Reductions in plasmin inhibitor and fibrinogen predict the improved fibrin clot lysis 6 months after obesity surgery.

Prothrombotic and metabolic variables are decreased after obesity surgery, and fibrin clot lysis is increased. It is unknown how fibrinolytic variables are affected, and whether fibrinolytic and metabolic changes predict the enhanced clot lysis. Study aims were to determine fibrinolytic biomarkers before and 6 months after Roux-en-Y gastric bypass (RYGB) and to identify predictors of the RYGB-induced increase in clot lysis. Women (n = 42) and men (n = 18) with obesity underwent RYGB, and factor XIII (FXIII), thrombin activatable fibrinolysis inhibitor (TAFI), plasminogen and plasmin inhibitor (PI) were measured before and 6 months after surgery. Regression analyses identified determinants of the RYGB-induced increase in clot lysis among changes in fibrinogen and in fibrinolytic and metabolic variables. Results showed that after RYGB, FXIII, TAFI, plasminogen and PI were reduced (P < .0005). Reductions in PI (ß = -0.59) and fibrinogen (ß = -0.35), together with age (ß = -0.22) and male sex (ß = 0.22), predicted the enhanced clot lysis with the model explaining 56% (P < .0005). Predictors of the reduction in PI were reductions in cholesterol (ß = 0.37) and glucose (ß = 0.29), together with male sex (ß = -0.28), whereas reductions in fibrinogen were predicted by lowering of interleukin-6 (IL-6) (ß = 0.32). In conclusion, fibrinolytic variables were reduced 6 months after RYGB. Targeting PI and fibrinogen, by reducing metabolic variables such as glucose, cholesterol and IL-6, has a profibrinolytic effect in obesity.

Plasma Fibrin Clot Properties Are Unfavorably Altered in Women following Venous Thromboembolism Associated with Combined Hormonal Contraception.

The use of hormonal contraception is associated with an increased risk of venous thromboembolism (VTE). Unfavorably altered fibrin clot phenotype has been reported in patients following unprovoked VTE who are at risk of recurrences. It remains unknown whether fibrin clot characteristics in women with contraception-related VTE differ from those in unprovoked VTE. We studied three age-matched groups of women: (1) after contraception-related VTE, (n = 48) (2) after unprovoked VTE (n = 48), and (3) controls (n = 48). Plasma fibrin clot permeability (K s), turbidity of clot formation, efficiency of fibrinolysis using clot lysis time (CLT), and rate of increase in D-dimer during lytic clot degradation (D-Drate), along with thrombin generation and fibrinolysis proteins were determined. Compared with the controls, patients following contraception-related and unprovoked VTE formed faster (lag phase, -8.8% and -20.4%, respectively) fibrin clots of increased density (K s , -8.6% and -13.4%, respectively) displaying impaired fibrinolysis as evidenced by prolonged CLT (+11.5% and +14.5%, respectively) and lower D-Drate (-7.1% and -5.6%, respectively), accompanied with higher plasminogen activator inhibitor-1 (PAI-1, +14.9% and +17.8%, respectively) and elevated peak thrombin generation (+63.8% and +36.7%, respectively). The only differences between women with unprovoked and contraception-related VTE were lower fibrin mass in plasma clots (D-Dmax, -8.6%), along with higher peak thrombin generation (+19.8%) and shorter lag phase (-6.8%) in the latter group. This study suggests that women after contraception-related VTE, similar to those following unprovoked VTE, have denser fibrin clot formation and impaired clot lysis. These findings might imply higher risk of VTE recurrence in women with the prothrombotic clot phenotype.

Inhibition of the procarboxypeptidase U (proCPU, TAFI, proCPB2) system due to hemolysis.

Essentials Hemolytic influence on the (pro)carboxypeptidase U ((pro)CPU) system is not known. In the current manuscript, this was assessed by spiking pooled normal plasma with hemolysate. CPU activity, proCPU levels, and clot lysis times showed a dose-dependent hemolytic bias. The observed bias in the several CPU related parameters is due to inhibition of CPU activity. INTRODUCTION: Spurious hemolysis of samples is the leading cause of interference in coagulation testing and was described to interfere in fibrinolysis assays. The influence of hemolysis on the procarboxypeptidase U (proCPU) system is not known. METHODS: By means of spiking of hemolysate in pooled normal plasma, the effect of hemolysis on CPU, proCPU, and functional clot lysis assays was assessed. The influence of hemolysis on CPU generation during in vitro clot lysis was also evaluated. Cutoffs corresponding to maximal acceptable bias were determined. RESULTS AND DISCUSSION: When active CPU was added to pooled plasma, a severe decrease in activity - up to 97.2% inhibition - was seen with increasing plasma concentrations of oxyhemoglobin (oxyHb) and the 10% cutoff value was found to be 0.3 g/L oxyHb. Using an activity-based assay, proCPU levels appeared to decrease gradually with increased hemolysis (maximal reduction of 19.5%) with a 10% cutoff value of 4.2 g/L oxyHb. The relative clot lysis time (CLT) showed a maximal negative bias of 68.5%. The reduction in CLT paralleled a significant reduction of the first CPU activity peak during clot lysis. The cutoff value for the CLT was 0.4 g/L oxyHb. In presence of thrombomodulin (TM), CLT+TM was not affected up to 8.0 g/L oxyHb. CONCLUSION: These data indicate a clear inhibition of the CPU system because of hemolysis resulting in an increase of lysis in functional fibrinolysis assays. We were able to quantify the inhibitory effect and to propose cutoff values for every parameter.

