Coagulation In Patients Research Articles

PEGylation of New Thrombin Inhibitor Peptide Ultravariegin for Prolonged In Vivo Circulation and Enhanced Antithrombotic Effects.

Anticoagulant therapy is commonly used to prevent and treat arterial and venous blood clots in patients with cardiovascular disease, cerebrovascular disease, and cancer. Venous blood clots are the third leading cause of cardiovascular death following acute coronary artery disease and stroke. There is a significant need for effective anticoagulant therapy with minimal risk of bleeding. Variegin and its variants are a new type of antithrombin peptide that has shown promising results in preclinical studies. Variegin and its best variant, ultravariegin (UV), can more effectively inhibit blood clot formation while causing less bleeding than traditional medications such as heparin and bivalirudin. However, the short lifespan of UV remains a limitation for its use in clinical settings. PEGylation, a method of conjugating poly(ethylene glycol) (PEG) chains to peptides or drugs, may help improve the effectiveness of UV by extending its circulation time in the body. In this study, UV was PEGylated using maleimide-PEG5k and 10k. The impact of PEGylation on the antithrombin activity of UV was assessed in vitro and ex vivo in rat and rabbit plasma, showing minimal effects on the efficacy. In vivo studies in rats and rabbits revealed that PEGylated UV had a longer half-life and greater anticoagulant effects than unmodified UV did, especially when it was administered subcutaneously. PEGylation significantly extended the half-life of UV in rabbits, resulting in sustained anticoagulant effects for up to 4 days. This demonstrated that increasing the size of UV and shielding it with PEG could reduce clearance by the kidneys and prolong its circulation time. The improved half-life and antithrombin activity of PEGylated UV make it a more favorable choice for anticoagulant therapy.

Risk factors associated with air embolism following computed tomography-guided percutaneous lung biopsy: a retrospective case-control study.

Retrospective analysis to identify the risk factors for air embolism following computed tomography (CT)-guided percutaneous transthoracic needle biopsy (TNB). A retrospective analysis of patients who underwent CT-TNB at The First Affiliated Hospital of Zhengzhou University and Xuzhou Cancer Hospital from January 2017 to December 2021 was performed. A total of 21 factors relevant to air embolisms were collected. Risk factors associated with air embolisms were determined by the least absolute shrinkage and selection operator (LASSO). The receiver-operator characteristic (ROC) was used to assess the ability of these factors to identify air embolisms. Of these 32,748 patients, 28 experienced air embolisms (19 at The First Affiliated Hospital of Zhengzhou University (incidence, 1.46%) and nine at Xuzhou Cancer Hospital (incidence, 0.69%); total incidence, 2.16%). Only seven patients exhibited symptoms (symptom rate, 25.00%). A total of 21 patients were asymptomatic at the time of swept-source CT. No deaths occurred. We found through univariate and multivariate analysis that eight out of these 21 factors are associated with the occurrence of air embolism. The area under the ROC curve was 0.721, indicating good predictive power (P<0.05). Cough during the procedure, hemoptysis during the procedure, the distance between the mass and the pulmonary vein, the presence of a cavity in the lesion, lesion location, number of samples, abnormalities in the patient's coagulation mechanism, and the puncture position may be the risk factors for air embolism in CT-TNB.

Clinical Practice Patterns for Transradial Coronary Artery Catheterisation in Australian and New Zealand: Mixed-Methods Survey and Interview Study

While there has been an increase in the use of the transradial approach when performing percutaneous coronary angiography and intervention, there is evidence of variations in international practice. Ensuring that operators' practices are supported by evidence is important to ensure optimal outcomes. Interventional cardiologists and advanced trainees completed a cross-sectional survey followed by semi-structured interviews to map current practices for transradial coronary artery procedures in Australia and New Zealand and explore factors that influence clinical decision-making around procedural practice. The right radial artery was the preferred access site (88%). Over a third (37%) of the participants indicated that they tested the hand circulation pre-procedure. Over a quarter of respondents (28.6%) reported that they would carry out transradial procedures regardless of the patient's coagulation status. Most participants (77.8%) described radial artery spasm in around 10% of transradial procedures performed. Only 62% of participants assessed for radial artery occlusion post-catheterisation. Interview data revealed four themes that guided clinical decision-making, namely (1) Decision-making based on research, (2) Using clinical experience, (3) Being led by their training, and (4) Individual patient factors. This study has demonstrated that despite clinical guidelines, substantial practice variation exists in transradial coronary artery catheterisation across Australia and New Zealand. The variation in practice and factors impacting clinical decision-making highlight a need for future strategies to optimise evidence translation and implementation across clinical settings.

