathy, direct cytotoxicity, and post-viral bacterial super infection. Cases: The patients in this case series were all admitted to the intensive care unit with respiratory failure from COVID-19 requiring invasive mechanical ventilation. They were all started on anticoagulation. All three patients developed acute kidney injuries. The first patient had hypertensive emergency at the time of the bleed. The second and third patient both had supratherapeutic heparin levels at the time of the bleed. Methods: We followed patients aged 18 years and above who were admitted to the ICU for COVID-19 during April and May 2020. We then followed those who required therapeutic anticoagulation for any indication and evaluated the ones that developed ICH. Results: Out of the 79 patients admitted to the ICU for COVID-19 related illness during April and May 2020, 31 were placed on therapeutic anticoagulation (intermediate or full-dose) for indications that included hypercoagulable state, ACS, atrial fibrillation, and deep vein thrombosis. 25% of patients on anticoagulation developed bleeding for which the anticoagulation had to be stopped. Three out of these 31 patients developed ICH while on anticoagulation, accounting for 3.8% of our ICU population with COVID-19 Discussion: Activation of coagulation pathways during cytokine storms can result in systemic thromboembolism, in both venous and arterial circulations posing risk of ischemic infarctions to any organ. Supratherapeutic heparin levels and acute kidney injuries are common in COVID-19 patients. The ideal candidates for anticoagulation, the recommended agent and dose, and duration of treatment remain unclear. Conclusion: The benefits of anticoagulation should be weighed against the potential risk of bleeding.

Atrial fibrillation and stroke risk factors in patients with cardiac implantable electronic devices

Purpose. Determination the proportion and burden of new-onset atrial fibrillation (AF) in patients with cardiac implantable electronic devices (CIED) and without prior AF and assessing the incidence of risk factors for stroke in patients with AF.Methods. The medical history of 111 patients with CIED with remote monitoring function were analyzed. AF diagnosed by the device was interpreted by an arrhythmologist and cases of significant AF were selected. The group of patients with and without AF was compared for several factors. To clarify the influence of risk factors on the duration of AF, all AF cases were divided into 3 categories depending on the AF burden per day. The first group included patients with an AF burden per day of 0.1% or less (n=10, (45.5%)), the second - from 0.3% to 12.2% (n=7, (31.8%)), and the third group - with 100% (n=5, (22.7%)). Patients with a burden of 0.2%, 12.3-99.9% were absent.Results. Newly diagnosed AF was registered in 19.8% of cases. The risk of stroke among these patients was high - 2 [1; 3] points on the CHA2 DS2 -VASc for men, and 3 [2,75; 3,75] points for women. Hypertension of 2 and 3 degrees was recorded in all patients in the group with an AF burden of 100% per day. That significantly differed from the other 2 groups (p=0.043). In the group with an AF burden of 100%, the levels of NT-proBNP, D-dimer, and creatinine were significantly higher than in the other groups (p=0.037, p=0.031 and p=0.036, respectively). When analyzing the dependence of creatinine level on the presence of AF, the area under the ROC-curve was 0.653 with 95% confidence interval 0.528-0.779 (p=0.017). The proportion of right ventricular pacing in patients with ICD was higher in the group of patients with AF.Conclusion. AF occurs in 1/5 of patients with CIED. All patients with AF were potential candidates for anticoagulation due to their high risk of stroke. The daily burden of AF is positively correlated with the presence and degree of hypertension, as well as with markers of renal dysfunction, chronic heart failure, and thrombosis. Elevated creatinine levels are a predictor of AF.

