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TH Open : Companion Journal To... Jan 2023Thrombocytopenia is common among critically ill sepsis patients, while they also hold an increased risk for thromboembolic events. Thus, the choice of anticoagulant...
Thrombocytopenia is common among critically ill sepsis patients, while they also hold an increased risk for thromboembolic events. Thus, the choice of anticoagulant prophylaxis for this patient population is challenging. We investigated the effect of low-molecular-weight heparin (dalteparin) and direct thrombin inhibitor (argatroban) on the hemostasis in blood from sepsis patients with new-onset thrombocytopenia. Thrombocytopenia was defined as a platelet count drop of ≥30% and/or from >100 × 10 /L to 30 to 100 × 10 /L within 24 hours prior to inclusion. We included five healthy individuals and ten patients. Analyses of thrombin generation (Calibrated Automated Thrombogram), thrombin-antithrombin (TAT) complex levels, prothrombin fragment 1+2 (F1+2), and rotational thromboelastometry (ROTEM) were performed. Based on dose-response relationships investigated in healthy blood, patient samples were spiked with prophylactic (0.25 IU/mL) and therapeutic (0.75 IU/mL) dalteparin and low (0.25 µg/mL) and high (0.50 µg/mL) argatroban concentrations, each with a sample without anticoagulant. In patients, the endogenous thrombin potential was markedly lower in therapeutic dalteparin samples than in samples without anticoagulant [median (range): 29 (0-388) vs. 795 (98-2121) nM × min]. In high argatroban concentration samples, thrombin lag time was longer than in samples without anticoagulant [median (range): 15.5 (10.5-20.2) versus 5.3 (2.8-7.3) min]. Dalteparin and argatroban both increased clotting time but did not affect maximum clot firmness in the ROTEM INTEM assay. Six patients had elevated TAT and eight patients had elevated F1 + 2. In conclusion, dalteparin mainly affected the amount of thrombin generated and argatroban delayed clot initiation in critically ill sepsis patients with new-onset thrombocytopenia. Neither anticoagulant affected clot strength.
PubMed: 36751302
DOI: 10.1055/a-2000-6576 -
BMC Musculoskeletal Disorders Jan 2023Tranexamic acid (TXA) has been widely applied in total knee arthroplasty (TKA) to significantly reduce perioperative blood loss and improve knee function recovery in... (Randomized Controlled Trial)
Randomized Controlled Trial
Effectiveness of different antithrombotic agents in combination with tranexamic acid for venous thromboembolism prophylaxis and blood management after total knee replacement: a prospective randomized study.
BACKGROUND
Tranexamic acid (TXA) has been widely applied in total knee arthroplasty (TKA) to significantly reduce perioperative blood loss and improve knee function recovery in patients after surgery. The choice of antithrombotic agents for venous thromboembolism (VTE) prevention after TKA is controversial. Therefore, this study aimed to compare the effects of different antithrombotic agents on patients after primary unilateral TKA in the context of applied TXA.
METHODS
A total of 180 patients undergoing primary unilateral TKA from October 2020 to December 2021 were included in this study. All patients were given an intraoperative drip of 60 mg/kg TXA. Thereafter, patients were divided into three groups (n = 60 each). Baseline data were comparable among the three groups. The average follow-up time was 3.02 ± 0.09 months. Group 1 enrolled patients receiving oral rivaroxaban (RA) at 10 mg, Group 2 included patients who received subcutaneous Dalteparin sodium at 2500 IU, while Group 3 included patients taking oral aspirin (ASA) at 100 mg. Patients in all the three groups received treatment once a day for 30 days at 12 h postoperatively. The primary outcomes in this study were post-treatment drainage volume and thrombotic complication rate. The secondary outcomes included hematologic parameters, transfusion rate, intraoperative blood loss, total blood loss (TBL), and bleeding complication rate.
RESULTS
The average drainage volume after treatment was significantly lower in Group 3 than in Group 1 and Group 2 (205.2 ± 69.0 vs 243.4 ± 72.5 vs 295.4 ± 72.5 ml, P < 0.001), and there was a significant difference between Group 1 and Group 2 (243.4 ± 72.5 mL vs 295.4 ± 72.5 mL, P < 0.001). The blood transfusion rate of Group 2 dramatically increased compared with Group 1 and Group 3 (20.0% vs 6.7% vs 5.0%, P = 0.01). The bleeding complication rate in Group 1 apparently increased relative to Group 2 and Group 3 (26.7% vs 10.0% vs 8.3%, P = 0.008). Besides, there was no significant difference in the thrombotic complication rate among the three groups.
