Thrombin-activatable Fibrinolysis Inhibitor Levels Research Articles

Assessment of thrombin-activatable fibrinolysis inhibitor levels in essential hypertension

Assessment of thrombin-activatable fibrinolysis inhibitor levels in essential hypertension

Elevated plasma protein carbonylation increases the risk of ischemic cerebrovascular events in patients with atrial fibrillation: association with a prothrombotic state.

Plasma protein carbonylation that reflects oxidative stress has been demonstrated to be associated with the prothrombotic fibrin clot phenotype. However, the role of protein carbonyls (PC) in predicting ischemic stroke in atrial fibrillation (AF) is largely unknown. This study aimed to investigate whether PC increase the risk of stroke in anticoagulated AF patients during follow-up. In 243 AF patients on anticoagulation (median age 69years; median CHA2DS2-VASc of 4), we measured plasma PC using the assay by Becatti, along with plasma clot permeability (Ks), clot lysis time (CLT), thrombin generation, and fibrinolytic proteins, including plasminogen activator inhibitor type 1 (PAI-1) and thrombin activatable fibrinolysis inhibitor (TAFI). Ischemic stroke, major bleeding, and mortality were recorded during a median follow-up of 53months. Plasma PC levels (median, 3.16 [2.54-3.99] nM/mg protein) at baseline showed positive associations with age (P < 0.001), CHA2DS2-VASc (P = 0.003), and N-terminal B-type natriuretic peptide (P = 0.001), but not with type of AF or comorbidities except for heart failure (P = 0.007). PC levels were correlated with CLT (r = 0.342, P < 0.001), endogenous thrombin potential (r = 0.217, P = 0.001) and weakly with Ks (r = -0.145, P = 0.024), but not with fibrinogen, PAI-1, or TAFI levels. Stroke was recorded in 20 patients (1.9%/year), who had at baseline 36% higher PC levels (P < 0.001). Elevated PC (P = 0.003) at baseline were independently associated with stroke risk. Our findings suggest that in patients with AF enhanced protein carbonylation is associated with increased "residual" risk of stroke despite anticoagulation, which is at least in part due to unfavorably altered fibrin clot phenotype.

Differences in fibrinolytic profile between patients with different localizations and types of venous thrombosis

Introduction. The role of the fibrinolytic system in venous thrombosis remains incompletely understood. This study aimed to evaluate the effectiveness of the fibrinolytic system in patients with various types and locations of venous thrombosis compared to healthy controls. Material and Methods. The study included 100 patients with venous thrombosis and 100 healthy controls. Patients were stratified based on the type of venous thrombosis (spontaneous vs. provoked) and the location (distal, proximal, and atypical). Global fibrinolytic activity was assessed using euglobulin clot lysis time, while specific fibrinolytic components measured included plasminogen, tissue plasminogen activator, thrombin-activatable fibrinolysis inhibitor, and plasminogen activator inhibitor-1. Results. Patients with isolated distal and provoked venous thrombosis exhibited significantly prolonged euglobulin clot lysis time compared to healthy controls (218.3 ? 41.1 vs. 185.6 ? 42.3 min, p=0.001; 208.2 ? 48.5 min vs. 185.6 ? 42.3 min, p=0.018, respectively). Patients with provoked venous thrombosis demonstrated higher plasminogen (127.1 ? 27.7 vs. 117.1 ? 24.5%, p=0.044) and tissue plasminogen activator levels (20.0 ? 11.1 vs. 16.8 ? 8.1 ng/ml, p=0.042) compared to controls. Thrombin-activatable fibrinolysis inhibitor levels were significantly elevated in patients with both provoked (19.9 ? 4.0 vs. 17.1 ? 4.3 ng/ml, p=0.000) and spontaneous venous thrombosis (19.5 ? 6.0 vs. 17.1 ? 4.3 ng/ml, p=0.02), as well as in cases of isolated distal (20.7 ? 5.0 vs. 17.1 ? 4.3 ng/ml, p=0.001) and proximal (19.4 ? 5.3 vs. 17.1 ? 4.3 ng/ml, p=0.013) venous thrombosis when compared to healthy controls. Conclusion. The study reveals significant variations in the fibrinolytic process across different types and anatomical locations of venous thrombosis compared to healthy individuals.

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).

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.

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.

Quality of glycemic control in type 2 diabetes mellitus (T2DM) and its association with markers of coagulation and inhibitors of fibrinolysis: A case-control study in the Upper West Region, Ghana.

Type 2 diabetes mellitus (T2DM) individuals are at a higher risk of developing diabetes complications, with approximately 80% complication-related mortality. The increased morbidity and mortality among T2DM patients are partly due to dysregulated hemostasis. This study determined the quality of glycemic control in T2DMand its association with markers of coagulation and inhibitors of fibrinolysis. This case-control study recruited 90 participants involving: 30 T2DM patients with good glycemic control, 30 with poor glycemic control, and 30 nondiabetic subjects as controls at a Municipal Hospital in Ghana. Fasting blood glucose, glycated hemoglobin, activated partial thromboplastin time (APTT), prothrombin time (PT), calculated international normalized ratio (INR), and full blood count (FBC) were determined for each respondent. Plasma levels of plasminogen activator inhibitor-1 (PAI-1) and thrombin activatable fibrinolysis inhibitor (TAFI) were determined using the solid-phase sandwich enzyme-linked immunosorbent assaymethod. Data wereanalyzed using R language software. Plasma PAI-1 antigen levels were significantly higher in the participants with poor glycemic control as compared to participants with good glycemic control (p < 0.0001). There was no significant difference in plasma TAFI levels between the participants with poor glycemic control as compared to participants with good glycemic control (p = 0.900). T2DM patients had significantly shorter APTT, PT, and INR than controls (p < 0.05). At a cut-off of ≥161.70 pg/μL, PAI was independently associated with increasing odds (adjusted odds ratio = 13.71, 95% confidence interval:3.67-51.26, p < 0.0001) of poor glycemic control and showed the best diagnostic accuracy for poor glycemic control (area under the curve = 0.85, p < 0.0001). PAI-1 levels were significantly increased in T2DM with poor glycemic control and emerged as the best predictor for poor glycemic control. Good glycemic management to control the plasma levels of PAI-1 is required to prevent hypercoagulability and thrombotic disorders.

Antithrombin Deficiency Is Associated with Prothrombotic Plasma Fibrin Clot Phenotype.

Deficiency of antithrombin increases risk of venous thromboembolism. We hypothesized that antithrombin deficiency affects fibrin clot structure and function. We evaluated 148 patients (age: 38 [32-50] years; 70% women) with genetically confirmed antithrombin deficiency and 50 healthy controls. Fibrin clot permeability (Ks) and clot lysis time (CLT) along with thrombin generation capacity were assessed before and after antithrombin activity normalization in vitro. Antithrombin-deficient patients had lower antithrombin activity (-39%) and antigen levels (-23%) compared with controls (both p < 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 p < 0.01). Antithrombin deficiency was associated with 18% reduced Ks and 35% prolonged CLT (both p < 0.001). Patients with type I (n = 65; 43.9%) compared with type II antithrombin deficiency (n = 83; 56.1%) had 22.5% lower antithrombin activity (p < 0.001) and despite similar fibrinogen levels, 8.4% reduced Ks, 18% prolonged CLT, and 30% higher ETP (all p < 0.01). Reduced Ks 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 Ks (+8%) and CLT (-12%; all p < 0.01). 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.

Differential Fibrinolysis Profile in COVID-19 Patients Dependent on Immunosuppressive Treatment Regimen: A Nested Case-Control Study

