The Experts below are selected from a list of 57750 Experts worldwide ranked by ideXlab platform
Elliott M Antman - One of the best experts on this subject based on the ideXlab platform.
-
hirudin in acute myocardial infarction thrombolysis and thrombin inhibition in myocardial infarction timi 9b trial
Circulation, 1996Co-Authors: Elliott M AntmanAbstract:Background The TIMI 9 trial evaluated whether the direct Antithrombin hirudin is more effective than an indirect-acting Antithrombin, heparin, as adjunctive therapy for thrombolysis in myocardial infarction. Methods and Results Patients (n=3002) with acute myocardial infarction were treated with aspirin and either accelerated-dose tissue plasminogen activator (TPA) or streptokinase. They were randomized within 12 hours of symptoms to receive either intravenous heparin (5000 U bolus followed by infusion of 1000 U/h) or hirudin (0.1 mg/kg bolus followed by infusion of 0.1 mg/kg per hour). The infusions of both Antithrombins were titrated to a target activated partial thromboplastin time (aPTT) of 55 to 85 seconds and were administered for 96 hours. Patients randomized to hirudin were significantly more likely to have an aPTT measurement in the target range (P<.0001). The primary end point (death, recurrent nonfatal myocardial infarction, or development of severe congestive heart failure or cardiogenic shock...
Klaus T Preissner - One of the best experts on this subject based on the ideXlab platform.
-
inhibition of thrombin by Antithrombin iii and heparin cofactor ii in vivo
Thrombosis and Haemostasis, 1995Co-Authors: Lori Dewar, Myron Kulczycky, Fenton Jw Nd, Maureen Andrew, Jeffrey S. Ginsberg, Maxence Delorme, Morris A. Blajchman, Y Song, Klaus T PreissnerAbstract:The critical role of thrombin in the pathogenesis of venous and arterial thrombosis, and the effectiveness of glycosaminoglycans as antithrombotic drugs are well known. Antithrombin III is a major inhibitor of thrombin and augmentation of its inhibitory actions by heparin is the basis for the clinical use,r of heparin. Recent clinical and experimental studies have demonstrated that another glycosaminoglycan, dermatan sulfate, is uneffective antithrombotic drug. Dermatan sulfate catalyses the inhibition of thrombin by heparin cofactor II. The concentrations of heparin cofactor II are higher in the plasmas of individuals with congenital Antithrombin III deficiency and pregnant women than controls. The role of heparin cofactor II as a physiologic thrombin inhibitor is unknown. Enzyme-linked immunosorbent assays were used to quantify-thrombin-heparin cofactor II and thrombin-Antithrombin III endogenous to the plasmas of adult Antithrombin III-Hamilton deficient subjects, their siblings with normal Antithrombin III levels, pregnant women at term and 3 to 5 days after delivery. Both thrombin-Antithrombin III and thrombin-heparin cofactor II complexed with vitronectin were detected in all the plasmas. Significantly, the concentrations of thrombin-heparin cotactor II-vitronectin were higher in the plasmas of congenital untithrombin III deficient subjects and in preand post-delivery plasmas than those of normal subjects. In addition, the concentrations at thrombin-heparin cofactor II decreased 3 to 5 days after delivery, reflecting the disappearance of the catalytically active dermatan sultate elaborated by the placenta. Thus, heparin cofactor II normally inactivates thrombin in vivo, with its role increasing in conditions associated with high levels of heparin cofactor II and/or dermatan sultate
Johan Stenflo - One of the best experts on this subject based on the ideXlab platform.
-
probing plasma clearance of the thrombin Antithrombin complex with a monoclonal antibody against the putative serpin enzyme complex receptor binding site
FEBS Journal, 2003Co-Authors: George L. Long, Margareta Kjellberg, Bruno O Villoutreix, Johan StenfloAbstract:A high-affinity monoclonal antibody (M27), raised against the human thrombin–Antithrombin complex, has been identified and characterized. The epitope recognized by M27 was located to the linear sequence FIREVP (residues 411–416), located in the C-terminal cleavage peptide of Antithrombin. This region overlaps, by two residues, the putative binding site of Antithrombin for the serpin–enzyme complex receptor. Studies in rats and with HepG2 cells in culture indicated that the Fab fragment of M27 does not block binding and uptake of the thrombin–Antithrombin complex, suggesting that this region does not play a major role in the recognition and clearance of the thrombin–Antithrombin complex. M27 blocked the ability of Antithrombin to inhibit thrombin as well as Antithrombin cleavage, both in the presence and absence of heparin.
Morris A. Blajchman - One of the best experts on this subject based on the ideXlab platform.
-
inhibition of thrombin by Antithrombin iii and heparin cofactor ii in vivo
Thrombosis and Haemostasis, 1995Co-Authors: Lori Dewar, Myron Kulczycky, Fenton Jw Nd, Maureen Andrew, Jeffrey S. Ginsberg, Maxence Delorme, Morris A. Blajchman, Y Song, Klaus T PreissnerAbstract:The critical role of thrombin in the pathogenesis of venous and arterial thrombosis, and the effectiveness of glycosaminoglycans as antithrombotic drugs are well known. Antithrombin III is a major inhibitor of thrombin and augmentation of its inhibitory actions by heparin is the basis for the clinical use,r of heparin. Recent clinical and experimental studies have demonstrated that another glycosaminoglycan, dermatan sulfate, is uneffective antithrombotic drug. Dermatan sulfate catalyses the inhibition of thrombin by heparin cofactor II. The concentrations of heparin cofactor II are higher in the plasmas of individuals with congenital Antithrombin III deficiency and pregnant women than controls. The role of heparin cofactor II as a physiologic thrombin inhibitor is unknown. Enzyme-linked immunosorbent assays were used to quantify-thrombin-heparin cofactor II and thrombin-Antithrombin III endogenous to the plasmas of adult Antithrombin III-Hamilton deficient subjects, their siblings with normal Antithrombin III levels, pregnant women at term and 3 to 5 days after delivery. Both thrombin-Antithrombin III and thrombin-heparin cofactor II complexed with vitronectin were detected in all the plasmas. Significantly, the concentrations of thrombin-heparin cotactor II-vitronectin were higher in the plasmas of congenital untithrombin III deficient subjects and in preand post-delivery plasmas than those of normal subjects. In addition, the concentrations at thrombin-heparin cofactor II decreased 3 to 5 days after delivery, reflecting the disappearance of the catalytically active dermatan sultate elaborated by the placenta. Thus, heparin cofactor II normally inactivates thrombin in vivo, with its role increasing in conditions associated with high levels of heparin cofactor II and/or dermatan sultate
-
Defining the heparin-binding domain of Antithrombin.
Blood Coagulation & Fibrinolysis, 1994Co-Authors: William P. Sheffield, Morris A. BlajchmanAbstract:Antithrombin is a serine protease inhibitor that participates in the inactivation and removal from the circulation of thrombin and a variety of other procoagulant serine proteases. Antithrombin is also the major plasma cofactor of heparin which exerts its therapeutic effect primarily through its ability to substantially increase the rate of inactivation by Antithrombin of the procoagulant serine proteases. Binding of heparin to Antithrombin is thus believed to be a prerequisite for this rate enhancement effect. Heparin binding to Antithrombin is mediated by a well-defined unique heparin pentasaccharide sequence. Interaction between this pentasaccharide sequence and Antithrombin induces a conformational change in Antithrombin, an alteration that appears to be sufficient to explain the enhanced ability of Antithrombin to inhibit factor Xa and related serine proteases, but not thrombin. Heparin species with longer polysaccharide chains appear to be required in order to enhance the inhibition of thrombin by Antithrombin. This may be because the enhancement of this reaction requires that heparin interacts simultaneously with both the Antithrombin and the thrombin molecules. This review describes the interactions between heparin and Antithrombin, focusing on the Antithrombin residues which are involved in the binding of heparin. The role of the heparin-induced conformational change in enhancing serine protease inhibition by Antithrombin is also explored. Then, based on available data, an hypothesis is proposed to explain the mechanisms by which heparin accelerates the rate of inactivation by Antithrombin of the various serine proteases.
Steven M Opal - One of the best experts on this subject based on the ideXlab platform.
