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


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.
Danielyan
Kristina
K
Pharmacology Department, Universityof Pennsylvania, Philadelphia, PA 19104-6068, USA.
Ganguly
Kumkum
K
Ding
Bi-Sen
BS
Atochin
Dmitriy
D
Zaitsev
Sergei
S
Murciano
Juan-Carlos
JC
Huang
Paul L
PL
Kasner
Scott E
SE
Cines
Douglas B
DB
Muzykantov
Vladimir R
VR
D000818:Animals; D002561:Cerebrovascular Disorders / Q000473:pathology / Q000517:prevention & control; D017707:Erythrocyte Transfusion / Q000379:methods*; D004912:Erythrocytes / Q000166:cytology; D006801:Humans; D020767:Intracranial Thrombosis / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D011918:Rats, Inbred SHR; D015912:Thrombolytic Therapy / Q000379:methods*; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage*
D010959:Tissue Plasminogen Activator
J Vasc Surg. 2007 May;45(5):867-72; discussion 872-4
17376643
Lancet. 2007 Jan 27;369(9558):283-92
17258668
Circulation. 2002 Aug 6;106(6):740-5
12163437
J Cereb Blood Flow Metab. 1988 Apr;8(2):282-4
3343300
Blood. 2007 Apr 15;109(8):3161-72
17110453
Rev Cardiovasc Med. 2002;3 Suppl 2:S7-16
12556738
Nat Biotechnol. 2003 Aug;21(8):891-6
12845330
Am J Cardiol. 2006 Aug 1;98(3):331-7
16860018
Am J Physiol Lung Cell Mol Physiol. 2002 Mar;282(3):L529-39
11839549
Eur J Haematol. 2007 Feb;78(2):161-6
17328717
Shock. 2001;16 Suppl 1:16-9
11770027
J Pharmacol Exp Ther. 2005 Mar;312(3):1106-13
15525799
J Pharmacol Exp Ther. 2007 Apr;321(1):158-64
17215448
Nat Med. 1998 Feb;4(2):228-31
9461198
Proc Natl Acad Sci U S A. 1999 Aug 3;96(16):8879-83
10430864
Science. 2003 Sep 19;301(5640):1677
14500967
Brain Res. 2000 Sep 29;878(1-2):64-71
10996136
Stroke. 2004 Nov;35(11 Suppl 1):2726-30
15459442
Stroke. 2005 Jul;36(7):1452-6
15947260
Stroke. 2000 Dec;31(12):3034-40
11108768
N Engl J Med. 2007 Feb 15;356(7):706-13
17301301
Stroke. 2004 Sep;35(9):2177-82
15256680
Circulation. 2000 Feb 8;101(5):570-80
10662756
N Engl J Med. 2001 Feb 8;344(6):395-402
11172175
Neurology. 2005 Dec 13;65(11):1799-801
16344525
Circulation. 2005 Dec 20;112(25):3833-8
16365207
Stroke. 2001 Jun;32(6):1365-9
11387500
Blood. 2006 Sep 15;108(6):1895-902
16735601
Stroke. 2002 Apr;33(4):1113-9
11935069
J Pharmacol Exp Ther. 2006 Mar;316(3):1130-6
16284278
Cardiovasc Drugs Ther. 1994 Dec;8(6):801-11
7742258
Semin Thromb Hemost. 2005;31(4):426-40
16149021
J Arthroplasty. 2005 Sep;20(6):763-71
16139714
Blood. 2000 Jul 15;96(2):569-76
10887120
J Am Coll Cardiol. 2007 Jun 5;49(22):2145-50
17543633
Circulation. 2003 Jun 10;107(22):2837-43
12756151
Blood. 2003 Jun 15;101(12):4797-801
12586611
N Engl J Med. 1996 Dec 19;335(25):1857-63
8948560
Curr Hematol Rep. 2005 Sep;4(5):405-13
16131443
Stroke. 2005 Aug;36(8):1735-40
16002764
Arch Intern Med. 2003 Apr 28;163(8):901-8
12719198
Neurology. 1998 Jun;50(6):1857-9
9633741
Circ Res. 2006 Jul 21;99(2):209-17
16778128
Nat Med. 2003 Oct;9(10):1313-7
12960961
Stroke. 2005 Sep;36(9):e77-9
16051897
Stroke. 2003 Mar;34(3):813-9
12624315
Circulation. 2003 Oct 21;108(16 Suppl 1):III28-37
14605017
Stroke. 1996 Sep;27(9):1616-22; discussion 1623
8784138