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An unmet clinical need: The history of thrombus imaging

  • Review Article
  • Published:
Journal of Nuclear Cardiology Aims and scope

Abstract

Robust thrombus imaging is an unresolved clinical unmet need dating back to the mid 1970s. While early molecular imaging approaches began with nuclear SPECT imaging, contrast agents for virtually all biomedical imaging modalities have been demonstrated in vivo with unique strengths and common weaknesses. Two primary molecular imaging targets have been pursued for thrombus imaging: platelets and fibrin. Some common issues noted over 40 years ago persist today. Acute thrombus is readily imaged with all probes and modalities, but aged thrombus remains a challenge. Similarly, anti-coagulation continues to interfere with and often negate thrombus imaging efficacy, but heparin is clinically required in patients suspected of pulmonary embolism, deep venous thrombosis or coronary ruptured plaque prior to confirmatory diagnostic studies have been executed and interpreted. These fundamental issues can be overcome, but an innovative departure from the prior approaches will be needed.

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References

  1. Furie B, Furie BC. Role of platelet P-selectin and microparticle PSGL-1 in thrombus formation. Trend Mol Med 2004;10:171-8.

    Article  CAS  Google Scholar 

  2. Foley JH, Conway EM. Cross talk pathways between coagulation and inflammation. Circ Res 2016;118:1392-408.

    Article  CAS  PubMed  Google Scholar 

  3. High KA. Antithrombin III, protein C, and protein S. Naturally occurring anticoagulant proteins. Arch Pathol Lab Med 1988;112:28-36.

    CAS  PubMed  Google Scholar 

  4. Litvinov RI, Farrell DH, Weisel JW, Bennett JS. The platelet integrin alpha IIb beta 3 differentially interacts with fibrin versus fibrinogen. J Biol Chem 2016;291:7858-67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Podolnikova NP, Podolnikov AV, Haas TA, Lishko VK, Ugarova TP. Ligand recognition specificity of leukocyte integrin alpha M beta 2 (Mac-1, CD11b/CD18) and its functional consequences. Biochemistry 2015;54:1408-20.

    Article  CAS  PubMed  Google Scholar 

  6. Wood JP, Ellery PE, Maroney SA, Mast AE. Biology of tissue factor pathway inhibitor. Blood 2014;123:2934-43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Scheraga H, Laskowski M Jr. The fibrinogen-fibrin conversion. Adv Protein Chem 1957;12:1-131.

    Article  CAS  Google Scholar 

  8. Waugh DF. Protein-protein interactions. Adv Protein Chem 1954;9:325-437.

    Article  CAS  PubMed  Google Scholar 

  9. Selmayr E, Mahn I, Muller-Berghaus G. Crosslinking of soluble fibrin and fibrinogen. Thromb Res 1985;39:467-74.

    Article  CAS  PubMed  Google Scholar 

  10. Fraser SR, Booth NA, Mutch NJ. The antifibrinolytic function of factor XIII is exclusively expressed through alpha(2)-antiplasmin cross-linking. Blood 2011;117:6371-4.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Walker JB, Bajzar L. The intrinsic threshold of the fibrinolytic system is modulated by basic carboxypeptidases, but the magnitude of the antifibrinolytic effect of activated thrombin-activable fibrinolysis inhibitor is masked by its instability. J Biol Chem 2004;279:27896-904.

    Article  CAS  PubMed  Google Scholar 

  12. Camiolo SM, Thorsen S, Astrup T. Fibrinogenolysis and fibrinolysis with tissue plasminogen activator, urokinase, streptokinase-activated human globulin, and plasmin. Proc Soc Exp Biol Med 1971;138:277-80.

    Article  CAS  PubMed  Google Scholar 

  13. O’Brien JR. Detection of thrombosis with iodine-125 fibrinogen. Lancet 1970;296:396-8.

    Article  Google Scholar 

  14. Kerrigan GNW, Buchanan MR, Cade JF, Regoeczi E, Hirsh J. Investigation of the mechanism of false positive 125I labelled fibrinogen scans. Br J Haematol 1974;26:469-73.

    Article  CAS  PubMed  Google Scholar 

  15. Hirsh J, Gallus AS. 125I-labeled fibrinogen scanning: use in the diagnosis of venous thrombosis. JAMA 1975;233:970-3.

    Article  CAS  PubMed  Google Scholar 

  16. Thakur ML, Welch MJ, Joist JH, Coleman RE. Indium-111 labeled platelets: studies on preparation and evaluation of in vitro and in vivo functions. Thromb Res 1976;9:345-57.

    Article  CAS  PubMed  Google Scholar 

  17. Jerne NK. The natural-selection theory of antibody formation. Proc Natl Acad Sci USA 1955;41:849-57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Jerne NK, Nordin AA. Plaque formation in agar by single antibody producing cells. Science 1963;140:405.

    Article  PubMed  Google Scholar 

  19. Köhler G, Milstein C. Continuous cultures of fused cells secreting antibodies of predefined specificity. Nature 1975;256:495-7.

