BβArg448Lys polymorphism is associated with altered fibrin clot structure and fibrinolysis in type 2 diabetes

SummaryBoth type 2 diabetes (T2DM) and Bß448Lys variant of fibrinogen are associated with dense fibrin clots, impaired fibrinolysis and increased cardiovascular risk. It was our objective to investigate whether BßArg448Lys adds to vascular risk by modulating fibrin network structure and/or fibrinolysis in diabetes. The primary aim was to study effects of BßArg448Lys on fibrin network characteristics in T2DM. Secondary aims investigated interactions between gender and BßArg448Lys substitution in relation to fibrin clot properties and vascular disease. Genotyping for BßArg448Lys and dynamic clot studies were carried out on 822 T2DM patients enrolled in the Edinburgh Type 2 Diabetes Study. Turbidimetric assays of individual plasma samples analysed fibrin clot characteristics with additional experiments conducted on clots made from purified fibrinogen, further examined by confocal and electron microscopy. Plasma clot lysis time in Bß448Lys was longer than Bß448Arg variant (mean ± SD; 763 ± 322 and 719 ± 351 seconds [s], respectively; p<0.05). Clots made from plasma-purified fibrinogen of individuals with Arg/Arg, Arg/Lys and Lys/Lys genotypes showed differences in fibre thickness (46.75 ± 8.07, 38.40 ± 6.04 and 25 ± 4.99 nm, respectively; p<0.001) and clot lysis time (419 ± 64, 442 ± 87 and 517 ± 65 s, respectively; p=0.02), directly implicating the polymorphism in the observed changes. Women with Bß448Lys genotype had increased risk of cerebrovascular events and were younger compared with Bß448Arg variant (67.2 ± 4.0 and 68.2 ± 4.4 years, respectively; p=0.035). In conclusion, fibrinogen Bβ448Lys variant is associated with thrombotic fibrin clots in diabetes independently of traditional risk factors. Prospective studies are warranted to fully understand the role of BβArg448Lys in predisposition to vascular ischaemia in T2DM with the potential to develop individualised antithrombotic management strategies.

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Abstract 16668: The Effects of Dabigatran on Fibrin Network Structure and Lysis: A Simple Technique to Monitor Efficacy of Treatment?

Circulation ◽

10.1161/circ.130.suppl_2.16668 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Francesco Franchi ◽

Rhodri King ◽

Fladia Phoenix ◽

Fabiana Rollini ◽

Jung Rae Cho ◽

...

Keyword(s):

Antiplatelet Therapy ◽

Placebo Treatment ◽

Fibrin Clot ◽

Clot Formation ◽

Clot Lysis ◽

Lag Phase ◽

Maximum Absorbance ◽

Lysis Time ◽

Fibrin Network ◽

Clot Lysis Time

Background: Thrombus formation represent the final step in the atherothrombotic process and occurs secondary to a complex interaction between platelets and coagulation factors. Increased platelet reactivity and enhanced clot formation can both determine predisposition to vascular events. Direct platelet inhibition by modern antiplatelet therapy is now effective at controlling the cellular component of coagulation but the fibrin network is not generally targeted in arterial disease. Our aim was to investigate the effects of dabigatran on fibrin network characteristics in individuals dual antiplatelet therapy (DAPT). Methods: This was a prospective, randomized, double-blind study conducted in 30 patients on maintenance (at least 30 days) DAPT with aspirin (81mg/day) and clopidogrel (75mg/day). Patients were randomized to receive either dabigatran 150mg bid or matching placebo for 7 days. Fibrin clot properties were studied using a validated turbidimetric assay and the following parameters were recorded: lag phase and time to full clot formation, both of which measure clotting potential; clot maximum absorbance, representing fibrin network density and fibre thickness; clot lysis time to assess fibrinolytic efficiency. Results: Dabigatran treatment was associated with an increase in lag phase, compared with baseline, of 1013±167 sec , whereas no difference was detected in placebo treated patients (-17±14 sec, p<0.001 for dabigatran vs placebo). Similar results were obtained for clot formation time with an increase of 240±37 sec in dabigatran treated patients with no change following placebo treatment (-24±18 sec; p<0.001 comparing the two groups). The change in clot maximum absorbance after dabigatran and placebo treatment showed no differences (-0.02±0.01 and 0.00±0.01 au, respectively; p=0.2) and clot lysis time was similar. Conclusions: In patients on DAPT with aspirin and clopidogrel, additional treatment with dabigatran delays fibrin clot formation without affecting fibrinolysis. Therefore, triple therapy with dabigatran may be one option to reduce thrombosis potential in high risk individuals. Moreover, our assay, which can be conducted on stored samples, offers the opportunity to monitor response to dabigatran therapy.

