Thrombin-activatable Fibrinolysis Inhibitor Research Articles

Impaired endogenous fibrinolysis status: a potential prognostic predictor in ischemic stroke.

Stroke confers a severe global healthcare burden, hence exploring risk factors for stroke occurrence and prognosis is important for stroke prevention and post-stroke management strategies. Endogenous fibrinolysis is a spontaneous physiological protective mechanism that dissolves thrombus to maintain vascular patency. Recently, impaired endogenous fibrinolysis has been considered as a potential novel cardiovascular risk factor, but its link with ischaemic stroke in the past has been underappreciated. In this review, we summarize the latest mechanisms of endogenous fibrinolysis, review the current evidence and data on endogenous fibrinolysis in ischemic stroke. It includes the structure of thrombus in ischemic stroke patients, the effect of fibrin structure on the endogenous fibrinolytic efficiency, and the association between intravenous thrombolytic therapy and endogenous fibrinolysis in ischemic stroke. It also includes the single factors (tissue plasminogen activator, urokinase plasminogen activator, plasminogen activator inhibitor-1, thrombin activatable fibrinolysis inhibitor, complement component 3, complement component 5, alpha-2-antiplasmin, plasmin-alpha-2-antiplasmin complex, and lipoprotein[a]), and the global assessments of endogenous fibrinolysis status (thromboelastography, rotational thromboelastometry, and global thrombosis test), and their potential as predictors to identify occurrence or unfavorable functional outcomes of ischemic stroke. All of these assessments present advantages and limitations, and we suggest that the global thrombosis test may be more appropriate for detecting impaired endogenous fibrinolysis status in ischemic stroke patients.

Cutting-Edge Techniques and Drugs for the Treatment of Pulmonary Embolism: Current Knowledge and Future Perspectives.

Pulmonary embolism (PE) is a potentially life-threatening condition requiring prompt diagnosis and treatment. Recent advances have led to the development of newer techniques and drugs aimed at improving PE management, reducing its associated morbidity and mortality and the complications related to anticoagulation. This review provides an overview of the current knowledge and future perspectives on PE treatment. Anticoagulation represents the first-line treatment of hemodynamically stable PE, direct oral anticoagulants being a safe and effective alternative to traditional anticoagulation: these drugs have a rapid onset of action, predictable pharmacokinetics, and low bleeding risk. Systemic fibrinolysis is suggested in patients with cardiac arrest, refractory hypotension, or shock due to PE. With this narrative review, we aim to assess the state of the art of newer techniques and drugs that could radically improve PE management in the near future: (i) mechanical thrombectomy and pulmonary embolectomy are promising techniques reserved to patients with massive PE and contraindications or failure to systemic thrombolysis; (ii) catheter-directed thrombolysis is a minimally invasive approach that can be suggested for the treatment of massive or submassive PE, but the lack of large, randomized controlled trials represents a limitation to widespread use; (iii) novel pharmacological approaches, by agents inhibiting thrombin-activatable fibrinolysis inhibitor, factor Xia, and the complement cascade, are currently under investigation to improve PE-related outcomes in specific settings.

Thrombin activatable fibrinolysis inhibitor plasma levels and TAFI Thr325Ile genetic polymorphism in a cohort of Egyptian sickle cell disease patients and impact on disease severity.

Thrombin is a critical protease modulating thrombosis as well as inflammation, which are one of the main pathophysiological mechanisms in sickle vasculopathy, and its levels were reported to be high in sickle cell disease (SCD). The thrombin-thrombomodulin complex activates the TAFI inhibitor of fibrinolysis, which acts by reducing plasmin affinity for its substrate thus hindering fibrinolysis. We aimed to determine the influence of the Thr325Ile single nucleotide polymorphism (SNP) on TAFI antigen levels and potential effects on the severity of SCD in a cohort of Egyptian patients. Genotyping of Thr325lle polymorphism using Taq-Man SNP genotyping assay and TAFI level measurement using an enzyme-linked immunosorbent assay were performed for 80 SCD patients (45 homozygous HbSS, 16 S/β0 and 19 Sβ+) as well as 80 age- and gender-matched healthy control subjects. Plasma TAFI levels were higher in SCD patients with Thr325Ile polymorphism, yet the difference was not statistically significant (p=.204). SCD patients with polymorphic genotypes had a greater number of hospital admissions (p=.03). Ten patients with acute chest syndrome had the homozygous polymorphic genotype (GG), and all patients with pulmonary hypertension had the polymorphic genotype (six were homozygous [GG] and five were heterozygous [GA]). Patients with SCD complicated with pulmonary hypertension showed significantly higher plasma TAFI levels (p=.044). The analysis of Thr325Ile polymorphisms combined with plasma TAFI levels suggests that the analyzed SNP could influence plasma TAFL levels and SCD disease severity and hospitalization rates, which could be predictors for complex disease.

