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Thrombosis and Haemostasis Sep 2023Deficiency of antithrombin increases risk of venous thromboembolism. We hypothesized that antithrombin deficiency affects fibrin clot structure and function.
BACKGROUND
Deficiency of antithrombin increases risk of venous thromboembolism. We hypothesized that antithrombin deficiency affects fibrin clot structure and function.
METHODS
We evaluated 148 patients (age: 38 [32-50] years; 70% women) with genetically confirmed antithrombin deficiency and 50 healthy controls. Fibrin clot permeability (K) and clot lysis time (CLT) along with thrombin generation capacity were assessed before and after antithrombin activity normalization in vitro.
RESULTS
Antithrombin-deficient patients had lower antithrombin activity (-39%) and antigen levels (-23%) compared with controls (both < 0.01). Prothrombin fragment 1 + 2 levels were 26.5% higher in patients with antithrombin deficiency than in controls along with 94% increased endogenous thrombin potential (ETP) and 108% higher peak thrombin (all < 0.01). Antithrombin deficiency was associated with 18% reduced K and 35% prolonged CLT (both < 0.001). Patients with type I ( = 65; 43.9%) compared with type II antithrombin deficiency ( = 83; 56.1%) had 22.5% lower antithrombin activity ( < 0.001) and despite similar fibrinogen levels, 8.4% reduced K, 18% prolonged CLT, and 30% higher ETP (all < 0.01). Reduced K was associated with lower antithrombin antigen level (β = - 6.1, 95% confidence interval [CI]: -1.7 to -10.5), while prolonged CLT was associated with lower antithrombin antigen (β = - 69.6, 95% CI: -9.6 to -129.7), activity (β = - 2.4, 95% CI: -0.3 to -4.5), higher PAI-1 (β = 12.1, 95% CI: 7.7-16.5), and thrombin-activatable fibrinolysis inhibitor levels (β = 3.8, 95% CI: 1.9-5.7). Addition of exogenous antithrombin reduced ETP (-42%) and peak thrombin (-21%), and improved K (+8%) and CLT (-12%; all < 0.01).
CONCLUSION
Our study suggests that enhanced thrombin generation and prothrombotic plasma fibrin clot phenotype can contribute to increased risk of thrombosis in patients with antithrombin deficiency.
Topics: Female; Humans; Male; Anticoagulants; Antithrombins; Fibrin; Fibrin Clot Lysis Time; Fibrinolysis; Phenotype; Thrombin; Thrombosis
PubMed: 37201530
DOI: 10.1055/s-0043-1768712 -
Circulation Jan 2024
Randomized Controlled Trial
Topics: Humans; Anticoagulants; Factor Xa Inhibitors; Hypertension, Pulmonary; Pyridines; Single-Blind Method; Thiazoles; Treatment Outcome; Warfarin
PubMed: 37956127
DOI: 10.1161/CIRCULATIONAHA.123.067528 -
Scientific Reports Dec 2023Disseminated intravascular coagulation (DIC) is a frequent complication in patients with sepsis and is associated with increased mortality. Anticoagulant therapy may be...
Risk stratification utilizing sequential organ failure assessment (SOFA) score, antithrombin activity, and demographic data in sepsis-associated disseminated intravascular coagulation (DIC).
Disseminated intravascular coagulation (DIC) is a frequent complication in patients with sepsis and is associated with increased mortality. Anticoagulant therapy may be appropriate for certain patients with DIC, particularly those with increased disease severity and deficiency in the physiologic anticoagulant antithrombin. We retrospectively analyzed post-marketing survey data from 1562 patients with sepsis-associated DIC and antithrombin activity of 70% or less. All the patients were treated with antithrombin concentrates. Baseline sequential organ failure assessment (SOFA) score, DIC score, and antithrombin activity were assessed. Cox multivariate regression analysis, Kaplan-Meier curve analysis, and receiver operating characteristic (ROC) curve analysis were performed to evaluate the performance of variables used to assess mortality. Furthermore, a decision tree was constructed to classify the risk of 28-day mortality. COX multivariate regression analysis demonstrated a significant association of age, sex, baseline SOFA score, baseline antithrombin activity, and the presence of pneumonia or skin/soft tissue infection with increased mortality. The area under the curve of SOFA score or antithrombin activity for mortality was 0.700 and 0.614, respectively. Kaplan-Meier analysis demonstrated that mortality was significantly higher in patients with SOFA score ≥ 12 and antithrombin activity < 47%. The decision tree analysis accurately classified the risk of death into high (> 40%), medium (40%-20%), and low (< 20%) categories in 86.1% of the cohort. Twenty eight-day mortality can be strongly predicted using baseline SOFA score, antithrombin activity, infection site, age, and sex as variables in the clinical decision tree for patients with sepsis-associated disseminated intravascular coagulation (DIC).
