Rationale for Exploring Treatment of HIT with New Anticoagulants

HIT is a marked hypercoagulability state with a high risk of venous and arterial thrombosis (see Chapter 2). In most patients with suspected or proven HIT, there is a need for rapidly acting and effective anticoagulation with an alternative non-heparin anticoagulant. In this chapter, the potential role of emerging, novel anticoagulants on the treatment of HIT will be explored. The mechanistic, pharmacologic, and clinical data of agents newly licensed or in a late-stage of clinical development will be summarized. Particular attention will be given to the pentasaccharide anticoagulant, fondaparinux, which has been used for the "off-label" treatment of HIT in a small number of patients.

Contact Pathway Tissue Factor Pathway

Contact Pathway Tissue Factor Pathway

FIGURE 1 Blood coagulation is initiated when factor VII(a) is exposed to membrane-bound TF. The TF/VII(a) complexes activate factor IX (to IXa) and factor X (to Xa), leading ultimately to the formation of thrombin (IIa). Amplification of the process occurs when trace amounts of thrombin formed during the initiation of coagulation activate factor XI (to XIa), and the cofactors, VIII and V, to VIIIa and Va, respectively, in a series of positive feedback loops (denoted by dashed [----] lines), resulting in the formation of the VIIIa/IXa ("tenase") and the Va/Xa ("prothrombinase") complexes, and the generation of large amounts of thrombin, and the formation of a fibrin clot. Thrombin also exerts an inhibitory effect on coagulation by a negative feedback loop (denoted by dotted [—] lines) that involves activation of the protein C anticoagulant pathway, resulting in degradation of factors Va and VIIIa. Anticoagulant drugs that inhibit factor Xa reduce the amount of thrombin formed. Anticoagulant drugs that inhibit IIa reduce thrombin activity and thus reduce (1) fibrin clot formation, (2) positive feedback amplification of thrombin generation (including contact activation that occurs when blood is exposed to foreign surfaces), and (3) negative feedback via the protein C pathway. Abbreviations: APC, activated protein C; TF, tissue factor; TAFI, thrombin activatable fibrinolysis inhibitor.

FIGURE 1 Blood coagulation is initiated when factor VII(a) is exposed to membrane-bound TF. The TF/VII(a) complexes activate factor IX (to IXa) and factor X (to Xa), leading ultimately to the formation of thrombin (IIa). Amplification of the process occurs when trace amounts of thrombin formed during the initiation of coagulation activate factor XI (to XIa), and the cofactors, VIII and V, to VIIIa and Va, respectively, in a series of positive feedback loops (denoted by dashed [----] lines), resulting in the formation of the VIIIa/IXa ("tenase") and the Va/Xa ("prothrombinase") complexes, and the generation of large amounts of thrombin, and the formation of a fibrin clot. Thrombin also exerts an inhibitory effect on coagulation by a negative feedback loop (denoted by dotted [—] lines) that involves activation of the protein C anticoagulant pathway, resulting in degradation of factors Va and VIIIa. Anticoagulant drugs that inhibit factor Xa reduce the amount of thrombin formed. Anticoagulant drugs that inhibit IIa reduce thrombin activity and thus reduce (1) fibrin clot formation, (2) positive feedback amplification of thrombin generation (including contact activation that occurs when blood is exposed to foreign surfaces), and (3) negative feedback via the protein C pathway. Abbreviations: APC, activated protein C; TF, tissue factor; TAFI, thrombin activatable fibrinolysis inhibitor.

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