Enhanced lysis and accelerated establishment of viscoelastic properties of fibrin clots are associated with pulmonary embolism

Martinez, Marissa; Cuker, Adam; Mills, Angela M.; Crichlow, Amanda; Lightfoot, Richard; Chernysh, Irina N.; Nagaswami, Chandrasekaran; Weisel, John W.; Ischiropoulos, Harry

doi:10.1152/ajplung.00265.2013

Cited by 41 publications

(38 citation statements)

References 27 publications

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“…These findings indicating a similar pattern of changes in fibrin characteristics as a predictor of recurrent PE and DVT 10 are surprising. Martinez et al 11 reported that clots made from plasma of patients with acute isolated PE were characterized by faster CLT and lower fiber density when compared with DVT alone. On the contrary, perfusion defects after PE and chronic thromboembolic pulmonary hypertension have been shown to be associated with impaired fibrinolysis.…”

Section: Discussionmentioning

confidence: 99%

Prothrombotic Fibrin Clot Phenotype Is Associated With Recurrent Pulmonary Embolism After Discontinuation of Anticoagulant Therapy

Ząbczyk

Plens

Wójtowicz

et al. 2017

ATVB

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Objective-Pulmonary embolism (PE) is a life-threatening manifestation of venous thromboembolism with a high recurrence rate after anticoagulation cessation. Recently, we have reported that prothrombotic clot phenotype in venous thromboembolism patients is associated with an increased risk of recurrent deep-vein thrombosis. Approach and Results-We tested whether abnormal clot properties are predictive of recurrent PE. We investigated 156 consecutive white patients aged 18 to 65 years after the first-ever provoked or unprovoked PE (n=89), with or without deep-vein thrombosis. Plasma fibrin clot permeability (K s ), turbidity measurements, calibrated automated thrombography, and efficiency of fibrinolysis using clot lysis time, maximum D-dimer levels, and rate of increase in D-dimer levels were evaluated at ≥3 months of anticoagulant therapy, at least 4 weeks since the anticoagulation withdrawal. The primary end point was recurrent PE during a median follow-up of 50 months. Recurrent PE was diagnosed in 23 (14.7%; 5%/ yr) patients. Recurrent PE was associated with formation of denser fibrin networks reflected by lower K s (P=0.007) and impaired fibrinolysis, as evidenced by prolonged clot lysis time (P=0.012) and reduced maximum rate of increase in D-dimer levels in the lysis assay (P=0.004). Patients with recurrent PE had higher plasma D-dimer (P<0.001) and thrombin peak (P=0.007) compared with the remainder, whereas turbidity measurements and maximum D-dimer levels did not differ in the recurrence. Multivariate model showed that independent predictors of recurrent PE were female sex, unprovoked venous thromboembolism, higher plasma D-dimer, reduced K s , and reduced maximum rate of increase in D-dimer levels in the lysis assay (all P<0.05). Conclusions-Altered

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Section: Discussionmentioning

confidence: 99%

Prothrombotic Fibrin Clot Phenotype Is Associated With Recurrent Pulmonary Embolism After Discontinuation of Anticoagulant Therapy

Ząbczyk

Plens

Wójtowicz

et al. 2017

ATVB

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“…Clots derived from the blood of subjects with pulmonary embolism showed accelerated establishment of viscoelastic properties compared to healthy donors (Martinez et al 2014). In addition, the stiffness of clots formed from the blood of patients who have had heart attacks at an early age is 50 % greater than that of controls (Collet et al 2006).…”