High thrombin-activatable fibrinolysis inhibitor expression in thrombi from stroke patients in elevated estrogen states

BackgroundThe risk of acute ischemic stroke (AIS) associated with high estrogen states, including pregnant patients and those using oral contraceptives, has been well documented. We described the histological composition of thrombi collected in these cases.MethodsFrom a prospective tissue registry (STRIP registry) of thrombi retrieved during mechanical thrombectomy for AIS, we identified 5 patients with high estrogen states: 1 post-partum patient, 1 undergoing hormone replacement therapy and 3 consuming oral contraceptive pills. Five male control patients were randomly chosen matched by age. Immunohistochemistry for CD42b (platelets), von Willebrand factor (vWF), thrombin-activatable fibrinolysis inhibitor (TAFI), fibrinogen and plasminogen activator inhibitor-1 (PAI-1) was performed. Expression was quantified using Orbit Image Software. Student’s t-test was performed as appropriate.ResultsMean TAFI content for the high estrogen state group was higher than controls (25.6 ± 11.9% versus 9.3 ± 9.0%, p = 0.043*). Mean platelet content for the high estrogen state group was lower than controls (41.7 ± 10.6% versus 61.8 ± 12.9%, p = 0.029*). No significant difference was found in vWF, fibrinogen and PAI-1 expression. Mean time to recanalize was higher in the high estrogen state group compared to the control group (57.8 ± 27.6 versus 22.6 ± 11.4 min, p = 0.0351*). The mean number of passes required was higher in the high estrogen group compared to controls 4.6 versus 1.2, p = 0.0261*).ConclusionsTAFI expression, a powerful driver of thrombosis, was significantly higher in stroke thrombi among patients with high estrogen states compared to controls.

TAFI phenomenon and its clinical significance

Thrombin activatable fi brinolysis inhibitor (TAFI) is one of the key proteins of fi brinolysis and infl ammation systems. Based on  literature data, information is presented on the biological eff ects of TAFI, the mechanisms of its activation, gene polymorphism  that determines the duration of its action and activity. Nosological forms are listed, where TAFI is important in the pathogenesis  of the development of diseases, its role in experimental and laboratory studies, and the possibility of pharmacological infl uence  on the activity of this protein.

Effects of proprotein convertase subtilisin-kexin type 9 inhibitors on inflammatory and hemostatic parameters in post myocardial infarction patients

Despite progress in treatment, elevated levels of low-density lipoprotein cholesterol (LDL-C) and lipoprotein (a) (Lp(a)), represent a significant part of the residual risk. Both are associated with inflammation and the coagulation fibrinolytic system. The purpose of our research was to evaluate the effect of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) on lipid parameters and indicators of inflammation, coagulation and fibrinolysis. We included 100 post myocardial infarction (MI) patients with insufficiently controlled LDL-C values despite the maximum dose of statin, and highly elevated Lp(a). Patients received alirocumab or evolocumab (150 mg sc or 140 mg sc every two weeks, respectively), or placebo for 6 months.In patients receiving PCSK9i, a significant decrease in total cholesterol (TC), LDL-C, triglycerides (TG) and Lp(a), and an increase in high density lipoprotein cholesterol (p < 0.001 for all) was found. Before treatment, the concentrations of TC, LDL-C and TG correlated with the concentrations of thrombin activatable fibrinolysis inhibitor (r = 0.41, p < 0.001; r = 0.353, p < 0.001; r = 0.311, p = 0.003, respectively), and plasminogen activator inhibitor-1 (r = 0.302, p = 0.007; r = 0.218, p = 0.049; r = 0.278; p = 0.013, respectively). The concentrations of TC and LDL-C correlated with overall fibrinolytic potential (r = −0.220, p = 0.034; r = −0.207, p = 0.047, respectively). The concentration of TG was related to the concentration of interleukin 6 (r = 0.290, p = 0.004) and interleukin 8 (r = 0.332, p = 0.001). No correlations between Lp(a) and inflammatory or hemostatic variables were found. No associations were found after treatment. Our results show that inflammatory cytokines and fibrinolytic parameters are related to LDL-C and not Lp(a) in post-MI patients before and with neither of them following PCSK9i treatment.The trial registration number: NCT04613167, Date of registration: November 3, 2020.

