Targeting novel protein may improve thrombolysis
MedWire News: French researchers suggest that protease nexin-1 (PN-1) may be an important regulator of thrombolysis.
Inhibition of the platelet component PN-1 by antibodies or synthetic compounds may improve the therapeutic efficacy of thrombolytic agents, they say.
PN-1, also known as SERPINE2, is serum protease inhibitor that accumulates at vascular injury sites and inhibits urokinase plasminogen activator, tissue plasminogen activator (tPA), plasmin, and thrombin, explain Marie-Christine Bouton (CHU Xavier Bichat, Paris) and colleagues.
Because of its action on plasma proteases, Bouton and team hypothesized that PN-1 may play a prominent role in thrombolysis resistance.
To investigate, the researchers carried out a series of in vitro and in vivo studies. They demonstrate that PN-1 inhibits plasmin generation by fibrin-bound tPA, and fibrinolysis induced by fibrin-bound plasmin.
They also found that that in the absence of PN-1, endogenous tPA-induced clot lysis increased within 24 hours, indicating that PN-1 is a regulator of endogenous clot lysis.
To determine whether the antifibrinolytic effect of PN-1 also occurs in vivo, Bouton and team developed a microscopy-based method to measure thrombolysis in mice.
First they used FeCl3 to induce vascular injury and thrombosis in the mice. They then treated wild-type (WT) and PN-1 deficient (PN-1-/-) mice with tPA to induce thrombolysis.
The team observed that the mean time to recanalization was longer than 1 hour in the WT mice but only 13 minutes in the PN-1-/-animals. Furthermore, only 15% of WT mice exhibited complete recanalization compared with 92% of PN-1-/-mice.
Thirty minutes after tPA treatment, thrombus size remained unchanged in WT mice (101.6% of initial size), but fell significantly in the PN-1-/-mice (56.1% of initial size).
"Considered together, these results confirm that PN-1 is a potent inhibitor of tPA-induced thrombolysis in vivo," write Bouton and co-authors in the journal Circulation.
Therefore, "inhibition of PN-1 is predicted to promote endogenous and exogenous tPA-mediated fibrinolysis and may enhance the therapeutic efficacy of thrombolytic agents," they conclude.
MedWire (www.medwire-news.md) is an independent clinical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2011
By Laura Dean