-
Arteriosclerosis, Thrombosis, and... Jul 2023Antithrombin, PC (protein C), and PS (protein S) are circulating natural anticoagulant proteins that regulate hemostasis and of which partial deficiencies are causes of...
BACKGROUND
Antithrombin, PC (protein C), and PS (protein S) are circulating natural anticoagulant proteins that regulate hemostasis and of which partial deficiencies are causes of venous thromboembolism. Previous genetic association studies involving antithrombin, PC, and PS were limited by modest sample sizes or by being restricted to candidate genes. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, we meta-analyzed across ancestries the results from 10 genome-wide association studies of plasma levels of antithrombin, PC, PS free, and PS total.
METHODS
Study participants were of European and African ancestries, and genotype data were imputed to TOPMed, a dense multiancestry reference panel. Each of the 10 studies conducted a genome-wide association studies for each phenotype and summary results were meta-analyzed, stratified by ancestry. Analysis of antithrombin included 25 243 European ancestry and 2688 African ancestry participants, PC analysis included 16 597 European ancestry and 2688 African ancestry participants, PSF and PST analysis included 4113 and 6409 European ancestry participants. We also conducted transcriptome-wide association analyses and multiphenotype analysis to discover additional associations. Novel genome-wide association studies and transcriptome-wide association analyses findings were validated by in vitro functional experiments. Mendelian randomization was performed to assess the causal relationship between these proteins and cardiovascular outcomes.
RESULTS
Genome-wide association studies meta-analyses identified 4 newly associated loci: 3 with antithrombin levels (, , and ) and 1 with PS levels (-). transcriptome-wide association analyses identified 3 newly associated genes: 1 with antithrombin level (), 1 with PC (), and 1 with PS (). In addition, we replicated 7 independent loci reported in previous studies. Functional experiments provided evidence for the involvement of , , and genes in antithrombin regulation.
CONCLUSIONS
The use of larger sample sizes, diverse populations, and a denser imputation reference panel allowed the detection of 7 novel genomic loci associated with plasma antithrombin, PC, and PS levels.
Topics: Protein C; Protein S; Genome-Wide Association Study; Antithrombins; Transcriptome; Anticoagulants; Antithrombin III; Polymorphism, Single Nucleotide
PubMed: 37128921
DOI: 10.1161/ATVBAHA.122.318213 -
Research and Practice in Thrombosis and... May 2023Thrombin is a key enzyme in the maintenance of normal hemostatic function and is the central product of an interconnected set of simultaneously occurring cellular and... (Review)
Review
Thrombin is a key enzyme in the maintenance of normal hemostatic function and is the central product of an interconnected set of simultaneously occurring cellular and proteolytic events. Antithrombin (AT) is a natural anticoagulant that downregulates different components of the clotting process, particularly thrombin generation. In good health, well-regulated hemostasis is the result of a balance between procoagulant and anticoagulant elements. Cumulative understanding of the regulation of thrombin generation and its central role in hemostasis and bleeding disorders has led to the clinical development of therapeutic strategies that aim to rebalance hemostasis in individuals with hemophilia and other coagulation factor deficiencies to improve bleeding phenotype. The aim of this review is to discuss the rationale for AT lowering in individuals with hemophilia, with a focus on fitusiran, its mechanism of action, and its potential as a prophylactic therapy for individuals with hemophilia A or B, with or without inhibitors. Fitusiran is an investigational small, interfering RNA therapeutic that targets and lowers AT. It is currently in phase III clinical trials and results have shown its potential to increase thrombin generation, leading to enhanced hemostasis and improved quality of life while reducing the overall treatment burden.
PubMed: 37358958
DOI: 10.1016/j.rpth.2023.100179 -
JAMA Surgery Mar 2022There is a lack of evidence regarding the effectiveness and safety of pharmacologic venous thromboembolism (VTE) prophylaxis among patients who undergo neurosurgical...