    Article  PubMed  Google Scholar 

  20. Alkan SS. Monoclonal antibodies: the story of a discovery that revolutionized science and medicine. Nat Rev Immunol 2004;4:153-6.

    Article  CAS  PubMed  Google Scholar 

  21. Bosnjakovic VB, Jankovic BD, Horvat J, Cvoric J. Radiolabelled anti human fibrin antibody: A new thrombus detecting agent. Lancet 1977;1:452-4.

    Article  CAS  PubMed  Google Scholar 

  22. Grossman ZD, Rosebrough SF, McAfee JG, Subramanian G, Ritter-Hrncirik CA, Witanowski LS, et al. Imaging fresh venous thrombi in the dog with I-131 and In-111 labeled fibrin-specific monoclonal antibody and F(ab’)2 fragments. Radiographics 1987;7:913-21.

    Article  CAS  PubMed  Google Scholar 

  23. Bosnjakovic V, Jankovic BD, Horvat J, Nastic-Miric D, Djukic V, Pavlovic S. The validity of radiolabeled anti fibrin antibody for deep vein thrombosis imaging. Eur J Nucl Med Mol Imaging 1988;14:489-94.

    Article  CAS  Google Scholar 

  24. Hashimoto Y, Stassen JM, Leclef B, De Roo M, Vandecruys A, Melin J, et al. Thrombus imaging with an I-123-labeled F(ab’)2 fragment of an anti-human fibrin monoclonal antibody in a rabbit model. Radiology 1989;171:223-6.

    Article  CAS  PubMed  Google Scholar 

  25. Edgell T, McEnvoy F, Webbon P, Gaffney P. Monoclonal antibodies to human fibrin: Interaction with other animal fibrins. Thromb Haemost 1996;75:595-9.

    CAS  PubMed  Google Scholar 

  26. Tymkewycz PM, Creighton Kempsford LJ, Gaffney PJ. Generation and partial characterization of five monoclonal antibodies with high affinities for fibrin. Blood Coagul Fibrinolysis 1993;4:211-21.

    Article  CAS  PubMed  Google Scholar 

  27. Tymkewycz PM, Creighton Kempsford LJ, Hockley D, Gaffney PJ. Screen for fibrin specific monoclonal antibodies: the development of a new procedure. Thromb Haemost 1992;68:48-53.

    Article  CAS  PubMed  Google Scholar 

  28. Tymkewycz PM, Creighton LJ, Gascoine PS, Zanelli GD, Webbon PM, Gaffney PJ. Imaging of human thrombi in the rabbit jugular vein: I: Comparison of two fibrin-specific monoclonal antibodies. Thromb Res 1989;54:411-21.

    Article  CAS  PubMed  Google Scholar 

  29. Kudryk BJ, Bini A, Kumar SR, Zlokovic BV. Monoclonal antibody designated T2G1 reacts with human fibrin β-chain but not with the corresponding chain from mouse fibrin. Arterioscler Thromb Vasc Biol 2000;20:1848-9.

    Article  CAS  PubMed  Google Scholar 

  30. Rosebrough S, McAfee J, Grossman Z, Kudryk B, Ritter-Hrncirik C, Witanowski L, et al. Thrombus imaging: A comparison of radiolabeled GC4 and T2G1s fibrin-specific monoclonal antibodies. J Nucl Med 1990;31:1048-54.

    CAS  PubMed  Google Scholar 

  31. Rosebrough SF, Grossman ZD, McAfee JG, Kudryk BJ, Subramanian G, Ritter-Hrncirik CA, et al. Thrombus imaging with indium-111 and iodine-131-labeled fibrin-specific monoclonal antibody and its F(ab’)2 and Fab fragments. J Nucl Med 1988;29:1212-22.

    CAS  PubMed  Google Scholar 

  32. Kudryk B, Rohoza A, Ahadi M, Chin J, Wiebe ME. Specificity of a monoclonal antibody for the NH2-terminal region of fibrin. Mol Immunol 1984;21:89-94.

    Article  CAS  PubMed  Google Scholar 

  33. Macfarlane DJ, Smart RC, Tsui WW, Gerometta M, Eisenberg PR, Scott AM. Safety, pharmacokinetic and dosimetry evaluation of the proposed thrombus imaging agent 99mTc-DI-DD-3B6/22-80B3 Fab′. Eur J Nucl Med Mol Imaging 2006;33:648-56.

    Article  CAS  PubMed  Google Scholar 

  34. Macfarlane D, Socrates A, Eisenberg P, Larcos G, Roach P, Gerometta M, et al. Imaging of deep venous thrombosis in patients using a radiolabelled anti-D-dimer Fab′ fragment (99mTc-DI-DD3B6/22-80B3): Results of a phase I trial. Eur J Nucl Med Mol Imaging 2009;36:250-9.

    Article  CAS  PubMed  Google Scholar 

  35. Morris TA, Gerometta M, Smart RC, Eisenberg P, Roach PJ, Tsui WW, et al. Pulmonary emboli imaging with 99mTc-labelled anti-D-dimer (DI-80B3) Fab’ followed by SPECT. Heart Lung Circ 2011;20:503-11.

