Effects of the Synthetic Thrombin Inhibitor Argatroban on Fibrin- or Clot-Incorporated Thrombin: Comparison with Heparin and Recombinant Hirudin

Cn, Berry; Girardot, C; Lecoffre, Catherine; Lunven, Catherine

doi:10.1055/s-0038-1648875

Cited by 166 publications

(98 citation statements)

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“…Direct inhibition promises to offer the important advantage of inhibiting both free and clot-bound thrombin as well as factor Xa present in the prothrombinase complex [63][64][65][66]. Direct inhibitors are also less likely to bind plasma proteins non-specifically, thus offering a more predictable patient response.…”

Section: Current Status Of Anticoagulation Therapymentioning

confidence: 99%

Recent Research Developments in the Direct Inhibition of Coagulation Proteinases – Inhibitors of the Initiation Phase

Henry¹,

Desai²

2008

CHAMC

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Physiologic clotting is a defensive action. The new cell-based model of hemostasis proposes three steps -initiation, amplification and propagation -occurring on specific cell surfaces to generate a thrombus in a tightly regulated manner. The initiation phase relies on key players including tissue factor (TF), factor VIIa (fVIIa), platelets, Ca 2+ , phospholipids, and factor X/Xa (fX/fXa). Exposure of TF on sub-endothelial and other blood cells triggers a coagulation response, which may have to be inhibited to prevent a deleterious thrombotic effect. Inhibiting TF-initiated coagulation, akin to 'nipping coagulation in the bud', is predicted to have major advantages, including a more efficient separation of the antithrombotic and hemorrhagic responses. The availability of crystal structures of TF, fVIIa and TFfVIIa complex makes structure-based drug design feasible. Although no initiation phase small molecule inhibitor has reached the clinic as yet, several molecules have displayed promise. We discuss recent results on the discovery of inhibitors of the initiation phase with special emphasis on peptides, peptidomimetics and organic small molecules.Key Words: Anticoagulants, coagulation, factor VIIa, tissue factor, thrombin, factor Xa, Enzyme Inhibition, small molecule inhibitors. CELL-BASED HEMOSTASISPhysiologic clotting is a defensive action preventing excessive loss of blood and infiltration of microbes. The physiologic mechanism that produces this defensive reaction is an enzymatic cascade ( Fig. 1), proposed nearly 50 years ago [1,2]. In vivo, the enzymatic reactions occur on specific cell surfaces. The cell-dependent coagulation cascade is proposed to proceed sequentially in three stepsinitiation, amplification and propagation -on specific cell surfaces to generate a thrombus in a tightly regulated manner [3][4][5]. InitiationTissue factor (TF) is an integral membrane protein present on several extravascular cells [6] and is the most important initiator of coagulation. Under normal conditions, it is sequestered from circulating proteinases, especially factor VII (fVII), thus preventing inappropriate initiation of clotting. Vascular injury exposes TF to blood, resulting in rapid complex formation with free activated fVII (fVIIa) on TF-bearing cells (Fig. 1). It is believed that some fVIIa is always present in blood (~1-2%), which can rapidly interact with TF to initiate clotting. The formation of TF/fVIIa complex activates the circulating factor X (fX) to fXa, the formation of which can induce further production of fVIIa and fXa [7][8][9]. The TF/fVIIa complex can also activate factor IX (fIX) to fIXa [10][11][12], which in turn can result in more fXa. The earliest fXa formed remains localized to the site of TF-bearing cells, yet is free enough to form the prothrombinase complex with factor Va (fVa). The small amount of the prothrombinase complex so formed is responsible for the initial production of thrombin from prothrombin [12]. The in vivo source of the initial fVa needed for the assembly of p...

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Section: Current Status Of Anticoagulation Therapymentioning

confidence: 99%

Recent Research Developments in the Direct Inhibition of Coagulation Proteinases – Inhibitors of the Initiation Phase

Henry¹,

Desai²

2008

CHAMC

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“…6,7,27 This ability likely reflects size-restricted diffusion of hirudin into intact thrombi because once thrombi are solubilized, hirudin and smaller inhibitors have equivalent activity against bound thrombin. 7 The potential advantages of direct thrombin inhibitors over heparin prompted comparisons of these agents for treatment of acute coronary syndromes.…”

Section: Potential Advantages Of Direct Thrombin Inhibitors Over Heparinmentioning