CONCLUSION
Under the background of TXA application, ASA, RA, and Dalteparin sodium were all effective on preventing VTE after TKA. In addition, ASA effectively reduced post-treatment Hemoglobin (Hb) loss, drainage volume, TBL, transfusion rate, and bleeding complications compared with RA and Dalteparin sodium.
TRIAL REGISTRATION
The trial was registered at the Chinese Clinical Trial Registry (ChiCTR2200060169). Date of Registration: 21/05/2022.
Topics: Humans; Tranexamic Acid; Arthroplasty, Replacement, Knee; Venous Thromboembolism; Fibrinolytic Agents; Antifibrinolytic Agents; Dalteparin; Prospective Studies; Blood Loss, Surgical; Rivaroxaban; Anticoagulants; Postoperative Hemorrhage
PubMed: 36600227
DOI: 10.1186/s12891-022-06117-8 -
Medicinski Glasnik : Official... Feb 2023Aim To determine differences between reviparin and dalteparin treatment in patients with extracapsular hip fractures treated with intramedullary nailing and their...
Comparative analysis of the effects of dalteparin and reviparin on perioperative blood loss in patients with extracapsular hip fractures treated with intramedullary nailing.
Aim To determine differences between reviparin and dalteparin treatment in patients with extracapsular hip fractures treated with intramedullary nailing and their effects on perioperative blood loss and early postoperative recovery. Methods Retrospective comparative study included 68 patients with extracapsular hip fracture who were divided into dalteparin and reviparin group. Medical records were used to obtain demographic data, laboratory parameters, haemoglobin and haematocrit levels, platelet count, mortality rate and medical complications. Results Out of total 68 patients, 31 were in reviparin and 37 in dalteparin group. Mean age of patients was 70.5 (±14.4) and 76.8 (±8.4) years in reviparin and dalteparin group, respectively (p=0.071). Median values of haemoglobin levels on the first postoperative day were lower in dalteparin group compared to reviparin group (p=0.012). On the first postoperative day haematocrit values were also lower in dalteparin than in reviparin group (p=0.015). Both groups showed an increase in platelet count on the first postoperative day, but without significant difference (p=0.084). There was no statistically significant difference in intrahospital mortality between the groups (6.4% vs. 2.7%; p=0.588). One case of pulmonary embolism was detected in the dalteparin group. Conclusion Low-molecular-weight heparin is the drug of choice in patients with hip fractures for thromboprophylaxis. Due to non-antithrombin-mediated actions, reviparin and dalteparin could have different effects on perioperative blood loss. Both dalteparin and reviparin are safe and effective agents for thromboprophylaxis in patients with proximal femur fractures.
PubMed: 36435999
DOI: 10.17392/1526-22 -
Cardiovascular Drugs and Therapy Jun 2024As of July 2022, the COVID-19 pandemic has affected over 555 million worldwide confirmed cases and caused more than 6.3 million deaths. The studies showed that the...
Promising Drug Fondaparinux for the Treatment of COVID-19: an In Silico Analysis of Low Molecular Weight Heparin, Direct Oral Anticoagulant, and Antiplatelet Drug Interactions with Host Protease Furin.
PURPOSE
As of July 2022, the COVID-19 pandemic has affected over 555 million worldwide confirmed cases and caused more than 6.3 million deaths. The studies showed that the D-dimer levels were increased in non-survivors compared to survivors and heparin treatment has begun to be administered to the patients in severe clinics. As we knew that the entrance of SARS-CoV-2 to the host cell needs to be facilitated by host proteases; we published our hypothesis that heparin as a serine protease inhibitor may block the interaction between spike protein receptor-binding domain and host proteases. In our study, we aimed to investigate the interactions between not only heparins but also other antiplatelet and anticoagulant drugs including fondaparinux.
METHODS
In this study, docking studies were carried out to evaluate the interactions between low molecular weight heparins (LMWHs) (enoxaparin, dalteparin, tinzaparin), direct oral anticoagulant, and antiplatelet drugs with host proteases. Molecular docking studies were performed by using Schrödinger molecular modeling software. 3D structures of the ligands were obtained from the 2D structures by assigning the OPLS-2005 force field using the Maestro 12.7. The 3D crystal structure of the furin complexed with an inhibitor, 2,5-dideoksistreptamin derivative, was extracted from the Protein Data Bank (PDB ID: 5MIM). Docking studies were carried out using the Grid-based Ligand Docking with Energetics module of the Schrödinger Software.
RESULTS
The docking studies revealed that fondaparinux was the most relevant molecule to interact with furin with a docking score of - 12.74. It showed better interaction than the natural ligand of furin with an increased score compared to the docking score of - 8.155 of the natural ligand. AnaGA*IsA structure representing LMWH structure has shown a docking score of - 11.562 which was also better than the score of the natural ligand of furin.
CONCLUSION
Our findings have shown that LMWHs and fondaparinux can be used for their possible antiviral effects in COVID-19 patients. Our results have shown that in accordance with heparin and LMWH, fondaparinux can also be a candidate for "drug repurposing" in COVID-19 therapy, not only because of their anticoagulant but also possible antiviral effects.
Topics: Fondaparinux; Humans; Molecular Docking Simulation; Anticoagulants; COVID-19 Drug Treatment; Platelet Aggregation Inhibitors; Heparin, Low-Molecular-Weight; Furin; SARS-CoV-2; COVID-19; Computer Simulation; Drug Interactions
PubMed: 36401727
DOI: 10.1007/s10557-022-07406-z -
BMC Medicine Nov 2022The Accelerating Innovation for Mothers (AIM) project established a database of candidate medicines in research and development (R&D) between 2000 and 2021 for five...
BACKGROUND
The Accelerating Innovation for Mothers (AIM) project established a database of candidate medicines in research and development (R&D) between 2000 and 2021 for five pregnancy-related conditions, including pre-eclampsia. In parallel, we published target product profiles (TPPs) that describe optimal characteristics of medicines for use in preventing/treating pre-eclampsia. The study objective was to use systematic double screening and extraction to identify all candidate medicines being investigated for pre-eclampsia prevention/treatment and rank their potential based on the TPPs.
METHODS
Adis Insight, Pharmaprojects, WHO international clinical trials registry platform (ICTRP), PubMed and grant databases were searched (Jan-May 2021). The AIM database was screened for all candidates being investigated for pre-eclampsia. Candidates in clinical development were evaluated against nine prespecified criteria from TPPs identified as key for wide-scale implementation, and classified as high, medium or low potential based on matching to the TPPs. Preclinical candidates were categorised by product type, archetype and medicine subclass.
RESULTS
The AIM database identified 153 candidates for pre-eclampsia. Of the 87 candidates in clinical development, seven were classified as high potential (prevention: esomeprazole, L-arginine, chloroquine, vitamin D and metformin; treatment: sulfasalazine and metformin) and eight as medium potential (prevention: probiotic lactobacilli, dalteparin, selenium and omega-3 fatty acid; treatment: sulforaphane, pravastatin, rosuvastatin and vitamin B3). Sixty-six candidates were in preclinical development, the most common being amino acid/peptides, siRNA-based medicines and polyphenols.
CONCLUSIONS
This is a novel, evidence-informed approach to identifying promising candidates for pre-eclampsia prevention and treatment - a vital step in stimulating R&D of new medicines for pre-eclampsia suitable for real-world implementation.
Topics: Humans; Pregnancy; Female; Pre-Eclampsia; Biological Products; Dietary Supplements; Vitamin D; Metformin
PubMed: 36329468
DOI: 10.1186/s12916-022-02582-z -
Experimental Hematology & Oncology Oct 2022Cancer-associated thrombosis (CAT) poses a significant disease burden and the incidence in Asian populations is increasing. Anticoagulation is the cornerstone of... (Review)
Review
Cancer-associated thrombosis (CAT) poses a significant disease burden and the incidence in Asian populations is increasing. Anticoagulation is the cornerstone of treatment, but can be challenging due to the high bleeding risk in some cancers and the high risk of recurrent venous thromboembolism (VTE) in patients with malignancies. Direct oral anticoagulants (DOACs) are well established as first-choice treatments for VTE in non-cancer patients, offering a more convenient and less invasive treatment option than low-molecular-weight heparin (LMWH). Asian patients have exhibited comparable efficacy and safety outcomes with other races in trials of DOACs for VTE in the general population. Although no specific data are available in Asian patients with CAT, results from randomized controlled trials of apixaban, edoxaban, or rivaroxaban versus the LMWH, dalteparin, indicate that DOACs are a reasonable alternative to LMWH for anticoagulation in Asian patients with CAT. This is further supported by analyses of real-world data in Asian populations demonstrating the efficacy and safety of DOACs in Asian patients with CAT. Apixaban, edoxaban, or rivaroxaban are recommended in the most recently updated international guidelines as first-line therapy for CAT in patients without gastrointestinal or genitourinary cancers and at low risk of bleeding. An increased risk of major gastrointestinal bleeding was evident with edoxaban or rivaroxaban, but not apixaban, versus dalteparin in the clinical trials, suggesting that apixaban could be a safe alternative to LMWH in patients with gastrointestinal malignancies. Determining the optimal anticoagulant therapy for patients with CAT requires careful consideration of bleeding risk, tumor type, renal function, drug-drug interactions, financial costs, and patients' needs and preferences.
PubMed: 36303259
DOI: 10.1186/s40164-022-00331-9 -
Proceedings of the National Academy of... Oct 2022The major cytoskeleton protein actin undergoes cyclic transitions between the monomeric G-form and the filamentous F-form, which drive organelle transport and cell...
The major cytoskeleton protein actin undergoes cyclic transitions between the monomeric G-form and the filamentous F-form, which drive organelle transport and cell motility. This mechanical work is driven by the ATPase activity at the catalytic site in the F-form. For deeper understanding of the actin cellular functions, the reaction mechanism must be elucidated. Here, we show that a single actin molecule is trapped in the F-form by fragmin domain-1 binding and present their crystal structures in the ATP analog-, ADP-Pi-, and ADP-bound forms, at 1.15-Å resolutions. The G-to-F conformational transition shifts the side chains of Gln137 and His161, which relocate four water molecules including W1 (attacking water) and W2 (helping water) to facilitate the hydrolysis. By applying quantum mechanics/molecular mechanics calculations to the structures, we have revealed a consistent and comprehensive reaction path of ATP hydrolysis by the F-form actin. The reaction path consists of four steps: 1) W1 and W2 rotations; 2) P-O bond cleavage; 3) four concomitant events: W1-PO formation, OH and proton cleavage, nucleophilic attack by the OH against P, and the abstracted proton transfer; and 4) proton relocation that stabilizes the ADP-Pi-bound F-form actin. The mechanism explains the slow rate of ATP hydrolysis by actin and the irreversibility of the hydrolysis reaction. While the catalytic strategy of actin ATP hydrolysis is essentially the same as those of motor proteins like myosin, the process after the hydrolysis is distinct and discussed in terms of Pi release, F-form destabilization, and global conformational changes.
Topics: Actins; Adenosine Diphosphate; Adenosine Triphosphate; Dalteparin; Hydrolysis; Myosins; Protons; Water
PubMed: 36252034
DOI: 10.1073/pnas.2122641119 -
Frontiers in Veterinary Science 2022Pulmonary thromboembolism (PTE) secondary to immune-mediated hemolytic anemia (IMHA) is rarely diagnosed in cats. In this report, a 3-year-old cat was referred to our...
Pulmonary thromboembolism (PTE) secondary to immune-mediated hemolytic anemia (IMHA) is rarely diagnosed in cats. In this report, a 3-year-old cat was referred to our private hospital with dyspnea, anorexia, and anemia. On the thoracic radiography, cardiac enlargement and pulmonary edema were noted. Echocardiography revealed right ventricular and right atrium enlargement with mild tricuspid regurgitation (tricuspid regurgitation velocity 3.28 m/s). A thrombus was recognized in the main pulmonary artery on the right parasternal short-axis view. Blood examination suggested regenerative anemia and autoagglutination. The findings suggested immune-mediated hemolytic anemia and PTE. Antithrombotic therapy (dalteparin) and immunosuppressive therapy (prednisolone) were administered under oxygen supplementation in the ICU cage. After treatment, regenerative anemia and right-heart failure were improved. During follow-up, the cat remained hemodynamically stable, and the owner reported no cardiac-related clinical signs. Further blood examination confirmed the anemia was improved. Prednisolone was discontinued on Day 56, and the cat continues in good health, administered only mycophenolate mofetil. The clinical outcome of PTE secondary to the IMHA throughout 100 days of periodical observation was reported.
PubMed: 36032299
DOI: 10.3389/fvets.2022.930210 -
Journal of Stroke and Cerebrovascular... Oct 2022Stroke is an independent risk factor for venous thromboembolism (VTE). Although the risk of VTE persists after hospital discharge, information on the utilization of...
