The search for replacements for unfractionated heparin.

Abstract

Antithrombotic therapy is central to the management of patients presenting with an acute coronary syndrome (ACS). In addition to powerful new antiplatelet therapies, multiple agents capable of inhibiting thrombin are now available to clinicians (Figure⇓). Figure 1. Activated coagulation cascade and platelet aggregation in patients with an ACS. A, With disruption of a vulnerable plaque, tissue factor (TF) is exposed and ultimately complexes with activated factor VII (VIIa). TF:VIIa complex converts factor X to its active form (Xa). Through a multiplier effect, a single molecule of factor Xa leads to downstream production of many molecules of thrombin through its participation in prothrombinase complex along with factor V and calcium (Ca++) on a phospholipid surface, such as membrane of activated platelets (Plt). Thrombin is a potent agonist for platelet activation via binding to thrombin receptor on platelets. Aggregates of platelets are formed by cross-bridging via attachments of ligands such as fibrinogen (FGN) to the GP IIb/IIIa receptors on adjacent platelets. B, Sites of action of antithrombin and antiplatelet agents. Relative strength of actions at various positions is shown semiquantitatively by size of font in diagram. Thus, UFH has similar inhibitory action against thrombin and factor Xa, whereas LMWH has greater relative inhibitory capacity against factor Xa than thrombin. Direct antithrombins have little effect on generation of thrombin but are potent inhibitors of thrombin that has been formed. In contrast, TFPI and related compounds act more proximally in coagulation cascade to inhibit formation of factor Xa and limit downstream production of thrombin. Combinations of antithrombins shown and antiplatelet agents (bottom of diagram) are effective in reducing propensity to thrombus formation at the site of a disrupted vulnerable plaque. Although familiar to the vast majority of clinicians, unfractionated heparin (UFH) has the disadvantages of a variable anticoagulant effect (necessitating frequent monitoring of …