Defibrotide blunts the prothrombotic effect of thalidomide on endothelial cells

Area of Science:

• Hematology
• Pharmacology
• Cell Biology

Background:

• Multiple myeloma (MM) patients face elevated risks of thromboembolic events, such as deep venous thrombosis (DVT).
• Thalidomide therapy, commonly used for MM, is known to exacerbate this risk.
• Endothelial cells (ECs) play a crucial role in regulating hemostasis and are affected by these therapies.

Purpose of the Study:

• To investigate the effects of thalidomide on ECs, specifically concerning fibrinolysis.
• To determine if Defibrotide (DF) can modulate thalidomide-induced changes in ECs.
• To assess DF's protective effects on ECs against thalidomide-induced damage.

Main Methods:

• In vitro study using endothelial cells.
• Assessed changes in tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) levels.
• Evaluated gene expression of t-PA and PAI-1.
• Monitored EC viability and potential interference with antitumor effects.

Main Results:

• MM and thalidomide alter ECs' profibrinolytic potential, decreasing t-PA and increasing PAI-1.
• Defibrotide counteracted these thalidomide-induced changes.
• DF upregulated t-PA and downregulated PAI-1 gene expression.
• DF protected ECs from thalidomide-mediated cell death without compromising antitumor effects.

Conclusions:

• Defibrotide effectively counteracts the prothrombotic changes in ECs induced by thalidomide.
• DF demonstrates potential as a protective agent against DVT in patients treated with immunomodulatory drugs.
• These findings support the clinical investigation of DF for DVT prevention in MM patients.