Association of Venous Thromboembolism Prophylaxis After Neurosurgical Intervention for Traumatic Brain Injury With Thromboembolic Complications, Repeated Neurosurgery, and Mortality.
IMPORTANCE
There is a lack of evidence regarding the effectiveness and safety of pharmacologic venous thromboembolism (VTE) prophylaxis among patients who undergo neurosurgical interventions for traumatic brain injury (TBI).
OBJECTIVE
To measure the association between timing of VTE prophylaxis after urgent neurosurgical intervention for TBI and thromboembolic and intracranial complications.
DESIGN, SETTING, AND PARTICIPANTS
This retrospective cohort study included adult patients (aged ≥16 years) who underwent urgent neurosurgical interventions (craniotomy/craniectomy or intracranial monitor/drain insertion within 24 hours after admission) for TBI at level 1 and 2 trauma centers participating in the American College of Surgeons Trauma Quality Improvement Program between January 1, 2012, and December 31, 2016. Data were analyzed from January to August 2020.
EXPOSURES
Timing of pharmacologic VTE prophylaxis initiation after urgent neurosurgical intervention (prophylaxis delay) measured in days (24-hour periods).
MAIN OUTCOMES AND MEASURES
The primary outcome was VTE (deep vein thrombosis or pulmonary embolism). Secondary outcomes were repeated neurosurgery (neurosurgical reintervention after initiation of VTE prophylaxis) and mortality. Hierarchical logistic regression models were used to evaluate the association between prophylaxis delay and each outcome at the patient level and were adjusted for patient baseline and injury characteristics.
RESULTS
The study included 4951 patients (3676 [74%] male; median age, 50 years [IQR, 31-64 years]) who underwent urgent neurosurgical intervention for TBI at 304 trauma centers. The median prophylaxis delay was 3 days (IQR, 1-5 days). After adjustment for patient baseline and injury characteristics, prophylaxis delay was associated with increased odds of VTE (adjusted odds ratio [aOR], 1.08 per day; 95% CI, 1.04-1.12). Earlier initiation of prophylaxis was associated with increased risk of repeated neurosurgery. During the first 3 days, each additional day of prophylaxis delay was associated with a 28% decrease in odds of repeated neurosurgery (aOR, 0.72 per day; 95% CI, 0.59-0.88). After 3 days, each additional day of prophylaxis delay was associated with an additional 15% decrease in odds of repeated neurosurgery (aOR, 0.85 per day; 95% CI, 0.80-0.90). Earlier prophylaxis was associated with greater mortality among patients who initially underwent intracranial monitor/drain procedures, such that each additional day of prophylaxis delay was associated with decreased odds of death (aOR, 0.94 per day; 95% CI, 0.89-0.99).
CONCLUSIONS AND RELEVANCE
In this cohort study of patients who underwent urgent neurosurgical interventions for TBI, early pharmacologic VTE prophylaxis was associated with reduced risk of thromboembolism. However, earlier initiation of prophylaxis was associated with increased risk of repeated neurosurgery. These findings suggest that although timely initiation of prophylaxis should be prioritized, caution should be used particularly during the first 3 days after the index procedure, when this risk appears to be highest.
Topics: Adult; Anticoagulants; Brain Injuries, Traumatic; Cohort Studies; Female; Humans; Male; Middle Aged; Neurosurgery; Retrospective Studies; Venous Thromboembolism
PubMed: 34910096
DOI: 10.1001/jamasurg.2021.5794 -
International Journal of Surgery... 2022Many of the effects of pneumoperitoneum on cardiovascular, respiratory and metabolic systems have been discussed in Literature, but very little is known about the...
BACKGROUND
Many of the effects of pneumoperitoneum on cardiovascular, respiratory and metabolic systems have been discussed in Literature, but very little is known about the variations of the hemocoagulative parameters in patients undergoing laparoscopic surgery. The purpose of this study is to analyze the variations of the hemocoagulative parameters in patients undergoing elective laparoscopic cholecystectomy for symptomatic gallbladder stones. An eventual statistically significant difference linked to different pressure settings of pneumoperitoneum will allow selecting a specific intrabdominal pressure for a more adequate treatment with a lower incidence of pneumoperitoneum related complications.
MATERIALS AND METHODS
The clinical trial was conducted on 43 patients assigned in two groups based on the intra-abdominal pressure: group A, 27 patients, 12 mmHg, and group B, 16 patients, 8 mmHg. Hemoglobin, hematocrit, platelets count, PT ratio, aPTT, Fibrinogen, D-dimer, Von Willebrand factor, Factor II, Lupus Anticoagulant, Antithrombin III, Protein C, Protein S, Anticardiolipin IgG and IgM, anti-beta 2-Glicoprotein IgG and IgM were evaluated.
RESULTS
For group A, patient's variations were observed for D-dimer, Factor II, von Willembrand factor and protein C reactive, while for patients belonging to group B the parameters most affected were PT ratio, anti-thrombin III and protein C reactive.D-dimer values increased significantly in group A, a statistically significant decrease in anti-thrombin III levels was detected in group B, and a statistically significant difference in PT ratio in patients belonging to group B was observed.
CONCLUSION
The statistical analysis showed no significant difference in the post-operative parameters when comparing the two groups of patients. Alterations of the coagulation parameters were present between pre- and post-operative data within the same group, namely a higher abdominal pressure is linked to a prothrombotic state. The question is worthy of further studies.
HIGHLIGHTS
- Variations of the hemocoagulative parameters in patients undergoing laparoscopy are still a matter of study;- Pneumoperitoneum seems to cause alterations in the hemocoagulative parameters, which could be influenced by the pneumoperitoneum pressure;- An eventual statistically significant difference linked to different pressure settings of pneumoperitoneum will allow selecting a specific intrabdominal pressure for a more adequate surgical treatment with a lower incidence of pneumoperitoneum related complications.
PubMed: 35800883
DOI: 10.29337/ijsp.173 -
Blood Jul 2022
Topics: Antithrombin III; Antithrombin III Deficiency; Antithrombins; Glycosylation; Humans; Sugars; Thrombophilia
PubMed: 35834281
DOI: 10.1182/blood.2022016677 -
Der Nephrologe 2021The aim of this article is to explain the clinical benefits of the growing knowledge about severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition to... (Review)
Review
The aim of this article is to explain the clinical benefits of the growing knowledge about severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition to the lungs, SARS-CoV‑2 can invade multiple cell types in other organs, such as the kidneys and replicate there. Important damaging pathways of the virus, such as vascular endotheliitis, thrombotic events and systemic cytokine release are still incompletely understood. Coronavirus disease 2019 (COVID-19) is a systemic disease that necessitates intensive medical care and in particular, internal medicine involvement and represents a major challenge for all disciplines of internal medicine. Among these, nephrology in particular is involved in the fight against COVID-19 in a variety of ways: urine investigations can provide indications of multiple organ involvement, endotheliitis, microthrombi and microcirculation damage, etc. Experience with low serum albumin levels and antithrombin III activity in nephrotic patients helps to point out the decreasing effects of loop diuretics and heparin to other specialist disciplines. Nephrological knowledge of the complications of hypoalbuminemia and "resistance" to diuretics must lead to an early implementation of renal replacement procedures in order to be able to prevent mechanical ventilation in COVID-19 intensive care patients with increased extracellular lung fluid. The kidneys can be used as a seismograph for severe courses of COVID-19 and nephrological knowledge can be brought to use to optimize the intensive medical care for critically ill patients. Both together have the potential to considerably reduce morbidity and mortality further.
PubMed: 33343739
DOI: 10.1007/s11560-020-00470-2 -
Journal of Thrombosis and Haemostasis :... Dec 2020Antithrombin (AT) is a major plasma glycoprotein of the serpin superfamily that regulates the proteolytic activity of the procoagulant proteases of both intrinsic and... (Review)
Review
Antithrombin (AT) is a major plasma glycoprotein of the serpin superfamily that regulates the proteolytic activity of the procoagulant proteases of both intrinsic and extrinsic pathways. Two important structural features that participate in the regulatory function of AT include a mobile reactive center loop that binds to active site of coagulation proteases, trapping them in the form of inactive covalent complexes, and a basic D-helix that binds to therapeutic heparins and heparan sulfate proteoglycans (HSPGs) on vascular endothelial cells. The binding of D-helix of AT by therapeutic heparins promotes the reactivity of the serpin with coagulation proteases by several orders of magnitude by both a conformational activation of the serpin and a template (bridging) mechanism. In addition to its essential anticoagulant function, AT elicits a potent anti-inflammatory signaling response when it binds to distinct vascular endothelial cell HSPGs, thereby inducing prostacyclin synthesis. Syndecans-4 has been found as a specific membrane-bound HSPG receptor on endothelial cells that relays the signaling effect of AT to the relevant second messenger molecules in the signal transduction pathways inside the cell. However, following cleavage by coagulation proteases and/or by spontaneous conversion to a latent form, AT loses both its anti-inflammatory activity and high-affinity interaction with heparin and HSPGs. Interestingly, these low-affinity heparin conformers of AT elicit potent proapoptotic and antiangiogenic activities by also binding to specific HSPGs by unknown mechanisms. This review article will summarize current knowledge about mechanisms through which different conformers of AT exert their serine protease inhibitory and intracellular signaling functions in these biological pathways.
Topics: Anticoagulants; Antithrombin III; Antithrombins; Endothelial Cells; Heparin; Signal Transduction
PubMed: 32780936
DOI: 10.1111/jth.15052 -
Journal of Anaesthesiology, Clinical... 2023The hemostatic system undergoes extensive alterations following surgical trauma leading to a hypercoagulable state. We assessed and compared the changes in platelet...
BACKGROUND AND AIMS
The hemostatic system undergoes extensive alterations following surgical trauma leading to a hypercoagulable state. We assessed and compared the changes in platelet aggregation, coagulation, and fibrinolysis status during normotensive and dexmedetomidine-induced hypotensive anesthesia in patients undergoing spine surgery.
MATERIAL AND METHODS
Sixty patients undergoing spine surgery were randomly allocated into two groups: normotensive and dexmedetomidine-induced hypotensive groups. Platelet aggregation was assessed preoperatively, 15 min after induction, 60 min, and 120 min after skin incision, at the end of surgery, 2 h and 24 h postoperatively. Prothrombin time (PT), activated partial thromboplastin time (aPTT), platelet count, antithrombin III, fibrinogen, and D-dimer levels were measured preoperatively, 2 h and 24 h postoperatively.
RESULTS
Preoperative platelet aggregation (%) was comparable between both groups. Platelet aggregation significantly increased intraoperative at 120 min after skin incision and postoperatively in the normotensive group compared to the preoperative value ( < 0.05) but it was insignificantly decreased during the intraoperative induced hypotensive period in the dexmedetomidine-induced hypotensive group ( > 0.05). Postoperative PT, aPTT significantly increased and platelet count, and antithrombin III significantly decreased in the normotensive group compared to the preoperative value ( < 0.05) but they were not significantly changed in the hypotensive group ( > 0.05). Postoperative D-dimer significantly increased in the two groups compared to the preoperative value ( < 0.05).
CONCLUSION
Intraoperative and postoperative platelet aggregation significantly increased in the normotensive group with significant alterations of the coagulation markers. Dexmedetomidine-induced hypotensive anesthesia prevented the increased platelet aggregation that occurred in the normotensive group with better preservation of platelet and coagulation factors.