    Article  CAS  PubMed  Google Scholar 

  36. Perrier A, Desmarais S, Goehring C, de Moerloose P, Morabia A, Unger PF, et al. D-dimer testing for suspected pulmonary embolism in outpatients. Am J Respir Crit Care Med 1997;156:492-6.

    Article  CAS  PubMed  Google Scholar 

  37. Smith GP. Filamentous fusion phage: Novel expression vectors that display cloned antigens on the virion surface. Science 1985;228:1315-7.

    Article  CAS  PubMed  Google Scholar 

  38. Overoye-Chan K, Koerner S, Looby RJ, Kolodziej AF, Zech SG, Deng Q, et al. EP-2104R: A fibrin-specific gadolinium-based MRI contrast agent for detection of thrombus. J Am Chem Soc 2008;130:6025-39.

    Article  CAS  PubMed  Google Scholar 

  39. Kolodziej AF, Nair SA, Graham P, McMurry TJ, Ladner RC, Wescott C, et al. Fibrin specific peptides derived by phage display: Characterization of peptides and conjugates for imaging. Bioconjug Chem 2012;23:548-56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Botnar RM, Buecker A, Wiethoff AJ, Parsons EC Jr, Katoh M, Katsimaglis G, et al. In vivo magnetic resonance imaging of coronary thrombosis using a fibrin-binding molecular magnetic resonance contrast agent. Circulation 2004;110:1463-6.

    Article  PubMed  Google Scholar 

  41. Spuentrup E, Buecker A, Katoh M, Wiethoff AJ, Parsons EC Jr, Botnar RM, et al. Molecular magnetic resonance imaging of coronary thrombosis and pulmonary emboli with a novel fibrin-targeted contrast agent. Circulation 2005;111:1377-82.

    Article  CAS  PubMed  Google Scholar 

  42. Spuentrup E, Katoh M, Wiethoff AJ, Parsons EC Jr, Botnar RM, Mahnken AH, et al. Molecular magnetic resonance imaging of pulmonary emboli with a fibrin-specific contrast agent. Am J Respir Crit Care Med 2005;172:494-500.

    Article  PubMed  Google Scholar 

  43. Spuentrup E, Fausten B, Kinzel S, Wiethoff AJ, Botnar RM, Graham PB, et al. Molecular magnetic resonance imaging of atrial clots in a swine model. Circulation 2005;112:396-9.

    Article  PubMed  Google Scholar 

  44. Spuentrup E, Botnar RM. Coronary magnetic resonance imaging: visualization of the vessel lumen and the vessel wall and molecular imaging of arteriothrombosis. Eur Radiol 2006;16:1-14.

    Article  PubMed  Google Scholar 

  45. Botnar RM, Perez AS, Witte S, Wiethoff AJ, Laredo J, Hamilton J, et al. In vivo molecular imaging of acute and subacute thrombosis using a fibrin-binding magnetic resonance imaging contrast agent. Circulation 2004;109:2023-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Sirol M, Fuster V, Badimon JJ, Fallon JT, Moreno PR, Toussaint JF, et al. Chronic thrombus detection with in vivo magnetic resonance imaging and a fibrin-targeted contrast agent. Circulation 2005;112:1594-600.

    Article  PubMed  Google Scholar 

  47. Spuentrup E, Katoh M, Buecker A, Fausten B, Wiethoff AJ, Wildberger JE, et al. Molecular MR imaging of human thrombi in a swine model of pulmonary embolism using a fibrin-specific contrast agent. Investig Radiol 2007;42:586-95.

    Article  CAS  Google Scholar 

  48. Spuentrup E, Botnar RM, Wiethoff AJ, Ibrahim T, Kelle S, Katoh M, et al. MR imaging of thrombi using EP-2104R, a fibrin-specific contrast agent: Initial results in patients. Eur Radiol 2008;18:1995-2005.

    Article  PubMed  Google Scholar 

  49. Edwards D, Lewis J, Battle M, Lear R, Farrar G, Barnett DJ, et al. 99mTc-NC100668, a new tracer for imaging venous thromboemboli: Pre-clinical biodistribution and incorporation into plasma clots in vivo and in vitro. Eur J Nucl Med Mol Imaging 2006;33:1258-65.

    Article  PubMed  Google Scholar 

  50. Edwards D, Lewis J, Battle M, Lear R, Farrar G, Barnett DJ, et al. The biodistribution of NC100668 and the effect of excess NC100668 on the biodistribution and kidney retention of 99mTc-NC100668 in the rat. Nucl Med Biol 2007;34:315-23.

    Article  CAS  PubMed  Google Scholar 

  51. Edwards D, Lewis J, Battle M, Lear R, Farrar G, Jon Barnett D, et al. 99mTc-NC100668, an agent for imaging venous thromboembolism: The effect of anticoagulant or thrombolytic therapy on the uptake and retention of radioactivity in blood clots in vivo. Nucl Med Commun 2007;28:55-62.

    Article  CAS  PubMed  Google Scholar 

  52. McIlmoyle G, Davis HH, Welch MJ. Scintigraphic diagnosis of experimental pulmonary embolism with In-111-labeled platelets. J Nucl Med 1977;18:910-4.

