A long-half-life and fibrin-specific form of tissue plasminogen activator in rabbit models of embolic stroke and peripheral bleeding.

Thomas, George; Thibodeaux, Harold; Errett, C J; Badillo, J M; Keyt, B. A.; Refino, Canio J.; Zivin, Justin A.; Bennett, William F.

doi:10.1161/01.str.25.10.2072

Cited by 63 publications

(45 citation statements)

References 40 publications

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“…Timely (within 3 h from the onset of cerebral ischemia) therapeutic use of fibrinolytic plasminogen activators improves the outcome of carotid arterial thrombosis; yet, the risk of intracranial hemorrhage and neurotoxicity remains unacceptably high (Thomas et al, 1994;Wang et al, 1998;Zivin, 1999;Liberatore et al, 2003;Lo et al, 2003). Rapid elimination from blood, inadequate delivery to the interior of clots, and serious side effects in the central nervous system restrict the therapeutic utility and preclude prophylactic use of these proteases and their existing derivatives (Verstraete et al, 1985;Wang et al, 1998;Rijken et al, 2004;Melchor and Strickland, 2005).…”

Section: Discussionmentioning

confidence: 99%

Delivery of Anti-Platelet-Endothelial Cell Adhesion Molecule Single-Chain Variable Fragment-Urokinase Fusion Protein to the Cerebral Vasculature Lyses Arterial Clots and Attenuates Postischemic Brain Edema

Danielyan

Ding²,

Gottstein³

et al. 2007

J Pharmacol Exp Ther

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Efficacy and safety of current means to prevent cerebrovascular thrombosis in patients at high risk of stroke are suboptimal. In theory, anchoring fibrinolytic plasminogen activators to the luminal surface of the cerebral endothelium might arrest formation of occlusive clots in this setting. We tested this approach using the recombinant construct antiplatelet-endothelial cell adhesion molecule (PECAM) single-chain variable fragment (scFv)-urokinase-type plasminogen activator (uPA), fusing lowmolecular-weight single-chain urokinase-type plasminogen activator with a scFv of an antibody directed to the stably expressed endothelial surface determinant PECAM-1, implicated in inflammation and thrombosis. Studies in mice showed that scFv-uPA, but not unconjugated uPA 1) accumulates in the brain after intravascular injection, 2) lyses clots lodged in the cerebral arterial vasculature without hemorrhagic complications, 3) provides rapid and stable cerebral reperfusion, and 4) alleviates post-thrombotic brain edema. Effective and safe thromboprophylaxis in the cerebral arterial circulation by anti-PECAM scFv-uPA represents a prototype of a new paradigm to prevent recurrent cerebrovascular thrombosis.

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Section: Discussionmentioning

confidence: 99%

Delivery of Anti-Platelet-Endothelial Cell Adhesion Molecule Single-Chain Variable Fragment-Urokinase Fusion Protein to the Cerebral Vasculature Lyses Arterial Clots and Attenuates Postischemic Brain Edema

Danielyan

Ding²,

Gottstein³

et al. 2007

J Pharmacol Exp Ther

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“…6) (Sakharov and Rijken, 1995;Fisher and Kohnert, 1997). Administering PAs before thrombosis would alleviate this problem, if 1) their half-lives can be prolonged beyond what is currently attainable by molecular modifications (Dawson et al, 1994;Thomas et al, 1994;Liberatore et al, 2003;Moreadith and Collen, 2003;Hagemeyer et al, 2004); and 2) bleeding and collateral tissue damage are avoided (Wang et al, 1998). Thus, a drug delivery system fundamentally changing pharmacokinetics is required for prophylactic use of PAs.…”

Section: Discussionmentioning

confidence: 99%

Fibrin Affinity of Erythrocyte-Coupled Tissue-Type Plasminogen Activators Endures Hemodynamic Forces and Enhances Fibrinolysis in Vivo

Ganguly

Goel²,

Krasik³

et al. 2005

J Pharmacol Exp Ther

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Plasminogen activators (PAs; e.g., tissue-type, tPA) coupled to red blood cells (RBCs) display in vivo features useful for thromboprophylaxis: prolonged circulation, minimal extravasation, and preferential lysis of nascent versus preexisting clots. Yet, factors controlling the activity of RBC-bound PAs in vivo are not defined and may not mirror the profile of soluble PAs. We tested the role of RBC/PA binding to fibrin in fibrinolysis. RBC/ tPA and RBC/tPA variant with low fibrin affinity (rPA) bound to and lysed plasminogen-containing fibrin clots in vitro comparably. In contrast, when coinjected in mice with fibrin emboli lodging in pulmonary vasculature, only RBC/tPA accumulated in lungs, which resulted in a more extensive fibrinolysis versus RBC/rPA (p Ͻ 0.01). Reconciling this apparent divergence between in vitro and in vivo behaviors, RBC/tPA, but not RBC/rPA perfused over fibrin in vitro at physiological shear stress bound to fibrin clots and caused greater fibrinolysis versus RBC/rPA (p Ͻ 0.001). These results indicate that because of high fibrin affinity, RBC/tPA binding to clots endures hemodynamic stress, which enhances fibrinolysis. Behavior of RBC/PAs under hemodynamic pressure is an important predictor of their performance in vivo.

