Advanced drug delivery systems for antithrombotic agents

Blood

Volumn 122, Issue 9, 2013, Pages 1565-1575

  Greineder, Colin F ^a,b   Howard, Melissa D ^a   Carnemolla, Ronald ^a   Cines, Douglas B ^c   Muzykantov, Vladimir R ^a  

^a University of Pennsylvania   (United States)

^b UNIVERSITY OF PENNSYLVANIA   (United States)

^c UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTICOAGULANT AGENT; DENDRIMER; LIGAND; LIPOSOME; MACROGOL;

BLEEDING; DRUG CONJUGATION; DRUG DELIVERY SYSTEM; DRUG HALF LIFE; DRUG PENETRATION; DRUG SOLUBILITY; ENDOTHELIUM CELL; ERYTHROCYTE; FIBRIN CLOT; HUMAN; MICROENVIRONMENT; NONHUMAN; PRIORITY JOURNAL; REVIEW; THROMBOSIS;

EID: 84888042478     PISSN: 00064971     EISSN: 15280020     Source Type: Journal    
DOI: 10.1182/blood-2013-03-453498     Document Type: Review

References (102)

1. Tafur AJ, McBane R II, Wysokinski WE, et al. Predictors of major bleeding in peri-procedural anticoagulation management. J Thromb Haemost. 2012;10(2):261-267.
2. Ortel TL. Perioperative management of patients on chronic antithrombotic therapy. Blood. 2012;120(24):4699-4705.
3. Spyropoulos AC, Douketis JD. How I treat anticoagulated patients undergoing an elective procedure or surgery. Blood. 2012;120(15):2954-2962.
4. Lanza GM, Marsh JN, Hu G, et al. Rationale for a nanomedicine approach to thrombolytic therapy. Stroke. 2010;41(10 Suppl):S42-S44.
5. Cheng Z, Al Zaki A, Hui JZ, Muzykantov VR, Tsourkas A. Multifunctional nanoparticles: cost versus benefit of adding targeting and imaging capabilities. Science. 2012;338(6109):903-910.
6. Duncan R. The dawning era of polymer therapeutics. Nat Rev Drug Discov. 2003;2(5):347-360. (Pubitemid 37361705)
7. Farokhzad OC, Langer R. Impact of nanotechnology on drug delivery. ACS Nano. 2009;3(1):16-20.
8. Buxton DB. Nanomedicine for the management of lung and blood diseases. Nanomedicine (Lond). 2009;4(3):331-339.
9. Howard MD, Jay M, Dziubla TD, Lu X. PEGylation of nanocarrier drug delivery systems: state of the art. J Biomed Nanotechnol. 2008;4(2):133-148.
10. Berger HJ Jr, Pizzo SV. Preparation of polyethylene glycol-tissue plasminogen activator adducts that retain functional activity: characteristics and behavior in three animal species. Blood. 1988;71(6):1641-1647.
11. Rajagopalan S, Gonias SL, Pizzo SV. A nonantigenic covalent streptokinasepolyethylene glycol complex with plasminogen activator function. J Clin Invest. 1985;75(2):413-419. (Pubitemid 15143480)
12. Sakuragawa N, Shimizu K, Kondo K, Kondo S, Niwa M. Studies on the effect of PEG-modified urokinase on coagulation-fibrinolysis using beagles. Thromb Res. 1986;41(5):627-635. (Pubitemid 16139647)
13. Moreadith RW, Collen D. Clinical development of PEGylated recombinant staphylokinase (PEG-Sak) for bolus thrombolytic treatment of patients with acute myocardial infarction. Adv Drug Deliv Rev. 2003;55(10):1337-1345. (Pubitemid 37464565)
14. Collen D, Sinnaeve P, Demarsin E, et al. Polyethylene glycol-derivatized cysteinesubstitution variants of recombinant staphylokinase for single-bolus treatment of acute myocardial infarction. Circulation. 2000;102(15):1766-1772.