    CAS  PubMed  Google Scholar 

  53. Knight LC, Primeau JL, Siegel BA, Welch MJ. Comparison of In-111-labeled platelets and iodinated fibrinogen for the detection of deep vein thrombosis. J Nucl Med 1978;19:891-4.

    CAS  PubMed  Google Scholar 

  54. Price DC, Lipton MJ, Lusby RJ, Engelstad BL, Stoney RJ, Prager RJ, et al. In vivo detection of thrombi with indium-111-labeled platelets. IEEE Trans Nucl Sci 1982;29:1191-7.

    Article  Google Scholar 

  55. Fedullo PF, Moser KM, Moser KS, Konopka R, Hartman MT. Indium-111-labeled platelets: Effect of heparin on uptake by venous thrombi and relationship to the activated partial thromboplastin time. Circulation 1982;66:632-7.

    Article  CAS  PubMed  Google Scholar 

  56. Stratton JR, Ritchie JL. The effects of antithrombotic drugs in patients with left ventricular thrombi: Assessment with indium-111 platelet imaging and two-dimensional echocardiography. Circulation 1984;69:561-8.

    Article  CAS  PubMed  Google Scholar 

  57. Ezekowitz MD, Leonard JC, Smith EO, Allen EW, Taylor FB. Identification of left ventricular thrombi in man using Indium-111-labeled autologous platelets. A preliminary report. Circulation 1981;63:803-10.

    Article  CAS  PubMed  Google Scholar 

  58. Vandenberg BF, Seabold JE, Schroder E, Kerber RE. Noninvasive imaging of left ventricular thrombi: Two-dimensional echocardiography and indium-111 platelet scintigraphy. Am J Card Imaging 1987;1:289-94.

    Google Scholar 

  59. Tsuda T, Kubota M, Iwakubo A, Akiba H, Shido M, Takahashi T, et al. Availability of 111In-labeled platelet scintigraphy in patients with postinfarction left ventricular aneurysm. Ann Nucl Med 1989;3:15-24.

    Article  CAS  PubMed  Google Scholar 

  60. Stratton JR, Ritchie JL. 111In platelet imaging of left ventricular thrombi: Predictive value for systemic emboli. Circulation 1990;81:1182-9.

    Article  CAS  PubMed  Google Scholar 

  61. Zoppo GJ, Copeland BR, Harker LA, Waltz TA, Zyroff J, Hanson SR, et al. Experimental acute thrombotic stroke in baboons. Stroke 1986;17:1254-65.

    Article  PubMed  Google Scholar 

  62. Hanson SR, Paxton LD, Harker LA. Iliac artery mural thrombus formation. Effect of antiplatelet therapy on 111In-platelet deposition in baboons. Arteriosclerosis 1986;6:511-8.

    Article  CAS  PubMed  Google Scholar 

  63. Siegel RS, Rae JL, Ryan NL, Edwards C, Fortune WP, Lewis RJ, et al. The use of indium-111 labeled platelet scanning for the detection of asymptomatic deep venous thrombosis in a high risk population. Orthopedics 1989;12:1439-43.

    CAS  PubMed  Google Scholar 

  64. Oster ZH, Srivastava SC, Som P, Meinken GE, Scudder LE, Yamamoto K, et al. Thrombus radioimmunoscintigraphy: An approach using monoclonal antiplatelet antibody. Proc Natl Acad Sci USA 1985;82:3465-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Gu J, Liu Y, Xia L, Wan H, Li P, Zhang X, et al. Construction and expression of mouse-human chimeric antibody SZ-51 specific for activated platelet P-selectin. Thromb Haemost 1997;77:755-9.

    Article  CAS  PubMed  Google Scholar 

  66. Wu G. Application of a monoclonal antibody SZ-51 specific for activated human platelets in canine thrombosis imaging. Zhonghua yi xue za zhi 1991;71:605-7, 42.

  67. Gu JM, Liu Y, Wan HY, Li PX, Ruan CG. Construction and expression of mouse-human chimeric antibody SZ-51 specific for human activated platelets. Acta Biochim Biophys Sin 1996;28:469-70.

    Google Scholar 

  68. Mousa SA, Bozarth JM, Edwards S, Carroll T, Barrett J. Novel technetium-99m-labeled platelet GPIIb/IIIa receptor antagonists as potential imaging agents for venous and arterial thrombosis. Coron Artery Dis 1998;9:131-41.

    CAS  PubMed  Google Scholar 

  69. Edwards DS, Liu S, Barrett JA, Harris AR, Looby RJ, Ziegler MC, et al. New and versatile ternary ligand system for technetium radiopharmaceuticals: Water soluble phosphines and tricine as coligands in labeling a hydrazinonicotinamide-modified cyclic glycoprotein IIb/IIIa receptor antagonist with 99mTc. Bioconjug Chem 1997;8:146-54.

