Cerebrovascular thromboprophylaxis in mice by erythrocyte-coupled tissue-type plasminogen activator

Kristina Danielyan, Kumkum Ganguly, Bi Sen Ding, Dmitriy Atochin, Sergei Zaitsev, Juan Carlos Murciano, Paul L. Huang, Scott E. Kasner, Douglas B. Cines, Vladimir R. Muzykantov

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

Background - Cerebrovascular thrombosis is a major source of morbidity and mortality after surgery, but thromboprophylaxis in this setting is limited because of the formidable risk of perioperative bleeding. Thrombolytics (eg, tissue-type plasminogen activator [tPA]) cannot be used prophylactically in this high-risk setting because of their short duration of action and risk of causing hemorrhage and central nervous system damage. We found that coupling tPA to carrier red blood cells (RBCs) prolongs and localizes tPA activity within the bloodstream and converts it into a thromboprophylactic agent, RBC/tPA. To evaluate the utility of this new approach for preventing cerebrovascular thrombosis, we examined the effect of RBC/tPA in animal models of cerebrovascular thromboembolism and ischemia. Methods and Results - Preformed fibrin microemboli were injected into the middle carotid artery of mice, occluding downstream perfusion and causing severe infarction and 50% mortality within 48 hours. Preinjected RBC/tPA rapidly lysed nascent cerebral thromboemboli, providing rapid, durable reperfusion and reducing morbidity and mortality. These beneficial effects were not achieved by preinjection of tPA, even at a 10-fold higher dose, which increased mortality from 50% to 90% by 10 hours after embolization. RBC/tPA injected 10 minutes after tail amputation to simulate postsurgical hemostasis did not cause bleeding from the wound, whereas soluble tPA caused profuse bleeding. RBC/tPA neither aggravated brain damage caused by focal ischemia in a filament model of middle carotid artery occlusion nor caused postthrombotic hemorrhage in hypertensive rats. Conclusions - These results suggest a potential RBC/tPA utility as thromboprophylaxis in patients who are at risk for acute cerebrovascular thromboembolism.

Original languageEnglish
Pages (from-to)1442-1449
Number of pages8
JournalCirculation
Volume118
Issue number14
DOIs
Publication statusPublished - 30 Sep 2008
Externally publishedYes

Fingerprint

Plasminogen Activators
Tissue Plasminogen Activator
Erythrocytes
Hemorrhage
Mortality
Thromboembolism
Carotid Arteries
Thrombosis
Ischemia
Morbidity
Hemostasis
Fibrin
Amputation
Infarction
Reperfusion
Tail
Central Nervous System
Animal Models
Perfusion

Keywords

  • Erythrocytes
  • Fibrinolysis
  • Plasminogen activators
  • Stroke

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Danielyan, K., Ganguly, K., Ding, B. S., Atochin, D., Zaitsev, S., Murciano, J. C., ... Muzykantov, V. R. (2008). Cerebrovascular thromboprophylaxis in mice by erythrocyte-coupled tissue-type plasminogen activator. Circulation, 118(14), 1442-1449. https://doi.org/10.1161/CIRCULATIONAHA.107.750257

Cerebrovascular thromboprophylaxis in mice by erythrocyte-coupled tissue-type plasminogen activator. / Danielyan, Kristina; Ganguly, Kumkum; Ding, Bi Sen; Atochin, Dmitriy; Zaitsev, Sergei; Murciano, Juan Carlos; Huang, Paul L.; Kasner, Scott E.; Cines, Douglas B.; Muzykantov, Vladimir R.

In: Circulation, Vol. 118, No. 14, 30.09.2008, p. 1442-1449.

Research output: Contribution to journalArticle

Danielyan, K, Ganguly, K, Ding, BS, Atochin, D, Zaitsev, S, Murciano, JC, Huang, PL, Kasner, SE, Cines, DB & Muzykantov, VR 2008, 'Cerebrovascular thromboprophylaxis in mice by erythrocyte-coupled tissue-type plasminogen activator', Circulation, vol. 118, no. 14, pp. 1442-1449. https://doi.org/10.1161/CIRCULATIONAHA.107.750257
Danielyan, Kristina ; Ganguly, Kumkum ; Ding, Bi Sen ; Atochin, Dmitriy ; Zaitsev, Sergei ; Murciano, Juan Carlos ; Huang, Paul L. ; Kasner, Scott E. ; Cines, Douglas B. ; Muzykantov, Vladimir R. / Cerebrovascular thromboprophylaxis in mice by erythrocyte-coupled tissue-type plasminogen activator. In: Circulation. 2008 ; Vol. 118, No. 14. pp. 1442-1449.
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abstract = "Background - Cerebrovascular thrombosis is a major source of morbidity and mortality after surgery, but thromboprophylaxis in this setting is limited because of the formidable risk of perioperative bleeding. Thrombolytics (eg, tissue-type plasminogen activator [tPA]) cannot be used prophylactically in this high-risk setting because of their short duration of action and risk of causing hemorrhage and central nervous system damage. We found that coupling tPA to carrier red blood cells (RBCs) prolongs and localizes tPA activity within the bloodstream and converts it into a thromboprophylactic agent, RBC/tPA. To evaluate the utility of this new approach for preventing cerebrovascular thrombosis, we examined the effect of RBC/tPA in animal models of cerebrovascular thromboembolism and ischemia. Methods and Results - Preformed fibrin microemboli were injected into the middle carotid artery of mice, occluding downstream perfusion and causing severe infarction and 50{\%} mortality within 48 hours. Preinjected RBC/tPA rapidly lysed nascent cerebral thromboemboli, providing rapid, durable reperfusion and reducing morbidity and mortality. These beneficial effects were not achieved by preinjection of tPA, even at a 10-fold higher dose, which increased mortality from 50{\%} to 90{\%} by 10 hours after embolization. RBC/tPA injected 10 minutes after tail amputation to simulate postsurgical hemostasis did not cause bleeding from the wound, whereas soluble tPA caused profuse bleeding. RBC/tPA neither aggravated brain damage caused by focal ischemia in a filament model of middle carotid artery occlusion nor caused postthrombotic hemorrhage in hypertensive rats. Conclusions - These results suggest a potential RBC/tPA utility as thromboprophylaxis in patients who are at risk for acute cerebrovascular thromboembolism.",
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