Inner clot diffusion and permeation during fibrinolysis

Diamond, Scott L.; Anand, Sriram

doi:10.1016/s0006-3495(93)81314-6

Cited by 178 publications

(200 citation statements)

References 45 publications

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“…Thick fibers undergoing digestion did not turn into thin fibers, as previously thought. 16,19 This increase in fiber diameter seems to be related to a progressive transection of thick fibers occurring simultaneously in different places over the length of the fibers rather than to aggregation of lysed fiber segments, as previously suspected. 10 Fiber aggregation was unusual and was mostly observed within clots with a tight network configuration digested with high concentrations of rtPA.…”

Section: Discussionsupporting

confidence: 58%

“…9,16 -18 Although much less was known about the physical changes in the fibrin matrix that precede solubilization, it has been assumed that fibrin was digested from the outside in, with products of degradation released layer by layer. 16,19 This model was based on the characterization of fibrin degradation products released from clots and confirmed later by confocal microscopy showing that plasma fibrin degradation resulted in 2 sequential phases. 7,8 During the prelysis phase, which is characterized by very few structural changes of the fibrin matrix, plasminogen accumulates on the surface as more C-terminal lysine binding sites are exposed.…”

Section: Discussionmentioning

confidence: 80%

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Influence of Fibrin Network Conformation and Fibrin Fiber Diameter on Fibrinolysis Speed

Collet

Park

Lesty

et al. 2000

ATVB

456

427

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Abstract-Abnormal fibrin architecture is thought to be a determinant factor of hypofibrinolysis. However, because of the lack of structural knowledge of the process of fibrin digestion, relationships between fibrin architecture and hypofibrinolysis remain controversial. To elucidate further structural and dynamic changes occurring during fibrinolysis, cross-linked plasma fibrin was labeled with colloidal gold particles, and fibrinolysis was followed by confocal microscopy. Morphological changes were characterized at fibrin network and fiber levels. The observation of a progressive disaggregation of the fibrin fibers emphasizes that fibrinolysis proceeds by transverse cutting rather than by progressive cleavage uniformly around the fiber. Plasma fibrin clots with a tight fibrin conformation made of thin fibers were dissolved at a slower rate than those with a loose fibrin conformation made of thicker (coarse) fibers, although the overall fibrin content remained constant. Unexpectedly, thin fibers were cleaved at a faster rate than thick ones. A dynamic study of FITC-recombinant tissue plasminogen activator distribution within the fibrin matrix during the course of fibrinolysis showed that the binding front was broader in coarse fibrin clots and moved more rapidly than that of fine plasma fibrin clots. These dynamic and structural approaches to fibrin digestion at the network and the fiber levels reveal aspects of the physical process of clot lysis. Furthermore, these results provide a clear explanation for the hypofibrinolysis related to a defective fibrin architecture as described in venous thromboembolism and in premature coronary artery disease. Key Words: fibrin Ⅲ fibrinolysis Ⅲ confocal microscopy T he fibrin matrix has a much more complicated role than that of providing the scaffolding of the thrombus or being the target of fibrinolysis. Abnormal fibrin structure in vitro has been related to in vivo premature coronary artery disease in young patients and to severe venous thromboembolic disease in patients with dysfibrinogenemias. 1,2 In those situations, an abnormal fibrin matrix made up of abnormally thin fibers has been shown to promote hypofibrinolysis and embolization. Although much is known about the molecular basis of fibrinolysis, relationships between fibrin conformation and fibrinolysis need to be clarified.Fibrin actively regulates its self-dissolution through numerous interactions with fibrinolytic and antifibrinolytic components. Activation of plasminogen by tissue plasminogen activator (tPA) that is initiated on the conversion of fibrinogen into fibrin is a critical step that is affected by fibrin structure. The theory of a decrease of plasminogen binding to fibrin 3 has been strengthened from observations showing that clots with a fine fibrin (tight) conformation display a slower lysis rate than those with a coarse fibrin (loose) conformation. 2,4,5 So far, neither a molecular nor a structural basis has been detected for these differences. Moreover, a recent report demonstrates that under othe...