Topics: Humans; Antithrombins; Organ Dysfunction Scores; Disseminated Intravascular Coagulation; Retrospective Studies; Anticoagulants; Antithrombin III; Sepsis; Risk Assessment; Demography
PubMed: 38110515
DOI: 10.1038/s41598-023-49855-y -
The New England Journal of Medicine May 2024
Topics: Humans; Administration, Oral; Anticoagulants; Cerebral Hemorrhage; Factor Xa; Factor Xa Inhibitors; Randomized Controlled Trials as Topic
PubMed: 38749038
DOI: 10.1056/NEJMe2403726 -
Paediatric Anaesthesia May 2024
Topics: Humans; Heparin; Hirudins; Anticoagulants; Peptide Fragments; Recombinant Proteins; Treatment Outcome
PubMed: 38440919
DOI: 10.1111/pan.14868 -
Journal de Medecine Vasculaire Sep 2023Current evidence-based clinical practice guidelines recommend the use of both low-molecular-weight heparin (LMWH) and direct factor Xa inhibitors (apixapan, edoxaban and... (Review)
Review
Current evidence-based clinical practice guidelines recommend the use of both low-molecular-weight heparin (LMWH) and direct factor Xa inhibitors (apixapan, edoxaban and rivaroxaban) as first-line options for the treatment of venous thromboembolism (VTE) in patients with cancer. However, most of these guidelines refer to the general cancer patient population and provide limited guidance for specific subgroups of patients at particularly high risk of bleeding, such as those with gastrointestinal cancers, primary or metastatic brain tumors, thrombocytopenia, or renal impairment. In these complex populations, the management of cancer-associated thrombosis (CAT) poses unique challenges and requires a nuanced approach based on the primum non nocere principle. This comprehensive review critically examines the relevant literature and discusses the therapeutic options currently available for the management of CAT in these special situations.
Topics: Humans; Heparin, Low-Molecular-Weight; Venous Thromboembolism; Neoplasms; Rivaroxaban; Factor Xa Inhibitors; Thrombosis
PubMed: 37914457
DOI: 10.1016/j.jdmv.2023.09.001 -
Clinical Laboratory Jul 2023Direct oral anticoagulants (DOAC) such as Xa inhibitors rivaroxaban (riva) and apixaban (apix) are increasingly replacing Vitamin K antagonists in prophylaxis and...
BACKGROUND
Direct oral anticoagulants (DOAC) such as Xa inhibitors rivaroxaban (riva) and apixaban (apix) are increasingly replacing Vitamin K antagonists in prophylaxis and treatment of venous thromboembolism (VTE). Measurements of DOAC plasma levels may be necessary in certain clinical conditions to determine the further dosage. Making decisions is made more difficult by the fact that the peak and trough plasma levels are subject to strong inter-individual fluctuations with overlapping reference ranges. We wanted to find out whether the peak and trough levels can be narrowed if they are determined based on age and gender.
METHODS
Therefore, we collected data on peak and trough anti-Xa concentrations in patients treated with either rivaroxaban (n = 93) or apixaban (n = 51) in one center. After exclusion of blood samples of uncertain oral intake, 83 samples for rivaroxaban and 49 samples for apixaban remained for further analysis. Differences between male (riva n = 42, apix n = 28) and female (riva n = 41 and apix n = 21) as well as young (≤ 60 years, riva n = 44, apix n = 23) and elder (> 60 years) patients (riva n = 39 and apix n = 26) were analyzed by Student`s t-test and retrospective regression.
RESULTS
We found no differences in age and gender for the apix peak levels. But women had significantly higher riva peak concentrations than men (308.8 ± 178.1 ng/mL versus 206.4 ± 80 ng/mL, p = 0.013). Patients older than 60 years had significantly higher riva peak levels than those younger than 60 (293.7 ± 126.7 ng/mL versus 211.7 ± 158.4 ng/mL, p = 1.29 x 10-8).
CONCLUSIONS
In search of narrowing standard peak and trough levels in patients' sera we found significant differ-ences between patients below and above sixty years of age. Gender-associated differences were found in rivaroxa-ban levels possibly explaining DOAC associated hypermenorrhea. In conclusion, gender and age should be included in the determination of peak blood concentration references.
Topics: Humans; Male; Female; Aged; Rivaroxaban; Factor Xa Inhibitors; Retrospective Studies; Anticoagulants; Venous Thromboembolism; Administration, Oral
PubMed: 37436398
DOI: 10.7754/Clin.Lab.2023.230101 -
Microvascular Research Nov 2023Livedoid vasculopathy (LV) is a rare, disabling disease characterized by painful ulcers, livedo reticularis and atrophy blanche. Hypercoagulation, endothelial, and...
BACKGROUND
Livedoid vasculopathy (LV) is a rare, disabling disease characterized by painful ulcers, livedo reticularis and atrophy blanche. Hypercoagulation, endothelial, and microcirculatory dysfunction are believed to be responsible for the pathogenesis of this difficult-to-treat disease.
OBJECTIVES
This study sought to investigate the frequency of endothelial dysfunction, hypercoagulability, and nailfold capillaroscopic features in LV patients to shed light on its etiology.