Introduction: Severe coronavirus disease 2019 (COVID-19) is associated with thrombotic complications, despite prophylactic and therapeutic anticoagulation. The disease course of critically ill COVID-19 patients has been characterized by severe hypercoagulability and hypofibrinolysis leading to an increased risk of venous thromboembolism. In COVID-19 (low molecular weight) heparins do not provide sufficient protection against venous thromboembolism. Since the start of the COVID-19 pandemic, several immune modulatory interventions have been introduced to improve outcome, including dexamethasone and tocilizumab. Whether dexamethasone and tocilizumab would alter the course of hypercoagulability by modifying inflammation, is unknown. Tocilizumab, that reduces IL-6 binding to its cellular receptors, has been shown to reduce the plasma plasminogen activator inhibitor-1 (PAI-1). On the other hand, dexamethasone can induce PAI-1 release. Data on the net impact of dexamethasone and tocilizumab on fibrinolysis in critically ill COVID-19 patients is lacking. Therefore, we aimed to characterize the fibrinolytic profile of severe COVID-19 patients on different treatment regimens and to unravel underlying mechanisms of the hypofibrinolytic state of these patients. Methods: A nested case-control study within the Maastricht Intensive Care COVID (MaastrICCht) cohort on mechanically ventilated COVID-19 patients was conducted. Patients receiving tocilizumab and dexamethasone (toci group) were age- and sex-matched with patients receiving only dexamethasone (dexa group) and patients receiving neither tocilizumab nor dexamethasone (control group). Whole blood was collected from these patients at three different time points after intubation (week 1, 2, and 3). The dexa and toci group received dexamethasone treatment before intubation and the toci group received one bolus of tocilizumab before or on the day of intubation. All blood samples were collected thereafter. Whole blood tissue plasminogen activator rotational thromboelastometry (tPA-ROTEM) was performed and subsequently inflammatory markers (c-reactive protein (CRP), ferritin, IL-6, fibrinogen), fibrinolysis parameters (tPA, PAI-1, thrombin activatable fibrinolysis inhibitor (TAFI), plasmin-alpha-2-antiplasmin complex (PAP)) and coagulation biomarkers (D-dimer, prothrombin fragment 1.2 (F1.2)) were measured in plasma samples. All markers were analyzed with linear mixed-effects regression models to estimate the differences between treatment groups over time. Results: Matching showed similar groups (Table 1.) for the baseline characteristics. At week 1 the dexagroup's IL-6 level was significantly lower, whereas the toci group's IL-6 level was significantly higher compared to the control group (difference[95%CI]: -198.37 [-350.86- -45.88], p=0.017 and 269.59 [113.91-425.27], p=0.002, respectively). CRP levels were significantly lower at week 1 in both dexa and toci groups compared to the control group (median [IQR] 60.50 [30.75 - 131.25] and 18.50 [6.00 - 60.00] vs. 296.00 [223.75 - 347.00]) suggesting effective immune suppression. Divergent fibrinolysis was seen at week 1 by tPA-ROTEM showing lower lysis time (LT) in the toci group compared to the control group (difference[95%CI]: -1,759.21 [-2752.05 - -766.34; p=0.002), whereas the dexa group did not differ. Interestingly, LT decreased over time in the control group, while an increase was seen in the toci group (Figure 1.). PAI-1 levels were lower in week 1 in the toci group compared to the control group (difference [95%CI] -7.32 [-14.95 - 0.30], p=0.071) and the tocigroup showed an overall increase in PAI-1 levels, while the control and dexa group showed a decrease over time. High TAFI and tPA levels were observed in all groups at week 1 and over time regardless of the treatment regimens. Coagulation biomarkers D-dimer and prothrombin fragment 1.2 were elevated but did not differ or change over time between groups. Conclusions: The differences and changes over time revealed by tPA-ROTEM and the fibrinolysis markers between the three different treatment regimens show the direct interaction between inflammation and fibrinolysis in these patients. The lower LT and PAI-1 levels upon tocilizumab treatment could be indicative for better fibrinolytic activity in these patients. This study was supported by the Dutch Covid and Thrombosis Coalition (DCTC). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Serum thrombin-activatable fibrinolysis inhibitor levels and its relation with pathogenesis and bleeding and prognosis in patients with Crimean Congo hemorrhagic fever.

