Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.5 (thrombin)
 33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Despite the use of potent anticoagulants such as r-hirudin and argatroban, the morbidity/mortality of heparin-induced thrombocytopenia (HIT) patients remains high. In the last several months, we have treated three HIT-positive patients with a combined therapy of thrombin inhibitor and GPIIb/IIIa inhibitor when treatment with thrombin inhibitor alone failed to alleviate acute thrombosis. Combination therapies included r-hirudin (Refludan) with tirofiban (Aggrastat) or argatroban (Novastan) with ReoPro. A reduced dose of the thrombin inhibitor with the standard dose of the antiplatelet drug was the dosing regimen used. In all cases, there was no overt bleeding that required intervention and all patients had improved or fully recovered. This first report of the use of GPIIb/IIIa inhibitors with thrombin inhibitors in HIT patients with active thrombosis suggests that this combined therapy may be more effective than thrombin inhibitor treatment alone. The data from these three cases warrant testing of this therapeutic regimen in larger studies to determine optimal dosing strategies.
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PMID:Clinical experience with combined treatment of thrombin inhibitors and GPIIb/IIIa inhibitors in patients with HIT. 1035 56

Platelets play an important role in the pathophysiology of acute myocardial infarction, unstable angina, and ischemic stroke. The expression of the glycoprotein IIb/IIIa (alphaIIb/beta3 integrin) receptor on the surface of activated platelets constitutes the common pathway for platelet aggregation. Glycoprotein IIb/IIIa has low affinity for its soluble ligands (fibrinogen and von Willebrand factor) in resting platelets. In the setting of vascular injury, platelet activation occurs after binding of the glycoprotein Ib-IX-V receptor to von Willebrand factor in the extracellular matrix (at high shear rate) and binding of soluble agonists to specific platelet membrane receptors. The ensuing inside-out signaling increases several-fold the affinity and avidity of alphaIIb/beta3 for its ligands. High affinity ligand binding to alphaIIb/beta3 triggers outside-in signaling, causing microskeletal contraction and platelet retraction. The signaling pathways for inside-out and outside-in signaling are incompletely understood. Glycoprotein IIb/IIIa antagonists were developed under the premise that these agents would abrogate platelet aggregation while preserving platelet monolayer deposition at sites of injury. A number of parenteral and oral agents have been developed and evaluated in clinical trials. Three of them are approved in the United States and other countries: abciximab (ReoPro; the Fab fragment of a chimeric human-mouse antibody), eptifibatide (Integrelin; a cyclic heptapeptide), and tirofiban (Aggrastat; a tyrosine-derived nonpeptide molecule). The greatest clinical impact of these parenteral agents (used in conjunction with aspirin and heparin) has been in the prevention of ischemic complications after percutaneous coronary intervention. In contrast, oral agents have yielded disappointing results in the secondary prevention of acute coronary syndromes, and none of them are approved at present. Eptifibatide and tirofiban are specific for alphaIIb/beta3, whereas abciximab also exhibits cross-reactivity with the alphavbeta3 and alphaMbeta2 integrins. Although alphaIIb/beta3 is unique to platelets and megakaryocytes, alphavbeta3 is more widely distributed and mediates several functions, including endothelial cell migration, monocyte adhesion, angiogenesis, and inhibition of apoptosis. alphaMbeta2 mediates leukocyte-platelet interactions. In the percutaneous coronary intervention trials, abciximab has been more efficacious than the other parenteral agents, perhaps because of cross-reactivity with these other integrins, the pharmacodynamic profile of abciximab, or other effects. Other documented effects of abciximab include acute dethrombosis, reduction of thrombin generation, and improved flow in the coronary microcirculation after percutaneous coronary intervention. Abciximab is presently under evaluation in the treatment of acute ischemic stroke. Promising data have been obtained in experimental models of tumor angiogenesis and sickle cell anemia.
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PMID:Platelet glycoprotein IIb/IIIa antagonists: lessons learned from clinical trials and future directions. 1200 56

Irrespective of their mechanism of action, anticoagulants reduce the formation and action of thrombin. Thus they interfere with a final step in coagulation. Among platelet inhibitors only the GPIIb/IIIa antagonists inhibit the common pathway of aggregation, namely the formation of platelet-to-platelet bridges which are mediated by fibrinogen or von Willebrand factor. In contrast, acetylsalicylic acid (ASA), NSAIDs, clopidogrel (Plavix) or ticlopidine (Tyklid) inhibit platelet activation by abrogating the formation or action of a secondary platelet agonist, namely of thromboxane A(2) or ADP. They do not block platelet aggregation which is directly induced by thrombin. Therefore, ASA, clopidogrel, or ticlopidine are not associated with a significant risk of bleeding as long as other factors such as an extensive thrombocytopenia or anticoagulation are not involved. Therefore, in contrast to anticoagulants, therapeutic drug monitoring is not necessary with ASA, clopidogrel, nor ticlopidine. On the other hand, ASA has even to be applied at a dosage that almost completely inhibits thromboxane synthesis in order to act on platelet aggregation at all. Among the GPIIb/IIIa-antagonists only parenteral drugs have been approved for therapeutic use, e. g. abciximab (ReoPro), eptifibatide (Integrilin), and tirofiban (Aggrastat). Clinical studies revealed an increased risk of bleeding without a sufficient therapeutic benefit of oral GPIIb/IIIa antagonists. GPIIb/IIIa antagonists may induce thrombocytopenia that is attributed to an out-side-in signalling or immunological phenomena. A test system (Ultegra, Accumetrics) is available for a therapeutic drug monitoring of GPIIb/IIIa antagonists. However, estimation of the bleeding risk always requires an evaluation of all factors influencing the haemostatic system, especially when heparin or other inhibitors are applied additionally.
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PMID:[Platelet aggregation disorders]. 1460 82