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“…We recorded the size of hemorrhage as the number of section faces showing hemorrhage. 12,13 Infarction was grossly visible as pale, softer tissue surrounded by pink, normal brain tissue on the brain sections. Three major types of hemorrhage were identified with the use of the grading system we used in previous studies.…”

Section: Methodsmentioning

confidence: 99%

The Nonpeptide Glycoprotein IIb/IIIa Platelet Receptor Antagonist SM-20302 Reduces Tissue Plasminogen Activator–Induced Intracerebral Hemorrhage After Thromboembolic Stroke

Lapchak

Araujo²,

Song³

et al. 2002

Stroke

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Background and Purpose-Platelet activation and deposition in brain microvessels appear to be key events in the pathogenesis of ischemia-induced neuronal degeneration and behavioral deficits. It has been hypothesized that activated platelets in combination with polymorphonuclear leukocytes and fibrin may play a role in vessel reocclusion leading to the "no-reflow" phenomenon after administration of the thrombolytic tissue plasminogen activator (tPA). We studied the effects of the novel glycoprotein IIb/IIIa platelet receptor antagonist SM-20302 when administered in combination with tPA on infarct and hemorrhage rate and volume to determine whether activated platelets are involved in either infarct or hemorrhage generation after a thromboembolic stroke. Methods-One hundred thirty-two male New Zealand White rabbits were included in the present study. Rabbits were embolized by injecting a blood clot into the middle cerebral artery via a catheter. Five or 65 minutes after embolization, SM-20302 (5 mg/kg) was infused intravenously. In drug combination studies, tPA was infused intravenously for 30 minutes starting 60 minutes after embolization, and SM-20302 was administered 5 or 65 minutes after embolization. Postmortem analysis included assessment of hemorrhage, infarct size and location, and clot lysis. Results-In the vehicle control group, the hemorrhage rate after a thromboembolic stroke was 33%. There was a significant increase (109%) in the hemorrhage rate in the group of rabbits treated with the thrombolytic tPA. SM-20302 by itself did not significantly alter the embolism-induced hemorrhage rate when administered either 5 or 65 minutes after embolism. The SM-20302 groups had a 42% and 33% incidence of hemorrhage in the 5-and 65-minute groups, respectively. In groups treated with a combination of drugs, the SM-20302/tPA group had a 31% and 71% incidence of hemorrhage when SM-20302 was administered 5 and 65 minutes after embolization, respectively. SM-20302 in combination with tPA also significantly increased infarct rate, but not hemorrhage or infarct volume. Conclusions-This study suggests that treatment of thromboembolic stroke with the combination of a platelet inhibitor and tPA may have a beneficial outcome on the basis of the following: First, acute administration of SM-20302 did not significantly increase hemorrhage rate. Second, SM-20302 in combination with tPA significantly reduced tPA-induced intracerebral hemorrhage. Third, there appears to be a specific window of opportunity when a platelet inhibitor must be administered to produce a beneficial effect. Overall, on the basis of our results, we hypothesize that the increased rate of intracerebral hemorrhage observed after tPA administration may be partly due to increased reocclusion of cerebral vessels following lysis of the emboli and that reocclusion can be controlled by administration of a platelet inhibitor.

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A long-half-life and fibrin-specific form of tissue plasminogen activator in rabbit models of embolic stroke and peripheral bleeding.

Cited by 63 publications

References 40 publications

Delivery of Anti-Platelet-Endothelial Cell Adhesion Molecule Single-Chain Variable Fragment-Urokinase Fusion Protein to the Cerebral Vasculature Lyses Arterial Clots and Attenuates Postischemic Brain Edema

Delivery of Anti-Platelet-Endothelial Cell Adhesion Molecule Single-Chain Variable Fragment-Urokinase Fusion Protein to the Cerebral Vasculature Lyses Arterial Clots and Attenuates Postischemic Brain Edema

Fibrin Affinity of Erythrocyte-Coupled Tissue-Type Plasminogen Activators Endures Hemodynamic Forces and Enhances Fibrinolysis in Vivo

The Nonpeptide Glycoprotein IIb/IIIa Platelet Receptor Antagonist SM-20302 Reduces Tissue Plasminogen Activator–Induced Intracerebral Hemorrhage After Thromboembolic Stroke

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