Platelet Microvesicles, Inflammation, and Coagulation Markers: A Pilot Study.

Platelet "Microvesicles" (MVs) are studied for their role in blood coagulation and inflammation. The study aimed to establish if MVs are related to age, plasma levels of inflammation, coagulation, and fibrinolysis markers in healthy individuals. We prospectively enrolled volunteers aged over 18 years. MVs, plasma levels of C-reactive protein (CRP), Interleukin 6 (IL-6), Interleukin 10 (IL-10), Interleukin 17 (IL-17), and transforming growth factor β (TGF-β), fibrinogen, plasminogen activator inhibitor-1 (PAI-1), von Willebrand factor (VWF), homocysteine, factor VII (FVII), thrombin activatable fibrinolysis inhibitor (TAFI), and Protein S were tested. A total of 246 individuals (median age 65 years ("IQR"54-72)) were evaluated. Both univariate analysis and logistic regression models showed that MVs positively correlate with age, CRP, IL-6, IL-10, IL-17, TGF-β, fibrinogen, PAI-1, VWF, FVII, and homocysteine, while inversely correlating with TAFI and Protein S. The ROC curve analysis performed to identify a cut off for MV values (700 kMP) showed a good accuracy with over-range cytokines fibrinolysis factor and coagulation markers. To the best of our knowledge, this study is the first to correlate MVs with an entire panel of cardiovascular risk factors in healthy individuals. A future possible role of MVs in screening exams is suggested.

Changes in the Fibrinolytic System of Patients Infected with Severe Acute Respiratory Syndrome Coronavirus 2

Introduction: In this study, coagulation and fibrinolysis parameters and their association with disease severity were investigated in coronavirus disease (COVID-19) patients. Materials and Methods: COVID-19 patients (n=446) admitted to our institute between February 21, 2021 and March 17, 2022, were recruited. Clinical data and staging were collected from all patients. Blood samples were collected and analyzed for several parameters of fibrinolysis and coagulation, including alpha-2-antiplasmin(α2AP) and plasminogen, thrombin activatable fibrinolysis inhibitor (TAFI), tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), D dimer, and fibrinogen levels. Results: The TAFI, fibrinogen, and tPA levels were significantly higher in participants who died compared to that of patients who recovered (P&amp;lt;0.001). However, PAI-1, tPA, and TAFI were significantly higher in patients admitted to the ICU than those of the healthy controls (P&amp;lt;0.001 for PAI-1 and tPA; P=0.0331 for TAFI). Our results showed that stage C and D COVID-19 patients had significantly higher levels of PAI-1 (P = 0.003). Furthermore, the stage D COVID-19 patients had significantly higher tPA and TAFI values (P=0.003). Conclusions: Hypofibrinolysis was the most prevalent condition among patients with severe COVID-19. In this study, several coagulation markers were elevated, making them suitable prognostic markers for hypofibrinolysis. Figure 1. Plasma levels of different coagulation factors in COVID-19 patients. Plasma isolated from patients that had died due to COVID-19 and those recovering from the disease (top panel).