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Some Aspects of Fibrin Clot Lysis and Its Inhibition by Human Serum

Thrombosis and Haemostasis ◽

10.1055/s-0038-1655021 ◽

1967 ◽

Vol 18 (01/02) ◽

pp. 101-113 ◽

Cited By ~ 3

Author(s):

M. J Gallimoke ◽

J. T. B Shaw

Keyword(s):

Sodium Chloride ◽

Fibrin Clot ◽

Chloride Ions ◽

Clot Lysis ◽

Irreversible Inhibitors ◽

Zero Order Kinetics ◽

Lysis Time ◽

Kinetics Of ◽

Clot Lysis Time ◽

Fibrin Clots

SummaryThe lysis by plasmin of fibrin clots prepared from plasminogen-deficient fibrinogen, and by urokinase of similar clots prepared from plasminogen-rich fibrinogen has been studied. In a simple system containing no plasminogen the clot lysis time is inversely proportional to the concentration of added plasmin, and zero order kinetics are obeyed. The reciprocal of the lysis time is a measure of the fibrinolytic activity in the system, and may be used to study antiplasmins. When serum was included a reduction in reciprocal lysis time resulted, the extent of which varied linearly with the amount of serum added. These relationships persisted whether soluble or insoluble plasmin preparations were used and whether or not chloride ions were present. They indicate that serum antiplasmins behave as irreversible or pseudo-irreversible inhibitors. It was found that sodium chloride exerts a potentiating effect on fibrinolysis by plasmin, but does not influence the extent to which the enzyme is inhibited by serum antiplasmins.When fibrin clots were prepared from plasminogen-rich fibrinogen, and urokinase was included, a direct relationship was found to exist between the concentration of urokinase and the square of the reciprocal clot lysis time. When serum was added, vigorous inhibition of fibrinolysis resulted when sodium chloride was present; no inhibition was observed in its absence. It is proposed that sodium chloride weakens the interaction between plasminogen and fibrin in the clots, and renders the plasmin produced by the action of urokinase more susceptible to inhibition by antiplasmins. Evidence in support of this hypothesis is presented and the kinetics of fibrinolysis by plasmin, and its inhibition, are discussed.

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The ABO Locus is Associated with Increased Fibrin Network Formation in Patients with Stable Coronary Artery Disease

Thrombosis and Haemostasis ◽

10.1055/s-0040-1713753 ◽

2020 ◽

Vol 120 (09) ◽

pp. 1248-1256

Author(s):

Anne Winther-Larsen ◽

Morten Krogh Christiansen ◽

Sanne Bøjet Larsen ◽

Mette Nyegaard ◽

Søs Neergaard-Petersen ◽

...

Keyword(s):

