Arg506 to Gln mutation in the factor V gene causes poor fibrinolytic response in children after venous occlusion
Related Experiment Videos
U Nowak-Göttl1, M Binder, A Dübbers
1Department of Paediatrics, University Hospital Münster, Germany.
Insights
The factor V gene mutation impairs fibrinolysis in children, leading to reduced tissue plasminogen activator (t-PA) activity and increased plasminogen activator inhibitor-1 (PAI-1) levels, particularly in symptomatic carriers.
Area of Science:
- Hematology
- Genetics
- Molecular Biology
Background:
- The Arg506 to Gln mutation in the factor V gene is a common cause of activated protein C (APC) resistance.
- APC resistance is a risk factor for venous thromboembolism.
- The impact of this mutation on the fibrinolytic system is not fully understood.
Purpose of the Study:
- To investigate the influence of the Arg506 to Gln factor V gene mutation on fibrinolytic response after venous occlusion (VO).
- To compare fibrinolytic parameters between APC resistant children and healthy controls.
Main Methods:
- Studied 60 children with APC resistance (30 symptomatic, 30 asymptomatic) and 25 healthy controls.
- Measured tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) activity and antigen levels before and after 20 minutes of venous occlusion (VO).
Main Results:
- Symptomatic carriers exhibited significantly reduced t-PA activity post-VO compared to asymptomatic carriers and controls (p <0.0001).
- PAI-1 activity was significantly higher in children with the factor V mutation before and after VO (p <0.0001).
- APC resistant children showed lower PAI-1 antigen decrease and t-PA antigen release post-VO compared to controls.
Conclusions:
- The factor V gene mutation may induce fibrinolytic impairment by increasing thrombin levels, subsequently elevating thrombin-activable fibrinolysis inhibitor (TAFI).
- Reduced t-PA activity post-VO in symptomatic carriers highlights a potential mechanism for thrombophilia associated with this mutation.
Abstract:
To determine to what extent the Arg506 to Gln mutation in the factor V gene influences the fibrinolytic response after 20 min venous occlusion (VO) we investigated a population of APC resistant children (n = 60) and a group of age-matched healthy controls (n = 25). After 20 min VO, symptomatic (n = 30) carriers of the common factor V mutation showed significantly reduced t-PA activities compared with asymptomatic (n = 30) carriers (p <0.0001) and healthy controls (p <0.0001). In contrast, PAI 1 activity was significantly (p <0.0001) higher before and after VO in children with the factor V mutation compared with healthy children. No difference was found between symptomatic and asymptomatic probands. A significantly lower PAI 1 antigen decrease along with a lower t-PA antigen release was found in the APC resistant children compared with the controls. No significant difference was seen between individuals with and without previous vascular insults. As the lack of t-PA activity after VO in symptomatic carriers is the most conspicuous result, we suggest that the factor V gene mutation itself might induce the fibrinolytic impairment by increasing the thrombin levels and thus increasing the recently described thrombin-activable fibrinolysis inhibitor (TAFI).