Crimean-Congo hemorrhagic fever (CCHF) is a viral hemorrhagic fever, which is common in Turkey and globally. The pathogenesis of coagulation disorders, which is seen in viral hemorrhagic fevers remains to be elucidated. Thrombin-activatable fibrinolysis inhibitor (TAFI) has a key role in this process In this study, we aimed to evaluate whether TAFI levels contributed to bleeding and whether it is related to prognosis in CCHF patients.Eighty-four patients older than 15 years of age, who were admitted to our hospital who had positive immunoglobulin M (enzyme-linked immunosorbent assay [ELISA]) and/or polymerase chain reaction test results for CCHF between 2009 and 2010, were included in the study. The control group included 30 healthy adults. The plasma TAFI levels were compared between patients and controls, and also between patients with bleeding and no bleeding, and between patients with mild-moderate and severe disease. The mean TAFI levels were lower in patients (mean: 87.82 ng/ml, median: 61.69 ng/ml (interquartile range [IQR] 30.49-537.95) than controls (mean: 313.5 ng/ml with a median: 338.5 ng/ml (IQR 182-418). However, median TAFI levels were significantly higher in patients with bleeding compared to those without bleeding (78.99 and 50.28 ng/ml, respectively; p = 0.032). Median IQR TAFI levels were similar between patients with mild-moderate and severe disease (64.72 (41.37-113.85), and, 58.66 (42.44-118.93) ng/ml, respectively; p = 0.09) and survivors and nonsurvivors (86.14 ± 77.98 and 103.48 ± 69.92, respectively; p = 0.3). Although TAFI levels were lower in the patients with CCHF compared to healthy controls, it does not seem to be a major player in the prognosis.

A randomized controlled trial of indobufen versus aspirin in the prevention of bridging restenosis after coronary artery bypass grafting

Objective: To compare the efficacy and safety between indobufen and aspirin in the prevention of restenosis of bridge vessels at 1 year after off-pump coronary artery bypass grafting. Methods: This study was a prospective cohort study. We selected 152 patients who received coronary artery bypass grafting in Beijing Anzhen Hospital from December 2016 to December 2018. Patients were divided into the indobufen group and the aspirin group. Patients in the aspirin group were treated with aspirin and clopidogrel, and patients in the indobufen group were treated with indobufen and clopidogrel. During the 1-year follow-up, the rate of restenosis of saphenous vein bridge and internal mammary artery bridge, the rate of adverse cardiac events and adverse reactions were compared between the two groups. The levels of fibrinogen (FIB), D-dimer (D-D), thrombomodulin (TM) and thrombin-activatable fibrinolysis inhibitor (TAFI) were compared before and after antiplatelet therapy. Results: There were 76 cases in the indobufen group, including 57 males (75.0%), aged (60.3±6.6) years. There were 76 cases in the aspirin group, including 62 males (81.6%), aged (59.7±7.2) years. Baseline data were comparable between the two groups (P>0.05). During the follow-up, 3 cases were lost to follow up. Follow-up was completed in 74 patients in the indobufen group and 75 in the aspirin group. A total of 268 bridging vessels were grafted in the indobufen group and 272 in the aspirin group. One year after surgery, the patency rates of great saphenous vein bridge and internal mammary artery bridge were 94.5% (189/200) and 97.1% (66/68) in the indobuphen group, and 91.3% (189/207) and 96.9% (63/65) in the aspirin group, respectively. There was no significant difference in patency rate of great saphenous vein bridge and internal mammary artery bridge between the two groups (χ²=0.282, 0.345, P>0.05). The total incidence of adverse cardiac events was 5.4% (4/74) in the indobufen group and 6.7% (5/75) in the aspirin group (χ²=0.126, P>0.05). The overall incidence of gastrointestinal adverse reactions was significantly lower in the indobufen group than in the aspirin group (4.1% (3/74) vs. 13.3% (10/75), χ²=4.547, P<0.05). The levels of FIB, D-D, TM and TAFI in the two groups were lower than those before surgery (P<0.05), and there was no statistical significance between the two groups at baseline and post-operation (P>0.05). Conclusion: The efficacy of indobufen combined with clopidogrel in the prevention of 1-year restenosis after coronary artery bypass graft is similar to that of aspirin combined with clopidogrel, but the incidence of adverse reactions is lower, and the safety is higher in patients treated with indobufen combined with clopidogrel compared to aspirin combined with clopidogrel strategy.

A Case-Control Study of the Dose-Response Relationship Between Thrombin Activatable Fibrinolysis Inhibitor and Acute Myocardial Infarction.