Coronary artery calcium in patients with atrial fibrillation undergoing catheter ablation – an opportunity to personalize cardiovascular and thromboembolic risk management

Abstract Introduction There is a well-established association between atrial fibrillation (AF) and coronary artery disease (CAD). Coronary artery calcium score (CACS) is a helpful tool to refine cardiovascular risk stratification and guide strategies of cardiovascular (CV) primary prevention. Purpose To evaluate the prevalence and clinical implications of CACS in terms of CV and thromboembolic risk stratification and preventive therapies, in patients with AF and atrial flutter (AFL) undergoing catheter ablation. Methods Cross-sectional study including patients with AF/AFL undergoing multidetector computed tomography (MDCT) for ablation procedure planning from 2017 to 2019. Baseline clinical and demographical data were collected. CV and thromboembolic risks were evaluated based on the SCORE (Systematic Coronary Risk Evaluation) system and CHA2DS2-VASc score. CACS was assessed in patients without history of coronary artery disease using the Agatston method. Results A total of 474 patients were included (441 with AF and 33 with AFL, mean age of 58±10 years, 62% male). Excluding those over 70 years of age (n=50, 11%), most patients had low (n=69, 22%) or moderate (n=188, 60%) CV risk and 277 (64%) patients had a CHA2DS2-VASc score ≥1 (male) or ≥2 (female). Overall, 265 patients (65%) were under chronic anticoagulation and 157 (39%) were under statin therapy. CAC was present in 254 (54%) patients and showed a multivessel distribution in 62% of the cases. The left main stem was affected in 81 (17%) patients and the left anterior descending artery in 211 (45%). Incorporating CACS&amp;gt;100 as a variable in CHA2DS2-VASc score (vascular disease parameter in patients without history of vascular disease) would have resulted in a significant score reclassification (n=87, 20%) and identification of new potential candidates for anticoagulation (n=12, 3%). Additional, anticoagulation would be indicated as a class IA recommendation in more 26 (6%) patients. Twenty three percent of patients with zero calcium were taking statins, and only 7% of patients with a CACS &amp;gt;300 were on high-intensity statin therapy. According to the recommendations and based on their CACS and current therapy, 103 (25%) patients would be candidates for statin therapy and 69 (17%) patients would be candidates for changes in the current statin therapy intensity (Table 1). Conclusion In our study, more than half of the patients undergoing MDCT before AF/AFL catheter ablation had coronary calcium above zero. Our findings suggest that an opportunistic evaluation of CACS can be clinically valuable in thromboembolic risk stratification and management of preventive pharmacological strategies such as anticoagulation and statins. Funding Acknowledgement Type of funding sources: None.

Thrombotic Risk Associated with Inferior Vena Cava Filter Placement in Patients with Heparin-Induced Thrombocytopenia

PurposeThis study sought to define thromboembolic risk and mortality in patients with heparin-induced thrombocytopenia (HIT) undergoing inferior vena cava filter (IVCF) placement, in light of the American Society of Hematology’s 2018 guidelines against routine use of IVCFs in this population. MethodsA total of 26 patients with HIT who received IVCFs were retrospectively reviewed, and the outcomes of this group were compared with those of 4,707 controls with either HIT or IVCFs alone and with reported outcomes in prior studies. ResultsThe patient group demonstrated 6- and 12-month mortality rates of 26.9% and 30.8%, respectively, which did not differ significantly from those of the control groups and were in line with published mortality rates in the literature. The measured thromboembolic risk of 19.2% in the patient group was also within the range of published rates for patients with HIT or IVCF alone. ConclusionsIVCF placement did not significantly increase the risk of thromboembolism or death in patients with HIT and may be a viable option in the subset of these patients who are not candidates for anticoagulation.

The Toxicology of Native Fucosylated Glycosaminoglycans and the Safety of Their Depolymerized Products as Anticoagulants.