Fibrinolysis Assessment with Tpa-ROTEM in Patients with Bleeding Disorders of Unknown Cause (BDUC)

Background: In 40-70% of patients referred to the hematologist for evaluation of bleeding symptoms, no cause for their increased bleeding tendency can be found using currently available hemostasis laboratory tests. This group is classified as patients with bleeding disorder of unknown cause (BDUC). The lack of clear guidelines concerning diagnosis, management and genetic counseling in BDUC-patients poses a challenge for patients, family members and treating physicians. Several hemostasis assays have been investigated in BDUC-patients, but little is known about the role of the fibrinolytic pathway in this patient group. This can be explained by the lack of standardized fibrinolysis tests and the limited availability of these tests in laboratories. To further unravel potential bleeding mechanisms in BDUC, in the present study we assessed fibrinolysis in BDUC patients by using a global whole blood tPA ROTEM assay and determining of individual fibrinolysis proteins. Aim: To investigate the capacity of the tPA-ROTEM assay to detect fibrinolytic abnormalities in BDUC-patients and to correlate these findings with fibrinolytic protein activity levels in plasma. Methods: Data from patients referred to the hematologist for bleeding evaluation and included in the Prediction of Evaluation in Adult Hematologic Patients with Bleeding Tendencies (ProBe-AHP) study (METC:14-4-036) were used. BDUC-patients were identified based on (1) a clinically relevant increased bleeding tendency and (2) no abnormalities in extended hemostasis laboratory testing. tPA-ROTEM assay was done according to the in 2016 validated and published method on the ROTEM device. Fibrinolysis protein plasma levels, including plasminogen, plasminogen activator inhibitor 1 (PAI-1) antigen and activity, tissue plasminogen activator (tPA) antigen, alpha2-antiplasmin and thrombin activatable fibrinolysis inhibitor (TAFI), were measured using ELISA assays. Pre-specified definitions of hyper- and hypofibrinolysis as measured by tPA-ROTEM were applied to identify hyper- and hypofibrinolytic profiles. Results: tPA-ROTEM identified a hyperfibrinolytic profile in 15/73 (20%) of BDUC-patients, a hypofibrinolytic profile in 16/73 (22%) of BDUC-patients and a normal profile in 42 BDUC-patients (58%). Plasminogen activity inhibitor 1 (PAI-1) activity and antigen levels and α2-antiplasmin levels were lower in BDUC-patients with a hyperfibrinolytic profile compared to BDUC-patients with a hypofibrinolytic profile. No statistically significant correlations between tPA-ROTEM parameters and fibrinolysis protein plasma levels were identified using multivariate regression analysis. Conclusion: tPA-ROTEM identified a hyperfibrinolytic profile in 20% of BDUC-patients. In this group, the lower PAI-1 activity and antigen levels and lower α2-antiplasmin levels are in concordance with the expected changes in case of hyperfibrinolysis. These findings indicate that these fibrinolysis protein plasma levels are within the lower functional range of their distribution, shifting the balance towards increased clot lysis leading to an increased bleeding tendency. These findings might deliver evidence to the use of antifibrinolytic therapies in BDUC-patients in case of bleeding or interventions. Informed consent and approval from the medical-ethical committee from Maastricht (METC azM/UM) were obtained.

Plasma thrombin-activatable fibrinolysis inhibitor and the 1040C/T polymorphism are risk factors for diabetic kidney disease in Chinese patients with type 2 diabetes.

Inflammatory and hemostatic disorders in diabetic microangiopathy (DMA) can be linked to thrombin-activatable fibrinolysis inhibitor (TAFI) and its own gene polymorphisms. Thus, the study aimed to investigate the associations of plasma TAFI and gene polymorphisms with DMA in Chinese patients with type 2 diabetes (T2D). Plasma TAFI of 223 patients with T2D was measured, and the genotypes and alleles of the 1040C/T, 438G/A, and 505G/A polymorphisms of the TAFI gene were analyzed. A ROC curve was constructed to evaluate the identifying power of TAFI between patients with T2D and DMA, and logistic regression analysis was used to observe the correlation of plasma TAFI and gene polymorphisms with the risk for DMA. Plasma TAFI was higher in patients with DMA than in patients with only T2D (p < 0.05). TAFI exhibited the largest area under ROC in identifying diabetic kidney disease (DKD) from only T2D (0.763, 95% CI [0.674-0.853], p < 0.01), and adjusted multivariate analysis showed a high odds ratio (OR: 15.72, 95% CI [4.573-53.987], p < 0.001) for DKD. Higher frequencies of the CT genotype and T allele of the 1040C/T polymorphism were found in DKD compared with only T2D (respectively p < 0.05), and the CT genotype exhibited a high OR (1.623, 95% CI [1.173-2.710], p < 0.05) for DKD. DKD patients with the CT genotype had higher plasma TAFI levels, while T2D and DKD patients with CC/TT genotypes had lower plasma TAFI levels. Plasma TAFI and the CT genotype and T allele of the 1040C/T polymorphism are independent risk factors for DKD in Chinese T2D patients.