Fibrinolysis in trauma patients: wide variability demonstrated by the Lysis Timer.

Hyperfibrinolysis contributes to the pathophysiology of trauma-induced coagulopathy. At present, systematic administration of tranexamic acid (TXA) is recommended in all patients in the early phase of trauma. However, there is some debate regarding whether TXA is beneficial in all trauma patients. A rapid and accurate tool to diagnose hyperfibrinolysis may be useful for tailoring TXA treatment. We conducted a proof-of-concept study of consecutive adult trauma patients. A first blood sample was obtained at the time of pre-hospital care (T1). Patients received 1 g of TXA after T1. A second sample was obtained on arrival at the emergency unit (T2). We examined coagulation, fibrin and fibrinogen formation and degradation. Fibrinolysis was assessed by determining tissue plasminogen activator (t-PA) antigen and plasminogen activator inhibitor 1 (PAI-1) activity and global fibrinolysis capacity assay using a device developed by Hyphen BioMed: the Lysis Timer (GFC/LT). The study population consisted of 20 patients (42 ± 21 years, index of severity score 32 ± 21). Both coagulation and fibrinolysis were altered at T1. GFC/LT values exhibited hyperfibrinolysis only in five patients. Principal component analysis carried out at T1 showed two main axes of alteration. The major axis was related to coagulation, altered in all patients, while the second axis was related to fibrinolysis. GFC/LT was mainly influenced by PAI-1 activity while fibrin monomers were related to the severity of trauma. At T2, GFC/LT exhibited the marked effect of TXA on clot lysis time. In conclusion, GFC/LT demonstrated huge variation in the fibrinolytic response to trauma.

Plasma fibrin clot properties affect blood loss after surgical aortic valve replacement for aortic stenosis.

OBJECTIVES: Cardiac surgery is associated with elevated bleeding risk. We sought to study whether fibrin clot phenotype influences postoperative blood loss after surgery for aortic stenosis (AS). METHODS: We studied 77 isolated AS patients, including 62 who underwent aortic valve replacement and 15 who underwent the Bentall procedure due to post-stenotic aortic dilation. Plasma clot properties, including the tPA-induced clot lysis time (CLT) and clot permeability (Ks), along with fibrinolysis inhibitors, a calibrated automated thrombogram and platelet activation markers, were assessed preoperatively. RESULTS: In the whole AS group, the median chest tube output after 12 h was 360 ml (range of 110-2290 ml). Patients with drainage in the top quartile after 12 h (≥600 ml) had lower fibrinogen, shorter CLT, higher Ks, lower plasma plasminogen activator inhibitor-1 antigen, peak thrombin generation and ß-thromboglobulin levels than those in the lowest drainage quartile (≤260 ml) with no difference in platelets or von Willebrand factor. A multivariable model that was built after the exclusion of Bentall patients, adjusted for age, sex, body mass index and fibrinogen, showed that high drainage, which was defined as the top quartile after 12 h postaortic valve replacement (≥460 ml), was predicted by ß-thromboglobulin [odds ratio (OR) 0.94, 95% confidence interval (CI) 0.90-0.99, P = 0.03], fibrinogen (OR 0.13, 95% CI 0.00-0.47, P = 0.02) and the CLT (OR 0.95, 95% CI 0.91-0.99, P = 0.02). The CLT was inversely related to the number of transfused platelet units (r = -0.27, P = 0.04). CONCLUSIONS: Fibrin clot susceptibility to lysis is a modulator of postoperative blood loss after cardiac surgery for AS, which may have practical implications.

The association of clot lysis time with total obesity is partly independent from the association of PAI-1 with central obesity in African adults.

INTRODUCTION: Preliminary evidence indicates that the association of fibrinolytic potential, measured as clot lysis time (CLT), with body composition may differ from that of plasminogen activator inhibitor type-1 (PAI-1). We therefore investigated the association between fibrinolytic markers (plasminogen activator inhibitor type-1 activity (PAI-1act) and CLT) and body composition using detailed body composition analyses. MATERIALS AND METHODS: Data from 1288 Africans were cross-sectionally analyzed. Body composition analysis included BMI, waist circumference (WC); waist to height ratio (WHtR), skinfolds and body fat percentage measured with air-displacement plethysmography and bioelectrical impedance analysis. RESULTS: PAI-1act and CLT were significantly higher in women than in men, despite adjustment for differences in body composition. PAI-1act and CLT showed similar linear positive relationships with body composition (BMI, WC, WHtR, skinfolds) in men. In women CLT also showed a linear relationship with body composition, while PAI-1act levels plateaued at higher BMI and did not differ across skinfold categories. PAI-1act showed stronger correlations with body composition markers in men than it did in women, while no sex differences existed for CLT. PAI-1act associated more strongly with central obesity, while CLT associated with total body fat. CONCLUSIONS: Observed differences may be related to differences in adipose tissue type, distribution and sequence of accumulation between sexes. PAI-1act is strongly influenced by accumulation of visceral adipose tissue, whereas CLT is associated with obesity independent of type and sequence of body fat accumulation in this African adult study population.