Fucosylated glycosaminoglycan (FG) from sea cucumber is a potent anticoagulant by inhibiting intrinsic coagulation tenase (iXase). However, high-molecular-weight FGs can activate platelets and plasma contact system, and induce hypotension in rats, which limits its application. Herein, we found that FG from T. ananas (TaFG) and FG from H. fuscopunctata (HfFG) at 4.0 mg/kg (i.v.) could cause significant cardiovascular and respiratory dysfunction in rats, even lethality, while their depolymerized products had no obvious side effects. After injection, native FG increased rat plasma kallikrein activity and levels of the vasoactive peptide bradykinin (BK), consistent with their contact activation activity, which was assumed to be the cause of hypotension in rats. However, the hemodynamic effects of native FG cannot be prevented by the BK receptor antagonist. Further study showed that native FG induced in vivo procoagulation, thrombocytopenia, and pulmonary embolism. Additionally, its lethal effect could be prevented by anticoagulant combined with antiplatelet drugs. In summary, the acute toxicity of native FG is mainly ascribed to pulmonary microvessel embolism due to platelet aggregation and contact activation-mediated coagulation, while depolymerized FG is a safe anticoagulant candidate by selectively targeting iXase.

Pharmacokinetics and Pharmacodynamics of a Depolymerized Glycosaminoglycan from Holothuria fuscopunctata, a Novel Anticoagulant Candidate, in Rats by Bioanalytical Methods.

dHG-5 (Mw 5.3 kD) is a depolymerized glycosaminoglycan from sea cucumber Holothuria fuscopunctata. As a selective inhibitor of intrinsic Xase (iXase), preclinical study showed it was a promising anticoagulant candidate without obvious bleeding risk. In this work, two bioanalytical methods based on the anti-iXase and activated partial thromboplastin time (APTT) prolongation activities were established and validated to determine dHG-5 concentrations in plasma and urine samples. After single subcutaneous administration of dHG-5 at 5, 9, and 16.2 mg/kg to rats, the time to peak concentration (Tmax) was at about 1 h, and the peak concentration (Cmax) was 2.70, 6.50, and 10.11 μg/mL, respectively. The plasma elimination half-life(T1/2β) was also about 1 h and dHG-5 could be almost completely absorbed after s.c. administration. Additionally, the pharmacodynamics of dHG-5 was positively correlated with its pharmacokinetics, as determined by rat plasma APTT and anti-iXase method, respectively. dHG-5 was mainly excreted by urine as the unchanged parent drug and about 60% was excreted within 48 h. The results suggested that dHG-5 could be almost completely absorbed after subcutaneous injection and the pharmacokinetics of dHG-5 are predictable. Studying pharmacokinetics of dHG-5 could provide valuable information for future clinical studies.

Left atrial appendage closure device implantation via transhepatic vascular access: a case report

BackgroundIn patients with non-valvular atrial fibrillation, an estimated 90% of thrombi are located in the left atrial appendage. The WATCHMAN device is a left atrial appendage closure device that is an alternative therapeutic option to reduce the risk of systemic embolization in patients who are intolerant of long-term oral anticoagulation. It can be deployed in the left atrial appendage using a transseptal approach via the femoral vein. Transhepatic venous access is an alternative route for the delivery of the device in a patient with difficult vascular access.Case summaryAn 81-year-old man with persistent non-valvular atrial fibrillation, heart failure with reduced ejection fraction (HFrEF), and diabetes mellitus was deemed a poor candidate for anticoagulation due to recurrent falls and gastrointestinal bleeding. He was selected for a left atrial appendage closure. The initial procedure was aborted after significant resistance to device advancement was encountered in the right femoral vein. Lower extremity venography demonstrated totally occluded femoral and iliac veins bilaterally. The decision was made to implant the device via a transhepatic approach. The procedure had no complications and the patient was discharged on rivaroxaban and aspirin after 3 days.DiscussionTranshepatic venous access is a viable option in patients with poor femoral access for implantation of the WATCHMAN device. It can be done safely. Knowledge of this procedural alternative can greatly enhance patient care.

The components and activities analysis of a novel anticoagulant candidate dHG-5.