OnyxTMGel or Coil versus Hydrogel as Embolic Agents in Endovascular Applications: Review of the Literature and Case Series.

This review focuses on the use of conventional gel or coil and "new" generation hydrogel used as an embolic agent in endovascular applications. In general, embolic agents have deep or multidistrict vascular penetration properties as they ensure complete occlusion of vessels by exploiting the patient's coagulation system, which recognises them as substances foreign to the body, thus triggering the coagulation cascade. This is why they are widely used in the treatment of endovascular corrections (EV repair), arteriovenous malformations (AVM), endoleaks (E), visceral aneurysms or pseudo-aneurysms, and embolisation of pre-surgical or post-surgical (iatrogenic) lesions. Conventional gels such as Onyx or coils are now commercially available, both of which are frequently used in endovascular interventional procedures, as they are minimally invasive and have numerous advantages over conventional open repair (OR) surgery. Recently, these agents have been modified and optimised to develop new embolic substances in the form of hydrogels based on alginate, chitosan, fibroin and other polymers to ensure embolisation through phase transition phenomena. The main aim of this work was to expand on the data already known in the literature concerning the application of these devices in the endovascular field, focusing on the advantages, disadvantages and safety profiles of conventional and innovative embolic agents and also through some clinical cases reported. The clinical case series concerns the correction and exclusion of endoleak type I or type II appeared after an endovascular procedure of exclusion of aneurysmal abdominal aortic (EVAR) with a coil (coil penumbra released by a LANTERN microcatheter), the exclusion of renal arterial malformation (MAV) with a coil (penumbra coil released by a LANTERN microcatheter) and the correction of endoleak through the application of Onyx 18 in the arteries where sealing by the endoprosthesis was not guaranteed.

Improved Dissolution and Solubility Characteristics of Clopidogrel Bisulphate using Gelucire 44/14

Clopidogrel bisulphate is a poorly aqueous soluble drug belonging to BCS Class II. The drug is widely used to treat blood clotting in patients with peripheral, coronary, and cerebrovascular disorders, but its low bioavailability raises concern. The present study involves an effort for enhancing the solubility and drug release by transforming the drug into solid dispersions. The solid dispersions of clopidogrel bisulphate were prepared with Gelucire 44/14 using solvent evaporation method. The prepared physical mixture and solid dispersions were characterized for drug-carrier interaction, drug content, solubility, and dissolution rate. Results confirmed the increase in drug solubility with increasing polymer concentration. The dissolution profile was found to substantially improve from solid dispersion with maximum drug release in the ratio of 1:5 on comparing it with pure drug and physical mixture. FT‐IR spectra of selected solid dispersion revealed no chemical interaction between drug and polymers while the presence of the drug in the amorphous state was confirmed by DSC thermograms and X-ray diffraction, indicating better dissolution characteristics. The solid dispersions were also found to be stable under accelerated stability conditions. Keywords: Clopidogrel bisulphate, Bioavailability, Solid dispersions, Gelucire 44/14, Solubility Enhancement

Effect of 3D laparoscopy versus traditional laparotomy on serum tumor markers and coagulation function in patients with early-stage endometrial cancer