Risk Allele ◽

Fibrin Clot ◽

Clot Lysis ◽

Risk Variant ◽

Risk Variants ◽

Lysis Time ◽

Fibrin Network ◽

Artery Disease ◽

Stable Cad ◽

Clot Lysis Time

Abstract Background The ABO locus has been associated with increased risk of myocardial infarction (MI) in patients with coronary artery disease (CAD), but the underlying mechanisms are unknown. As altered fibrin clot structure has been demonstrated to predict MI in CAD patients, we examined the association between the ABO risk variant and fibrin clot properties, and investigated the effects of other CAD-associated risk variants. Methods We included 773 stable CAD patients. Patients were genotyped for 45 genome-wide CAD risk variants, including rs495828 at the ABO locus. We used a genetic risk score (GRS) for CAD calculated as the weighted sum of the number of risk alleles based on all 45 variants. Fibrin clot properties were evaluated using a turbidimetric assay. We studied clot maximum absorbance, a measure of clot density and fiber thickness, together with clot lysis time, an indicator of fibrinolysis potential. Results The rs495828 risk allele was present in 13.2% of patients and associated with higher clot maximum absorbance (adjusted effect size per risk allele: 1.05 [1.01 − 1.09], p = 0.01) but not with clot lysis time (p = 0.97). The rs12936587 (p = 0.04), rs4773144 (p = 0.02), and rs501120 (p = 0.04) were associated with clot lysis time; however, after Bonferroni correction, no significant associations were found between any of the remaining 44 CAD-associated variants and fibrin clot properties. The GRS was not associated with fibrin clot properties (p-values > 0.05). Conclusion The ABO risk allele was associated with a more compact fibrin network in stable CAD patients, which may represent a mechanism for increased MI risk in ABO risk variant carriers.

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FRI0232 ALTERED FIBRIN CLOT PROPERTIES IN PATIENTS WITH SYSTEMIC SCLEROSIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.5506 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 699.2-700

Author(s):

J. Colic ◽

A. Antovic ◽

I. Pruner ◽

J. Vojinovic ◽

M. Sefik Bukilica ◽

...

Keyword(s):

Systemic Sclerosis ◽

Activity Index ◽

Pulmonary Function Tests ◽

Inverse Correlation ◽

Fibrin Clot ◽

Clot Lysis ◽

Sem Images ◽

Plasma Clot ◽

Lysis Time ◽

Clot Lysis Time

Background:Vasculopathy in Systemic sclerosis (SSc) is connected with the activation of coagulation. However, the fibrinolytic activity still remains unclear since the most preliminary evidences are discordant (1, 2).Objectives:To assess the haemostatic function, fibrin clot density and clot lysis time in SSc patients and healthy controls (HC) to determine their relation to disease findings.Methods:Patients who fulfilled the 2013 ACR/EULAR SSc criteria and have never been treated with endothelin receptor antagonist, phosphodiesterase 5 inhibitors or prostanoids were eligibile. Our study included 58 SSc patients [36 limited (lcSSc) and 22 diffuse cutaneous SSc (dcSSc)] and 46 sex/age-matched HC. Clinical evaluation of patients was performed, including high-resolution CT (HRCT), pulmonary function tests and the revised EUSTAR activity index. The interstitial lung disease (ILD) group (n = 15) was defined as moderate or severe changes on HRCT, with a forced vital capacity (FVC) < 85% predicted, without evidence of significant pulmonary arterial hypertension. The serum concentration of ICAM1 and von Willebrand factor antigen (VWF) were measured by ELISA. Haemostatic potential parameters; including overall haemostasis (OHP), overall coagulation (OCP) and overall fibrinolysis (OFP) potential, were assessed and endogenous thrombin potential (ETP) was determined. Maximum absorbance (Cmax), reflects the fibrin clot density and clot lysis time (Lys50t0), reflects fibrinolytic susceptibility, were calculated from OHP and OCP curves (3). Fibrin structure was visualised using scanning electron microscopy (SEM).Results:The OFP value was significantly decreased, Lys50t0 prolonged (p<0.05), while OHP and ETP were increased (p<0.05) in patients. In dSSc group ETP, OHP, Cmax and Lys50t0 were higher compared to HC (p<0.05). In SSc group, a positive association was found between coagulation parameters (OCP, OHP, Cmax) and the erythrocyte sedimentation rate (ESR), fibrinogen and ICAM1 (respectively p<0.05). Lys50t0 was positively correlated with ICAM1, ESR and VWF (respectively p<0.001, p<0.05, p<0.05). An inverse correlation was found between Cmax and both the diffusing capacity of the lungs for carbon monoxide (r=-0.408, p<0.01) and FVC (r=-0.318, p<0.01). Increased Cmax was found in ILD respect to HC (p<0.01). Denser plasma clot was associated with active disease (p<0.01). Longer Lys50t0 was observed in pitting scars group (p<0.01). Prolonged Lys50t0 was independently predicted by ICAM1 (OR 1.12, 95% CI 1.03–1.2, p<0.01).Conclusion:Our results provide evidences of denser plasma fibrin clot among patients with lung involvement and impaired fibrinolysis, selectively presented among SSc patients with piting scars. Thus, these patients might be at risk for thrombotic complications. Raised ICAM-1 levels could reflect impaired fibrinolysis, giving insight the important role of this molecule in endothelial homeostasis.References:[1]Cerinic MM, et al. Blood coagulation, fibrinolysis, and markers of endothelial dysfunction in systemic sclerosis. Semin Arthritis Rheum. 2003;32:285–95[2]Lippi G, et al. Plasma D-dimer concentration in patients with systemic sclerosis.Thromb J. 2006;4:2.[3]Carter AM, et al. Heritability of clot formation, morphology, and lysis: the EuroCLOT study. Arterioscler Thromb Vasc Biol. 2007 Dec;27(12):2783-9Figure 1.SEM images of fibrin network in 1 representative sample from a SSc (A) and 1from HC sample (B).Disclosure of Interests:Jelena Colic: None declared, Aleksandra Antovic: None declared, Iva Pruner: None declared, Jelena Vojinovic Consultant of: Roche, Abbvie, Pfizer, MSD, Speakers bureau: Roche, Abbvie, Pfizer, MSD, Mirjana Sefik Bukilica: None declared, Nemanja Damjanov Grant/research support from: from AbbVie, Pfizer, and Roche, Consultant of: AbbVie, Gedeon Richter, Merck, Novartis, Pfizer, and Roche, Speakers bureau: AbbVie, Gedeon Richter, Merck, Novartis, Pfizer, and Roche