BackgroundAcute myocardial infarction (AMI) is considered an acute coronary syndrome (ACS), which is caused by the death of myocardial cells after prolonged ischemia, and there is a high risk of sudden death during AMI. Therefore, the purpose of this study is to explore the relationship between thrombin activatable fibrinolysis inhibitor (TAFI) and AMI and provide evidence for their association and potentially the prevention of AMI.MethodsThere were 228 subjects included in this retrospective study, which included 78 AMI patients and 150 controls. The immune turbidimetry was used to measure TAFI concentration in the serum. Mann–Whitney U test was used to compare serum TAFI levels. The logistic regression analysis was used to construct a model of influencing factors of AMI. The dose-response relationship between serum TAFI level and AMI was explored by using the restricted cubic spline (RCS) functions combined with logistic regression analysis.ResultsThe serum TAFI levels of the AMI group were higher than the control group’s (P = 0.003). The risk of AMI in the high-TAFI level group was 2.24 times higher than the low-TAFI level group (P = 0.007) and it was 2.74 times higher after adjustment of other risk factors (P = 0.025). According to the dose-response curve, the risk of AMI increased significantly with an increase of serum TAFI concentration (P = 0.0387).ConclusionAcute myocardial infarction patients had higher serum TAFI levels, and TAFI was an independent risk factor for AMI patients. Serum TAFI levels demonstrated a dose- dependent response to the risk of AMI. Our study provides evidence that TAFI could be used for risk stratification of AMI patients.

An evaluation of circulating activated TAFI in septic DIC: a case series and review of the literature

BackgroundAdministration of recombinant human soluble thrombomodulin (rTM) is often used in Japan to treat septic disseminated intravascular coagulation (DIC). Thrombin-activatable fibrinolysis inhibitor (TAFI) is a fibrinolysis inhibitor activated by the thrombin-thrombomodulin complex, however, it is unknown whether circulating activated TAFI is increased after rTM administration in patients with DIC. Furthermore, the relationship between TAFI activation and the prognosis of septic DIC is not defined yet.Case presentationWe report a series of 8 patient’s TAFI activation with septic DIC treated by rTM. We sought to investigate the effect of rTM on TAFI activation and the association of plasma activated TAFI (TAFIa/ai) levels with the prognosis of septic DIC.Using plasma samples from clinical studies conducted from May 2016–March 2017 on eight patients with septic DIC at Kagoshima University Hospital, we measured plasma levels of total TAFI, TAFIa/ai, thrombin-antithrombin complex (TAT), prothrombin fragment 1 + 2 (F1 + 2), soluble fibrin (SF), antithrombin (AT), protein C (PC), protein S (PS), and plasminogen activator inhibitor-1 (PAI-1) before and after intravenous rTM administration. Then, we evaluated the relationship of these marker levels to prognosis. The thrombin-rTM complex activated TAFI in vitro in plasma from a healthy volunteer. However, TAFIa/ai levels did not significantly increase over baseline in the septic DIC patients after intravenous rTM administration. Baseline TAFIa/ai levels in non-survivors were significantly higher than those in survivors.ConclusionsPlasma TAFIa/ai did not increase with rTM administration. Elevated baseline TAFIa/ai concentration may be a negative prognostic indicator in septic DIC. Larger studies are needed to confirm the in vivo effect of rTM on TAFI activation.

Altered fibrin clot structure and dysregulated fibrinolysis contribute to thrombosis risk in severe COVID-19