15. Nguyen PD, O'Rear EA, Johnson AE, Lu R, Fung BM. Thrombolysis using liposomalencapsulated streptokinase: an in vitro study. Proc Soc Exp Biol Med. 1989;192(3):261-269. (Pubitemid 20051480)
16. Perkins WR, Vaughan DE, Plavin SR, Daley WL, Rauch J, Lee L, Janoff AS. Streptokinase entrapment in interdigitation-fusion liposomes improves thrombolysis in an experimental rabbit model. Thromb Haemost. 1997;77(6):1174-1178. (Pubitemid 27311990)
17. Kim I-S, Choi H-G, Choi H-S, Kim B-K, Kim C-K. Prolonged systemic delivery of streptokinase using liposome. Arch Pharm Res. 1998;21(3):248-252. (Pubitemid 128661005)
18. Heeremans JL, Prevost R, Bekkers ME, Los P, Emeis JJ, Kluft C, Crommelin DJ. Thrombolytic treatment with tissue-type plasminogen activator (t-PA) containing liposomes in rabbits: a comparison with free t-PA. Thromb Haemost. 1995;73(3):488-494.
19. Leach JK, O'Rear EA, Patterson E, Miao Y, Johnson AE. Accelerated thrombolysis in a rabbit model of carotid artery thrombosis with liposome-encapsulated and microencapsulated streptokinase. Thromb Haemost. 2003;90(1):64-70. (Pubitemid 36873860)
20. Wang S-S, Chou N-K, Chung T-W. The t-PA-encapsulated PLGA nanoparticles shelled with CS or CS-GRGD alter both permeation through and dissolving patterns of blood clots compared with t-PA solution: an in vitro thrombolysis study. J Biomed Mater Res A. 2009;91(3):753-761.
21. Jin H, Tan H, Zhao L, et al. Ultrasound-triggered thrombolysis using urokinase-loaded nanogels. Int J Pharm. 2012;434(1-2):384-390.
22. Fernandes EG, de Queiroz AA, Abraham GA, San Román J. Antithrombogenic properties of bioconjugate streptokinase-polyglycerol dendrimers. J Mater Sci Mater Med. 2006;17(2):105-111.
23. Wang X, Inapagolla R, Kannan S, Lieh-Lai M, Kannan RM. Synthesis, characterization, and in vitro activity of dendrimer-streptokinase conjugates. Bioconjug Chem. 2007;18(3):791-799. (Pubitemid 47010799)
24. Leach JK, Patterson E, O'Rear EA. Improving thrombolysis with encapsulated plasminogen activators and clinical relevance to myocardial infarction and stroke. Clin Hemorheol Microcirc. 2004;30(3-4):225-228. (Pubitemid 38951508)
25. Collen D, Lijnen HR. Thrombolytic agents. Thromb Haemost. 2005;93(4):627-630. (Pubitemid 40485396)
26. Varjú I, Sótonyi P, Machovich R, et al. Hindered dissolution of fibrin formed under mechanical stress. J Thromb Haemost. 2011;9(5):979-986.
27. Shaw GJ, Meunier JM, Huang S-L, Lindsell CJ, McPherson DD, Holland CK. Ultrasoundenhanced thrombolysis with tPA-loaded echogenic liposomes. Thromb Res. 2009;124(3):306-310.
28. Laing ST, Moody MR, Kim H, et al. Thrombolytic efficacy of tissue plasminogen activator-loaded echogenic liposomes in a rabbit thrombus model. Thromb Res. 2012;130(4):629-635.
29. Uesugi Y, Kawata H, Jo J-i, Saito Y, Tabata Y. An ultrasound-responsive nano delivery system of tissue-type plasminogen activator for thrombolytic therapy. J Control Release. 2010;147(2):269-277.
30. Härdig BM, Persson HW, Olsson SB. Lowenergy ultrasound exposure of the streptokinase molecule may enhance but also attenuate its fibrinolytic properties. Thromb Res. 2006;117(6):713-720.
31. Korin N, Kanapathipillai M, Matthews BD, et al. Shear-activated nanotherapeutics for drug targeting to obstructed blood vessels. Science. 2012;337(6095):738-742.
32. Holme MN, Fedotenko IA, Abegg D, et al. Shearstress sensitive lenticular vesicles for targeted drug delivery. Nat Nanotechnol. 2012;7(8):536-543.
33. Doshi N, Orje JN, Molins B, Smith JW, Mitragotri S, Ruggeri ZM. Platelet mimetic particles for targeting thrombi in flowing blood. Adv Mater. 2012;24(28):3864-3869.
34. Merkel TJ, Jones SW, Herlihy KP, et al. Using mechanobiological mimicry of red blood cells to extend circulation times of hydrogel microparticles. Proc Natl Acad Sci U S A. 2011;108(2):586-591.
35. Doshi N, Zahr AS, Bhaskar S, Lahann J, Mitragotri S. Red blood cell-mimicking synthetic biomaterial particles. Proc Natl Acad Sci USA. 2009;106(51):21495-21499.
36. Kim Y, Dalhaimer P, Christian DA, Discher DE. Polymeric worm micelles as nano-carriers for drug delivery. Nanotechnology. 2005;16(7):S484-S491. (Pubitemid 40878515)
37. Dziubla TD, Shuvaev VV, Hong NK, et al. Endothelial targeting of semi-permeable polymer nanocarriers for enzyme therapies. Biomaterials. 2008;29(2):215-227. (Pubitemid 350017841)
38. Simone EA, Dziubla TD, Arguiri E, Vardon V, Shuvaev VV, Christofidou-Solomidou M, Muzykantov VR. Loading PEG-catalase into filamentous and spherical polymer nanocarriers. Pharm Res. 2009;26(1):250-260.
39. Muzykantov VR. Drug delivery carriers on the fringes: natural red blood cells versus synthetic multilayered capsules. Expert Opin Drug Deliv. 2013;10(1):1-4.
40. Muzykantov VR. Drug delivery by red blood cells: vascular carriers designed by mother nature. Expert Opin Drug Deliv. 2010;7(4):403-427.
41. Magnani M. Erythrocytes as carriers for drugs: the transition from the laboratory to the clinic is approaching. Expert Opin Biol Ther. 2012;12(2):137-138.
42. Bax BE, Bain MD, Fairbanks LD, Webster AD, Chalmers RA. In vitro and in vivo studies with human carrier erythrocytes loaded with polyethylene glycol-conjugated and native adenosine deaminase. Br J Haematol. 2000;109(3):549-554. (Pubitemid 30415181)
43. Biagiotti S, Rossi L, Bianchi M, et al. Immunophilin-loaded erythrocytes as a new delivery strategy for immunosuppressive drugs. J Control Release. 2011;154(3):306-313.
44. Rossi L, Serafini S, Cenerini L, Picardi F, Bigi L, Panzani I, Magnani M. Erythrocyte-mediated delivery of dexamethasone in patients with chronic obstructive pulmonary disease. Biotechnol Appl Biochem. 2001;33(Pt 2):85-89. (Pubitemid 32304285)
45. Annese V, Latiano A, Rossi L, et al. Erythrocytes-mediated delivery of dexamethasone in steroid-dependent IBD patients-a pilot uncontrolled study. Am J Gastroenterol. 2005;100(6):1370-1375. (Pubitemid 40904364)
46. Domenech C, Thomas X, Chabaud S, et al. l-asparaginase loaded red blood cells in refractory or relapsing acute lymphoblastic leukaemia in children and adults: results of the GRASPALL 2005-01 randomized trial. Br J Haematol. 2011;153(1):58-65.
47. Muzykantov VR, Murciano JC, Taylor RP, Atochina EN, Herraez A. Regulation of the complement-mediated elimination of red blood cells modified with biotin and streptavidin. Anal Biochem. 1996;241(1):109-119. (Pubitemid 26337220)
48. Muzykantov VR, Sakharov DV, Smirnov MD, Samokhin GP, Smirnov VN. Immunotargeting of erythrocyte-bound streptokinase provides local lysis of a fibrin clot. Biochim Biophys Acta. 1986;884(2):355-362. (Pubitemid 17188780)
49. Murciano JC, Medinilla S, Eslin D, Atochina E, Cines DB, Muzykantov VR. Prophylactic fibrinolysis through selective dissolution of nascent clots by tPA-carrying erythrocytes. Nat Biotechnol. 2003;21(8):891-896. (Pubitemid 36936194)
50. Ganguly K, Krasik T, Medinilla S, Bdeir K, Cines DB, Muzykantov VR, Murciano JC. Blood clearance and activity of erythrocyte-coupled fibrinolytics. J Pharmacol Exp Ther. 2005;312(3):1106-1113. (Pubitemid 40293770)
51. Ganguly K, Goel MS, Krasik T, et al. Fibrin affinity of erythrocyte-coupled tissue-type plasminogen activators endures hemodynamic forces and enhances fibrinolysis in vivo. J Pharmacol Exp Ther. 2006;316(3):1130-1136. (Pubitemid 43348697)
52. Ganguly K, Murciano JC, Westrick R, Leferovich J, Cines DB, Muzykantov VR. The glycocalyx protects erythrocyte-bound tissue-type plasminogen activator from enzymatic inhibition. J Pharmacol Exp Ther. 2007;321(1):158-164. (Pubitemid 46456958)
53. Murciano JC, Higazi AA, Cines DB, Muzykantov VR. Soluble urokinase receptor conjugated to carrier red blood cells binds latent pro-urokinase and alters its functional profile. J Control Release. 2009;139(3):190-196.
