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Clinical Pharmacokinetics May 2022The pathophysiology of sepsis alters drug pharmacokinetics, resulting in inadequate drug exposure and target-site concentration. Suboptimal exposure leads to treatment... (Review)
Review
The pathophysiology of sepsis alters drug pharmacokinetics, resulting in inadequate drug exposure and target-site concentration. Suboptimal exposure leads to treatment failure and the development of antimicrobial resistance. Therefore, we seek to optimize antimicrobial therapy in sepsis by selecting the right drug and the correct dosage. A prerequisite for achieving this goal is characterization and understanding of the mechanisms of pharmacokinetic alterations. However, most infections take place not in blood but in different body compartments. Since tissue pharmacokinetic assessment is not feasible in daily practice, we need to tailor antibiotic treatment according to the specific patient's pathophysiological processes. The complex pathophysiology of sepsis and the ineffectiveness of current targeted therapies suggest that treatments guided by biomarkers predicting target-site concentration could provide a new therapeutic strategy. Inflammation, endothelial and coagulation activation markers, and blood flow parameters might be indicators of impaired tissue distribution. Moreover, hepatic and renal dysfunction biomarkers can predict not only drug metabolism and clearance but also drug distribution. Identification of the right biomarkers can direct drug dosing and provide timely feedback on its effectiveness. Therefore, this might decrease antibiotic resistance and the mortality of critically ill patients. This article fills the literature gap by characterizing patient biomarkers that might be used to predict unbound plasma-to-tissue drug distribution in critically ill patients. Although all biomarkers must be clinically evaluated with the ultimate goal of combining them in a clinically feasible scoring system, we support the concept that the appropriate biomarkers could be used to direct targeted antibiotic dosing. ADAMTS-13 a disintegrin-like and metalloprotease with thrombospondin type 1 motif no. 13, ALAT alanine amino transferase, APACHE IV Acute Physiology and Chronic Health Evaluation-IV, aPPT activated partial thromboplastin time, ASAT aspartate amino transferase, AT antithrombin, Ca-V-O oxygen content difference, arterial-venous, CRP C-reactive protein, ELAM endothelial leukocyte adhesion molecule, ICAM intercellular adhesion molecule, IL interleukin, INR international normalized ratio, LBP lipopolysaccharide-binding protein, MCP monocyte chemoattractant protein, mHLA monocytic human leukocyte antigen, MIF migration inhibitory factor, MIP macrophage inflammatory protein, PAI plasminogen activator inhibitor, PCO partial pressure of carbon dioxide, PT prothrombin time, RRT renal replacement therapy, SAPSS III Simplified Acute Physiology Score-III, sO oxygen saturation, SOFA Sequential [Sepsis-related] Organ Failure Assessment, sTREM soluble triggering receptor expressed on myeloid cells 1, TLR toll-like receptor, TNF tumor necrosis factor, VCAM vascular cell adhesion molecule, VEGF vascular endothelial growth factor, vWf von Willebrand factor.
Topics: Anti-Infective Agents; Biomarkers; Critical Illness; Humans; Sepsis; Vascular Endothelial Growth Factor A
PubMed: 35218003
DOI: 10.1007/s40262-021-01102-1 -
Biomedicines May 2021Antithrombin, the main physiological inhibitor of the coagulation cascade, exerts anti-tumor effects on glioblastoma multiforme cells. Antithrombin has different...
Antithrombin, the main physiological inhibitor of the coagulation cascade, exerts anti-tumor effects on glioblastoma multiforme cells. Antithrombin has different conformations: native, heparin-activated, prelatent, latent, and cleaved. The prelatent form has an intermediate affinity between latent and native antithrombin, although it is the most antiangiogenic form. Herein, we investigate the effect of this conformation on the tumorigenic processes of glioblastoma multiforme cells. Antithrombin forms were purified by chromatography. Chromogenic/fluorogenic assays were carried out to evaluate enteropeptidase and hepsin inhibition, two serine proteases involved in these processes. Wound healing, Matrigel invasion and BrdU incorporation assays were performed to study migration, invasion and proliferation. E-cadherin, Vimentin, VEGFA, pAKT, STAT3, pSTAT3, and pERK1/2 expression was assessed by Western blot and/or qRT-PCR. Prelatent antithrombin inhibited both enteropeptidase and hepsin, although it was less efficient than the native conformation. Exposure to prelatent antithrombin significantly reduced migration and invasion but not proliferation of U-87 MG, being the conformation most efficient on migration. Prelatent antithrombin down-regulated VEGFA, pSTAT3, and pERK1/2 expression in U-87 MG cells. Our work elucidates that prelatent antithrombin has surprisingly versatile anti-tumor properties in U-87 MG glioblastoma multiforme cells. This associates with resistance pathway activation, the decreased expression of tumorigenic proteins, and increased angiogenesis, postulating the existence of a new, formerly unknown receptor with potential therapeutic implications.
PubMed: 34067120
DOI: 10.3390/biomedicines9050523 -
International Journal of Molecular... Jul 2023Stroke, a complex and heterogeneous disease, is a leading cause of morbidity and mortality worldwide. The timely therapeutic intervention significantly impacts patient... (Review)
Review
Unlocking the Potential of Stroke Blood Biomarkers: Early Diagnosis, Ischemic vs. Haemorrhagic Differentiation and Haemorrhagic Transformation Risk: A Comprehensive Review.
Stroke, a complex and heterogeneous disease, is a leading cause of morbidity and mortality worldwide. The timely therapeutic intervention significantly impacts patient outcomes, but early stroke diagnosis is challenging due to the lack of specific diagnostic biomarkers. This review critically examines the literature for potential biomarkers that may aid in early diagnosis, differentiation between ischemic and hemorrhagic stroke, and prediction of hemorrhagic transformation in ischemic stroke. After a thorough analysis, four promising biomarkers were identified: Antithrombin III (ATIII), fibrinogen, and ischemia-modified albumin (IMA) for diagnostic purposes; glial fibrillary acidic protein (GFAP), micro RNA 124-3p, and a panel of 11 metabolites for distinguishing between ischemic and hemorrhagic stroke; and matrix metalloproteinase-9 (MMP-9), s100b, and interleukin 33 for predicting hemorrhagic transformation. We propose a biomarker panel integrating these markers, each reflecting different pathophysiological stages of stroke, that could significantly improve stroke patients' early detection and treatment. Despite promising results, further research and validation are needed to demonstrate the clinical utility of this proposed panel for routine stroke treatment.
Topics: Humans; Brain Ischemia; Hemorrhagic Stroke; Biomarkers; Serum Albumin; Stroke
PubMed: 37511304
DOI: 10.3390/ijms241411545 -
Eye (London, England) Oct 2022To assess patients with indirect carotid-cavernous fistulas (CCF) for evidence of hypercoagulable state (HS) by combination of comprehensive medical questionnaire and...
BACKGROUND
To assess patients with indirect carotid-cavernous fistulas (CCF) for evidence of hypercoagulable state (HS) by combination of comprehensive medical questionnaire and laboratory testing.
METHODS
Patients with confirmed diagnosis of CCF treated between 2003 and 2019 were included and administered a questionnaire screening for HS risk factors and undergone laboratory investigations which included complete blood count (CBC), prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen, antiphospholipid antibodies (lupus anticoagulant and anticardiolipin antibody titres), Factor V Leiden, prothrombin, protein C, protein S, antithrombin III, homocysteine, prothrombin G20210, CALR and JAK2 mutation screening. Participants with abnormal laboratory testing and/or past history of ischemic stroke, atrial fibrillation, cancer or hypercoagulability-associated hereditary disorders were deemed to have HS.
RESULTS
Twenty-two patients were enrolled. Seventeen were women and the mean age at diagnosis was 60. Fourteen (64%) had evidence of HS: six on medical history, three with laboratory evidence and five with both. Eight (36%) had current abnormal hypercoagulability markers. One had a diagnosis of Klippel-Trenaunay Syndrome, but no others had evidence of hereditary thrombophilia. Nine were on anti-coagulation initiated after diagnosis of stroke or atrial fibrillation discovered on average 5.5 years after the diagnosis of CCF.
CONCLUSION
A total of 64% percent of patients with previous indirect CCF had evidence of underlying HS indicating that hypercoagulability might play a role in the pathogenesis of CCF. The results support need for comprehensive testing for underlying HS in patients with indirect CCFs to better identify, manage, and prevent further thromboembolic events.
Topics: Antibodies, Anticardiolipin; Antithrombin III; Atrial Fibrillation; Female; Fibrinogen; Fistula; Homocysteine; Humans; Lupus Coagulation Inhibitor; Male; Protein C; Prothrombin; Thrombophilia
PubMed: 34635794
DOI: 10.1038/s41433-021-01801-w -
Korean Journal of Neurotrauma Jun 2023Immune reactions following traumatic brain injury (TBI) cause many complications, including intravascular dissemination. Antithrombin III (AT-III) plays an important...