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Does Fibrin Structure Contribute to the Increased Risk of Thrombosis in COVID-19 ICU Patients?

Blood ◽

10.1182/blood-2021-145307 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3208-3208

Author(s):

Judith Juliana De Vries ◽

Chantal Visser ◽

Lotte Geers ◽

Johan A. Slotman ◽

Henrik Endeman ◽

...

Keyword(s):

Clot Lysis ◽

Healthy Controls ◽

Similar Time ◽

Icu Patients ◽

Lysis Time ◽

Increased Risk ◽

Fibrin Network ◽

Fibrin Fiber ◽

Clot Lysis Time ◽

Time Point

Abstract Introduction: SARS-CoV-2 is responsible for a global pandemic, with almost 200 million confirmed cases. SARS-CoV-2 infection can lead to various disease states, from only mild symptoms in the majority of cases to severe disease, which is associated with an increased incidence of venous thromboembolism (VTE). We hypothesized that an altered fibrin network structure contributes to VTE in COVID-19 patients by affecting thrombus stability and fibrinolysis sensitivity. By studying the fibrin network of COVID-19 patients, we aimed to unravel the mechanisms that contribute to the increased risk of VTE in COVID-19 patients. Methods: Between April 2020 and December 2020, we collected plasma samples from patients with COVID-19 admitted to the intensive care unit (ICU) of the Erasmus Medical Center. We included patients with confirmed VTE diagnosed on CT-angiography, and COVID-19 patients without confirmed VTE during ICU admission. Samples were collected on admission to the ICU and after confirmed VTE or at similar time points in ICU patients without confirmed VTE. In addition, we collected plasma from COVID-19 patients at admission to general wards without confirmed VTE and from healthy controls. Clots were formed by mixing citrated plasma with thrombin (final concentration 1 U/ml) and calcium (17 mM). We imaged the clots using stimulated emission depletion (STED) microscopy, a super-resolution technique in which a depletion laser is used to selectively switch off fluorophores surrounding the focal point, thereby increasing the resolution. In these images, fibrin fiber diameters were measured using the Local Thickness plugin of ImageJ. Fiber density was quantified as percentage of area in Z-stacks of confocal microscopy images. Finally, a clot lysis assay based on turbidity was used to determine sensitivity to fibrinolysis (clot lysis time) and clot density (difference between maximum and baseline absorbance). Differences in fibrin network properties between groups were tested using One-Way ANOVA with Bonferroni post-hoc tests and linear regression with and without adjustment for fibrinogen levels. Results: We included 21 COVID-19 ICU patients with confirmed VTE, 20 COVID-19 ICU patients without confirmed VTE, 10 COVID-19 ward patients and 7 healthy controls. Mean age was comparable between the groups, while BMI was higher in COVID-19 patients than in healthy controls (Table 1). Levels of fibrinogen, D-dimer and anti-Xa were significantly higher in COVID-19 ICU patients than in COVID-19 ward patients and healthy controls. FVIII levels were significantly higher in COVID-19 ICU patients than in healthy controls, while FXIII levels were significantly lower. On admission to the ICU, clot density was significantly higher in COVID-19 ICU patients with and without confirmed VTE than in healthy controls (Figure 1 and Table 2). However, after adjustment for fibrinogen levels, this difference disappears. Clot lysis time was significantly longer in clots from COVID-19 ICU patients than in clots from healthy controls, regardless of fibrinogen levels (Table 2). COVID-19 ICU patients with confirmed VTE also showed a significant longer clot lysis time than COVID-19 ward patients. Interestingly, in the clot lysis assay, fibrinolysis did not occur in 25% of COVID-19 ICU patients with VTE versus 9.5% of COVID-19 ICU patients without VTE (Figure 2). This fibrinolysis shutdown was never observed in clots from healthy controls and COVID-19 ward patients. Fibrin fiber diameters were comparable between the groups. In the clots from plasma samples collected at admission to the ICU, there were no differences between COVID-19 ICU patients with and without VTE (Figure 2). However, when comparing clots prepared from plasma collected at the second time point (after VTE or at a similar time point for patients without VTE), we observed significant longer clot lysis times in patients with confirmed VTE (97.4 [88.5-158.8] min) than in patients without confirmed VTE (80.0 [76.0-97.8] min) (p=0.03). Finally, there were no significant changes between clots from plasma before and after VTE or between the two time points in patients without VTE, except for a decreased clot lysis time over time for COVID-19 ICU patients without confirmed VTE. Conclusion: Our results suggest that SARS-CoV-2 infection increases clot density and decreases clot susceptibility to fibrinolysis, and that these changes relate to the severity of the disease. Figure 1 Figure 1. Disclosures Kruip: Daiichi Sankyo: Research Funding; Bayer: Honoraria, Research Funding.

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3309Complement activation leads to C3 and C5 dependent prothrombotic alterations of fibrin clots

European Heart Journal ◽

10.1093/eurheartj/ehz745.0073 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

K A Schutt ◽

S Maxeiner ◽

K Lysaja ◽

M Berger ◽

S Ruetten ◽

...

Keyword(s):