ObjectivesTo investigate the impact of Three-Dimensional (3D) laparoscopy compared to traditional laparotomy on serum tumor markers and coagulation function in patients diagnosed with early-stage Endometrial Cancer (EC). MethodThe authors retrospectively analyzed the clinical data of 75 patients diagnosed with early-stage EC and categorized them into two groups based on the surgical techniques employed. The 3D group consisted of 36 patients who underwent 3D laparoscopic surgery, while the Laparotomy group comprised 39 patients who underwent traditional laparotomy. The authors then compared the alterations in serum tumor markers and coagulation function between the two groups. ResultsPostoperatively, serum levels of CA125, CA199, and HE4 were notably reduced in both groups on the third day, with the levels being more diminished in the 3D group than in the Laparotomy Group (p < 0.05). Conversely, FIB levels escalated significantly in both groups on the third-day post-surgery, with a more pronounced increase in the 3D group. Additionally, PT and APTT durations were reduced and were more so in the 3D group than in the laparotomy group (p < 0.05). ConclusionsWhen juxtaposed with traditional laparotomy, 3D laparoscopic surgery for early-stage EC appears to be more efficacious, characterized by reduced complications, and expedited recovery. It can effectively mitigate serum tumor marker levels, attenuate the inflammatory response and damage to immune function, foster urinary function recovery, and enhance the quality of life. However, it exerts a more significant influence on the patient's coagulation parameters, necessitating meticulous prevention and treatment strategies for thromboembolic events in clinical settings.

Thrombosis Caused By a Novel Coagulation Factor IX Mutation (FIX Shanghai II)

Most thrombophilia patients are caused by insufficient suppression of coagulation reactions, which could be either mediated by deficiencies of protein C, protein S,antithrombin, or inhibition-resistant coagulation factor mutants, such as Factor V Leiden and prothrombin Yukuhashi. The thrombosis caused by coagulation factor mutants with increased procoagulant activity is very rare and so far only two Factor IX (FIX) variants involving residue Arg384, FIX Padua (p.Arg384Leu) and Shanghai (p.Arg384Gln), which increased FIX activity by up to 8 folds, had been reported to be associated with the incidence of thrombosis. In a young male venous thrombosis patient we had identified a novel F9 gene missense mutation c.1018G&amp;gt;A, resulting in p. Glu340Lys substitution (designated as FIX Shanghai II). The patient's APTT time was 28.9 seconds (normal reference 22.3~38.7s), and his PT was also within the normal reference range (11.5 seconds, normal reference 10.0~16.0s). Although the patient had the FIX: Ag comparable to the normal reference, 128.20±6.07%, the his FIX:C was around 201.69±10.38% of normal control (normal reference 50~150%). Thrombin generation assay (TGA) showed that compared with normal control, the patient had a shorter Lag time (2.67 vs 3.33 min), elevated ETP (1649.43 vs 1311.62 nM*min), and higher Peak value (387.34 vs 200.86 nM), indicating increased global coagulation activity of the patient. The activity of protein C, protein S, and antithrombin were all within the normal reference ranges and the patient was negative for antiphospholipid antibodies. Consistent with the patient's coagulation laboratory manifestations, the purified recombinant FIX Glu340Lys mutant showed 1.82 folds higher procoagulant activity than wild type FIX as determined by FIX:C/FIX:Ag ratio. The recombinant FIX Shanghai II mutant can be converted into FIXa by activated factor XI (FXIa) in a similar fashion as FIX WT. The kinetic study of FIXa-catalyzed FX activation showed that p. Glu340Lys mutation led to accelerated FX activation by FIXa. The p.Glu340Lys mutation also enhanced the procoagulant activity of previously reported thrombosis-causing FIX mutants, FIX Shanghai and Padua, in a similar fashion as it did on FIX WT. The FIX:C/FIX:Ag ratio of double mutants containing Glu340Lys and Arg384Gln (FIX Shanghai) or Arg384Leu (FIX Padua) was about twice of FIX Shanghai or Padua alone, 11.48- and 22.53-folds vs 6.16- and 8.13- folds higher than FIX WT respectively.