BACKGROUND
Stroke is an independent risk factor for venous thromboembolism (VTE). Although the risk of VTE persists after hospital discharge, information on the utilization of anticoagulants among stroke patients after discharge remains limited.
OBJECTIVE
To evaluate changes in post-discharge thromboprophylaxis among stroke patients between 2006 and 2019.
METHODS
We conducted a retrospective repeated cross-sectional analysis using a commercial healthcare insurance database in the United States. We included patients aged ≥ 18 years with incident stroke diagnosis and assessed prophylactic use of anticoagulants in the 30 days following hospital discharge including low-molecular-weight heparin (enoxaparin ≤40 mg/day, dalteparin ≤5000 IU/day), unfractionated heparin ≤5000 IU/ twice daily or 3 times a day, apixaban 2.5 mg twice daily, and rivaroxaban 10 mg/day. Patients with atrial fibrillation, VTE, mechanical heart valves, cancer, antiphospholipid antibody syndrome, and users of therapeutic doses of anticoagulants were excluded. We used the Cochrane-Armitage test to assess changes in the use of anticoagulants across the study period.
RESULTS
There was a small increase in the overall use of post-discharge prophylactic anticoagulants among stroke patients between 2006 and 2019 from 0.5% to 1.9%. The use of heparin decreased from 0.5% in 2006 to 0.3% in 2019 (P-value for trend = 0.001). In contrast, the use of apixaban or rivaroxaban increased from 0.1% in 2013 to 1.6% in 2019 (P-value for trend < 0.001). Apixaban was more commonly used than rivaroxaban.
CONCLUSIONS
In this population-based study of stroke patients, we found that post-discharge anticoagulant use remains low through 2019. Prophylactic use of heparin or rivaroxaban was relatively low but the use of apixaban increased over the study period. Further research is needed to determine if these agents are safe and effective for VTE prevention in stroke patients.
Topics: Aftercare; Anticoagulants; Atrial Fibrillation; Cross-Sectional Studies; Dalteparin; Enoxaparin; Heparin; Heparin, Low-Molecular-Weight; Humans; Patient Discharge; Pyridones; Retrospective Studies; Risk Factors; Rivaroxaban; Stroke; United States; Venous Thromboembolism
PubMed: 35964533
DOI: 10.1016/j.jstrokecerebrovasdis.2022.106700 -
The Journal of Thoracic and... Dec 2022The optimal duration of thromboprophylaxis in patients undergoing resection of primary lung cancer is not known. We investigated the incidence of pulmonary emboli and... (Review)
Review
OBJECTIVE
The optimal duration of thromboprophylaxis in patients undergoing resection of primary lung cancer is not known. We investigated the incidence of pulmonary emboli and venous thromboembolism in patients undergoing early-stage lung cancer resection and the impact of change from short duration to extended thromboprophylaxis.
METHODS
We reviewed the outcomes of consecutive patients who underwent resection of early-stage primary lung cancer following a change in protocol from inpatient-only to extended thromboprophylaxis to 28 days. Propensity-score matching of control (routine inpatient pharmacologic thromboprophylaxis) and treatment group (extended pharmacologic thromboprophylaxis) was performed. Adjustment for covariates based on the Caprini risk assessment model was undertaken. Thromboembolic outcomes were compared between the 2 groups.
RESULTS
Seven hundred fifty consecutive patients underwent resection of primary lung cancer at Oxford University Hospitals NHS Foundation Trust between January 2013 and December 2018. Six hundred patients were included for analysis and propensity-score matching resulted in 253 matched pairs. Extended prophylaxis was associated with a significant reduction in pulmonary emboli (10 of 253 patients [4%] vs 1 of 253 patients [0.4%], P = .01). One patient (0.4%) developed a bleeding complication within the treatment cohort. Multivariable logistic regression model demonstrated that extended thromboprophylaxis was independently associated with a reduction in postoperative pulmonary emboli.
CONCLUSIONS
Patients undergoing lung cancer resection surgery are at moderate-to-high risk of postoperative thromboembolic disease. Extended dalteparin for 28 days is safe and is associated with reduced incidence of pulmonary embolus in patients undergoing resection of early-stage primary lung cancer.
Topics: Humans; Venous Thromboembolism; Anticoagulants; Drug Administration Schedule; Pulmonary Embolism; Postoperative Complications; Lung Neoplasms
PubMed: 35953309
DOI: 10.1016/j.jtcvs.2022.06.016