bivalirudin and Inflammation

The goal of this study was to evaluate glycoprotein IIb/IIIa inhibition with eptifibatide when administered with indirect thrombin inhibition as compared with monotherapy with direct thrombin inhibition with bivalirudin among patients with non-ST-segment elevation acute coronary syndromes (ACS).. The optimal combination of antiplatelet and antithrombin regimens that maximizes efficacy and minimizes bleeding among patients with non-ST-segment elevation ACS undergoing percutaneous coronary intervention (PCI) is unclear.. A total of 857 patients with non-ST-segment elevation ACS were assigned randomly to eptifibatide + reduced dose unfractionated heparin (n = 298), eptifibatide + reduced-dose enoxaparin (n = 275), or bivalirudin monotherapy (n = 284).. Among angiographically evaluable patients (n = 754), the primary end point of post-PCI coronary flow reserve was significantly greater with bivalirudin (1.43 vs. 1.33 for pooled eptifibatide arms, p = 0.036). Thrombolysis In Myocardial Infarction (TIMI) myocardial perfusion grade more often was normal with eptifibatide treatment compared with bivalirudin (57.9% vs. 50.9%, p = 0.048). The duration of ischemia on continuous Holter monitoring after PCI was significantly longer among patients treated with bivalirudin (169 vs. 36 min, p = 0.013). There was no excess of TIMI major bleeding among patients treated with eptifibatide compared with bivalirudin (0.7%, n = 4 vs. 0%, p = NS), but TIMI minor bleeding was increased (2.5% vs. 0.4%, p = 0.027) as was transfusion (4.4% to 0.4%, p < 0.001).. Among moderate- to high-risk patients with ACS undergoing PCI, coronary flow reserve was greater with bivalirudin than eptifibatide. Eptifibatide improved myocardial perfusion and reduced the duration of post-PCI ischemia but was associated with higher minor bleeding and transfusion rates. Ischemic events and biomarkers for myonecrosis, inflammation, and thrombin generation did not differ between agents.

Topics: Acute Disease; Angina, Unstable; Angioplasty, Balloon, Coronary; Antithrombins; Drug Therapy, Combination; Enoxaparin; Eptifibatide; Female; Fibrinolytic Agents; Heparin; Hirudins; Humans; Inflammation; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Peptide Fragments; Peptides; Platelet Glycoprotein GPIIb-IIIa Complex; Postoperative Complications; Postoperative Hemorrhage; Recombinant Proteins; Syndrome

Antithrombogenicity, anti-inflammation, and rapid re-endothelialization are central requirements for the long-term success of cardiovascular stents. In this work, a plant-inspired phenolic-amine chemistry strategy was developed to combine the biological functions of a plant polyphenol, tannic acid (TA), and the thrombin inhibitor bivalirudin (BVLD) for tailoring the desired multiple surface functionalities of cardiovascular stents. To realize the synergistic modification of TA and BVLD on a stent surface, an amine-bearing coating of plasma polymerized allylamine was firstly prepared on the stent surface, followed by the sequential conjugation of TA and BVLD in alkaline solution based on phenolic-amine chemistry (i.e., Michael addition reaction). TA and BVLD were successfully immobilized onto the stent surface with considerable amounts of 330 ± 12 and 930 ± 80 ng/cm

Topics: Amines; Antithrombins; Hirudins; Humans; Inflammation; Peptide Fragments; Polyphenols; Recombinant Proteins; Stents; Tannins; Thrombosis

Despite high-dose heparin anticoagulation, cardiopulmonary bypass (CPB) is still associated with marked hemostatic activation. The purpose of this study was to determine whether a reduced dose of bivalirudin, added as an adjunct to heparin, would reduce thrombin generation and circulating markers of inflammatory system activation during CPB as effectively as full-dose bivalirudin, without adversely affecting postoperative hemostasis.. Using a model of normothermic CPB in rats, the authors prospectively compared markers of thrombin generation (thrombin-antithrombin complexes) and inflammatory markers (tumor necrosis factor alpha, interleukin 1beta, interleukin 6, and interleukin 10) in three groups: conventional high-dose heparin (H), full-dose bivalirudin (B), and a combined group (standard high-dose heparin with the addition of reduced dose bivalirudin or H&B), at baseline, after 60 min of CPB, and 60 min after CPB. Postoperative hemostasis was also assessed.. Groups H&B and B showed reduced thrombin-antithrombin complex formation during CPB compared with group H (P = 0.0003), and this persisted after CPB for group B (P = 0.009). Perioperative increases in interleukin 6 and interleukin 10 showed a trend toward being reduced in animals receiving bivalirudin (P = 0.06). Evidence of residual anticoagulation was found in group H&B as measured by activated clotting time (P = 0.04) and activated partial thromboplastin time (P = 0.02), but no intergroup difference in primary hemostasis was found.. Bivalirudin attenuates hemostatic activation during experimental CPB with potential effects on markers of the inflammatory response. However, with this dosing regimen, the combination of heparin and bivalirudin does not seem to confer any measurable advantages over full-dose bivalirudin anticoagulation.

Topics: Animals; Anticoagulants; Antithrombin III; Cardiopulmonary Bypass; Hemostasis; Heparin; Hirudins; Inflammation; Male; Peptide Fragments; Peptide Hydrolases; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Thrombin

Unfractionated heparin (UFH) does not effectively inhibit clot-bound thrombin and increases platelet reactivity, expression of P-selectin and inflammatory responses. These negative effects of UFH cannot be entirely overcome by the addition of a glycoprotein antagonist and may help explain the REPLACE-2 results.