Elevated plasma factor XI is predicts cardiovascular complications in patients with type 2 diabetes mellitus

Abstract Background Atherothrombotic complications are common in patients with type 2 diabetes mellitus (T2DM), reflecting a chronic prothrombotic state. Circulating factor XI (FXI) has been associated with a prothrombotic fibrin clot phenotype and predicted myocardial infarction, stroke and cardiovascular (CV) death in a number of diseases, including CAD. Its role in T2DM is largely unknown. Purpose The purpose of this study was to assess plasma FXI as a predictor of atherothrombotic events in T2DM patients. We also aimed to establish the determinants of elevated plasma FXI in this group of patients. Methods In a cohort of 156 patients aged 43–83 years, 56% male, with T2DM of a median duration time of five years, 64.7% with diagnosed CAD, we measured FXI along with a number of fibrin clot parameters, including turbidity, permeation, compaction, lysability, maximum concentration of D-dimer (D-D max), and rate of D-dimer release during tissue plasminogen activator-induced clot lysis. Patients were followed for a median time of 72 (68-74) months for a composite endpoint of nonfatal myocardial infarction (MI), nonfatal stroke, and cardiovascular (CV) death. Results Follow-up was complete for 133 (85.3%) patients. There were 21 (16%) cases of the composite endpoint, including one nonfatal MI, four nonfatal strokes and 16 cases of CV death. Patients with and without the composite endpoint shared a similar demographic and clinical profile with the exception of age and white blood cell count – patients with the endpoint were older (69.4 [8.4] vs. 65.4 [7.8] years, p=0.03) and had a higher leukocyte count (7.8 [1.9] vs. 7.0 [1.3], p=0.02) as compared with the remainder. FXI was elevated above the upper limit of 120% in 25 (18.8%) patients, including 16 (61.9%) with the composite endpoint vs. 12 (10.7%) without the composite endpoint, p&amp;lt;0.001. Individuals with the composite endpoint had higher baseline FXI concentrations as compared with the remainder (120.1±16.8 vs. 104.9±10.7%. p &amp;lt; 0.001), along with higher D-D max (4.1 [3.8-4.3] vs. 3.8 [3.6-4.1] mg/l, p = 0.006) and slightly longer lysis time (t50% 10.1 [9.8-10.9] vs. 9.8 [8.9-10.4] min, p = 0.03). On multivariable analysis, co-existing CAD, LDL cholesterol, and thrombin activatable fibrinolysis inhibitor activity were independent predictors of elevated FXI in T2DM patients. Conclusion Elevated plasma FXI in T2DM patients is associated with CAD, LDL cholesterol and TAFI, and predicts myocardial infarction, stroke, and CV death in long term follow-up. Our finding may have implications for risk stratification and suggests a role for FXI inhibitors in T2DM patients with a high risk of atherothrombotic complications.

Abstract 16617: Effects of Proprotein Convertase Subtilisin-Kexin Type 9 Inhibitors on Inflammatory and Haemostatic Parameters in Coronary Artery Disease Patients

