Analysis of intraarticular fibrinolytic pathways in patients with inflammatory and noninflammatory joint diseases.
OBJECTIVE
Intraarticular activation of the fibrinolytic system has been suspected to occur in patients with arthritis. We undertook the present study to investigate the relation of this activation to clinical symptoms, and the molecular pathways involved.


METHODS
We quantitatively assessed levels of plasmin-alpha 2-antiplasmin (PAP) complexes in synovial fluid (SF) from 25 patients with rheumatoid arthritis (RA), 7 with seronegative spondylarthropathy (SSA), and 10 with osteoarthritis (OA), and conducted an analysis to determine the plasminogen-activating pathway via which these complexes were generated. In addition, we studied the relationship of intraarticular fibrinolysis to clinical and biochemical parameters.


RESULTS
All patients studied had increased SF levels of PAP complexes. Levels in patients with RA and SSA were slightly higher than those in patients with OA. These complexes were probably formed by activation of urokinase-type plasminogen activator (u-PA), and not tissue-type plasminogen activator (t-PA), since SF levels of both u-PA antigen and u-PA-plasminogen activator inhibitor (PAI) complexes were increased in 27 of the 42 patients. Conversely, SF levels of t-PA were below normal in all but 1 patient. In some patients, activation of factor XII presumably also contributed to plasminogen activation in SF, since levels of factor XIIa-C1 inhibitor in SF were increased in 8 of the 42 patients and correlated, as did u-PA-PAI levels, with levels of PAP complexes. Several of the parameters of fibrinolysis in SF, particularly u-PA antigen and u-PA-PAI-1 complexes, were found to correlate with clinical and biochemical parameters.


CONCLUSIONS
Our results suggest that plasminogen is frequently activated in the joints of patients with inflammatory or noninflammatory arthropathy and that this activation mainly occurs via a u-PA-, and in some cases also via a factor XII-, dependent pathway. The possible relation of this activation process to stimulation of synovial cells by cytokines is discussed.
Kummer
J A
JA
Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, Amsterdam.
Abbink
J J
JJ
de Boer
J P
JP
Roem
D
D
Nieuwenhuys
E J
EJ
Kamp
A M
AM
Swaak
T J
TJ
Hack
C E
CE
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000503:physiopathology*; D002358:Cartilage, Articular / Q000503:physiopathology*; D004591:Electrophoresis, Polyacrylamide Gel; D005174:Factor XII / Q000502:physiology; D005260:Female; D005341:Fibrinolysin / Q000032:analysis; D005342:Fibrinolysis / Q000502:physiology*; D006801:Humans; D007592:Joint Diseases / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D010003:Osteoarthritis / Q000097:blood / Q000503:physiopathology*; D015849:Plasminogen Inactivators / Q000032:analysis / Q000378:metabolism; D013167:Spondylitis, Ankylosing / Q000097:blood / Q000503:physiopathology*; D013582:Synovial Fluid / Q000737:chemistry; D013942:Thymine Nucleotides / Q000032:analysis; D014568:Urokinase-Type Plasminogen Activator / Q000032:analysis / Q000378:metabolism / Q000502:physiology; D000511:alpha-Macroglobulins / Q000032:analysis
D015849:Plasminogen Inactivators; D013942:Thymine Nucleotides; D000511:alpha-Macroglobulins; C024668:plasmin-alpha(2)-macroglobulin complex; D005174:Factor XII; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator; C024157:thymidine 5'-triphosphate