Cyclosporine A improves ulcerative colitis complicated with deep vein thrombosis with coagulation abnormalities

Ulcerative colitis (UC) is a chronic inflammatory disease of the colon and rectum. UC patients are at increased risk of deep vein thrombosis. Cyclosporine A (CyA) is an immunosuppressant drug that is used to treat severe UC. A 49-year-old man with UC complicated by DVT was treated with CyA. The patient presented with severe bloody diarrhea, lower extremity edema, and a clinical activity index of 16. The patient's coagulation test results were also abnormal. After CyA administration, the patient's leg pain and swelling improved. In addition, the extrinsic coagulation abnormalities improved first after CyA administration, followed by a gradual improvement in the intrinsic coagulation abnormalities. CyA may be effective in correcting coagulation abnormalities that contribute to DVT in UC patients.

Precision medicine in hemostasis: a review of prothrombin complex concentrates and the role of viscoelastic tests in tailoring therapy

This review explores the role of precision medicine in the management of bleeding disorders and anticoagulation therapy, with a focus on the use of visco-elastic tests such as Thromboelastography (TEG) and Rotational Thromboelastometry (ROTEM). These tests provide real-time, dynamic insight into a patient's coagulation status, guiding the choice between three-factor prothrombin complex concentrate (PCC3) and four-factor PCC (PCC4), as well as the use of activated four-factor PCC (FEIBA). The specific ROTEM tests, INTEM and EXTEM, further enhance our understanding of the intrinsic and extrinsic coagulation pathways. Moreover, the use of tranexamic acid (TXA) and fibrinogen, guided by these visco-elastic tests, has shown promise in trauma patients. TXA has been associated with survival benefit when administered immediately or within 3 hours of injury. Fibrinogen, a key factor in clot formation, can be monitored and supplemented as needed to optimize hemostasis. In conclusion, the practice of precision medicine, with the aid of TEG and ROTEM, offers the potential to enhance the safety and efficacy of PCC therapy, TXA administration, and fibrinogen supplementation. These tools are invaluable in tailoring therapy to the specific needs of each patient, potentially optimizing patient outcomes and minimizing the risk of adverse events.

PB0766 Decreased Compactness and Increased Fluid Permeability of Ex-Vivo Fibrin Clots in Patients After Traumatic Brain Injury

PB0766 Decreased Compactness and Increased Fluid Permeability of Ex-Vivo Fibrin Clots in Patients After Traumatic Brain Injury

Coagulation management during liver transplantation: monitoring and decision making for hemostatic interventions.

Rebalanced hemostasis describes the precarious balance of procoagulant and antithrombotic proteins in patients with severe liver failure. This review is aimed to discuss currently available coagulation monitoring tests and pertinent decision-making process for plasma coagulation factor replacements during liver transplantation (LT). Contemporary viscoelastic coagulation monitoring systems have demonstrated advantages over conventional coagulation tests in assessing the patient's coagulation status and tailoring hemostatic interventions. There is increasing interest in the use of prothrombin complex and fibrinogen concentrates, but it remains to be proven if purified factor concentrates are more efficacious and safer than allogeneic hemostatic components. Furthermore, the decision to use antifibrinolytic therapy necessitates careful considerations given the risks of venous thromboembolism in severe liver failure. Perioperative hemostatic management and thromboprophylaxis for LT patients is likely to be more precise and patient-specific through a better understanding and monitoring of rebalanced coagulation. Further research is needed to refine the application of these tools and develop more standardized protocols for coagulation management in LT.

Electro-Osmotic Blood Flow of Shear-Thinning Fluid with Hall Current and Wall Flexibility

The presented article aims to present the flow of blood in microchannels such as veins and arteries via peristaltic flow. The magnetic field is imposed to regulate the flow as laminar. Also, its impacts in terms of Hall current have been considered. The rate of heat transfer is further based on Joule heating and viscous dissipation aspects. Mathematical analysis has been conducted given long wavelength and small Reynolds number. Such preferences are relatable to the medical domain where the magnetic field regulates the flow stream and aids in the melting of blood clots in patients with various heart diseases. The solution for electric potential is calculated analytically while the velocity, temperature, and heat transfer rate are executed directly via the built-in command of Mathematica software. Since the magnetic field acts as an opposing force. Results show that the velocity and temperature are decreasing functions of the magnetic field. However, the temperature is increasing for Weissenberg number.