    Article  CAS  PubMed  Google Scholar 

  70. Barrett JA, Damphousse DJ, Heminway SJ, Liu S, Scott Edwards D, Looby RJ, et al. Biological evaluation of 99mTc-labeled cyclic glycoprotein IIb/IIIa receptor antagonists in the canine arteriovenous shunt and deep vein thrombosis models: Effects of chelators on biological properties of 99mTc chelator-peptide conjugates. Bioconjug Chem 1996;7:203-8.

    Article  CAS  PubMed  Google Scholar 

  71. Knight LC, Romano JE, Maurer AH. In vitro platelet binding compared with in vivo thrombus imaging using α(IIb)β3-targeted radioligands. Thromb Haemost 1998;80:845-51.

    Article  CAS  PubMed  Google Scholar 

  72. Knight LC, Baidoo KE, Romano JE, Gabriel JL, Maurer AH. Imaging pulmonary emboli and deep venous thrombi 99mTc-bitistatin, a platelet-binding polypeptide from viper venom. J Nucl Med 2000;41:1056-64.

    CAS  PubMed  Google Scholar 

  73. Baidoo KE, Knight LC, Lin KS, Gabriel JL, Romano JE. Design and synthesis of a short-chain bitistatin analogue for imaging thrombi and emboli. Bioconjug Chem 2004;15:1068-75.

    Article  CAS  PubMed  Google Scholar 

  74. Mitchel J, Waters D, Lai T, White M, Alberghini T, Salloum A, et al. Identification of coronary thrombus with a IIb/IIIa platelet inhibitor radiopharmaceutical, technetium-99m DMP-444: A canine model. Circulation 2000;101:1643-6.

    Article  CAS  PubMed  Google Scholar 

  75. Taillefer R, Edell S, Innes G, Lister-James J, Multicenter Trial Investigators. Acute thromboscintigraphy with 99mTc-apcitide: results of the phase 3 multicenter clinical trial comparing 99mTc-apcitide scintigraphy with contrast venography for imaging acute DVT. J Nucl Med 2000;41:1214-23.

    CAS  PubMed  Google Scholar 

  76. Scharn DM, Oyen WJG, Klemm PL, Wijnen MHWA, VanderVliet JA. Assessment of prosthetic vascular graft thrombogenicity using the technetium-99m labeled glycoprotein IIb/IIIa receptor antagonist DMP444 in a dog model. Vascular 2002;10:566-9.

    Google Scholar 

  77. Tung CH, Quinti L, Jaffer FA, Weissleder R. A branched fluorescent peptide probe for imaging of activated platelets. Mol Pharm 2005;2:92-5.

    Article  CAS  PubMed  Google Scholar 

  78. Klink A, Lancelot E, Ballet S, Vucic E, Fabre JE, Gonzalez W, et al. Magnetic resonance molecular imaging of thrombosis in an arachidonic acid mouse model using an activated platelet targeted probe. Arterioscler Thromb Vasc Biol 2010;30:403-10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Lanza G, Wallace K, Scott M, Cacheris W, Abendschein D, Christy D, et al. A novel site-targeted ultrasonic contrast agent with broad biomedical application. Circulation 1996;94:3334-40.

    Article  CAS  PubMed  Google Scholar 

  80. Lanza GM, Wallace KD, Fischer SE, Christy DH, Scott MJ, Trousil RL, et al. High-frequency ultrasonic detection of thrombi with a targeted contrast system. Ultrasound Med Biol 1997;23:863-70.

    Article  CAS  PubMed  Google Scholar 

  81. Lanza G, Trousil R, Wallace K, Rose J, Hall C, Scott M, et al. In vitro characterization of a novel, tissue-targeted ultrasonic contrast system with acoustic microscopy. J Acoust Soc Am 1998;104:3665-72.

    Article  CAS  PubMed  Google Scholar 

  82. Hughes MS, Marsh JN, Hall CS, Fuhrhop RW, Lacy EK, Lanza GM, et al. Acoustic characterization in whole blood and plasma of site-targeted nanoparticle ultrasound contrast agent for molecular imaging. J Acoust Soc Am 2005;117:964-72.

    Article  CAS  PubMed  Google Scholar 

  83. Hughes MS, Marsh JN, Hall CS, Savery D, Lanza GM, Wickline SA. Characterization of digital waveforms using thermodynamic analogs: Applications to detection of materials defects. IEEE Trans Ultrasonics Ferroelectr Freq Control 2005;52:1555-64.

    Article  Google Scholar 

  84. Hughes MS, Marsh JN, Zhang H, Woodson AK, Allen JS, Lacy EK, et al. Characterization of digital waveforms using thermodynamic analogs: Detection of contrast-targeted tissue in vivo. IEEE Trans Ultrasonics Ferroelectr Freq Control 2006;53:1609-16.

    Article  Google Scholar 

  85. Hughes MS, McCarthy JE, Marsh JN, Arbeit JM, Neumann RG, Fuhrhop RW, et al. Properties of an entropy-based signal receiver with an application to ultrasonic molecular imaging. J Acoust Soc Am 2007;121:3542-57.

    Article  CAS  PubMed  Google Scholar 

  86. Hughes MS, Marsh JN, Arbeit JM, Neumann RG, Fuhrhop RW, Wallace KD, et al. Application of Renyi entropy for ultrasonic molecular imaging. J Acoust Soc Am 2009;125:3141-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Alkan-Onyuksel H, Demos S, Lanza G, Vonesh M, Klegerman M, Kane B, et al. Development of inherently echogenic liposomes as an ultrasonic contrast agent. J Pharm Sci 1996;85:486-90.

    Article  CAS  PubMed  Google Scholar 

  88. Demos S, Onyuksel H, Gilbert J, Roth S, Kane B, Jungblut P, et al. In vitro targeting of antibody-conjugated echogenic liposomes for site-specific ultrasonic image enhancement. J Pharm Sci 1997;86:161-71.

    Article  Google Scholar 

  89. Demos S, Alkan-Onyuksel H, Kane B, Ramani K, Nagaraj A, Greene R, et al. In vivo targeting of acoustically reflective liposomes for intravascular and transvascular ultrasonic enhancement. J Am Coll Cardiol 1999;33:867-75.

    Article  CAS  PubMed  Google Scholar 

  90. Tiukinhoy-Laing SD, Huang S, Klegerman M, Holland CK, McPherson DD. Ultrasound-facilitated thrombolysis using tissue-plasminogen activator-loaded echogenic liposomes. Thromb Res 2007;119:777-84.

    Article  CAS  PubMed  Google Scholar 

  91. Huang SL, Kee PH, Kim H, Moody MR, Chrzanowski SM, Macdonald RC, et al. Nitric oxide-loaded echogenic liposomes for nitric oxide delivery and inhibition of intimal hyperplasia. J Am Coll Cardiol 2009;54:652-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Shaw GJ, Meunier JM, Huang SL, Lindsell CJ, McPherson DD, Holland CK. Ultrasound-enhanced thrombolysis with tPA-loaded echogenic liposomes. Thromb Res 2009;124:306-10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Britton GL, Kim H, Kee PH, Aronowski J, Holland CK, McPherson DD, et al. In vivo therapeutic gas delivery for neuroprotection with echogenic liposomes. Circulation 2010;122:1578-87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Kim H, Britton GL, Peng T, Holland CK, McPherson DD, Huang SL. Nitric oxide-loaded echogenic liposomes for treatment of vasospasm following subarachnoid hemorrhage. Int J Nanomed 2014;9:155-65.

    Google Scholar 

  95. Alonso A, Martina AD, Stroick M, Fatar M, Griebe M, Pochon S, et al. Molecular imaging of human thrombus with novel abciximab immunobubbles and ultrasound. Stroke 2007;38:1508-14.

    Article  CAS  PubMed  Google Scholar 

  96. Savitha F, Forsberg F, Gilmore SC, Shevchuk SV, Kerschen A, Matsunaga TO et al. Adherence of platelet and fibrin targeted ultrasound contrast bubbles to human blood clots in vitro. 2008 IEEE International Ultrasonics Symposium; 2008. pp. 349-52.

  97. Wang X, Hagemeyer CE, Hohmann JD, Leitner E, Armstrong PC, Jia F, et al. Novel single-chain antibody-targeted microbubbles for molecular ultrasound imaging of thrombosis: Validation of a unique noninvasive method for rapid and sensitive detection of thrombi and monitoring of success or failure of thrombolysis in mice. Circulation 2012;125:3117-26.

    Article  CAS  PubMed  Google Scholar 

  98. Hu G, Liu C, Liao Y, Yang L, Huang R, Wu J, et al. Ultrasound molecular imaging of arterial thrombi with novel microbubbles modified by cyclic RGD in vitro and in vivo. Thromb Haemost 2012;107:172-83.

    Article  CAS  PubMed  Google Scholar 

  99. Wu W, Wang Y, Shen S, Wu J, Guo S, Su L, et al. In vivo ultrasound molecular imaging of inflammatory thrombosis in arteries with cyclic Arg-Gly-Asp-modified microbubbles targeted to glycoprotein IIb/IIIa. Investig Radiol 2013;48:803-12.

    Article  CAS  Google Scholar 

  100. Hua X, Liu P, Gao YH, Tan KB, Zhou LN, Liu Z, et al. Construction of thrombus-targeted microbubbles carrying tissue plasminogen activator and their in vitro thrombolysis efficacy: A primary research. J Thromb Thrombolysis 2010;30:29-35.

    Article  PubMed  Google Scholar 

  101. Wang X, Gkanatsas Y, Palasubramaniam J, Hohmann JD, Chen YC, Lim B, et al. Thrombus-targeted theranostic microbubbles: A new technology towards concurrent rapid ultrasound diagnosis and bleeding-free fibrinolytic treatment of thrombosis. Theranostics 2016;6:726-38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Lanza GM, Lorenz CH, Fischer SE, Scott MJ, Cacheris WP, Kaufmann RJ, et al. Enhanced detection of thrombi with a novel fibrin-targeted magnetic resonance imaging agent. Acad Radiol 1998;5:S173-6.

