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  • 1
    Online Resource
    Online Resource
    Georg Thieme Verlag KG ; 2013
    In:  Thrombosis and Haemostasis Vol. 110, No. 07 ( 2013), p. 173-183
    In: Thrombosis and Haemostasis, Georg Thieme Verlag KG, Vol. 110, No. 07 ( 2013), p. 173-183
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 0340-6245 , 2567-689X
    Language: English
    Publisher: Georg Thieme Verlag KG
    Publication Date: 2013
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  • 2
    In: Thrombosis and Haemostasis, Georg Thieme Verlag KG, Vol. 120, No. 07 ( 2020-07), p. 1056-1065
    Abstract: Background von Willebrand factor (VWF) is crucial for optimal dosing of factor VIII (FVIII) concentrate in hemophilia A patients as it protects FVIII from premature clearance. To date, it is unknown how VWF behaves and what its impact is on FVIII clearance in the perioperative setting. Aim To investigate VWF kinetics (VWF antigen [VWF:Ag]), VWF glycoprotein Ib binding (VWF:GPIbM), and VWF propeptide (VWFpp) in severe and moderate perioperative hemophilia A patients included in the randomized controlled perioperative OPTI-CLOT trial. Methods Linear mixed effects modeling was applied to analyze VWF kinetics. One-way and two-way analyses of variance were used to investigate perioperative VWFpp/VWF:Ag ratios and associations with surgical bleeding. Results Fifty-nine patients with median age of 48.8 years (interquartile range: 34.8–60.0) were included. VWF:Ag and VWF:GPIbM increased significantly postoperatively. Blood type non-O or medium risk surgery were associated with higher VWF:Ag and VWF:GPIbM levels compared with blood type O and low risk surgery. VWFpp/VWF:Ag was significantly higher immediately after surgery than 32 to 57 hours after surgery (p  〈  0.001). Lowest VWF:Ag quartile (0.43–0.92 IU/mL) was associated with an increase of FVIII concentrate clearance of 26 mL/h (95% confidence interval: 2–50 mL/h) compared with highest VWF antigen quartile (1.70–3.84 IU/mL). VWF levels were not associated with perioperative bleeding F(4,227) = 0.54, p = 0.710. Conclusion VWF:Ag and VWF:GPIbM levels increase postoperatively, most significantly in patients with blood type non-O or medium risk surgery. Lower VWF antigen levels did not lead to clinically relevant higher FVIII clearance. VWF:Ag or VWF:GPIbM levels were not associated with perioperative hemorrhage.
    Type of Medium: Online Resource
    ISSN: 0340-6245 , 2567-689X
    Language: English
    Publisher: Georg Thieme Verlag KG
    Publication Date: 2020
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  • 3
    Online Resource
    Online Resource
    Georg Thieme Verlag KG ; 2014
    In:  Thrombosis and Haemostasis Vol. 112, No. 11 ( 2014), p. 1044-1050
    In: Thrombosis and Haemostasis, Georg Thieme Verlag KG, Vol. 112, No. 11 ( 2014), p. 1044-1050
    Abstract: Joint bleeds in haemophilia result in iron-mediated synovitis and cartilage damage. It was evaluated whether deferasirox, an iron chelator, was able to limit the development of haemophilic synovitis and cartilage damage. Haemophilic mice were randomly assigned to oral treatment with deferasirox (30 mg/kg) or its vehicle (control) (30 mg/kg). Eight weeks after start of treatment, haemarthrosis was induced. After another five weeks of treatment, blood-induced synovitis and cartilage damage were determined. Treatment with deferasirox resulted in a statistically significant (p 〈 0.01) decrease in plasma ferritin levels as compared to the control group (823 ng/ml ± 56 and 1220 ng/ml ±114, respectively). Signs of haemophilic synovitis, as assessed by the Valentino score [range 0 (normal) – 10 (most affected)], were not different (p=0.52) when comparing the control group with the deferasirox group. However, deferasirox treatment resulted in a statistically significant (p 〈 0.01) reduction in cartilage damage, as assessed by the loss in Safranin O staining [range 0 (normal) – 6 (most affected)], when comparing the deferasirox group with the control group: score 2 (65.4 % vs 4.2 %), score 3 (26.9 % vs 4.2 %), score 4 (7.7 % vs 20.8 %), score 5 (0 % vs 54.2 %), and score 6 (0 % vs 16.7 %). Treatment with deferasirox limits cartilage damage following the induction of a haemarthrosis in haemophilic mice. This study demonstrates the role of iron in blood-induced cartilage damage. Moreover, these data indicate that iron chelation may be a potential prevention option to limit the development of haemophilic arthropathy.
    Type of Medium: Online Resource
    ISSN: 0340-6245 , 2567-689X
    Language: English
    Publisher: Georg Thieme Verlag KG
    Publication Date: 2014
    Location Call Number Limitation Availability
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