54. Gersh KC, Zaitsev S, Muzykantov V, Cines DB, Weisel JW. The spatial dynamics of fibrin clot dissolution catalyzed by erythrocyte-bound vs. free fibrinolytics. J Thromb Haemost. 2010;8(5):1066-1074.
55. Gersh KC, Zaitsev S, Cines DB, Muzykantov V, Weisel JW. Flow-dependent channel formation in clots by an erythrocyte-bound fibrinolytic agent. Blood. 2011;117(18):4964-4967.
56. Danielyan K, Ganguly K, Ding BS, et al. Cerebrovascular thromboprophylaxis in mice by erythrocyte-coupled tissue-type plasminogen activator. Circulation. 2008;118(14):1442-1449.
57. Stein SC, Ganguly K, Belfield CM, et al. Erythrocyte-bound tissue plasminogen activator is neuroprotective in experimental traumatic brain injury. J Neurotrauma. 2009;26(9):1585-1592.
58. Pisapia JM, Xu X, Kelly J, et al. Microthrombosis after experimental subarachnoid hemorrhage: time course and effect of red blood cell-bound thrombin-activated pro-urokinase and clazosentan. Exp Neurol. 2012;233(1):357-363.
59. Armstead WM, Ganguly K, Kiessling JW, et al. Red blood cells-coupled tPA prevents impairment of cerebral vasodilatory responses and tissue injury in pediatric cerebral hypoxia/ischemia through inhibition of ERK MAPK activation. J Cereb Blood Flow Metab. 2009;29(8):1463-1474.
60. Armstead WM, Ganguly K, Riley J, et al. Red blood cell-coupled tissue plasminogen activator prevents impairment of cerebral vasodilatory responses through inhibition of c-Jun-N-terminal kinase and potentiation of p38 mitogen-activated protein kinase after cerebral photothrombosis in the newborn pig. Pediatr Crit Care Med. 2011;12(6):e369-e375.
61. Armstead WM, Ganguly K, Kiessling JW, et al. Signaling, delivery and age as emerging issues in the benefit/risk ratio outcome of tPA For treatment of CNS ischemic disorders. J Neurochem. 2010;113(2):303-312.
62. Nordt TK, Bode C. Thrombolysis: newer thrombolytic agents and their role in clinical medicine. Heart. 2003;89(11):1358-1362. (Pubitemid 37311107)
63. Carnemolla R, Muzykantov VR. Vascular targeting of antithrombotic agents. IUBMB Life. 2011;63(8):632-639.
64. Runge MS, Quertermous T, Zavodny PJ, et al. A recombinant chimeric plasminogen activator with high affinity for fibrin has increased thrombolytic potency in vitro and in vivo. Proc Natl Acad Sci USA. 1991;88(22):10337-10341. (Pubitemid 21915830)
65. Holvoet P, Laroche Y, Stassen JM, et al. Pharmacokinetic and thrombolytic properties of chimeric plasminogen activators consisting of a single-chain Fv fragment of a fibrin-specific antibody fused to single-chain urokinase. Blood. 1993;81(3):696-703. (Pubitemid 23040862)
66. Bdeir K, Kuo A, Sachais BS, et al. The kringle stabilizes urokinase binding to the urokinase receptor. Blood. 2003;102(10):3600-3608. (Pubitemid 37409377)
67. Husain SS. Single-chain urokinase-type plasminogen activator does not possess measurable intrinsic amidolytic or plasminogen activator activities. Biochemistry. 1991;30(23):5797-5805.
68. Zhang L, Strickland DK, Cines DB, Higazi AA. Regulation of single chain urokinase binding, internalization, and degradation by a plasminogen activator inhibitor 1-derived peptide. J Biol Chem. 1997;272(43):27053-27057. (Pubitemid 27452660)
69. Yang WP, Goldstein J, Procyk R, Matsueda GR, Shaw SY. Design and evaluation of a thrombinactivable plasminogen activator. Biochemistry. 1994;33(8):606-612.