Background and aims: Despite progress in treatment, elevated levels of low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) (Lp(a)) represent a significant part of the residual risk. Both are associated with inflammation and the coagulation fibrinolytic system. The purpose of our research was to evaluate the effect of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) on lipid parameters and indicators of inflammation, coagulation and fibrinolysis. Methods: We included 100 patients after a myocardial infarction with insufficiently controlled LDL-C values despite the maximum dose of statin, and highly elevated Lp(a). Patients received alirocumab or evolocumab (150mg sc or 140g sc every two weeks; respectively) or placebo for 6 months. Results: In the group receiving PCSK9i, a significant decrease in total cholesterol (TC), LDL-C, triglycerides (TG) and Lp(a), and an increase in high density lipoprotein cholesterol (p&lt;0.001 for all) was found. Before treatment concentrations of TC, LDL-C and TG correlated with the concentration of thrombin activatable fibrinolysis inhibitor (r=0.41, p&lt;0.001; r=0.353, p&lt;0.001; r=0.311, p=0.003; respectively), and plasminogen activator inhibitor-1 (r=0.302, p=0.007; r=0.218, p=0.049; r=0.278; p=0.013; respectively). The concentration of TC and LDL-C correlated with overall fibrinolytic potential (r=-0.220, p=0.034; r=-0.207, p=0.047; respectively). The concentration of TG was related to the concentration of interleukin 6 (r=0.290, p=0.004) and interleukin 8 (r=0.332, p=0.001). No correlations between Lp(a) and inflammatory or haemostatic variables were found. No associations were found after treatment. Conclusion: Our results show that fibrinolytic parameters and inflammatory cytokines are related to the concentration of LDL-C and not Lp(a) before and with neither of them after treatment with PCSK9i.

Thrombin-activatable fibrinolysis inhibitor and sex modulate thrombus stability and pulmonary embolism burden in a murine model

BackgroundThrombin-activatable fibrinolysis inhibitor (TAFI) levels are positively correlated with the risk of thrombosis. The mechanism of how TAFI affects venous thromboembolism (VTE) remains uncertain. In addition, the role of sex on the risk of VTE has also been studied. However, their association also remains unclear. ObjectivesTo investigate how TAFI and/or sex affect venous thrombus stability and consequent pulmonary embolism (PE). MethodsFerric chloride-induced thrombi were formed within the femoral veins of male and female wild-type (WT) or TAFI-knockout (Cpb2-/-) mice. Thrombi were imaged over 2 hours using intravital videomicroscopy to quantify embolization and thrombus size over time. Lungs were examined by immunohistochemistry to quantify (a) emboli and (b) fibrin composition of these emboli. ResultsEmbolization events in female mice were higher than in males (7.9-fold in WT and 3.1-fold in Cpb2-/- mice). Although the maximal thrombus sizes were not different across groups, Cpb2-/- mice had thrombi that were, on average, 24% smaller at the end of the 2-hour experiment than WT mice. Loss of TAFI led to a 4.0- and 2.8-fold increase in PE burden in males and females, respectively, while sex had no influence. Pulmonary emboli in Cpb2-/- mice had higher fibrin composition compared with WT mice. ConclusionFemale mice had less stable venous thrombi than male mice, suggesting a higher risk of PE in females with deep vein thrombosis. Mice lacking TAFI had more thrombus degradation and higher PE burden than WT mice. These results confirm the role of TAFI in venous thrombosis.

Is there a potential role of inhibition of thrombin-activatable fibrinolysis inhibitor in regulation of local fibrinolytic activities on fibrin thrombi in patients with pulmonary embolism?

Is there a potential role of inhibition of thrombin-activatable fibrinolysis inhibitor in regulation of local fibrinolytic activities on fibrin thrombi in patients with pulmonary embolism?

Identification of Genes and miRNAs Associated with TAFI-Related Thrombosis: An in Silico Study.

Thrombin-Activatable Fibrinolysis Inhibitor (TAFI) is a carboxypeptidase B-like proenzyme encoded by the CPB2 gene. After thrombin activation, TAFI downregulates fibrinolysis, thus linking the latter with coagulation. TAFI has been shown to play a role in venous and arterial thrombotic diseases, yet, data regarding the molecular mechanisms underlying its function have been conflicting. In this study, we focused on the prediction and functional enrichment analysis (FEA) of the TAFI interaction network and the microRNAs (miRNAs) targeting the members of this network in an attempt to identify novel components and pathways of TAFI-related thrombosis. To this end, we used nine bioinformatics software tools. We found that the TAFI interactome consists of 28 unique genes mainly involved in hemostasis. Twenty-four miRNAs were predicted to target these genes. Co-annotation analysis of the predicted interactors with respect to Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and transcription factors (TFs) pointed to the complement and coagulation cascades as well as neutrophil extracellular trap formation. Cancer, stroke, and intracranial aneurysm were among the top 20 significant diseases related to the identified miRNAs. We reason that the predicted biomolecules should be further studied in the context of TAFI-related thrombosis.