The Yin and the Yang of Hemostasis in End-Stage Liver Disease.

Patients with end-stage liver disease (ESLD) undergoing liver transplantation (LT) are prone to thromboses both while on the waiting list and in the perioperative period. This hypercoagulability is associated with significant endothelial dysfunction (ED) due to nitric oxide dysregulation. ED and increased thrombin generation are the main factors responsible for this hypercoagulability. Sepsis alone can significantly alter a patient's coagulation profile. In combination with ESLD, however, sepsis or septic shock are responsible for very complex changes. This makes both the assessment and management of coagulation in septic patients with ESLD very challenging. Viscoelastic testing (VET) is the preferred method of coagulation management in patients with cirrhosis because, as with standard laboratory testing, VET can assess the entire coagulation system including the interaction between both pro- and anticoagulants and platelets.

Removal of obstructive organized tracheo-bronchial clots under respiratory support using veno-venous extracorporeal membrane oxygenation in a patient with blunt thoracic trauma: a case report

BackgroundIt has been reported that veno-venous extracorporeal membrane oxygenation is useful for treating patients with acute respiratory failure following severe thoracic trauma. However, the removal of an obstructive organized tracheo-bronchial clot under respiratory support using extracorporeal membrane oxygenation in a patient with trauma has never been reported.Case presentationA teenage female was injured in a fall and experienced right open hemopneumothorax and bilateral lung contusions. Since she was in refractory shock due to bleeding into the right thoracic cavity, we performed right thoracotomy and resection of the lacerated right middle lobe. After hemorrhage control, her respiratory status could not be maintained under mechanical respiratory support. Therefore, we initiated veno-venous extracorporeal membrane oxygenation. Although her respiratory failure gradually improved, the removal of obstructing tracheo-bronchial organized blood clots using bronchoscopy was required daily. Because of the size and firm adherence of organized clots to the airway membrane, we performed a tracheostomy to remove organized clots directly through the incision under extracorporeal membrane oxygenation without any adverse events on day 9. The next day, she was successfully removed from extracorporeal membrane oxygenation.ConclusionsExtracorporeal membrane oxygenation could provide respiratory support not only for acute respiratory failure but also for removal of obstructing tracheo-bronchial organized clots in patients with severe lung injury following trauma.

PO-01-002 ASSOCIATION OF NOVEL COMBINED GENETIC POLYMORPHISMS WITH RISK OF THROMBOEMBOLISM IN PATIENTS WITH ATRIAL FIBRILLATION

AF patients remain on oral anticoagulation (OAC) or left atrial appendage (LAA) closure is performed for thromboprophylaxis. However, clots on the closure device as well as stroke/transient ischemic attack (TIA) are observed to occur in some patients despite of being on blood thinners or after being off-OAC for a very brief period. Therefore, we evaluated if genetic variants were associated with TE events in this subset of AF population. This prospective study (NCT04115436) included consecutive AF patients that were managed for AF at our center. SNP Genotyping Analysis was performed on the blood sample of the study participants using a combination of microarray and next-generation sequencing (NGS). We screened for common single nucleotide polymorphisms (SNPs) reported in the literature to be associated with stroke and thromboembolism at a genome-wide significance level. We genotyped 29 AF patients (age: 66.5±3.53 years; female: 6 (20.7%)) with thromboembolic events following AF ablation. Of these patients, device (Watchman)-associated thrombus was reported in 13 (44.8%), stroke/TIA off-OAC in 14 (48.3%) and left atrial appendage thrombus while on OAC in 2 (6.9%). One or more of the following 4 SNPs were detected in 27/29 patients (93.1%): rs11833579, rs12476527, rs505922 and rs6891174. They were homozygous for the recessive allele in all 27 patients. Of the 27, 19 (70.3%) patients including the 13 with device-clot had >2 of the 4 genetic variants reported. Location of these SNPs and their clinical significance is provided in table 1. Our findings, for the first time, document the association of four stroke-related genetic variants with prothrombotic events such as device-related clot in patients with atrial fibrillation.