Electron Microscopy ◽

Complement Activation ◽

Fibrin Clot ◽

Complement C3 ◽

Clot Lysis ◽

Lysis Time ◽

Patients With Diabetes ◽

Clot Structure ◽

Clot Lysis Time ◽

Fibrin Clots

Abstract Background and aims Alterations of clot structure with thin fibres, small pores and prolonged fibrinolysis are associated with an increased cardiovascular risk. We previously demonstrated complement C3 to be incorporated into fibrin clots resulting in prolongation of fibrinolysis, an effect which was exaggerated in patients with diabetes. Patients with diabetes are known to display higher levels of complement activation. However, the role of complement activation in particular activation of C3 and C5 on clot lysis time remains unexplored. Thus, the present study seeks to determine whether activation of complement C3 and C5 by cobra venom factor (CVF) has an impact on fibrin clot structure and clot lysis. Materials and methods Fibrin clot structure and lysis were determined in a plasma pool of healthy controls in the presence and absence of the complement C3 and C5 activator CVF using a validated turbidimetric assay and scanning electron microscopy. C3 activation was inhibited by the addition of the small 14-AA-peptide Cp40, while C5 activation was blocked by the addition of the FDA approved monoclonal antibody eculizumab (Emab). Results Complement activation with CVF leads to a prothrombotic clot structure with thinner fibres (Co 0.20±0.001 au, CVF 0.13±0.001 au; p<0.0001) and prolongation of clot lysis time (Co 864±32 sec, CVF 1665±17 sec; p<0.0001), which was confirmed by electron microscopy (Co 94.7±1.44 nm, CVF 60.7±0.96 nm; p<0.0001). Inhibition of C3 activation by Cp40 improved clot structure resulting in thicker fibres (Co 0.20±0.001 au, CVF 0.13±0.001 au, CP40 0.20±0.002 au; p<0.0001) and shorter clot lysis time (Co 100%, CVF 181±8.9%, CP40 139±7.8%; p<0.0001), while scrambled protein had no effect on either clot structure or lysis time. As CVF can also activate C5 convertase we next investigated the inhibition of complement C5 activation with eculizumab. The latter improved both fibre thickness (Co 0.20±0.002 au, CVF 0.13±0.003 au, Emab 0.16±0.006 au; p<0.0001) and clot lysis time (Co 100%, CVF 192±12%, Emab 140±11%; p<0.001). The combined inhibition of C3 and C5 activation using both, Cp40 and eculizumab in combination optimized clot structure (Co 0.22±0.001 au, CVF 0.13±0.0006 au, Cp40/Emab 0.21±0.001 au; Co vs. Cp40/Emab p=0.003) and restored clot lysis time (Co 100%, CVF 226±6%, CP40/Emab 104±1%; Co vs. Cp40/Emap p=0.8). The results were confirmed by electron microscopy (fibre thickness: Co 93±1.4 nm, CVF 68±1.3 nm, Cp40 83±1.4 nm, Emab 78±1.7 nm, CP40/Emap 95±1.6 nm). Conclusions Complement activation at the level of complement C3 and C5 has a detrimental impact on clot properties. Blocking C3 and C5 activation can restore both clot density and prolongation of clot lysis time. Further studies are needed to determine the underlying binding sites on fibrin(ogen) to pave the way for molecules improving clot properties without affecting immune responses. Acknowledgement/Funding KS is supported by the German Research Foundation (DFG) (SFB/TRR219 C-07; HE 5666/1-2 to KS (née Hess)]

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Altered fibrin clot structure/function in patients with antiphospholipid syndrome: association with thrombotic manifestation

Thrombosis and Haemostasis ◽

10.1160/th13-11-0980 ◽

2014 ◽

Vol 112 (08) ◽

pp. 287-296 ◽

Cited By ~ 21

Author(s):

Magdalena Celińska-Löwenhoff ◽

Teresa Iwaniec ◽

Agnieszka Padjas ◽

Jacek Musiał ◽

Anetta Undas

Keyword(s):

Structure Function ◽

Antiphospholipid Syndrome ◽

Thrombotic Event ◽

Fibrin Clot ◽

Clot Lysis ◽

Lag Phase ◽

Lysis Time ◽

Clot Structure ◽

Clot Lysis Time ◽

D Dimer

SummaryWe tested the hypothesis that plasma fibrin clot structure/function is unfavourably altered in patients with antiphospholipid syndrome (APS). Ex vivo plasma clot permeability, turbidity and susceptibility to lysis were determined in 126 consecutive patients with APS enrolled five months or more since thrombotic event vs 105 controls. Patients with both primary and secondary APS were characterised by 11% lower clot permeability (p<0.001), 4.8% shorter lag phase (p<0.001), 10% longer clot lysis time (p<0.001), and 4.7% higher maximum level of D-dimer released from clots (p=0.02) as compared to the controls. Scanning electron microscopy images confirmed denser fibrin networks composed of thinner fibres in APS. Clots from patients with “triple-antibody positivity” were formed after shorter lag phase (p=0.019) and were lysed at a slower rate (p=0.004) than in the remainder. Clots from APS patients who experienced stroke and/or myocardial infarction were 8% less permeable (p=0.01) and susceptible to lysis (10.4% longer clot lysis time [p=0.006] and 4.5% slower release of D-dimer from clots [p=0.01]) compared with those following venous thromboembolism alone. Multivariate analysis adjusted for potential confounders showed that in APS patients, lupus anticoagulant and “triple-positivity” were the independent predictors of clot permeability, while “triple-positivity” predicted lysis time. We conclude that APS is associated with prothrombotic plasma fibrin clot phenotype, with more pronounced abnormalities in arterial thrombosis. Molecular background for this novel prothrombotic mechanism in APS remains to be established.

