Thromb Haemost 2013; 110(01): 173-183
DOI: 10.1160/TH13-01-0080
Animal Models
Schattauer GmbH

Haemarthrosis stimulates the synovial fibrinolytic system in haemophilic mice

Laurens Nieuwenhuizen
1   Rheumatology & Clinical Immunology, University Medical Center, Utrecht, The Netherlands
2   Haematology & Van Creveldkliniek, University Medical Center, Utrecht, The Netherlands
,
Goris Roosendaal
2   Haematology & Van Creveldkliniek, University Medical Center, Utrecht, The Netherlands
,
Katja Coeleveld
1   Rheumatology & Clinical Immunology, University Medical Center, Utrecht, The Netherlands
,
Erik Lubberts
3   Rheumatology and Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
,
Douwe H. Biesma
2   Haematology & Van Creveldkliniek, University Medical Center, Utrecht, The Netherlands
,
Floris P. J. G. Lafeber
1   Rheumatology & Clinical Immunology, University Medical Center, Utrecht, The Netherlands
,
Roger E. G. Schutgens
2   Haematology & Van Creveldkliniek, University Medical Center, Utrecht, The Netherlands
› Author Affiliations

Financial support: This study was supported by an unrestricted grant from Novo Nordisk.
Further Information

Publication History

Received: 31 January 2013

Accepted after minor revision: 21 April 2013

Publication Date:
30 November 2017 (online)

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Summary

Recurrent joint bleeding is the most common manifestation of haemophilia resulting in haemophilic arthropathy (HA). The exact pathophysiology is unknown, but it is suggested that arthropathy is stimulated by liberation of fibrinolytic activators from the synovium during haemarthrosis. The aim of this study was to test the hypothesis that haemarthrosis activates the local synovial fibrinolytic system in a murine haemophilia model. The right knees of haemophilic and control mice were punctured to induce haemarthrosis. The left knees served as internal control joints. Synovial levels of urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor 1 (PAI-1), plasmin, and alpha-2-antiplasmin (A2AP) were compared between the punctured and control knees. In haemophilic mice, an increase in synovial cells expressing urokinase-type plasminogen activator (uPA) in the right punctured knee versus the left unaffected knee was observed: (47% vs 43%) (p=0.03). Additionally, in haemophilic mice, haemar-throsis induced an increase in uPA (0.016 ng/ml vs 0.01 ng/ml) (p=0.03) and plasmin (0.53 μg/ml vs 0.46 μg/ml) (p=0.01) as promoters of fibrinolysis. Synovial levels of PAI-1 (0.32 ng/ml vs 0.17 ng/ ml) (p<0.01) was also increased, whereas synovial levels of A2AP were unchanged: (0.021 μg/ml vs 0.021 μg/ml) (p=0.15). Enhanced uPA production was confirmed in human stimulated synovial fibroblast cultures and elevated levels of plasmin were confirmed harmful to human cartilage tissue explants. In this study we demonstrate that haemarthrosis in haemophilic mice induces synovial uPA expression and results in an increase in synovial plasmin levels, making the joint more vulnerable to prolonged and subsequent bleedings, and adding directly to cartilage damage.