OBJECTIVE
Immune reactions following traumatic brain injury (TBI) cause many complications, including intravascular dissemination. Antithrombin III (AT-III) plays an important role in suppressing abnormal clot formation and ensuring hemostasis. Therefore, we investigated the efficacy of serum AT-III in patients with severe TBI.
METHODS
This retrospective study included 224 patients with severe TBI who visited a single regional trauma center between 2018 and 2020. AT-III levels were measured immediately after the TBI diagnosis. AT-III deficiency was defined as an AT-III serum level <70%. Patient characteristics, injury severity, and procedures were also investigated. Patient outcomes included Glasgow Outcome Scale scores at discharge and mortality.
RESULTS
AT-III levels were significantly lower in the AT-III deficient group (n=89; 48.27% ± 1.91%) than in the AT-III sufficient group (n = 135, 78.90% ± 1.52%) (p < 0.001). Mortality occurred in 72 of the 224 patients (33.04%), indicating that there were significantly more patients in the AT-III-deficient group (45/89, 50.6%) than in the AT-III-sufficient group (27/135, 20%). Significant risk factors for mortality included the Glasgow Coma Scale score (P = 0.003), pupil dilatation (P = 0.031), disseminated intravascular coagulopathy (P = 0.012), serum AT-III level (P = 0.033), and procedures including barbiturate coma therapy (P = 0.010). Serum AT-III levels were significantly correlated with Glasgow Outcome Scale scores at discharge (correlation coefficient = 0.455, p < 0.001).
CONCLUSION
Patients with AT-III deficiency after severe TBI may require more intensive care during treatment, because AT-III levels reflect injury severity and correlate with mortality.
PubMed: 37431370
DOI: 10.13004/kjnt.2023.19.e29 -
Journal of Clinical Medicine Jul 2023The measurement and identification of plasma biomarkers can support the estimation of risk and diagnosis of deep vein thrombosis (DVT) associated with the use of a... (Review)
Review
BACKGROUND
The measurement and identification of plasma biomarkers can support the estimation of risk and diagnosis of deep vein thrombosis (DVT) associated with the use of a peripherally inserted central catheter (PICC).
OBJECTIVES
This systematic review and meta-analysis aimed to identify the association between the levels of potential biomarkers that reflect the activation of the blood system, long-term vascular complications, inflammatory system, and the occurrence of PICC-related DVT.
METHODS
Seven electronic databases (Embase, Web of Science, Medline, Scopus, Cinahl, Cochrane Central Register of Controlled Trials, and ERIC) were searched to identify literature published until December 2022. Studies were required to report: (I) adult and pediatric patients, outpatient or admitted to clinical, surgical, or ICU with PICC; (II) patients with PICC-related DVT and patients without PICC-related DVT as a comparator; and (III) at least one biomarker available. The Newcastle-Ottawa Scale was used to evaluate the quality of the studies. Study precision was evaluated by using a funnel plot for platelets level. We provided a narrative synthesis and meta-analysis of the findings on the biomarkers' outcomes of the studies. We pooled the results using random effects meta-analysis. The meta-analysis was conducted using Review Manager software v5.4. This systematic review is registered in PROSPERO (CRD42018108871).
RESULTS
Of the 3564 studies identified (after duplication removal), 28 were included. PICC-related DVT was associated with higher D-dimers (0.37 μg/mL, 95% CI 0.02, 0.72; = 0.04, I = 92%; for heterogeneity < 0.00001) and with higher platelets (8.76 × 10/L, 95% CI 1.62, 15.91; = 0.02, I = 41%; for heterogeneity = 0.06).
CONCLUSIONS
High levels of D-dimer and platelet were associated with DVT in patients with PICC. However, biomarkers such as APTT, fibrinogen, FDP, glucose, hemoglobin, glycated hemoglobin, INR, prothrombin time, prothrombin fragment 1.2, the thrombin-antithrombin complex, and WBC were not related to the development of DVT associated with PICC.
PubMed: 37445515
DOI: 10.3390/jcm12134480 -
The Journal of Trauma and Acute Care... Jul 2021Neuroinflammation and cerebral edema development following severe traumatic brain injury (TBI) affect subsequent cognitive recovery. Independent of its anticoagulant...
BACKGROUND
Neuroinflammation and cerebral edema development following severe traumatic brain injury (TBI) affect subsequent cognitive recovery. Independent of its anticoagulant effects, antithrombin III (AT-III) has been shown to block neurovascular inflammation after severe TBI, reduce cerebral endothelial-leukocyte interactions, and decrease blood-brain barrier permeability. We hypothesized that AT-III administration after TBI would improve post-TBI cognitive recovery, specifically enhancing learning, and memory.
