Topology of the fibrinolytic system within the mural thrombus of human abdominal aortic aneurysms.
Development and progression of acquired abdominal aortic aneurysms (AAAs) involve proteolytic activity. In the present study, we investigate the distribution of fibrinolytic system components within mural thrombi of human AAAs. 20 mural thrombi and the remaining AAA walls were dissected. The luminal, intermediate and abluminal thrombus layers, and media and adventitia were separately incubated in cell culture medium. Conditioned media were then analysed for plasminogen activators (PAs), plasminogen activator inhibitor-1 (PAI-1), free-plasmin, plasmin alpha(2)-antiplasmin complexes (PAPs) and D-dimers release. In parallel, PA and PAI-1 mRNA expression analysis was performed by RT-PCR. The study was completed by immunohistochemical localization of these components in AAA, ex vivo functional imaging using (99m)Tc-aprotinin as a ligand and measurement of PAP and D-dimer plasma levels. All fibrinolytic system components were present in each aneurysmal layer. However, the mural thrombus was the main source of active serine-protease release. Interestingly, the luminal layer of the thrombus released greater amounts of PAPs and D-dimers. This paralleled the preferential immunolocalization of plasminogen and PAs, and the (99m)Tc-aprotinin scintigraphic signal observed in the luminal pole of the thrombus. In contrast, mRNA expression analysis showed an exclusive synthesis of tPA and PAI-1 within the wall, whereas uPA mRNA was also expressed within the thrombus. Taken together, these results suggest that the increased plasma concentrations of PAPs and D-dimers found in AAA patients are related to mural thrombus proteolytic activity, thus explaining their known link with AAA progression. Components of the fibrinolytic system could also represent a target for functional imaging of thrombus activities in AAA.
Houard
X
X
INSERM U698, Cardiovascular Haematology, Bioengineering and Remodelling, Bichat-Claude Bernard Hospital, 46 Rue Henri Huchard, 75877 Paris Cedex 18, France.
Rouzet
F
F
Touat
Z
Z
Philippe
M
M
Dominguez
M
M
Fontaine
V
V
Sarda-Mantel
L
L
Meulemans
A
A
Le Guludec
D
D
Meilhac
O
O
Michel
J-B
JB
D000368:Aged; D000369:Aged, 80 and over; D001012:Aorta, Abdominal / Q000737:chemistry / Q000378:metabolism*; D017544:Aortic Aneurysm, Abdominal / Q000000981:diagnostic imaging / Q000378:metabolism*; D007611:Aprotinin / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005338:Fibrin Fibrinogen Degradation Products / Q000032:analysis / Q000235:genetics; D005341:Fibrinolysin / Q000032:analysis / Q000235:genetics; D005343:Fibrinolytic Agents / Q000032:analysis*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D010958:Plasminogen / Q000032:analysis / Q000235:genetics; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D011877:Radionuclide Imaging; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013927:Thrombosis / Q000000981:diagnostic imaging / Q000378:metabolism*; D010959:Tissue Plasminogen Activator / Q000032:analysis / Q000235:genetics; D014568:Urokinase-Type Plasminogen Activator / Q000032:analysis / Q000235:genetics; D000979:alpha-2-Antiplasmin / Q000032:analysis / Q000235:genetics
D005338:Fibrin Fibrinogen Degradation Products; D005343:Fibrinolytic Agents; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D000979:alpha-2-Antiplasmin; C036309:fibrin fragment D; D010958:Plasminogen; D007611:Aprotinin; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator