1697P - Semuloparin efficiently inhibits thrombin generation triggered by pancreas adenocarcinoma cells BXPC3. Distinct roles of anti-XA and anti-IIA activity

Date 30 September 2012
Event ESMO Congress 2012
Session Poster presentation II
Topics Basic Science
Hepatobiliary Cancers
Presenter Grigoris Gerotziafas
Authors G. Gerotziafas1, M.P. Roman1, E. Mdemba1, M. Hatmi1, J. Fareed2, J.F. Bernaudin1, I. Elalamy1
  • 1Er2upmc, Faculty of Medicin, Université Pierre et Marie Curie (Paris VI), 75020 - Paris/FR
  • 2Pathology, Loyola University Medical Center, Maywood/US

Abstract

Background

Venous thromboembolism (VTE) is a common complication in patients with cancer receiving chemotherapy. Currently no anticoagulant is approved for VTE prophylaxis in this setting. Semuloparin is an ultra-LMWH generated through a highly selective depolymerization of heparin which protects the antithrombin (AT) binding site in order to improve the benefit/risk ratio compared to existing anitcoagulants.

Aims

We studied in vitro the mechanism of action of semuloparin on the inhibition of thrombin generation (TG) of human platelet poor plasma (PPP) triggered by human pancreatic cancer cells BXPC3. We compared the antithrombotic efficiency of semuloparin to that of enoxaparin and the specific AT-dependent factor Xa inhibitor fondaparinux.

Materials and methods

BXPC3 cells were suspended in PPP spiked with clinically relevant concentrations of semuloparin, enoxaparin and fondaparinux. The endogenous thrombin potential (ETP) and the mean rate index (MRI) of the propagation phase of TG were monitored with the CAT assay (Stago France) as described previously (Gerotziafas et al Thromb Res 2011). Anti-Xa and anti-IIa specific activities were assessed assays obtained from Diagnostica Stago.

Results

Both semuloparin and enoxaparin, at the concentration of 0.4 anti-Xa IU/ml, completely abrogated TG. Total inhibition of TG occured in the presence of 0.002 anti-IIa IU/ml of semuloparin and 0.05 anti-IIa IU/ml of enoxaparin. Fondaparinux, even at concentrations higher than 2 µg/ml, reduced the MRI but did not significantly affect the ETP and did not completely inhibited TG,. The IC50 for the ETP of the anti-IIa activity of enoxaparin was 37-fold higher as compared to that of semuloparin.

Conclusion

In a cancer cell model of hypercoagulability, semuloparin reduced efficiently thrombin generation. The unique anticoagulant profile of semuloparin based on its high AT-affinity differentiates it from enoxaparin and fondaparinux. The residual anti-IIa activity of semuloparin amplifies its antithrombotic efficacy. This profile is expected to translate into an improved benefit/risk ratio.

Disclosure

All authors have declared no conflicts of interest.