Intrinsic Xase (iXase), the last and rate-limiting enzyme complex in the intrinsic coagulation pathway, may be an ideal target for antithrombotic treatment. A depolymerized fraction of fucosylated glycosaminoglycan from sea cucumber Holothuria fuscopunctata, dHG-5 (Mw 5.2kDa), showed potent and selective inhibition of iXase (IC50, 14nM). In this work, the series of oligosaccharides contained in dHG-5 were purified and their precise structures were confirmed by 2D NMR and MS spectra. The relationships between anti-iXase, f.IXa-binding, anticoagulant and antithrombotic activities (y) and molecular weight (x) could be approximately expressed as the power function (y=a×xb), and these activity potencies of dHG-5 were approximately equivalent to the weighted average sum of that of its oligosaccharides. Given the prominent pharmacological properties, well-defined chemical composition and explicable relationships between dHG-5 and its oligosaccharides in pharmacological behaviors, dHG-5 is expected to be an ideal novel anticoagulant medicine.

1918 A Case of Recurrent Pneumatosis Intestinalis and Portal Venous Gas

INTRODUCTION: Mesenteric ischemia (MI) is caused by inadequate blood flow through the mesenteric vessels resulting in ischemic bowel. The most serious cases cause gangrenous bowel, leading to pneumatosis intestinalis (PI) and portal venous gas (PVG), often an ominous sign. CASE DESCRIPTION/METHODS: This is a case of a 63-year-old male who presented to the hospital with hematemesis and severe anemia. After massive transfusion, an EGD revealed actively bleeding gastric ulcers, requiring serial EGDs for successful control of bleeding. A CT revealed gastric distention with thickening of the duodenum and bilateral femoral vein opacities, later confirmed as deep vein thromboses. An IVC filter was subsequently placed, as he was not a candidate for anticoagulation. The patient was subsequently discharged on oral pantoprazole. Of note, there was no history of NSAID use or evidence of H. pylori. Repeat EGD 2 months later noted mild gastritis, but no ulcers were seen. A screening colonoscopy at the time noted only diverticulosis. He was continued on pantoprazole. 3 months later he presented to the hospital with acute onset nausea, vomiting, and diarrhea. A CT revealed PI at the gastric fundus, as well as PVG. An infectious work-up was negative, lactate was normal, and his symptoms resolved quickly. A subsequent repeat CT noted resolution of the PVG and reduction in PI. He represented to the hospital 1 month later again with nausea, vomiting, and diarrhea. A CT noted small bowel dilatation with air fluid levels, PI at the esophagus, stomach, and jejunum, and significant PVG. The initial lactate level was mildly elevated and his symptoms resolved quickly after bowel decompression. A subsequent CTA noted a significant reduction in PVG without evidence of vascular occlusion. A follow up EGD showed diffuse subepithelial hemorrhages without any evidence of recurrent ulcers. A subsequent CTE noted a thrombus above the IVC filter and an evolving hepatic infarction. He was asymptomatic at the time, however, he was admitted to the hospital for anticoagulation. He has since remained on warfarin without any recurrence of symptoms, PI, or PVG. A follow-up CTA showed a full resolution of venous thromboses. DISCUSSION: Previous case reports have described the development of PI and PVG secondary to underlying MI. This case highlights an example of MI secondary to an increase in the resistance of mesenteric blood flow due to venous thromboses. When investigating IP and PVG, underlying venous thromboses should always be considered.

