Low-molecular-weight heparins (
LMWH) exhibit potent
anticoagulant efficacy via their plasmatic effects on
thrombin and
factor Xa. These agents are also effective in releasing endothelial
tissue factor pathway inhibitor (
TFPI), the natural inhibitor of
tissue factor, and exhibit significant anti-metastatic effects in experimental animal models. However, the potential for
bleeding complications has slowed down the more widespread adoption of
LMWH therapy in
cancer patients. In this study, the effect of a non-
anticoagulant form of
LMWH (
NA-LMWH) on experimental lung
metastasis and
tumor cell-induced platelet aggregation in vivo was compared to the
LMWH enoxaparin. Using the
B16 melanoma mouse model of
metastasis, subcutaneous (s.c.) injection of
NA-LMWH or
enoxaparin (10 mg/kg), three hours before intravenous (i.v.) injection of metastatic
melanoma cells, followed by daily doses for 14 days, reduced lung
tumor formation by 70% (P < 0.001). I.v. injection of
tumor cells resulted in a significant (50-62%, P < 0.01) fall in platelet counts. Pre-injection (i.v.) of
enoxaparin completely abolished the
tumor cell-induced
thrombocytopenia, whereas
NA-LMWH had no effect. Four hours after a single s.c. dose,
enoxaparin but not
NA-LMWH prolonged the clotting time three-fold and delayed the time to clot initiation more than 10-fold as measured by a Sonoclot analyzer and by thromboelastography, respectively.
Enoxaparin but not
NA-LMWH demonstrated a significant
anticoagulant effect in mice. Both
NA-LMWH and
enoxaparin caused similar
TFPI release from endothelial cells in vitro. These data provide evidence to support the potential of
NA-LMWH as an anti-metastatic agent without any significant impact on coagulation.