    Article  PubMed  Google Scholar 

  103. Winter P, Caruthers S, Yu X, Song S, Fuhrhop R, Chen J, et al. Improved molecular imaging contrast agent for detection of human thrombus. Magn Reson Med 2003;50:411-6.

    Article  CAS  PubMed  Google Scholar 

  104. Pham CT, Mitchell LM, Huang JL, Lubniewski CM, Schall OF, Killgore JK, et al. Variable antibody-dependent activation of complement by functionalized phospholipid nanoparticle surfaces. J Biol Chem 2011;286:123-30.

    Article  CAS  PubMed  Google Scholar 

  105. Temme S, Grapentin C, Quast C, Jacoby C, Grandoch M, Ding Z, et al. Noninvasive imaging of early venous thrombosis by 19F magnetic resonance imaging with targeted perfluorocarbon nanoemulsions. Circulation 2015;131:1405-14.

    Article  CAS  PubMed  Google Scholar 

  106. Yu X, Song S-K, Chen J, Scott M, Fuhrhop R, Hall C, et al. High-resolution MRI characterization of human thrombus using a novel fibrin-targeted paramagnetic nanoparticle contrast agent. Magn Reson Med 2000;44:867-72.

    Article  CAS  PubMed  Google Scholar 

  107. Flacke S, Fischer S, Scott M, Fuhrhop R, Allen J, Mc Lean M, et al. A novel MRI contrast agent for molecular imaging of fibrin:implications for detecting vulnerable plaques. Circulation 2001;104:1280-5.

    Article  CAS  PubMed  Google Scholar 

  108. Johansson LO, Bjornerud A, Ahlstrom HK, Ladd DL, Fujii DK. A targeted contrast agent for magnetic resonance imaging of thrombus: Implications of spatial resolution. J Magn Reson Imaging 2001;13:615-8.

    Article  CAS  PubMed  Google Scholar 

  109. von zur Muhlen C, von Elverfeldt D, Moeller JA, Choudhury RP, Paul D, Hagemeyer CE, et al. Magnetic resonance imaging contrast agent targeted toward activated platelets allows in vivo detection of thrombosis and monitoring of thrombolysis. Circulation 2008;118:258-67.

    Article  CAS  Google Scholar 

  110. Gleich B, Weizenecker J. Tomographic imaging using the nonlinear response of magnetic particles. Nature 2005;435:1214-7.

    Article  CAS  PubMed  Google Scholar 

  111. Starmans LWE, Burdinski D, Haex NPM, Moonen RPM, Strijkers GJ, Nicolay K, et al. Iron oxide nanoparticle-micelles (ION-Micelles) for sensitive (Molecular) magnetic particle imaging and magnetic resonance imaging. PLoS ONE 2013;8:e57335.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Phinikaridou A, Andia ME, Saha P, Modarai B, Smith A, Botnar RM. In vivo magnetization transfer and diffusion-weighted magnetic resonance imaging detects thrombus composition in a mouse model of deep vein thrombosis. Circ Cardiovasc Imaging 2013;6:433-40.

    Article  PubMed  PubMed Central  Google Scholar 

  113. Myerson J, He L, Lanza G, Tollefsen D, Wickline S. Thrombin-inhibiting perfluorocarbon nanoparticles provide a novel strategy for the treatment and magnetic resonance imaging of acute thrombosis. J Thromb Haemost 2011;9:1292-300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Winter PM, Shukla HP, Caruthers SD, Scott MJ, Fuhrhop RW, Robertson JD, et al. Molecular imaging of human thrombus with computed tomography. Acad Radiol 2005;12:S9-13.

    Article  PubMed  Google Scholar 

  115. Mattrey RF, Scheible FW, Gosink BB, Leopold GR, Long DM, Higgins CB. Perfluoroctylbromide: a liver/spleen-specific and tumor-imaging ultrasound contrast material. Radiology 1982;145:759-62.

    Article  CAS  PubMed  Google Scholar 

  116. Sartoris DJ, Guerra J Jr, Mattrey RF, Resnick D, Haghighi P, Mitten R, et al. Perfluoroctylbromide as a contrast agent for computed tomographic imaging of septic and aseptic arthritis. Investig Radiol 1986;21:49-55.

    Article  CAS  Google Scholar 

  117. Mattrey RF, Hajek PC, Gylys-Morin VM, Baker LL, Martin J, Long DC, et al. Perfluorochemicals as gastrointestinal contrast agents for MR imaging: Preliminary studies in rats and humans. AJR Am J Roentgenol 1987;148:1259-63.

    Article  CAS  PubMed  Google Scholar 

  118. Schirra CO, Brendel B, Anastasio MA, Roessl E. Spectral CT: A technology primer for contrast agent development. Contrast Media Mol Imaging 2014;9:62-70.