Section: 5 Fibrin Mechanical Properties and Their Structural Originsmentioning

confidence: 99%

Fibrin Formation, Structure and Properties

Weisel

Litvinov

2017

Subcellular Biochemistry

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Fibrinogen and fibrin are essential for hemostasis and are major factors in thrombosis, wound healing, and several other biological functions and pathological conditions. The X-ray crystallographic structure of major parts of fibrin(ogen), together with computational reconstructions of missing portions and numerous biochemical and biophysical studies, have provided a wealth of data to interpret molecular mechanisms of fibrin formation, its organization, and properties. On cleavage of fibrinopeptides by thrombin, fibrinogen is converted to fibrin monomers, which interact via knobs exposed by fibrinopeptide removal in the central region, with holes always exposed at the ends of the molecules. The resulting half-staggered, double-stranded oligomers lengthen into protofibrils, which aggregate laterally to make fibers, which then branch to yield a three-dimensional network. Much is now known about the structural origins of clot mechanical properties, including changes in fiber orientation, stretching and buckling, and forced unfolding of molecular domains. Studies of congenital fibrinogen variants and post-translational modifications have increased our understanding of the structure and functions of fibrin(ogen). The fibrinolytic system, with the zymogen plasminogen binding to fibrin together with tissue-type plasminogen activator to promote activation to the active proteolytic enzyme, plasmin, results in digestion of fibrin at specific lysine residues. In spite of a great increase in our knowledge of all these interconnected processes, much about the molecular mechanisms of the biological functions of fibrin(ogen) remains unknown, including some basic aspects of clotting, fibrinolysis, and molecular origins of fibrin mechanical properties. Even less is known concerning more complex (patho)physiological implications of fibrinogen and fibrin.

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“…Based on viscoelastic properties of incipient blood clots, a new biomarker of healthy, bleeding or prothrombotic clot microstructure was proposed, named the fractal dimension, which has been shown to have clinically important correlations [31-33]. Clots derived from the blood of subjects with pulmonary embolism showed accelerated establishment of viscoelastic properties compared to healthy donors [34]. Studies have shown that the stiffness of clots formed from the blood of patients who have had heart attacks at an early age is 50% greater than that of controls, indicating that these clots are abnormal [35].…”

Section: Viscoelastic Properties Of Fibrin (Fibrin Rheology)mentioning

confidence: 99%

Fibrin mechanical properties and their structural origins

2017

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Fibrin is a protein polymer that is essential for hemostasis and thrombosis, wound healing, and several other biological functions and pathological conditions that involve extracellular matrix. In addition to molecular and cellular interactions, fibrin mechanics has been recently shown to underlie clot behavior in the highly dynamic intra- and extravascular environment. Fibrin has both elastic and viscous properties. Perhaps the most remarkable rheological feature of the fibrin network is an extremely high elasticity and stability despite very low protein content. Another important mechanical property that is common to many filamentous protein polymers but not other polymers is stiffening occurring in response to shear, tension, or compression. New data has begun to provide a structural basis for the unique mechanical behavior of fibrin that originates from its complex multi-scale hierarchical structure. The mechanical behavior of the whole fibrin gel is governed largely by the properties of single fibers and their ensembles, including changes in fiber orientation, stretching, bending, and buckling. The properties of individual fibrin fibers are determined by the number and packing arrangements of double-stranded half-staggered protofibrils, which still remain poorly understood. It has also been proposed that forced unfolding of sub-molecular structures, including elongation of flexible and relatively unstructured portions of fibrin molecules, can contribute to fibrin deformations. In spite of a great increase in our knowledge of the structural mechanics of fibrin, much about the mechanisms of fibrin's biological functions remains unknown. Fibrin deformability is not only an essential part of the biomechanics of hemostasis and thrombosis, but also a rapidly developing field of bioengineering that uses fibrin as a versatile biomaterial with exceptional and tunable biochemical and mechanical properties.

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Enhanced lysis and accelerated establishment of viscoelastic properties of fibrin clots are associated with pulmonary embolism

Cited by 41 publications

References 27 publications

Prothrombotic Fibrin Clot Phenotype Is Associated With Recurrent Pulmonary Embolism After Discontinuation of Anticoagulant Therapy

Prothrombotic Fibrin Clot Phenotype Is Associated With Recurrent Pulmonary Embolism After Discontinuation of Anticoagulant Therapy

Fibrin Formation, Structure and Properties

Fibrin mechanical properties and their structural origins

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