AbstractThe high incidence of thrombotic events suggests a possible role of the contact system pathway in COVID-19 pathology. In this study, we determined the altered levels of factor XII (FXII) and its activation products in critically ill patients with COVID-19 in comparison with patients with severe acute respiratory distress syndrome related to the influenza virus (acute respiratory distress syndrome [ARDS]-influenza). Compatible with those data, we found rapid consumption of FXII in COVID-19 but not in ARDS-influenza plasma. Interestingly, the lag phase in fibrin formation, triggered by the FXII activator kaolin, was not prolonged in COVID-19, as opposed to that in ARDS-influenza. Confocal and electron microscopy showed that increased FXII activation rate, in conjunction with elevated fibrinogen levels, triggered formation of fibrinolysis-resistant, compact clots with thin fibers and small pores in COVID-19. Accordingly, clot lysis was markedly impaired in COVID-19 as opposed to that in ARDS-influenza. Dysregulated fibrinolytic system, as evidenced by elevated levels of thrombin-activatable fibrinolysis inhibitor, tissue-plasminogen activator, and plasminogen activator inhibitor-1 in COVID-19 potentiated this effect. Analysis of lung tissue sections revealed widespread extra- and intravascular compact fibrin deposits in patients with COVID-19. A compact fibrin network structure and dysregulated fibrinolysis may collectively contribute to a high incidence of thrombotic events in COVID-19.

The G505A Nonsynonymous Single-Nucleotide Polymorphism (SNP) in TAFI, the Gene Encoding Thrombin-Activatable Fibrinolysis Inhibitor (TAFI) Is Pleiotropically Associated with TAFI Antigen Levels and Coronary Heart Disease (CHD) in Mexican Americans of South Texas

Studies have reported that the G505A nonsynonymous (ns)-SNP encoding the Ala147Thr amino acid substitution in TAFI, is associated with a reduction in risk of venous thrombosis and myocardial infarction. Interestingly, homozygosity for the A-allele (AA) of G505A is associated with increased TAFI antigen (TAFI:Ag) levels in plasma. In our study of the genetic determinants of cardiovascular disease (CVD) in Mexican Americans of South Texas, we performed an exome-wide scan in relation to plasma TAFI antigen levels in 784 individuals. While accounting for age, sex, and their interactions as confounders in linear mixed model, we found a heritability of 59% for TAFI:Ag levels (p=1.4E-19), and that ns-SNP G505A was the only variant showing exome-wide significance (p=3.5E-14; Figure A). Figure B shows the quantile-quantile distribution of the p-values from all the exome-wide tests. Clearly, the p-value distribution reveals that there is no systematic bias that may act to skew the p-values, and that the lone exception¾in agreement between observed and expected quantiles¾is due to this TAFI SNP, which strongly suggests a truly significant effect. Consistent with previous reports, the regression coefficient for G505A as a predictor of TAFI:Ag levels showed them to be increasing from the homozygous for the major G-allele (GG), to the heterozygous individuals (GA), to the individuals homozygous for the minor A-allele (AA) (Figure B). We also investigated if G505A is associated with our CHD variable. Using a statistical genetic model for the liability to disease conditional on a threshold, which is equivalent to a probit mixed model, we found that the G505A ns-SNP in TAFI, encoding TAFI Ala147Thr, is significantly associated with a reduction in the risk of CHD (p=0.002). As observed in existing literature, potential limitations of this study include the ELISA assay used for the quantification of TAFI levels. Some ELISA assays measure proTAFI, TAFIa, and TAFIi. However, recent evidence suggests that there may be cross reactivity between TAFIa and TAFIi. This can result in measuring ongoing TAFI activation peptides and elevated levels of TAFIa which ultimately goes on to make resistant fibrin. This is likely the marker that results in the increased risk of venous thromboembolism. To mitigate this confounding factor, an ELISA assay specific to measuring TAFI antigen is needed. In conclusion, we found that TAFI G505A is pleiotropically associated with TAFI:Ag levels and risk of CHD. [Display omitted] DisclosuresDeFronzo: AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Membership on an entity's Board of Directors or advisory committees, Research Funding; Intarcia: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding.

Evaluation of Thrombin Activatable Fibrinolysis Inhibitor (TAFI) in Patients with β-Thalassemia