70. Vyas SP, Vaidya B. Targeted delivery of thrombolytic agents: role of integrin receptors. Expert Opin Drug Deliv. 2009;6(5):499-508.
71. Runge MS, Bode C, Matsueda GR, Haber E. Antibody-enhanced thrombolysis: targeting of tissue plasminogen activator in vivo. Proc Natl Acad Sci USA. 1987;84(21):7659-7662.
72. Peter K, Graeber J, Kipriyanov S, et al. Construction and functional evaluation of a single-chain antibody fusion protein with fibrin targeting and thrombin inhibition after activation by factor Xa. Circulation. 2000;101(10):1158-1164. (Pubitemid 30146618)
73. Chen H, Mo W, Su H, Zhang Y, Song H. Characterization of a novel bifunctional mutant of staphylokinase with platelet-targeted thrombolysis and antiplatelet aggregation activities. BMC Mol Biol. 2007;8:88.
74. Modery CL, Ravikumar M, Wong TL, Dzuricky MJ, Durongkaveroj N, Sen Gupta A. Heteromultivalent liposomal nanoconstructs for enhanced targeting and shear-stable binding to active platelets for siteselective vascular drug delivery. Biomaterials. 2011;32(35):9504-9514.
75. Gupta AS, Huang G, Lestini BJ, Sagnella S, Kottke-Marchant K, Marchant RE. RGD-modified liposomes targeted to activated platelets as a potential vascular drug delivery system. Thromb Haemost. 2005;93(1):106-114. (Pubitemid 40124263)
76. Bode C, Meinhardt G, Runge MS, et al. Platelettargeted fibrinolysis enhances clot lysis and inhibits platelet aggregation. Circulation. 1991;84(2):805-813.
77. van den Brand M J BM, Simoons ML, de Boer MJ, van Miltenburg A, van der Wieken LR, de Feyter PJ. Antiplatelet therapy in therapy-resistant unstable angina. A pilot study with REO PRO (c7E3). Eur Heart J. 1995;16(Suppl L):36-42. (Pubitemid 26031521)
78. Knight LC, Baidoo KE, Romano JE, Gabriel JL, Maurer AH. Imaging pulmonary emboli and deep venous thrombi with 99mTc-bitistatin, a plateletbinding polypeptide from viper venom. J Nucl Med. 2000;41(6):1056-1064. (Pubitemid 30396658)
79. Sakharov DV, Rijken DC. Superficial accumulation of plasminogen during plasma clot lysis. Circulation. 1995;92(7):1883-1890.
80. Zaitsev S, Danielyan K, Murciano JC, et al. Human complement receptor type 1-directed loading of tissue plasminogen activator on circulating erythrocytes for prophylactic fibrinolysis. Blood. 2006;108(6):1895-1902. (Pubitemid 44403687)
81. Zaitsev S, Spitzer D, Murciano JC, et al. Targeting of a mutant plasminogen activator to circulating red blood cells for prophylactic fibrinolysis. J Pharmacol Exp Ther. 2010;332(3):1022-1031.
82. Zaitsev S, Spitzer D, Murciano JC, et al. Sustained thromboprophylaxis mediated by an RBC-targeted pro-urokinase zymogen activated at the site of clot formation. Blood. 2010;115(25):5241-5248.
83. Kumada T, Dittman WA, Majerus PW. A role for thrombomodulin in the pathogenesis of thrombin-induced thromboembolism in mice. Blood. 1988;71(3):728-733.
84. Zaitsev S, Kowalska MA, Neyman M, et al. Targeting recombinant thrombomodulin fusion protein to red blood cells provides multifaceted thromboprophylaxis. Blood. 2012;119(20):4779-4785.
85. Esmon CT. Inflammation and thrombosis. J Thromb Haemost. 2003;1(7):1343-1348.
86. Dichek DA, Anderson J, Kelly AB, Hanson SR, Harker LA. Enhanced in vivo antithrombotic effects of endothelial cells expressing recombinant plasminogen activators transduced with retroviral vectors. Circulation. 1996;93(2):301-309. (Pubitemid 26031489)
87. Kim AY, Walinsky PL, Kolodgie FD, et al. Early loss of thrombomodulin expression impairs vein graft thromboresistance: implications for vein graft failure. Circ Res. 2002;90(2):205-212. (Pubitemid 34627090)
88. Kiely JM, Cybulsky MI, Luscinskas FW, Gimbrone MA Jr. Immunoselective targeting of an anti-thrombin agent to the surface of cytokineactivated vascular endothelial cells. Arterioscler Thromb Vasc Biol. 1995;15(8):1211-1218.