-
Antithrombin, heparin, and heparan sulfate
Critical Care Medicine, 2002Co-Authors: Steven M Opal, Craig M Kessler, Juergen Roemisch, Sigurd KnaubAbstract:Objectives: To review the experimental and clinical evidence that Antithrombin has multiple mechanisms for both its anticoagulant and anti-inflammatory properties. The interaction between Antithrombin and specific polysulfated, acidic oligosaccharide moieties found on heparin and related proteoglycan molecules within the circulation and on endothelial surfaces will also be examined. Data Sources: Review of the literature relating to Antithrombin published during the past 25 yrs. Data Summary: Antithrombin is the most abundant endogenous anticoagulant circulating in human plasma. This serine protease inhibitor participates in the regulation of clotting in both physiologic and pathologic states. Reduced Antithrombin activity in the early phases of sepsis contributes to a procoagulant state with excess activation of the innate immune response. Antithrombin binds to specific pentasaccharides expressed on heparin, glycosaminoglycans, and related proteoglycans within the circulation and along endothelial surfaces. The functions of neutrophils, monocytes, and endothelial cells are altered as a result of their interaction with Antithrombin. These effects are mediated by the enzyme inhibitory action of Antithrombin and its ability to function as a ligand for Antithrombin receptors on cell surfaces. In addition, Antithrombin exerts anti-inflammatory properties by both prostacyclin-dependent and prostacyclin-independent actions; heparin interferes with these anti-inflammatory properties. The role of Antithrombin in sepsis, its therapeutic utility in severe sepsis, and its combination with heparin remain the subject of considerable debate. The results of a recent phase 3 clinical trials with high-dose Antithrombin in sepsis suggested a beneficial effect in patients who did not concomitantly receive heparin, thereby generating new challenges in the understanding of interactions between Antithrombin and heparin or heparin-like proteoglycans. Conclusions: Antithrombin has complex interactions with host coagulopathic and systemic inflammatory responses under physiologic conditions and in sepsis. The impact of these interactions in critically ill patients and the therapeutic implications of administration of Antithrombin, and various doses and types of heparin in such patients, need further clarification.
-
Antithrombin, heparin, and heparan sulfate.
Critical care medicine, 2002Co-Authors: Steven M Opal, Craig M Kessler, Juergen Roemisch, Sigurd KnaubAbstract:To review the experimental and clinical evidence that Antithrombin has multiple mechanisms for both its anticoagulant and anti-inflammatory properties. The interaction between Antithrombin and specific polysulfated, acidic oligosaccharide moieties found on heparin and related proteoglycan molecules within the circulation and on endothelial surfaces will also be examined. Review of the literature relating to Antithrombin published during the past 25 yrs. Antithrombin is the most abundant endogenous anticoagulant circulating in human plasma. This serine protease inhibitor participates in the regulation of clotting in both physiologic and pathologic states. Reduced Antithrombin activity in the early phases of sepsis contributes to a procoagulant state with excess activation of the innate immune response. Antithrombin binds to specific pentasaccharides expressed on heparin, glycosaminoglycans, and related proteoglycans within the circulation and along endothelial surfaces. The functions of neutrophils, monocytes, and endothelial cells are altered as a result of their interaction with Antithrombin. These effects are mediated by the enzyme inhibitory action of Antithrombin and its ability to function as a ligand for Antithrombin receptors on cell surfaces. In addition, Antithrombin exerts anti-inflammatory properties by both prostacyclin-dependent and prostacyclin-independent actions; heparin interferes with these anti-inflammatory properties. The role of Antithrombin in sepsis, its therapeutic utility in severe sepsis, and its combination with heparin remain the subject of considerable debate. The results of a recent phase 3 clinical trials with high-dose Antithrombin in sepsis suggested a beneficial effect in patients who did not concomitantly receive heparin, thereby generating new challenges in the understanding of interactions between Antithrombin and heparin or heparin-like proteoglycans. Antithrombin has complex interactions with host coagulopathic and systemic inflammatory responses under physiologic conditions and in sepsis. The impact of these interactions in critically ill patients and the therapeutic implications of administration of Antithrombin, and various doses and types of heparin in such patients, need further clarification.
-
therapeutic rationale for Antithrombin iii in sepsis
Critical Care Medicine, 2000Co-Authors: Steven M OpalAbstract:Objective: To review the preclinical evidence that provides the therapeutic rationale for Antithrombin as a novel treatment for human sepsis. Data Sources: A summary of published medical literature from MEDLINE search files and other reviews published about Antithrombin use in sepsis. Data Summary: Antithrombin has a variety of anti-inflammatory properties in addition to its functions as an endogenous anticoagulant that appear to have an important therapeutic role in the prevention of microvascular dysfunction and multiple organ injury in sepsis. Appropriate timing and dosing of Antithrombin III is critical to realize its full therapeutic potential as an anti-sepsis therapy. Conclusions: Antithrombin is a potent inhibitor of thrombin-mediated vascular injury in the microcirculation in severe sepsis. This endogenous anticoagulant is rapidly depleted in the early phases of sepsis as a result of decreased synthesis, increased destruction, and enhanced clearance by thrombin-Antithrombin complex formation. The therapeutic efficacy of Antithrombin in experimental sepsis is readily demonstrable in numerous animal systems. Appropriately defined patient populations with early onset severe sepsis and/or septic shock may benefit from Antithrombin therapy if it is administered in adequate doses at the optimal time interval.
