Researchers characterized a mechanism for factor VIIa (FVIIa) treatment of patients with hemophilia involving the release of extracellular vesicles (EVs) that contain components that may contribute to hemostatic response separate from platelet activity. Results of this study were reported in the Journal of Thrombosis and Haemostasis.

The researchers had previously found that FVIIa bound to a receptor called the endothelial cell protein C receptor led to release of EVs, which contributed to the correcting of bleeding in mice that were platelet depleted or had hemophilia. They also reported that this occurred without systemic activation of coagulation processes.

“To determine the relevance of FVIIa-released EVs in the treatment of hemophilia and pathophysiology, it is important to obtain proof that FVIIa treatment increases circulating EVs in human subjects,” the authors wrote.

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This study sought to address the need for evidence of the release of EVs with FVIIa treatment. They received plasma samples from 10 patients with severe hemophilia who were being treated with recombinant FVIIa (rFVIIa) and from whom preinfusion plasma was also available for analysis. Additionally, they analyzed pre- and postinfusion samples from 9 patients with severe factor VIII deficiency being treated with recombinant factor VIII (rFVIII), and from another 3 patients with severe hemophilia who were receiving rFVIIa treatment. The researchers quantified EVs in plasma samples collected at various time points from these patients using nanoparticle tracking analysis. Plasma samples from healthy volunteers were also noted to be included in some analyses.

In patients with hemophilia receiving rFVIIa, compared with preinfusion plasma and plasma of healthy volunteers, the abundance of EVs was higher after treatment with rFVIIa. Contrarily, in patients receiving rFVIII, EV abundance did not increase after treatment with rFVIII.

The researchers also examined isolated EVs and found an endothelial marker called VE-cadherin was more abundant in postinfusion EV samples from patients treated with rFVIIa, compared with preinfusion levels. This suggested that the EVs originated from endothelial cells. The researchers did not find a difference in VE-cadherin levels in patients treated with rFVIII. 

Further exploration of the contents of EVs following rFVIIa infusion revealed that they contained components with the apparent capacity to provide anti-inflammatory and barrier-protective effects in cells. Postinfusion EVs that were taken up by human monocyte-derived macrophages appeared to confer anti-inflammatory effects. Uptake of postinfusion EVs by endothelial cells appeared to result in a decrease in endothelial barrier disruption.

“The present information may stimulate further research on the analysis of FVIIa-released EVs in patients and their potential significance in the treatment of bleeding disorders of hemophilia patients and other groups, and off-label use of rFVIIa,” the researchers concluded.

Disclosures: Some authors have declared affiliations with or received grant support from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.


Das K, Pendurthi UR, Manco-Johnson M, Martin EJ, Brophy DF, Rao LVM. Factor VIIa treatment increases circulating extracellular vesicles in hemophilia patients: implications for the therapeutic hemostatic effect of FVIIa. J Thromb Haemost. Published online May 24, 2022. doi:10.1111/jth.15768