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Deficient fibrinolytic response in patients with Raynaud's phenomenon and its correction with defibrotide
C Cimminiello1, M Milani, A Pietra
1Center of Vascular and Thrombotic Diseases, Hospital S. Carlo, Milano, Italy.
Abstract:
Twenty outpatients presenting with Raynaud's phenomenon secondary to clinical or preclinical inflammation of connective tissue were treated orally with defibrotide 400 mg three times daily or a matching placebo in a randomized double-blind study. The test product defibrotide (a polydeoxyribonucleic acid compound of animal origin with demonstrated profibrinolytic activity when administered parenterally) was administered orally for 3 weeks in order to explore its effects on the parameters of extrinsic fibrinolysis before and after venous stasis. The antigen of t-PA and its inhibitor PAI, free and total, and the biologic activity of PAI were assayed in basal conditions and after treatment. Although a marked increase of t-PA was seen with the active treatment, PAI activity was significantly reduced by defibrotide. Immunoreactive PAI was not significantly modified by treatment, even though it dropped considerably after venous stasis in the defibrotide group. Thus, the disturbance of endothelial function that seems to occur in vasculitis and in Raynaud's phenomenon secondary to inflammation of connective tissue (or so suspected to be) would constitute the basis of a disturbance of fibrinolysis, which oral defibrotide seems able to correct. Further studies are warranted to define the clinical effectiveness of this treatment in patients with Raynaud's phenomenon.
Insights
Oral defibrotide improved fibrinolysis in patients with Raynaud's phenomenon. This study suggests defibrotide may correct fibrinolysis disturbances linked to connective tissue inflammation.
Area of Science:
- Pharmacology
- Hematology
- Rheumatology
Background:
- Raynaud's phenomenon is often secondary to connective tissue inflammation.
- Endothelial dysfunction and fibrinolysis disturbances are suspected in these cases.
Purpose of the Study:
- To evaluate the effect of oral defibrotide on extrinsic fibrinolysis in Raynaud's phenomenon patients.
- To assess changes in tissue plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI) levels.
Main Methods:
- A randomized, double-blind, placebo-controlled study.
- Twenty outpatients received oral defibrotide (400 mg TID) or placebo for 3 weeks.
- Assays for t-PA antigen, PAI antigen and activity were performed before and after treatment and venous stasis.
Main Results:
- Defibrotide significantly reduced PAI activity.
- A marked increase in t-PA was observed with active treatment.
- Immunoreactive PAI was not significantly altered, but decreased post-venous stasis in the defibrotide group.
Conclusions:
- Oral defibrotide appears to correct fibrinolysis disturbances in Raynaud's phenomenon.
- Further research is needed to confirm clinical efficacy in Raynaud's phenomenon patients.