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Kinetics of fibrin clot lysis

Biochemical Journal ◽

10.1042/bj1060101 ◽

1968 ◽

Vol 106 (1) ◽

pp. 101-105 ◽

Cited By ~ 9

Author(s):

R. J. Merrills ◽

J. T. B. Shaw

Keyword(s):

Plasminogen Activator ◽

Experimental Studies ◽

Fibrin Clot ◽

Clot Lysis ◽

Lysis Time ◽

Kinetics Of ◽

Fibrin Clots

The principles relating the lysis times of fibrin clots to their contents of fibrin, plasminogen and plasminogen-activator were investigated. Mathematical considerations suggested that the square of the lysis time should correlate linearly with the fibrin content, and inversely with the activator and the plasminogen contents of the system. Experimental studies, during which these parameters were independently varied, showed that the predicted relationships were valid for concentrations that gave clot-lysis times in the range normally used for studies of fibrinolysis.

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Impaired Fibrinolysis Predicts Adverse Outcome in Acute Coronary Syndrome Patients with Diabetes: A PLATO Sub-Study

Thrombosis and Haemostasis ◽

10.1055/s-0039-1701011 ◽

2020 ◽

Vol 120 (03) ◽

pp. 412-422 ◽

Cited By ~ 3

Author(s):

Wael Sumaya ◽

Lars Wallentin ◽

Stefan K. James ◽

Agneta Siegbahn ◽

Katja Gabrysch ◽

...

Keyword(s):

Acute Coronary Syndrome ◽

Fibrin Clot ◽

Clot Lysis ◽

Bleeding Events ◽

Coronary Syndrome ◽

Lysis Time ◽

Increased Risk ◽

Patients With Diabetes ◽

The Relationship ◽

Maximum Turbidity

AbstractHypofibrinolysis is a key abnormality in diabetes but the role of impaired clot lysis in predicting vascular events and mortality in this population is yet to be determined. We aimed to investigate the relationship between fibrin clot properties and clinical outcomes in patients with diabetes and recent acute coronary syndrome (ACS). Plasma samples were collected at hospital discharge from 974 ACS patients with diabetes randomised to clopidogrel or ticagrelor in the PLATO trial. A validated turbidimetric assay was employed to study fibrin clot lysis and maximum turbidity. One-year rates of cardiovascular (CV) death, spontaneous myocardial infarction (MI) and PLATO-defined major bleeding events were assessed after sample collection. Hazard ratios (HRs) were determined using Cox proportional analysis. After adjusting for CV risk factors, each 50% increase in lysis time was associated with increased risk of CV death/MI (HR 1.21; 95% confidence interval [CI] 1.02–1.44; p = 0.026) and CV death alone (HR 1.38; 1.08–1.76; p = 0.01). Similarly, each 50% increase in maximum turbidity was associated with increased risk of CV death/MI (HR 1.25; 1.02–1.53; p = 0.031) and CV death alone (HR 1.49; 1.08–2.04; p = 0.014). The relationship between lysis time and the combined outcome of CV death and MI remained significant after adjusting for multiple prognostic vascular biomarkers (p = 0.034). Neither lysis time nor maximum turbidity was associated with major bleeding events. Impaired fibrin clot lysis predicts 1-year CV death and MI in diabetes patients following ACS. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier NCT00391872.

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