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Section: Discussionsupporting

confidence: 58%

Section: Discussionmentioning

confidence: 80%

Influence of Fibrin Network Conformation and Fibrin Fiber Diameter on Fibrinolysis Speed

Collet

Park

Lesty

et al. 2000

ATVB

456

427

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“…Intact, threedimensional clots were used in these experiments to model dissociation of thrombin from thrombi. fusion in the fluid phase and binding with the fibrin phase (29). Therefore, the data were analyzed using a two-phase exponential decay model (lines), where the rates reflect macroscopic dissociation from the intact clot.…”

Section: Resultsmentioning

confidence: 99%

Bivalent Binding to γA/γ′-Fibrin Engages Both Exosites of Thrombin and Protects It from Inhibition by the Antithrombin-Heparin Complex

Fredenburgh

Stafford

Leslie

et al. 2008

Journal of Biological Chemistry

109

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Thrombin exosite 1 binds the predominant ␥ A /␥ A -fibrin form with low affinity. A subpopulation of fibrin molecules, ␥ A /␥-fibrin, has an extended COOH terminus ␥-chain that binds exosite 2 of thrombin. Bivalent binding to ␥ A /␥-fibrin increases the affinity of thrombin 10-fold, as determined by surface plasmon resonance. Because of its higher affinity, thrombin dissociates 7-fold more slowly from ␥ A /␥-fibrin clots than from ␥ A /␥ A -fibrin clots. After 24 h of washing, however, both ␥ A /␥-and ␥ A /␥ A -fibrin clots generate fibrinopeptide A when incubated with fibrinogen, indicating the retention of active thrombin. Previous studies demonstrated that heparin heightens the affinity of thrombin for fibrin by simultaneously binding to fibrin and exosite 2 on thrombin to generate a ternary heparinthrombin-fibrin complex that protects thrombin from inhibition by antithrombin and heparin cofactor II. In contrast, dermatan sulfate does not promote ternary complex formation because it does not bind to fibrin. Heparin-catalyzed rates of thrombin inhibition by antithrombin were 5-fold slower in ␥ A /␥-fibrin clots than they were in ␥ A /␥ A -fibrin clots. This difference reflects bivalent binding of thrombin to ␥ A /␥-fibrin because (a) it is abolished by addition of a ␥-chaindirected antibody that blocks exosite 2-mediated binding of thrombin to the ␥-chain and (b) the dermatan sulfate-catalyzed rate of thrombin inhibition by heparin cofactor II also is lower with ␥ A /␥-fibrin than with ␥ A /␥ A -fibrin clots. Thus, bivalent binding of thrombin to ␥ A /␥-fibrin protects thrombin from inhibition, raising the possibility that ␥ A /␥-fibrin serves as a reservoir of active thrombin that renders thrombi thrombogenic.

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“…Whereas rabbit ear-vein clots treated with tPA alone only partially recanalized by 5 hours, complete recanalization was observed when tPA was administered in combination with pulsed-HIFU. tPA binds to fibrin, thus limiting the extent to which it can diffuse into clots, and reducing its thrombolytic effect [22]. Our recent in vitro work, using scanning electron microscopy, has shown that pulsed-HIFU creates channels within clots, providing new routes for transport into their interior.…”

Section: Discussionmentioning

confidence: 99%

Pulsed-high intensity focused ultrasound enhanced tPA mediated thrombolysis in a novel in vivo clot model, a pilot study

Frenkel

Dromi

et al. 2007

Thrombosis Research

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Introduction-Thrombotic disease continues to account for significant morbidity and mortality. Ultrasound energy has been investigated as a potential primary and adjunctive treatment for thrombotic disease. We have previously shown that pulsed-high intensity focused ultrasound (HIFU) enhances thrombolysis induced by tissue plasminogen activator (tPA) in vitro, including describing the non-destructive mechanism by which tPA availability and consequent activity is increased. In this study we aimed to determined if the same effects could be achieved in vivo.

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Inner clot diffusion and permeation during fibrinolysis

Cited by 178 publications

References 45 publications

Influence of Fibrin Network Conformation and Fibrin Fiber Diameter on Fibrinolysis Speed

Influence of Fibrin Network Conformation and Fibrin Fiber Diameter on Fibrinolysis Speed

Bivalent Binding to γA/γ′-Fibrin Engages Both Exosites of Thrombin and Protects It from Inhibition by the Antithrombin-Heparin Complex

Pulsed-high intensity focused ultrasound enhanced tPA mediated thrombolysis in a novel in vivo clot model, a pilot study

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