Superficial Accumulation of Plasminogen During Plasma Clot Lysis

Sakharov, D.V.; Rijken, D.C.

doi:10.1161/01.cir.92.7.1883

Cited by 126 publications

(122 citation statements)

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“…3b). The correlation coefficient (r ¼ 0.734) confirmed a sound concurrence with confocal microscopy studies of model clots in vitro, where platelets were shown to impede the transport of thrombolytics into the clot (24,27). The correlation could serve for estimation of thrombolysis outcome if the initial platelet proportion is known.…”

Section: Discussionsupporting

confidence: 71%

“…Thrombolysis is retarded in platelet-rich regions due to the tight platelet connections by means of glycoprotein receptors (GP IIb/IIIa) and fibrinogen as well as by the lack of serum containing plasminogen (22)(23)(24)(25). On the contrary, thrombolysis is more efficient in RBC-rich regions, which have a loose fibrin network with abundant extracellular space filled with serum (20).…”

Section: Discussionmentioning

confidence: 99%

“…5). Conversely, RBC-rich regions were well perfused, so that thrombolysis was efficient in deeper regions, which was demonstrated by the presence of randomly emerging reperfusion channels (24,25,28,29). The final proportion of lysed thrombi depended on the proportion of platelet-rich regions (Fig.…”

Section: Discussionmentioning

confidence: 99%

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An MRI study of the differences in the rate of thrombolysis between red blood cell‐rich and platelet‐rich components of venous thrombi ex vivo

Vidmar

Blinc

Kralj³

et al. 2011

Magnetic Resonance Imaging

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Purpose: To test whether T 1 -weighted MRI can detect the differences in the rate of thrombolysis induced by recombinant tissue plasminogen activator (rt-PA) between platelet-rich regions and red blood cell (RBC)-rich regions of venous thrombi ex vivo. Materials and Methods:Each of 21 venous thrombi ex vivo (8 pulmonary emboli and 13 in situ thrombi) was dissected along the longitudinal axis. Half of it was analyzed for the presence of platelet, fibrin, and RBC components by immunohistochemistry and the other half was imaged serially by high-resolution T 1 -weighted three-dimensional MRI to assess the progression of thrombolysis. The MR images were analyzed for proportions of the remaining platelet-rich and RBC-rich regions.Results: Laminated platelet-rich regions, corresponding to Zahn lines, were confirmed immunohistochemically and by MRI in 18/21 venous thrombi. In T 1 -weighted MR images (TE/TR ¼ 10/105 ms) the mean signal intensity of platelet-rich regions was on average 2.3 higher than that of RBC-rich regions. The rate of thrombolysis in plateletrich regions was on average 30% lower than in RBC-rich regions. After 120 min of thrombolysis the proportion of lysed platelet-rich regions was 0.27 6 0.04 versus 0.40 6 0.08 in RBC regions, which resulted in 1.4% decrease of lysed thrombus volume per 1% increase of platelet-rich content.Conclusion: Venous thrombi are most often composed of interspersed platelet-rich and RBC-rich regions. T 1 -weighted MRI is capable of noninvasive discrimination between those two components of venous thrombi ex vivo which have a different susceptibility to thrombolysis by rt-PA.

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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

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An MRI study of the differences in the rate of thrombolysis between red blood cell‐rich and platelet‐rich components of venous thrombi ex vivo

Vidmar

Blinc

Kralj³

et al. 2011

Magnetic Resonance Imaging

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“…6 Recent structural studies have emphasized that fibrin digestion proceeds locally by transverse cutting across fibers rather than by progressive cleavage uniformly around the fiber and that changes of the fibrin network structure are spatially restricted to a zone in which high accumulation of fibrinolytic components takes place. [7][8][9][10] However, none of these findings provide sufficient conclusions regarding the impact of the fibrin network structure and the fibrin fiber diameter on fibrinolysis speed.…”

mentioning

confidence: 99%

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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“…Therefore, even though more HE-SAKK (33 kDa) can be trapped inside the clots in proportion to the amounts of fibrin- bound thrombin, those HE-SAKK molecules located in the interior of the clot would not be able to activate plasminogen. This is simply because plasminogen is too big to diffuse into the interior of the clot as illustrated by the superficial accumulation of plasminogen only on the clot surface in the confocal microscopic study (52). In comparison with fibrin clots formed under in vitro conditions, it is logical to predict that HE-SAKK would be able to lyse the freshly formed pathologic thrombi more efficiently.…”

Section: Reshuffling Of Disulfide Bonds In Hirudin-e Coil and He-sakk-bmentioning

confidence: 98%

Engineering of a Staphylokinase-based Fibrinolytic Agent with Antithrombotic Activity and Targeting Capability toward Thrombin-rich Fibrin and Plasma Clots

Lian¹,

Szarka²,

et al. 2003

Journal of Biological Chemistry

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Current clinically approved thrombolytic agents have significant drawbacks including reocclusion and bleeding complications. To address these problems, a staphylokinase-based thrombolytic agent equipped with antithrombotic activity from hirudin was engineered. Because the N termini for both staphylokinase and hirudin are required for their activities, a Y-shaped molecule is generated using engineered coiled-coil sequences as the heterodimerization domain. This agent, designated HE-SAKK, was produced and assembled from Bacillus subtilis via secretion using an optimized co-cultivation approach. After a simple in vitro treatment to reshuffle the disulfide bonds of hirudin, both staphylokinase and hirudin in HE-SAKK showed biological activities comparable with their parent molecules. This agent was capable of targeting thrombin-rich fibrin clots and inhibiting clot-bound thrombin activity. The time required for lysing 50% of fibrin clot in the absence or presence of fibrinogen was shortened 21 and 30%, respectively, with HE-SAKK in comparison with staphylokinase. In plasma clot studies, the HE-SAKK concentration required to achieve a comparable 50% clot lysis time was at least 12 times less than that of staphylokinase. Therefore, HE-SAKK is a promising thrombolytic agent with the capability to target thrombin-rich fibrin clots and to minimize clot reformation during fibrinolysis.

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Superficial Accumulation of Plasminogen During Plasma Clot Lysis

Cited by 126 publications

References 50 publications

An MRI study of the differences in the rate of thrombolysis between red blood cell‐rich and platelet‐rich components of venous thrombi ex vivo

An MRI study of the differences in the rate of thrombolysis between red blood cell‐rich and platelet‐rich components of venous thrombi ex vivo

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

Engineering of a Staphylokinase-based Fibrinolytic Agent with Antithrombotic Activity and Targeting Capability toward Thrombin-rich Fibrin and Plasma Clots

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