Changes in the Fibrinolytic System of Patients Infected with Severe Acute Respiratory Syndrome Coronavirus 2.

In this study, coagulation and fibrinolysis parameters and their association with disease severity were investigated in coronavirus disease (COVID-19) patients. COVID-19 patients (n = 446) admitted to our institute between 21 February 2021 and 17 March 2022, were recruited. Clinical data and staging were collected from all patients. Blood samples were collected and analyzed for several parameters of fibrinolysis and coagulation, including alpha-2-antiplasmin(α2AP) and plasminogen, thrombin activatable fibrinolysis inhibitor (TAFI), tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), D-dimer, and fibrinogen levels. The TAFI, fibrinogen, and tPA levels were significantly higher in participants who died compared to that of patients who recovered (p < 0.001). However, PAI-1, tPA, and TAFI were significantly higher in patients admitted to the ICU than those of the healthy controls (p < 0.001 for PAI-1 and tPA; p = 0.0331 for TAFI). Our results showed that stage C and D COVID-19 patients had significantly higher levels of PAI-1 (p = 0.003). Furthermore, stage D COVID-19 patients had significantly higher tPA and TAFI values (p = 0.003). Hypofibrinolysis was the most prevalent condition among patients with severe COVID-19. In this study, several coagulation markers were elevated, making them suitable prognostic markers for hypofibrinolysis.

Elevated plasma factor XI predicts cardiovascular events in patients with type 2 diabetes: a long-term observational study

Background Type 2 diabetes mellitus (T2DM) patients are at high risk of cardiovascular (CV) events. Factor XI (FXI) is associated with arterial thromboembolism, including myocardial infarction (MI), stroke, and CV mortality. The role of FXI in T2DM is unknown. We investigated whether plasma FXI is associated with CV events in T2DM patients in long-term observation.MethodsIn 133 T2DM patients (aged 66 ± 8 years, 40.6% women, median T2DM duration 5 [2–10] years) we assessed plasma FXI levels, along with fibrin clot properties, thrombin generation, and fibrinolysis proteins. A composite endpoint of MI, stroke, or CV death, as well as CV mortality alone were assessed during a median follow-up of 72 months.ResultsPlasma FXI above the 120% upper normal limit was detected in 25 (18.8%) patients and showed positive association with LDL cholesterol and thrombin activatable fibrinolysis inhibitor, but not glycated hemoglobin, inflammatory markers or thrombin generation. The composite endpoint (n = 21, 15.8%) and CV death alone (n = 16, 12%) were more common in patients with elevated FXI (hazard ratio [HR] 10.94, 95% confidence interval [CI] 4.46–26.87, p < 0.001 and HR 7.11, 95% CI 2.61–19.31, p < 0.001, respectively). On multivariable analysis, FXI remained an independent predictor of the composite endpoint and CV death, regardless of concomitant coronary artery disease.ConclusionsTo our knowledge, this study is the first to show that in T2DM patients, elevated FXI could predict major CV events, including mortality, which suggest that anti-FXI agents might be a potential novel antithrombotic option in this disease.

#2728 THROMBOINFLAMMATORY BIOMARKERS AND THEIR RELATIONSHIP WITH CIRCULATING GLYCOSAMINOGLYCANS IN END-STAGE RENAL DISEASE PATIENTS