    Article  CAS  PubMed  Google Scholar 

  119. Pan D, Roessl E, Schlomka JP, Caruthers SD, Senpan A, Scott MJ, et al. Computed tomography in color: NanoK-enhanced spectral CT molecular imaging. Angew Chem Int Ed Engl 2010;49:9635-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Pan D, Schirra CO, Senpan A, Schmieder AH, Stacy AJ, Roessl E, et al. An early investigation of ytterbium nanocolloids for selective and quantitative “multicolor” spectral CT imaging. ACS Nano 2012;6:3364-70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Schirra CO, Senpan A, Roessl E, Thran A, Stacy AJ, Wu L, et al. Second generation gold nanobeacons for robust K-edge imaging with multi-energy CT. J Mater Chem 2012;22:23071-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Pan D, Schirra CO, Wickline SA, Lanza GM. Multicolor computed tomographic molecular imaging with noncrystalline high-metal-density nanobeacons. Contrast Media Mol Imaging 2014;9:13-25.

    Article  CAS  PubMed  Google Scholar 

  123. Chrastina A, Valadon P, Massey KA, Schnitzer JE. Lung vascular targeting using antibody to aminopeptidase P: CT-SPECT imaging, biodistribution and pharmacokinetic analysis. J Vasc Res 2010;47:531-43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Clausen DM, Guo J, Parise RA, Beumer JH, Egorin MJ, Lazo JS, et al. In vitro cytotoxicity and in vivo efficacy, pharmacokinetics, and metabolism of 10074-G5, a novel small-molecule inhibitor of c-Myc/Max dimerization. J Pharmacol Exp Ther 2010;335:715-27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Conti G, Tambalo S, Villetti G, Catinella S, Carnini C, Bassani F, et al. Evaluation of lung inflammation induced by intratracheal administration of LPS in mice: Comparison between MRI and histology. Magn Reson Mater Phys Biol Med 2010;23:93-101.

    Article  CAS  Google Scholar 

  126. Cormode DP, Roessl E, Thran A, Skajaa T, Gordon RE, Schlomka J-P, et al. Atherosclerotic plaque composition: analysis with multicolor CT and targeted gold nanoparticles. Radiology 2010;256:774-82.

    Article  PubMed  PubMed Central  Google Scholar 

  127. Jaffer FA, Tung CH, Wykrzykowska JJ, Ho NH, Houng AK, Reed GL, et al. Molecular imaging of factor XIIIa activity in thrombosis using a novel, near-infrared fluorescent contrast agent that covalently links to thrombi. Circulation 2004;110:170-6.

    Article  CAS  PubMed  Google Scholar 

  128. Hara T, Bhayana B, Thompson B, Kessinger CW, Khatri A, McCarthy JR, et al. Molecular imaging of fibrin deposition in deep vein thrombosis using fibrin-targeted near-infrared fluorescence. JACC 2012;5:607-15.

    PubMed  Google Scholar 

  129. Stein-Merlob AF, Kessinger CW, Sibel Erdem S, Zelada H, Hilderbrand SA, Lin CP, et al. Blood accessibility to fibrin in venous thrombosis is thrombus age-dependent and predicts fibrinolytic efficacy: An in vivo fibrin molecular imaging study. Theranostics 2015;5:1317-27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Pan D, Pramanik M, Senpan A, Yang X, Song KH, Scott MJ, et al. Molecular photoacoustic tomography with colloidal nanobeacons. Angew Chem Int Ed Engl 2009;48:4170-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Pan D, Caruthers SD, Senpan A, Yalaz C, Stacy AJ, Hu G, et al. Synthesis of NanoQ, a copper-based contrast agent for high-resolution magnetic resonance imaging characterization of human thrombus. J Am Chem Soc 2011;133:9168-71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Zhang R, Pan D, Cai X, Yang X, Senpan A, Allen JS, et al. Alpha nu beta 3-targeted copper nanoparticles incorporating an Sn 2 lipase-labile fumagillin prodrug for photoacoustic neovascular imaging and treatment. Theranostics 2015;5:124-33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Ciesienski KL, Yang Y, Ay I, Chonde DB, Loving GS, Rietz TA, et al. Fibrin-targeted PET probes for the detection of thrombi. Mol Pharm 2013;10:1100-10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Blasi F, Oliveira BL, Rietz TA, Rotile NJ, Day H, Naha PC, et al. Radiation dosimetry of the fibrin-binding probe 64Cu-FBP8 and Its feasibility for PET imaging of deep vein thrombosis and pulmonary embolism in rats. J Nucl Med 2015;56:1088-93.

    Article  CAS  PubMed  Google Scholar 

  135. Blasi F, Oliveira BL, Rietz TA, Rotile NJ, Naha PC, Cormode DP, et al. Multisite thrombus imaging and fibrin content estimation with a single whole-body PET scan in rats. Arterioscler Thromb Vasc Biol 2015;35:2114-21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Correspondence to Gregory M. Lanza MD, PhD.

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This review was supported in whole or part by Grants from the CA199092 (G.M.L.) CA154737 (G.M.L.), HL122471 (G.M.L.), HL112518 (G.M.L.), HL113392 (G.M.L.), HHSN26820140042C (G.M.L.), and HL112518 (G.M.L.)

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Lanza, G.M., Cui, G., Schmieder, A.H. et al. An unmet clinical need: The history of thrombus imaging. J. Nucl. Cardiol. 26, 986–997 (2019). https://doi.org/10.1007/s12350-017-0942-8

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