Background: Thalassemia is an inherited disorder of hemoglobin (Hb) synthesis that results in reduced or absent production of globin chain. Hypercoagulable state in thalassemia is a well-recognized event. Thrombin activatable fibrinolysis inhibitor (TAFI) is an enzyme considered to play an important role in the regulation of fibrinolysis by the coagulation system. With this background, the present study was conducted to know the role of TAFI as a contributing factor in hemostatic alteration state in adults with β-thalassemia. Aim: The aim of this article is to evaluate the level of TAFI and hematological parameters in splenectomized and non-splenectomized β-thalassemia patients and to compare their levels with normal subjects. Materials and Methods: This case–control study was conducted in 56 adult thalassemic patients. The plasma TAFI level was evaluated by the ELISA technique. Results: There was a significant reduction in TAFI levels in all thalassemic patients when compared with thalassemia minor patients and controls (P &lt; 0.0001). The TAFI level was significantly lower in the splenectomized group when compared with the non-splenectomized group (P &lt; 0.0001), and the TAFI level was significantly lower in the thalassemia major group when compared with the thalassemia intermediate group (P &lt; 0.0001). There was a significantly higher prothrombin time and activated partial thromboplastin time level in thalassemic major and intermediate patients when compared with thalassemia minor patients and controls (P &lt; 0.001). Conclusion: The TAFI enzyme level could be an important predictor for hemostatic alteration. Its level can be considered as a helpful marker for monitoring and follow-up of thalassemic patients for early and proper intervention to minimize complications.

Polycystic ovary syndrome: clinical and laboratory variables related to new phenotypes using machine-learning models.

Polycystic Ovary Syndrome (PCOS) is the most frequent endocrinopathy in women of reproductive age. Machine learning (ML) is the area of artificial intelligence with a focus on predictive computing algorithms. We aimed to define the most relevant clinical and laboratory variables related to PCOS diagnosis, and to stratify patients into different phenotypic groups (clusters) using ML algorithms. Variables from a database comparing 72 patients with PCOS and 73 healthy women were included. The BorutaShap method, followed by the Random Forest algorithm, was applied to prediction and clustering of PCOS. Among the 58 variables investigated, the algorithm selected in decreasing order of importance: lipid accumulation product (LAP); abdominal circumference; thrombin activatable fibrinolysis inhibitor (TAFI) levels; body mass index (BMI); C-reactive protein (CRP), high-density lipoprotein cholesterol (HDL-c), follicle-stimulating hormone (FSH) and insulin levels; HOMA-IR value; age; prolactin, 17-OH progesterone and triglycerides levels; and family history of diabetes mellitus in first-degree relative as the variables associated to PCOS diagnosis. The combined use of these variables by the algorithm showed an accuracy of 86% and area under the ROC curve of 97%. Next, PCOS patients were gathered into two clusters in the first, the patients had higher BMI, abdominal circumference, LAP and HOMA-IR index, as well as CRP and insulin levels compared to the other cluster. The developed algorithm could be applied to select more important clinical and biochemical variables related to PCOS and to classify into phenotypically different clusters. These results could guide more personalized and effective approaches to the treatment of PCOS.

Thrombin-Activatable Fibrinolysis Inhibitor (TAFI) Antigen Levels and TAFI Gene Polymorphisms in Patients with Budd-Chiari Syndrome and Portal Vein Thrombosis.

Background Budd-Chiari syndrome (BCS) and Portal Vein Thrombosis (PVT) have been associated with several hypercoagulable states. Thrombin-activatable fibrinolysis inhibitor (TAFI) potently attenuates fibrinolysis. Elevated TAFI antigen levels form a risk factor for deep venous thrombosis and are to a high extend genetically determined. To establish the pathogenetic role of TAFI in BCS and PVT, we studied TAFI antigen levels and gene polymorphisms in patients with BCS, PVT and matched controls.Methods In a multicenter case-control study, 39 patients with BCS, 85 patients with PVT and 118 population-based controls were identified. Plasma levels of TAFI antigen were determined by a commercially available ELISA and polymorphisms of the TAFI gene (TAFI 505A/G and TAFI 1040C/T) were analysed by PCR. Because TAFI antigen levels are decreased in patients with impaired liver synthesis, plasma levels were corrected for antithrombin activity levels. ANOVA techniques were used to correlate TAFI polymorphisms with TAFI antigen levels.Results Mean plasma TAFI antigen levels were significantly lower in BCS and/or PVT patients as compared to controls, even after adjusting for impaired liver function by antithrombin activity levels (all p<0.002). There was a strong correlation between the TAFI 505 A/G and TAFI 1040 C/T polymorphisms and plasma TAFI antigen levels in all groups (all p<0.001). The G-allele of the 505A/G polymorphism was associated with a low antigen level of TAFI. Carriers of the GG genotype had an increased risk for BCS and/or PVT (OR=4.4; 95% CI 1.5–12.6). Carriers of the G allele showed a risk of 4.1 (95% CI 1.5–11.5). For the 1040C/T polymorphism, the T allele was associated with lower levels of TAFI antigen, and carriers of at least one copy of the T allele showed an OR of 1.6 (95% CI 0.9–2.7).Conclusion We found lower TAFI levels in patients with BCS and/or PVT than in healthy controls. In addition two TAFI genotypes, associated with lower TAFI antigen levels were found more frequently in patients with BCS and/or PVT than in healthy controls. Therefore low TAFI levels appear to be a risk factor for the development of BCS and PVT. These results suggest a different pathogenetic mechanism of TAFI in BCS and PVT than in deep venous thrombosis.