confidence: 99%

Direct Thrombin Inhibitors in Acute Coronary Syndromes

2002

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M ost acute coronary syndromes are caused by intracoronary thrombus superimposed on disrupted atherosclerotic plaque. Platelets adhere to subendothelial proteins exposed at sites of plaque disruption where they become activated, release vasoactive and procoagulant substances, and aggregate. 1 Tissue factor in the lipid-rich core of the plaque initiates coagulation, which leads to thrombin generation. A potent platelet agonist, thrombin recruits additional platelets to the site of vascular injury. Thrombin also converts fibrinogen to fibrin, which serves to stabilize platelet-rich thrombi formed at sites of plaque disruption. Depending on the extent and duration of coronary artery obstruction, clinical manifestations range from unstable angina to acute myocardial infarction. 1 Aspirin and heparin, the cornerstones of therapy for acute coronary syndromes, reduce the risk of myocardial infarction and death. 2,3 Despite the widespread use of these treatments, however, patients with unstable angina or acute myocardial infarction remain at risk for recurrent ischemic events, suggesting that intracoronary thrombus formation is incompletely attenuated by aspirin and heparin. High concentrations of thrombin are generated by tissue factor exposed at sites of arterial injury. 4 When bound to fibrin, 5,6 fibrin degradation products, 7 or subendothelial matrix, 8 thrombin is resistant to inactivation by the heparin/antithrombin complex. Bound thrombin, which remains enzymatically active, triggers thrombus growth by activating factors V, VIII, and XI, 9 thereby amplifying thrombin generation. Bound thrombin also activates platelets, 10 at least in part, via thromboxane A 2 -independent pathways that are not blocked by aspirin.Because thrombin plays a central role in arterial thrombogenesis, the goal of most treatment regimens is to block thrombin generation or inhibit its activity. Direct thrombin inhibitors were developed to overcome the inability of the heparin/antithrombin complex to inactivate bound thrombin. In contrast to heparin and low-molecular-weight heparin, which catalyze the inactivation of thrombin by antithrombin, 11,12 direct thrombin inhibitors bind to the enzyme and block its interaction with its substrates. This paper will outline the mechanisms responsible for protection of fibrinbound thrombin from inhibition by the heparin/antithrombin complex, describe the potential advantages of direct thrombin inhibitors over heparin and low-molecular-weight heparin, review the clinical data with hirudin, bivalirudin (formerly known as Hirulog), and argatroban, and outline the opportunities and challenges for direct thrombin inhibitors in the face of new anticoagulant drugs currently under development.

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“…9,10 Argatroban and melagatran (like bivalirudin) dissociate from thrombin, leaving a small amount of free, enzymatically active thrombin available for hemostatic interactions. 11,12 By reducing the thrombin-mediated activation of platelets, DTIs also have an antiplatelet effect. 13,14 Since DTIs do not bind to plasma proteins, these agents should produce a more predictable response than does unfractionated heparin and should be more effective than low-molecular-weight heparins because they inhibit fibrin-bound thrombin.…”

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confidence: 99%

Direct Thrombin Inhibitors

2005

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irect thrombin inhibitors (dti s ) are a new class of anticoagulants that bind directly to thrombin and block its interaction with its substrates. Some DTIs -such as recombinant hirudins, bivalirudin, and ximelagatran, either alone or in combination with melagatran -have undergone extensive evaluation in phase 3 trials for the prevention and treatment of arterial and venous thrombosis. The evidence concerning the clinical applicability of other DTIs, such as argatroban and dabigatran, is limited to phase 2 studies. Four parenteral DTIs have been approved by the Food and Drug Administration (FDA) in North America: hirudin and argatroban for the treatment of heparin-induced thrombocytopenia, bivalirudin as an alternative to heparin in percutaneous coronary intervention, and desirudin as prophylaxis against venous thromboembolism in hip replacement. This review discusses FDA-approved DTIs as well as those under evaluation in phase 2 or 3 clinical trials. coagulation cascade and generation of thrombinAfter injury to a vessel wall, tissue factor is exposed on the surface of the damaged endothelium. The interaction of tissue factor with plasma factor VII activates the coagulation cascade, producing thrombin by stepwise activation of a series of proenzymes ( Fig. 1). Thrombin is central in the clotting process: it converts soluble fibrinogen to fibrin; activates factors V, VIII, and XI, which generates more thrombin; and stimulates platelets. Furthermore, by activating factor XIII, thrombin favors the formation of cross-linked bonds among the fibrin molecules, stabilizing the clot. The coagulation cascade is regulated by natural anticoagulants, such as tissue factor pathway inhibitor, the protein C and protein S system, and antithrombin, all of which help to restrict the formation of the hemostatic plug to the site of injury. differences from heparinsThrombin-inhibiting drugs can block the action of thrombin by binding to three domains: the active site or catalytic site and two exosites (Fig. 2). Located next to the active site, exosite 1 acts as a dock for substrates such as fibrin, thereby orienting the appropriate peptide bonds in the active site. Exosite 2 serves as the heparin-binding domain. 1 Thrombin is inhibited indirectly by low-molecular-weight heparins, because these drugs strongly catalyze the function of antithrombin. A heparin-thrombin-antithrombin complex is formed in which heparin binds simultaneously to exosite 2 in thrombin and to antithrombin. Furthermore, heparin can act as a bridge between thrombin and fibrin by binding both to fibrin and exosite 2 (Fig. 2). Because both thrombin exosites are occupied within this fibrin-heparin-thrombin complex, the enzymatic activity of thrombin is relatively protected from inactivation by the heparin-antithrombin complex. 2-4 Thus, heparins have a reduced capacity for the inhibition of fibrin-bound thrombin, which ap- pears to be detrimental, because active thrombin further triggers thrombus growth.Since DTIs act independently of antithrombin, they can inhibit t...

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Effects of the Synthetic Thrombin Inhibitor Argatroban on Fibrin- or Clot-Incorporated Thrombin: Comparison with Heparin and Recombinant Hirudin

Cited by 166 publications

References 37 publications

Recent Research Developments in the Direct Inhibition of Coagulation Proteinases – Inhibitors of the Initiation Phase

Recent Research Developments in the Direct Inhibition of Coagulation Proteinases – Inhibitors of the Initiation Phase

Direct Thrombin Inhibitors in Acute Coronary Syndromes

Direct Thrombin Inhibitors

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