ABSTRACT
Unfractionated heparin has enjoyed the sole anticoagulant status for almost half a
century. Besides an effective anticoagulant, this drug has been used in several additional
indications. Despite the development of newer anticoagulant drugs, unfractionated
heparin has remained the drug of choice for surgical anticoagulation and interventional
cardiology. In the area of hematology and transfusion medicine, unfractionated heparin
has continued to play a major role as an anticoagulant drug. The development of low-molecular-weight
heparins (LMWHs) represents a refinement for the use of heparin. These drugs represent
a class of depolymerized heparin derivatives with a distinct pharmacologic profile
that is largely determined by their composition. These drugs produce their major effects
by combining with antithrombin and exerting antithrombin and anti-Xa inhibition. In
addition, the LMWHs also increase non-antithrombin-dependent effects such as TFPI
release, modulation of adhesion molecules, and release of profibrinolytic and antithrombotic
mediators from the blood vessels. The cumulative effects of each of the different
LMWHs differ and each product exhibits a distinct profile. Initially these agents
were developed for the prophylaxis of postsurgical deep-vein thrombosis. However,
at this time these drugs are used not only for prophylaxis, but also for the treatment
of thrombotic disorders of both the venous and arterial type. To a large extent, the
LMWHs have replaced unfractionated heparin in most subcutaneous indications. With
the use of these refined heparins, outpatient anticoagulant management has gone through
a dramatic evolution. For the first time, patients with thrombotic disorders can be
treated in an outpatient setting. Thus, the introduction of LMWHs represents a major
advance in improving the use of heparin. The development of the oral formulation of
heparin and LMWHs also provides an important area that may impact on the use of heparin
and LMWHs. The increased awareness of heparin-induced thrombocytopenia has necessitated
the development of newer methods to identify patients at risk of developing this catastrophic
syndrome. Furthermore, a strong interest has developed in alternate drugs or the management
of patients with this syndrome. Despite the development of alternate anticoagulants
that are mostly antithrombin derived (hirudins, hirulog), these agents have failed
to provide similar clinical outcome as heparin in many indications. However, antithrombin
drugs are useful in the anticoagulant management of heparin-compromised patients.
The FDA has approved a recombinant hirudin (Refludan℗) and a synthetic antithrombin agent, argatroban (Novastan℗), for this indication. The development of synthetic heparin pentasaccharide and anti-Xa
agents may have an impact on the prophylaxis of thrombotic disorders. However, these
monotherapeutic agents do not mimic the polytherapeutic actions of heparin. Furthermore,
these agents do not inhibit thrombin. Heparin and LMWHs are capable of inhibiting
not only factor Xa and thrombin, but other serine proteases in the coagulation network.
The only way the newer drugs can mimic the actions of heparin is in combination modalities
(polytherapeutic approaches).
It has been suggested that newer antiplatelet drugs also exhibit anticoagulant actions.
While these drugs may exhibit weak effects on thrombin generation, none of the currently
available antiplatelet drugs exhibit any degree of antithrombin actions. It is likely
that heparins synergize or augment the effects of the new antiplatelet drugs. Currently,
combination approaches are used to anticoagulate patients in these studies. The dosage
of heparins has been arbitrarily reduced. This may not be an optimal procedure. Additional
clinical studies are needed to study these combinations where the alterations of these
drugs are compared. Such combinations will require newer monitoring approaches. The
development of oral thrombin agents, GP IIb/IIIa inhibitors, has met with some significant
obstacles. Thus, it is unlikely that this approach will be very feasible in the indications
where heparins are used. It is fair to state that heparins will continue to play a
major role in the overall management of thrombotic disorders in monotherapeutic and
polytherapeutic modalities.
KEYWORD
Heparin - LMW heparin - heparinomimetics - pentasaccharide - tissue factor pathway
inhibitor