METHODS
Fifteen CD1 male mice were randomized to undergo severe TBI (controlled cortical impact [CCI]: velocity, 6 m/s; depth, 1 mm; diameter, 3 mm) or sham craniotomy and received either intravenous AT-III (250 IU/kg) or vehicle (VEH/saline) 15 minutes and 24 hours post-TBI. Animals underwent Morris water maze testing from 6 to 14 days postinjury consisting of cued learning trials (platform visible), spatial learning trials (platform invisible, spatial cues present), and probe (memory) trials (platform removed, spatial cues present). Intergroup differences were assessed by the Kruskal-Wallis test (p < 0.05).
RESULTS
Morris water maze testing demonstrated that cumulative cued learning (overall mean time in seconds to reach the platform on days 6-8) was worst in CCI-VEH animals (26.1 ± 2.4 seconds) compared with CCI-AT-III counterparts (20.3 ± 2.1 seconds, p < 0.01). Cumulative noncued spatial learning was also worst in the CCI-VEH group (23.4 ± 1.8 seconds) but improved with AT-III (17.6 ± 1.5 seconds, p < 0.01). In probe trials, AT-III failed to significantly improve memory ability. Animals that underwent sham craniotomy demonstrated preserved learning and memory compared with all CCI counterparts (p < 0.05).
CONCLUSION
Antithrombin III improves neurocognitive recovery weeks after TBI. This improvement is particularly related to improvement in learning but not memory function. Pharmacologic support of enhanced learning may support new skill acquisition or relearning to improve outcomes after TBI.
LEVEL OF EVIDENCE
Therapeutic/care management, level II.
Topics: Animals; Antithrombin III; Blood-Brain Barrier; Chronic Traumatic Encephalopathy; Cognition; Cues; Disease Models, Animal; Male; Mice; Morris Water Maze Test; Random Allocation
PubMed: 33605694
DOI: 10.1097/TA.0000000000003112 -
BMC Cancer Oct 2022Coagulation and fibrinolysis are distinct processes that are highly correlated. Cells control coagulation and fibrinolysis by expression of tissue factor and...
BACKGROUND
Coagulation and fibrinolysis are distinct processes that are highly correlated. Cells control coagulation and fibrinolysis by expression of tissue factor and urokinase-type plasminogen activator receptor on their surface. Tumor cells express these proteins, adjust their microenvironment and induce tumor exacerbation. We hypothesized that the expression of plasma markers for coagulation and fibrinolysis in patients with soft tissue sarcomas (STSs) was dependent on the level of tumor malignancy. To elucidate which markers are predictive of recurrence, metastasis and prognosis, coagulation or fibrinolysis, we analyzed the correlation between plasma levels of thrombin-antithrombin III complex (TAT), soluble fibrin (SF), plasmin-α2 plasmin inhibitor complex (PIC), D-dimer (DD) and clinical parameters in patients with STSs.
METHODS
TAT, SF, PIC or DD were measured in pre-treatment blood samples from 64 patients with primary STSs and analyzed with clinicopathological parameters, and 5-year recurrence free survival (RFS), 5-year metastasis free survival (MFS) and 5-year overall survival (OS) were evaluated.
RESULTS
The metastasis group had significantly higher DD (p = 0.0394), PIC (p = 0.00532) and SF (p = 0.00249) concentrations than the group without metastasis. The group that died of disease showed significantly higher DD (p = 0.00105), PIC (p = 0.000542), SF (p = 0.000126) and TAT (p = 0.0373) than surviving patients. By dividing the patients into low and high groups, the group with high DD, PIC, SF and TAT showed significantly lower 5-year MFS and 5-year OS than the corresponding low group. Furthermore, in multivariate COX proportional hazard analysis of continuous variables for 5-year MFS, only PIC was found to be a significant factor (HR: 2.14).
CONCLUSION
Fibrinolysis was better than coagulation at reflecting the disease condition of patients with STS. Notably, PIC levels ≥ 1.1 can not only predict the risk of metastasis and poor prognosis, but also increasing PIC levels correspond to further increases in risks of metastasis and poor prognosis.
Topics: Humans; Fibrinolysis; Fibrinolysin; Receptors, Urokinase Plasminogen Activator; Antifibrinolytic Agents; Thromboplastin; Peptide Hydrolases; Biomarkers; Sarcoma; Tumor Microenvironment
PubMed: 36258189
DOI: 10.1186/s12885-022-10106-4 -
JACC. Asia Jun 2022The role of congenital thrombophilia in chronic thromboembolic pulmonary hypertension (CTEPH) remains unresolved.
