Medical needs associated with diverse thromboembolic conditions are not fully met by currently available
anticoagulants. Of those,
unfractionated heparin (UFH) is gradually replaced by
low molecular weight heparin (
LMWH) for prevention and treatment of
venous thromboembolism and
acute coronary syndromes, along with supportive treatment with oral
anticoagulants, such as
warfarin derivatives. While generally effective these agents have several shortcomings involving compliance, delivery, efficacy and safety considerations in various disease settings, and for these reasons new
anticoagulants are sought, to target more specifically the critical effectors and steps in the blood coagulation process, namely: (i) initiation, (ii) propagation and (iii) the phase of
thrombin activity. The emerging agents that block
tissue factor/
factor VIIa-dependent initiation phase of the coagulation cascade, include: recombinant
tissue factor pathway inhibitor (rTFPI), nematode
anticoagulant peptide (NAPc2), active site-blocked
factor VIIa (FVIIai) and TF targeting
antibodies. Some of them are currently evaluated in clinical trials with promising results. Propagation phase of
thrombus formation (e.g. the activity of factors IXa, Xa, VIIIa or Va) is targeted mainly by various indirect, direct and bimodal inhibitors, such as
fondaparinux, indraparinux,
tick anticoagulant peptide (TAP), antistatin (ANT) and
antithrombin-
heparin covalent complex (ATH), all endowed mostly with an anti-Xa activity. Although promising, some of these agents (TAP, ANT and ATH) have not progressed beyond animal testing while others (
fondaparinux) was already assessed for prevention and treatment of
venous thromboembolism and for treatment of arterial
thrombosis. Lastly, inhibitors of
thrombin activity are composed of either indirect (UFH,
LMWH), or direct
thrombin (
FIIa) inhibitors including:
hirudin,
argatroban,
melagatran,
ximelagatran,
dabigatran, and
bivalirudin. These agents are either in advanced development or already approved for clinical use. Bimodal
FIIa inhibitory activity of ATH was demonstrated in animal models of venous and arterial
thrombosis, but is in need of further development. In conclusion, while some of these emerging
anticoagulants, such as
fondaparinux,
idraparinux,
ximelagatran and ATH appear to possess superior efficacy-safety profile, as compared to their conventional predecessors (UFH,
LMWH and
warfarin), their cost-effectiveness, side effects and
antidote availability have to be considered. More importantly,
coagulation factors that are targets of these inhibitory activities also affect coagulation independent processes, such as wound healing,
inflammation, angiogenesis, mitogenesis and cell survival. Thus the consequences of both coagulation-dependent and -independent effects of new agents should be carefully considered before proper clinical indications are established.