METHODS
This case-control study included 16 patients with LV, 24 with systemic sclerosis (SSc), and 23 control subjects. Serum markers of endothelial dysfunction soluble endoglin, endocan, endothelin-1, lipoprotein a, plasminogen activator inhibitor-1 (PAI-1), soluble thrombomodulin, and von Willebrand factor were measured using enzyme-linked immunosorbent assays. Flow-mediated dilation and carotid intima-media thickness were examined as markers of endothelial dysfunction, and microcirculation was assessed with nailfold capillaroscopy. Thrombophilia-related parameters, including gene polymorphisms of factor V Leiden, prothrombin, PAI-1 genes, methylenetetrahydrofolate reductase (MTHFR) and factor XIII mutation and serum levels of protein C, protein S, antithrombin, homocysteine, D-dimer and antiphospholipid antibodies were investigated in LV patients.
RESULTS
Plasminogen activator inhibitor-1 and soluble thrombomodulin levels were significantly higher in LV patients compared to control subjects (2.3 [2.05-2.79] ng/ml vs. 1.89 [1.43-2.33] ng/ml, p = 0.007; 1.15 [0.88-1.4] ng/ml vs. 0.76 [0.56-0.9] ng/ml, p = 0.004, respectively). Flow-mediated dilation was 25.4 % lower in the LV patients compared to the control group (14.77 % [11.26-18.26] vs. 19.80 % [16.47-24.88], p = 0.034). Capillaroscopic features, including ramifications (75 % vs. 8.7 %, p < 0.001), avascular areas (25 % vs. 0 %, p = 0.011) and dilatations (33.2 % vs. 0 %, p = 0.016), were significantly higher in LV patients than in controls. LV patients had multiple biochemical or genetic abnormalities related to thrombophilia, including heterozygous factor V Leiden mutations (6.3 %), MTHFR (C677T) mutations (heterozygous 43.8 %, homozygous 18.8 %), MTHFR (A1298C) mutations (heterozygous 37.5 %, homozygous 12.5 %), factor XIII heterozygous mutation (12.5 %), antithrombin deficiency (31.3 %), protein S deficiency (12.5 %), hyperhomocysteinemia (31.3 %), D-dimer elevation (25 %), anti-β2-glycoprotein I (12.5 %), lupus anticoagulant antibodies (6.3 %), and anticardiolipin antibodies (6.3 %).
CONCLUSIONS
In conclusion, LV patients were characterized by an increased presence of thrombophilia-related parameters, and also exhibited vascular endothelial and microcirculatory dysfunction, resembling SSc. These findings support the complex interaction of thrombophilia, endothelial dysfunction, and microcirculation dysregulation in the pathogenesis of LV. Thus, the treatment of LV patients should be individualized, based on the identification of the predominant pathological pathways.
Topics: Humans; Livedo Reticularis; Plasminogen Activator Inhibitor 1; Thrombomodulin; Case-Control Studies; Factor XIII; Carotid Intima-Media Thickness; Microcirculation; Microscopic Angioscopy; Thrombophilia; Livedoid Vasculopathy; Antithrombins
PubMed: 37543163
DOI: 10.1016/j.mvr.2023.104591 -
Expert Review of Cardiovascular Therapy 2023Currently approved direct oral anticoagulants (DOACs) target thrombin or coagulation factor Xa. Administered in fixed doses without routine laboratory monitoring, DOACs... (Review)
Review
INTRODUCTION
Currently approved direct oral anticoagulants (DOACs) target thrombin or coagulation factor Xa. Administered in fixed doses without routine laboratory monitoring, DOACs have simplified the approach to oral anticoagulation, when previously the choice was limited to vitamin K antagonists (VKAs).
AREA COVERED
We discuss a) unresolved issues related to optimal use of DOACs and b) new developments including the potential for FXIa inhibitors to be effective and safer anticoagulants.
EXPERT OPINION
By simplifying oral anticoagulation, DOACs have facilitated the uptake of anticoagulation. The DOACs are approved for stroke prevention in atrial fibrillation and for the prevention and treatment of venous thromboembolism, and their indications are expanding to include the prevention of atherothrombosis. DOACs have now replaced vitamin K antagonists (VKAs) for most indications, but not all. DOACs are inferior to VKAs for patients with mechanical heart valves, left ventricular assist device, rheumatic atrial fibrillation, and those with antiphospholipid syndrome, and their safety and efficacy are uncertain in some populations (e.g. advanced renal and liver disease). Impediments to use include concerns for bleeding and cost. The newly developed FXIa and FXIIa inhibitors have the potential to be safer than current anticoagulants, but phase 3 trials are needed to confirm their clinical efficacy and safety.
Topics: Humans; Factor Xa Inhibitors; Atrial Fibrillation; Anticoagulants; Hemorrhage; Fibrinolytic Agents; Vitamin K; Administration, Oral; Stroke
PubMed: 37837206
DOI: 10.1080/14779072.2023.2271388 -
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