BACKGROUND
The role of congenital thrombophilia in chronic thromboembolic pulmonary hypertension (CTEPH) remains unresolved.
OBJECTIVES
The purpose of this study was to investigate the prevalence, genetic background, and clinical phenotype of congenital thrombophilia in CTEPH.
METHODS
In total, 367 patients with CTEPH from May 2013 to December 2020 were consecutively enrolled in this cross-sectional study in FuWai Hospital and Peking Union Medical College Hospital in China. The primary outcome was the occurrence of congenital thrombophilia diagnosed through tests for congenital anticoagulants activity (including protein C, protein S, and antithrombin III), factor V Leiden and prothrombin G20210A sequence variants. Next-generation sequencing was conducted for patients with congenital thrombophilia. Clinical phenotype was compared between patients with and without thrombophilia.
RESULTS
A total of 36 (9.8%; 95% CI: 6.8%-12.9%) patients were diagnosed as congenital thrombophilia, including 13 protein C deficiency (3.5%; 95% CI: 1.6%-5.4%), 19 protein S deficiency (5.2%; 95% CI: 2.9%-7.5%), and 4 antithrombin III deficiency (1.1%; 95% CI: 0%-2.2%). No factor V Leiden or prothrombin G20210A sequence variants were identified. Genotype for patients with thrombophilia revealed that 10 (76.9%) protein C deficiency patients were PROC sequence variant carriers, 4 (21.1%) protein S deficiency were PROS1 sequence variant carriers, and 2 (50.0%) antithrombin III deficiency were SERPINC1 sequence variant carriers. In the logistic regression model, male sex (OR: 3.24; 95% CI: 1.43-7.31) and proximal lesion in pulmonary arteries (OR: 4.10; 95% CI: 1.91-8.85) had significant differences between the congenital thrombophilia and nonthrombophilia group in CTEPH patients.
CONCLUSIONS
Congenital thrombophilia was not rare. Male sex and proximal lesion in pulmonary arteries might be the specific clinical phenotype for CTEPH patients with congenital thrombophilia.
PubMed: 36338413
DOI: 10.1016/j.jacasi.2022.02.010 -
American Journal of Translational... 2022This study aimed to investigate the role of antithrombin III (AT-III) and D-dimer (D-Dimer) in patients with unexplained recurrent spontaneous abortion (URSA); Methods:...
OBJECTIVE
This study aimed to investigate the role of antithrombin III (AT-III) and D-dimer (D-Dimer) in patients with unexplained recurrent spontaneous abortion (URSA); Methods: Sixty pregnant women with URSA (AEP group), 80 non-pregnant women with a history of URSA (ANP group), 50 healthy women in early pregnancy (NEP group) and 50 healthy non-pregnant women (NNP group) were retrospectively enrolled. Their serum AT-III and D-Dimer levels were measured. The patients in the ANP group were divided into three subgroups according to the number of miscarriages: 3 miscarriages (32 cases), 4 miscarriages (22 cases), and >4 miscarriages (26 cases), and the differences in serum AT-III and D-Dimer levels among these subgroups were compared. The patients in the AEP group were monitored for changes in AT-III and D-Dimer levels, and finally the diagnostic value of AT-III and D-Dimer levels were calculated for the prethrombotic state of URSA.
RESULTS
(1) AT-III and D-Dimer levels differed significantly among the 4 groups (P<0.05); (2) As the number of miscarriages increased, D-Dimer levels elevated and AT-III levels decreased, with significant differences among three subgroups (P<0.05); (3) As the treatment proceeded, patients in AEP and ANP groups showed a tendency for a gradual increase in AT-III levels and a significant decrease in D-Dimer levels, with significant differences before and after treatment (P<0.05); (4) The diagnostic AUC of AT-III and D-Dimer in the prediction of prethrombotic state of URSA were 0.8922 (95% CI=0.8026-0.9819, P<0.0001) and 0.8776 (95% CI=0.7643-0.9909, P<0.0001).
CONCLUSION
AT-III and D Dimer levels are closely associated with URSA. The results of this study have preliminarily confirmed the feasibility of applying AT-III and D Dimer to screen the prethrombotic state of URSA, and their clinical application will help provide a reference for determining the cause of miscarriage in the infertile population with URSA and facilitate successful pregnancy.
PubMed: 35559371
DOI: No ID Found