Abstract Background and Aims End stage renal disease (ESRD) is a complex progressive medical condition that affects multiple organ systems. Given the high risk of morbidity and mortality of ESRD as well as its rising incidence, it is critical to understand the relevance of thromboinflammatory biomarkers in disease development and progression of kidney dysfunction. The purpose of this study is to profile the levels of thromboinflammatory biomarkers in ESRD patients including D-Dimer, C-reactive protein (CRP), von Willebrand factor (vWF), plasminogen activator inhibitor 1 (PAI-1), and thrombin activatable fibrinolysis inhibitor (TAFI). In addition, the levels of anti-PF4 IgG and endogenous circulating glycosaminoglycans (GAGs) were measured. Method Citrated plasma samples were collected from seventy-three ESRD patients. Control plasma samples (NHP) from healthy, non-smoking adults aged 19 to 53 were obtained commercially. Validated ELISA methods have been used to profile each of the biomarkers. The levels of endogenous GAGs were determined (Redprobes UG, Germany). To compare the levels of thromboinflammatory biomarkers, anti-PF4 IgG, and endogenous GAGs in different groups, appropriate statistical methods included Mann-Whitney U, t-tests, Kruskal-Wallis ANOVA and experiment correlation analysis methods were performed. Results All of the biomarkers and GAGs were significantly elevated, with the exception of TAFI, in ESRD patients. The ESRD patients exhibited varying levels of increase in the D-Dimer, CRP, vWF, PAI-1, anti-PF4 IgG, and GAGs as shown in Figure 1 (p &amp;lt; 0.05). D-Dimer showed the most pronounced increase (1075%) followed by PAI-1 (361.31%), anti-PF4 IgG (209.78%), CRP (101.77%) and endogenous GAGs (17.29%). The correlation analysis revealed varying degrees of association among these biomarkers (Figure 2). Conclusion These results suggest that thromboinflammatory biomarkers offer the potential utility of identifying inflammation in end-stage renal disease. Marked increase in thromboinflammatory mediators due to endothelial damage may result in the upregulation of glycosaminoglycans and anti-PF4 IgG antibodies in the ESRD patients.

Profibrinolytic effects of rivaroxaban are mediated by thrombin-activatable fibrinolysis inhibitor and are attenuated by a naturally occurring stabilizing mutation in enzyme

Profibrinolytic effects of rivaroxaban are mediated by thrombin-activatable fibrinolysis inhibitor and are attenuated by a naturally occurring stabilizing mutation in enzyme

[Relationship between plasma levels of thrombin activatable fibrinolysis inhibitor, plasminogen activator inhibitor-1 and tissue-type plasminogen activator and deep venous thrombosis in patients with systemic lupus erythematosus].

Objective: To investigate the plasma levels of thrombin activatable fibrinolysis inhibitor (TAFI), plasminogen activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (t-PA) in patients with systemic lupus erythematosus (SLE), and their relationship with deep venous thrombosis of the lower limbs. Methods: A case-control study was conducted to retrospectively select 32 SLE patients with deep venous thrombosis of the lower extremities (thrombus group) admitted to Liaocheng People's Hospital in Shandong Province from June 2018 to June 2021, including 4 males and 28 females, with a mean age of (49.7±5.5) years. Meanwhile, 64 SLE patients without deep venous thrombosis of the lower extremities (control group) were also selected, including 11 males and 53 females, with a mean age of (50.8±5.5) years. The plasma levels of TAFI, PAI-1 and t-PA of the two groups were compared. A logistic regression model was used to analyze the correlation of TAFI, PAI-1 and t-PA with SLE in patients. Results: The plasma levels of TAFI, PAI-1 and t-PA were (32.77±5.17) mg/L, (29.43±5.51) μg/L and (6.58±1.40) μg/L in the thrombotic group, while the plasma levels of TAFI, PAI-1 and t-PA in the control group were (23.56±4.40) mg/L, (19.00±4.40) μg/L and (9.40±2.23) μg/L. The levels of TAFI and PAI-1 in the thrombotic group were higher than those in the control group, while the level of t-PA was lower than that in the control group (all P<0.05). The results of logistic regression model showed that higher TAFI levels (OR=1.75, 95%CI: 1.05-2.90, P=0.043), higher PAI-1 levels (OR=1.85, 95%CI: 1.04-3.29, P=0.046), and lower t-PA levels (OR=0.72, 95%CI: 0.52-0.99, P=0.048) were related factors for the occurrence of deep venous thrombosis of the lower limbs in SLE patients. Conclusion: The plasma levels of TAFI and PAI-1 in SLE patients with deep venous thrombosis of the lower extremities increase, while the t-PA level decreases, which are related factors for the occurrence of deep venous thrombosis of the lower extremities in SLE patients.