Global observational survey verifying surgeon utilization of the Validated Intraoperative Bleeding (VIBe) scale for use in clinical practice

Based on US-FDA guidelines to create tools for development and evaluation of medical devices in non-clinical and clinical studies, the Validated Intraoperative Bleeding (VIBe) Scale was developed. The current investigation expands upon the earlier validation study with multi-specialty surgeons to further corroborate these findings and establish feasibility to implement VIBe SCALE into clinical practice and surveys degree of anticipated bleeding across common procedures in multiple surgical disciplines. Following online didactic VIBe SCALE training, participating surgeons graded bleeding in ten porcine model videos corresponding to the original validation study. Surgeon and practice information were collected along with percentage of hemostatic product utilization in surgical procedures, the top three surgical procedures performed in their specialty, together with self-reported percentage of bleeding per VIBe SCALE bleeding grade typically encountered in those procedures. Using a web-based interface, survey data were collected from 585 participating surgeons; 339 (58%) participants were from academic or university setting, 170 (29%) had >20 years of surgical experience, 217 (37%) performed 11-20 surgeries per month. Overall, 125 (21%) surgeons reported conducting up to 10% minimally invasive surgeries in their practice. Total, 334 (57%) participants considered patient's coagulation status while selecting intraoperative adjunctive hemostatic product, if required; majority (n=552 [94%]) considered bleeding intensity important when selecting a hemostatic product intraoperatively. Interobserver concordance for VIBe SCALE of 0.89 (perfect concordance=1.0) as a measure of reproducibility, was achieved. This survey strengthens the findings of the earlier validation study and provides human factors verification of the VIBe SCALE as a relevant tool to evaluate and assess bleeding severity across multiple surgical specialties, while demonstrating the useability in contemporary clinical practice and may facilitate hemostatic product choice.

Effect of clopidogrel on post extraction clotting in patients on dual antiplatelet therapy

Purpose: To evaluate the association between the platelet inhibition rate of clopidogrel (CLO-PIR) and post-extraction clotting status in DAPT patients.&#x0D; Methods: Ninety (90) eligible patients scheduled for a single tooth extraction were enrolled in this study. The CLO-PIR and platelet inhibition rate of aspirin (ASA-PIR) were determined by thromboelastography platelet mapping assay. Post-extraction clotting assessments were performed, and a complete intra-alveolar clot formation within 30 min post-operation was defined as normal clotting. For clot formation exceeding 30 min, it was defined as prolonged bleeding.&#x0D; Results: At a similar level of ASA-PIR, a higher proportion of patients with normal CLO-PIR (≤ 75 %) exhibited normal clotting, compared with those featuring high CLO-PIR (&gt;75 %, p &lt; 0.001). However, in patients with similar CLO-PIRs, the clotting results varied insignificantly, with increase in ASA-PIR. The effect of CLO-PIR was further validated using logistic regression analysis (odds ratio = 1.071, 95 % confidence interval: 1.024 - 1.120, p = 0.003), and receiver operating characteristic curve analysis revealed that a 78.6 % CLO-PIR was the rational cut-off point.&#x0D; Conclusion: This study preliminarily demonstrates the prominence of high clopidogrel responsiveness in slowing the post-extraction clotting process in DAPT patients.

Pitfalls in Coagulation Testing

Assays in the coagulation laboratory are affected by numerous variables. Variables which have impact on the test result can lead to incorrect results, and potentially to consequences for further diagnostic and therapeutic decisions made by the clinician. The interferences can be separated into three main groups: biological interferences, with an actual impairment of the patient's coagulation system (congenital or acquired); physical interferences, which usually occur in the pre-analytical phase; and chemical interferences, because of the presence of drugs (mainly anticoagulants) in the blood to be tested. This article discusses some of these interferences in seven instructive cases of (near) miss events as an approach to generate more attention to these issues.