89. Spragg DD, Alford DR, Greferath R, et al. Immunotargeting of liposomes to activated vascular endothelial cells: a strategy for siteselective delivery in the cardiovascular system. Proc Natl Acad Sci USA. 1997;94(16):8795-8800. (Pubitemid 27335119)
90. Muzykantov VR, Barnathan ES, Atochina EN, Kuo A, Danilov SM, Fisher AB. Targeting of antibody-conjugated plasminogen activators to the pulmonary vasculature. J Pharmacol Exp Ther. 1996;279(2):1026-1034. (Pubitemid 27166881)
91. Muzykantov VR, Atochina EN, Kuo A, et al. Endothelial cells internalize monoclonal antibody to angiotensin-converting enzyme. Am J Physiol. 1996;270(5 Pt 1):L704-L713.
92. Murciano JC, Harshaw DW, Ghitescu L, Danilov SM, Muzykantov VR. Vascular immunotargeting to endothelial surface in a specific macrodomain in alveolar capillaries. Am J Respir Crit Care Med. 2001;164(7):1295-1302. (Pubitemid 33052266)
93. Murciano JC, Muro S, Koniaris L, et al. ICAM-directed vascular immunotargeting of antithrombotic agents to the endothelial luminal surface. Blood. 2003;101(10):3977-3984. (Pubitemid 36857875)
94. Muro S, Muzykantov VR. Targeting of antioxidant and anti-thrombotic drugs to endothelial cell adhesion molecules. Curr Pharm Des. 2005;11(18):2383-2401. (Pubitemid 40872703)
95. Scherpereel A, Wiewrodt R, Christofidou-Solomidou M, Gervais R, Murciano JC, Albelda SM, Muzykantov VR. Cell-selective intracellular delivery of a foreign enzyme to endothelium in vivo using vascular immunotargeting. FASEB J. 2001;15(2):416-426. (Pubitemid 32141433)
96. Muzykantov VR, Christofidou-Solomidou M, Balyasnikova I, Harshaw DW, Schultz L, Fisher AB, Albelda SM. Streptavidin facilitates internalization and pulmonary targeting of an anti-endothelial cell antibody (platelet-endothelial cell adhesion molecule 1): a strategy for vascular immunotargeting of drugs. Proc Natl Acad Sci USA. 1999;96(5):2379-2384. (Pubitemid 29117923)
97. Ding BS, Gottstein C, Grunow A, et al. Endothelial targeting of a recombinant construct fusing a PECAM-1 single-chain variable antibody fragment (scFv) with prourokinase facilitates prophylactic thrombolysis in the pulmonary vasculature. Blood. 2005;106(13):4191-4198. (Pubitemid 41775926)
98. Danielyan K, Ding BS, Gottstein C, Cines DB, Muzykantov VR. Delivery of anti-plateletendothelial cell adhesion molecule single-chain variable fragment-urokinase fusion protein to the cerebral vasculature lyses arterial clots and attenuates postischemic brain edema. J Pharmacol Exp Ther. 2007;321(3):947-952. (Pubitemid 46762681)
99. Ding BS, Hong N, Murciano JC, et al. Prophylactic thrombolysis by thrombin-activated latent prourokinase targeted to PECAM-1 in the pulmonary vasculature. Blood. 2008;111(4):1999-2006. (Pubitemid 351451510)
100. Ding BS, Hong N, Christofidou-Solomidou M, et al. Anchoring fusion thrombomodulin to the endothelial lumen protects against injuryinduced lung thrombosis and inflammation. Am J Respir Crit Care Med. 2009;180(3):247-256.
101. Braunwald E. Unstable angina and non-ST elevation myocardial infarction. Am J Respir Crit Care Med. 2012;185(9):924-932.
102. Trost JC, Lange RA. Treatment of acute coronary syndrome: Part 1: Non-ST-segment acute coronary syndrome. Crit Care Med. 2011;39(10):2346-2353.