PubMed: 37250254
DOI: 10.4103/joacp.JOACP_111_21 -
Antithrombin Activity and Association with Risk of Thrombosis and Mortality in Patients with Cancer.International Journal of Molecular... Dec 2022Venous and arterial thromboembolism (VTE/ATE) are common complications in cancer patients. Antithrombin deficiency is a risk factor for thrombosis in the general... (Observational Study)
Observational Study
Venous and arterial thromboembolism (VTE/ATE) are common complications in cancer patients. Antithrombin deficiency is a risk factor for thrombosis in the general population, but its connection to risk of cancer-associated thrombosis is unclear. We investigated the association of antithrombin activity levels with risk of cancer-associated VTE/ATE and all-cause mortality in an observational cohort study including patients with cancer, the Vienna Cancer and Thrombosis Study. In total, 1127 patients were included (45% female, median age: 62 years). Amongst these subjects, 110 (9.7%) patients were diagnosed with VTE, 32 (2.8%) with ATE, and 563 (49.9%) died. Antithrombin was not associated with a risk of VTE (subdistribution hazard ratio (SHR): 1.00 per 1% increase in antithrombin level; 95% CI: 0.99-1.01) or ATE (SHR: 1.00; 95% CI: 0.98-1.03). However, antithrombin showed a u-shaped association with the risk of all-cause death, i.e., patients with very low but also very high levels had poorer overall survival. In the subgroup of patients with brain tumors, higher antithrombin levels were associated with ATE risk (SHR: 1.02 per 1% increase; 95% CI: 1.00-1.04) and mortality (HR: 1.01 per 1% increase; 95% CI: 1.00-1.02). Both high and low antithrombin activity was associated with the risk of death. However, no association with cancer-associated VTE and ATE across all cancer types was found, with the exception of in brain tumors.
Topics: Humans; Female; Middle Aged; Male; Antithrombins; Venous Thromboembolism; Antithrombin III; Thrombosis; Risk Factors; Brain Neoplasms
PubMed: 36555414
DOI: 10.3390/ijms232415770 -
European Journal of Gastroenterology &... Aug 2023Patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) are characterized by severe liver function impairment, coagulation disorder, and...
OBJECTIVE
Patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) are characterized by severe liver function impairment, coagulation disorder, and multiple organ function impairment. The aim of this study was to explore the predictive value of antithrombin Ⅲ activity to the prognosis of HBV-ACLF patients.
METHODS
A total of 186 HBV-ACLF patients were included in the analysis, and the baseline clinical data of patients were recorded to analyze the risk factors affecting the 30-day survival outcome of patients. Bacterial infection, sepsis, and hepatic encephalopathy were observed in ACLF patients. Antithrombin Ⅲ activity and serum cytokine levels were determined.
RESULTS
The antithrombin Ⅲ activity of ACLF patients in the death group was significantly lower than that in the survival group, and antithrombin Ⅲ activity was independent factors affecting the 30-day outcome. The areas under the receiver operation characteristic (ROC) curve of antithrombin Ⅲ activity to predict the 30-day mortality of ACLF was 0.799. Survival analysis showed that the mortality of patients with antithrombin Ⅲ activity less than 13% was significantly increased. Patients with bacterial infection and sepsis had lower antithrombin Ⅲ activity than those without infection. Antithrombin Ⅲ activity was positively correlated with platelet count, fibrinogen, interferon (IFN)-γ, interleukin (IL)-13, IL-1β, IL-4, IL-6, tumor necrosis factor-α, IL-23, IL-27, and IFN-α, but negatively correlated with C-reactive protein, D dimer, total bilirubin, and creatinine levels.
CONCLUSION
As a natural anticoagulant, antithrombin Ⅲ can be regarded as a marker of inflammation and infection in patients with HBV-ACLF, and as a predictor of survival outcome in patients with ACLF.
Topics: Humans; Hepatitis B virus; Antithrombin III; Acute-On-Chronic Liver Failure; Prognosis; Inflammation; Anticoagulants; Sepsis; Hepatitis B, Chronic; Hepatitis B; Retrospective Studies
PubMed: 37395245
DOI: 10.1097/MEG.0000000000002571