Aptamer-Small Molecule Conjugates As Potent and Reversible Surgical Anticoagulants Targeting Thrombin

Unfractionated heparin (UFH) is the first-line anticoagulant used in millions of heart surgeries annually. The high potency of UFH is attributed to its effective activation of the antithrombin-mediated anticoagulation pathway. However, the prolonged use of heparin in heart surgeries is often associated with bleeding disorders as it depletes both patient's coagulation and anticoagulation capacity. Moreover, UFH is immunogenic, which can trigger potentially life-threatening heparin-induced thrombocytopenia (HIT) when used repeatedly. Aptamers are short oligonucleotides isolated in vitro that bind to protein or small molecule targets with high affinity and specificity. Several aptamers have been created that act as anticoagulants as they can competitively block substrate binding to anticoagulation protease exosites. Compared to UFH, aptamers have advantages, including not activating antithrombin, reversibility by administration of a well-tolerated antisense oligonucleotide, and low immunogenicity. However, the anticoagulant potency of aptamers is often limited by their inability to effectively inhibit the catalytic sites of their protease targets. Here we provide a strategy to solve this potency problem by conjugating a protease active-site inhibitor to an exosite-binding aptamer via a polynucleotide linker. The resulting bivalent conjugate binds to both the active site and exosite of the target protease to completely inhibit protease function. Meanwhile, the synergy between two binding elements significantly improves the binding affinity compared to the small molecule inhibitor or the aptamer alone. As a proof of concept, we conjugated the thrombin active site inhibitor DAB to the 5’ terminus of anti-thrombin aptamer HD22 via a poly (7) adenosine linker (HD22-7A-DAB) and characterized its thrombin inhibition activity using a fluorogenic substrate cleavage assay. The results reveal that HD22-7A-DAB has a much higher thrombin inhibition activity (IC50 = 0.2 nM) than DAB (IC50 = 80 nM) or the unconjugated aptamer (IC50 > 1000 nM). The significantly higher inhibitory effect of HD22-7A-DAB compared to a 1:1 mixture of unconjugated DAB and HD22 also indicates that conjugation is essential to create an effective synergistic inhibitor. Notably, in the presence of 2 µM complementary DNA to HD22, the effect of HD22-7A-DAB conjugate was drastically diminished (IC50 > 1000 nM), which indicates that both aptamer and small molecule in ADIC can be reversed using an antidote oligonucleotide. HD22-7A-DAB also shows a UFH-rivaling anticoagulation effect and antidote-reversible behavior in a series of in vitro clotting assays, including thrombin time (TT), prothrombin time (PT), and activated partial thromboplastin time (aPTT). Thus the development of a thrombin-targeting small molecule aptamer conjugate inhibitor yields a potent and reversible anticoagulant with clinically relevant anticoagulant activity. In addition, these studies describe a generalizable strategy for rapidly developing aptamer-small molecule active site inhibitor conjugates for generate other potent and reversible inhibitors of the other coagulation proteases. These potent and reversible anticoagulant aptamer-active site drug conjugates have the potential to become UFH substituents in surgeries to reduce the risk of UFH-associated bleeding, UFH-insensitivity and HIT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Central Venous Catheter Malposition into the Left Internal Mammary Vein in Patient with Coagulation Disorder and Safe Removal: A Case Report

A 61-year-old male patient with underlying diseases of hypertension and alcoholic liver cirrhosis was hospitalized for liver transplantation due to advanced liver cirrhosis. In preparation for liver transplant surgery, a multi-lumen access catheter and Swan-ganz catheter are inserted into the right internal jugular vein. And another central venous catheter is inserted into the subclavian vein for central venous pressure measurement and drug administration. There was no abnormal resistance of the guide wire or catheter that the operator could feel during the insertion process, and there was no abnormality in the function of the catheter. But the postoperative chest image showed that the left subclavian central vein catheter was malpositioned. Through venography at the angiography room, it was confirmed that the central venous catheter was inserted into the left internal mammary vein. Since the patient with coagulation disorder, special attention was required to remove the catheter. In addition, due to the location of the internal mammary vein, it was expected that it would be difficult to compress for hemostasis after removal of the catheter. Therefore, it was necessary to check the patient's coagulation test to determine the appropriate time of the catheter removal and cooperation of the radiologist.