Association of Thrombin-Activatable Fibrinolysis Inhibitor with Acute Pulmonary Embolism.

Thrombin-activatable fibrinolysis inhibitor (TAFI) inhibits fibrinolysis and high levels may have an association with thrombosis. The aim of the current study was to investigate the association of TAFI antigen levels with pulmonary thromboembolism (PTE). A case-control study was conducted with 29 patients with PTE and 17 age- and gender-matched control individuals. Plasma levels of TAFI were measured at the time of diagnosis, then at 3 and 6 months after the event. Initial TAFI levels (%) were higher in patients with PTE than in the control group (190,0 [65,0-250,0] vs 133,0 [83,0-153,0]; p = 0.003). TAFI levels significantly decreased at the third and sixth months after initial diagnosis (p < 0.05). The percentage reductions in TAFI levels were 12 and 36.8% at 3 and 6 months, respectively. The Odss ratio (OR) of TAFI level for PTE was found to be 1.024 (95% CI: 1.007-1.040; p = 0.005). There was no significant correlation of initial TAFI levels with age, gender, smoking status, history of thrombosis, pulmonary artery pressure, and D-dimer levels (p > 0.05). In the sixth month of treatment, patients with residual thrombosis were seen to have similar baseline levels and reductions of TAFI as patients without residual thrombosis (p > 0.05). The result of this study suggests that high TAFI levels may have a role in the occurrence of PTE without impact on treatment outcome.

S62798, a potent TAFIa inhibitor, accelerates endogenous fibrinolysis in a murine model of pulmonary thromboembolism

Enhancement of fibrinolysis constitutes a promising approach to treat thrombotic diseases. Venous thrombosis and thromboembolism risks are associated with increased plasma levels of TAFI (Thrombin Activatable Fibrinolysis Inhibitor) as well as its active form TAFIa. A new TAFIa inhibitor, namely S62798 has been identified. Its ability to enhance fibrinolysis was investigated both in vitro and in vivo in a mouse model of pulmonary thromboembolism, as well as its effect on bleeding.S62798 is a highly selective human, mouse and rat TAFIa inhibitor (IC50 = 11; 270; 178 nmol/L, respectively). It accelerates lysis of a human clot in vitro, evaluated by thromboelastometry (EC50 = 27 nmol/L). In a rat tail bleeding model, no effect of S62798 treatment was observed up to 20 mg/kg. Enhancement of endogenous fibrinolysis by S62798 was investigated in a mouse model of Tissue Factor-induced pulmonary thromboembolism. Intravenous administration of S62798 decreased pulmonary fibrin clots with a minimal effective dose of 0.03 mg/kg. Finally, effect of S62798 in combination with heparin was evaluated. When treatment of heparin was done in a curative setting, no effect was observed whereas a significantly decreased pulmonary fibrin deposition was observed in response to S62798 alone or in combination with heparin.This study demonstrates that S62798 is a potent TAFIa inhibitor with minimal risk of bleeding. In vivo, curative S62798 intravenous treatment, alone or associated with heparin, accelerated clot lysis by potentiating endogenous fibrinolysis and thus decreased pulmonary fibrin clots. S62798 is expected to be a therapeutic option for pulmonary embolism patients on top of anticoagulants.