Topics: Antithrombins; Blood Platelets; Clinical Trials as Topic; Hirudins; Humans; Inflammation; Peptide Fragments; Platelet Glycoprotein GPIIb-IIIa Complex; Recombinant Proteins; Thrombin; Thrombosis

The study evaluated the role of thrombin in activation of vascular smooth muscle cells early after vascular injury. The direct thrombin inhibitor Hirulog (10 mg/kg SQ tid) or vehicle was administered to rabbits over 3 days following balloon injury to the abdominal aorta and the right iliac artery. Hirulog treatment yielded marked systemic anticoagulation as evidenced by an about 3.5-fold prolongation of quantitative thrombin time one hour after an injection, but with a reduction to almost baseline levels at the end of the dosing interval. After 3 days, proliferating cells in the right iliac artery were enumerated. The expression of intercellular adhesion molecule 1, macrophage-colony stimulating factor, tumor necrosis factor alpha, and interleukin-1beta as markers for inflammatory activation of the vessel wall was examined by immunohistochemistry and graded semiquantitatively. Mitotic indices did not differ between control and Hirulog-treated animals. There was also no difference in the expression of markers of inflammatory activation between both groups. In conclusion, thrombin inhibition by Hirulog administration does not reduce acutely (within 3 days) vascular smooth muscle cell proliferation or inflammatory activation after angioplasty. Thrombin inhibitors may therefore limit restenosis in the rabbit by acting later or via other, unknown pathways. The lack of effect of the thrombin inhibitor on the cellular events during the early phase of the response to balloon injury may explain the failure of such strategies to reduce restenosis in recent clinical trials despite effects towards acute thrombotic complications. Together, these results suggest that acute thrombin generation is not a crucial stimulus for early smooth muscle cell proliferation and inflammatory activation after vascular injury.

Topics: Animals; Antithrombins; Aorta, Abdominal; Blood Coagulation; Cell Division; Hirudins; Iliac Artery; Inflammation; Intercellular Adhesion Molecule-1; Male; Muscle, Smooth, Vascular; Peptide Fragments; Rabbits; Recombinant Proteins; Thrombin

Coagulation proteases were tested in a rat model of acute inflammation. Subplantar injection of Factor Xa (10-30 microg) produced a time- and dose-dependent edema in the rat paw, and potentiated carrageenin-induced edema. In contrast, the homologous protease Factor IXa was ineffective. This inflammatory response was recapitulated by the Factor Xa sequence L83FTRKL88(G), which mediates ligand binding to effector cell protease receptor-1 (EPR-1), while a control scrambled peptide did not induce edema in vivo. Conversely, injection of the EPR-1-derived peptide S123PGKPGNQNSKNEPP137 (corresponding to the receptor binding site for Factor Xa) inhibited carrageenin-induced rat paw edema, while the adjacent EPR-1 sequence P136PKKRERERSSHCYP150 was without effect. EPR-1-Factor Xa-induced inflammation was characterized by fast onset and prominent perivascular accumulation of activated and degranulated mast cells, was inhibited by the histamine/serotonin antagonists cyproheptadine and methysergide, but was unaffected by the thrombin-specific inhibitor, Hirulog. These findings suggest that through its interaction with EPR-1, Factor Xa may function as a mediator of acute inflammation in vivo. This pathway may amplify both coagulation and inflammatory cascades, thus contributing to the pathogenesis of tissue injury in vivo.

Topics: Amino Acid Sequence; Analysis of Variance; Animals; Antithrombins; Blood Coagulation; Carrageenan; Cyproheptadine; Edema; Factor Xa; Hirudins; Histamine H1 Antagonists; Inflammation; Male; Mast Cells; Methysergide; Molecular Sequence Data; Peptide Fragments; Rats; Rats, Wistar; Recombinant Proteins; Serotonin Antagonists; Time Factors

A rat model of inflammation was used to investigate the biological effects of thrombin. The thrombin-specific inhibitor Hirulog markedly attentuated the carrageenin-induced edema of the paw of the rat. Injection of thrombin into the paw also produced edema. The effect of thrombin was due to activation of its receptor; a thrombin receptor activating peptide (TRAP) reproduced the effects of thrombin in causing edema. TRAP also increased vascular permeability as demonstrated by extravasation of Evans blue and 125I-labeled serum albumin. The release of bioactive amines played an important role in mediating the TRAP-induced edema; the serotonin/histamine antagonist cryproheptadine and the histamine H2 receptor antagonist cimetidine reduced significantly the edema caused by TRAP. Treatment of rats with the mast cell degranulator 48/80 to deplete these cells of their stores of histamine and serotonin abolished completely the ability of TRAP to produce edema. Histochemical examination confirmed that TRAP treatment led to mast cell degranulation. Thus, it has been possible to demonstrate that thrombin acts as an inflammatory mediator in vivo by activating its receptor, which in turn leads to release of vasoactive amines from mast cells.

Topics: Amino Acid Sequence; Animals; Antithrombins; Carrageenan; Cytoplasmic Granules; Edema; Hirudins; Histamine; Inflammation; Male; Mast Cells; Molecular Sequence Data; Peptide Fragments; Rats; Rats, Wistar; Receptors, Thrombin; Recombinant Proteins; Serotonin; Thrombin