End-point modification of recombinant thrombomodulin with enhanced stability and anticoagulant activity

Thrombomodulin (TM) is an endothelial cell membrane protein that plays essential roles in controlling vascular haemostatic balance. The 4, 5, 6 EGF-like domain of TM (TM456) has cofactor activity for thrombin binding and subsequently protein C activation. Therefore, recombinant TM456 is a promising anticoagulant candidate but has a very short half-life. Ligation of poly (ethylene glycol) to a bioactive protein (PEGylation) is a practical choice to improve stability, extend circulating life, and reduce immunogenicity of the protein. Site-specific PEGylation is preferred as it could avoid the loss of protein activity resulting from nonspecific modification. We report herein two site-specific PEGylation strategies, enzymatic ligation and copper-free click chemistry (CFCC), for rTM456 modification. Recombinant TM456 with a C-terminal LPETG tag (rTM456-LPETG) was expressed in Escherichia coli for its end-point modification with NH2-diglycine-PEG5000-OMe via Sortase A-mediated ligation (SML). Similarly, an azide functionality was easily introduced at the C-terminus of rTM456-LPETG via SML with NH2-diglycine-PEG3-azide, which facilitates a site-specific PEGylation of rTM456via CFCC. Both PEGylated rTM456 conjugates retained protein C activation activity as that of rTM456. Also, they were more stable than rTM456 in Trypsin digestion assay. Further, both PEGylated rTM456 conjugates showed a concentration-dependent prolongation of thrombin clotting time (TCT) compared to non-modified protein, which confirms the effectiveness of these two site-specific PEGylation schemes.

Computer-aid drug design, synthesis, and anticoagulant activity evaluation of novel dabigatran derivatives as thrombin inhibitors

In this study, computer-aided drug design techniques were adopted to explore the structural and chemical features for dabigatran and design novel derivatives. The built 3D-QSAR models demonstrated significant statistical quality and excellent predictive ability by internal and external validation. Based on QSAR information, 11 novel dabigatran derivatives (12a–12k) were designed and predicted, then ADME prediction and molecular docking were performed. Furthermore, all designed compounds were synthesized and characterized by 1H NMR, 13C NMR and HR-MS. Finally, they were evaluated for anticoagulant activity in vitro. The activity results showed that the 10 obtained compounds exhibited comparable activity to the reference dabigatran (IC50 = 9.99 ± 1.48 nM), except for compound 12i. Further analysis on molecular docking was performed on three compounds (12a, 12c and 12g) with better activity (IC50 = 11.19 ± 1.70 nM, IC50 = 10.94 ± 1.85 nM and IC50 = 11.19 ± 1.70 nM). MD simulations (10 ns) were carried out, and their binding free energies were calculated, which showed strong hydrogen bond and pi–pi stacking interactions with key residues Gly219, Asp189 and Trp60D. The 10 novel dabigatran derivatives obtained can be further studied as anticoagulant candidate compounds.

Percutaneous devices for left atrial appendage occlusion: A contemporary review.

Patient with atrial fibrillation (AF) are at risk of developing stroke with the left atrial appendage (LAA) being the most common site for thrombus formation. If left untreated, AF is associated with 4 to 5 folds increase in the risk of ischemic stroke in all age groups. About 5% to 15% of AF patients have atrial thrombi on transesophageal echocardiography, and 91% of those thrombi are located in the LAA in patient with nonrheumatic AF. Although oral anticoagulants are the gold-standard treatment for stroke prevention in patients with non-valvular AF, some patients are at high risk of bleeding and deemed not candidates for anticoagulation. Therefore, LAA occlusion (LAAO) has emerged as alternative approach for stroke prevention in those patients. Surgical LAAO is associated with high rate of unsuccessful closure and recommended only in patients with AF and undergoing cardiac surgery. Percutaneous LAAO uses transvenous access with trans-septal puncture and was first tested using the PLAATO device. Watchman is the most common and only Food and Drug Administration (FDA) approved device for LAAO. LAAO using Watchman device is non-inferior to warfarin therapy in preventing ischemic stroke/systemic thromboembolism. However, it is associated with lower rates of hemorrhagic stroke, bleeding and death. Amplatzer is another successful LAAO device that has CE mark and is waiting for FDA approval. Optimal antithrombotic therapy post LAAO is still under debate and highly patient-specific. The aim of this paper is to systematically review the current literature to evaluate the efficacy and safety of different LAAO devices.