BACKGROUNDExtracellular histones exert cytotoxic and procoagulant effects which contribute to immunothrombosis in vascular diseases such as sepsis. Heparin has been shown to neutralize the pathologic effects of histones in vitro and in animal models.OBJECTIVESTo compare the effectiveness of unfractionated heparin (UFH), low-molecularweight heparin (LMWH), Vasoflux (lacks anticoagulant activity), and fondaparinux in neutralizing the cytotoxic and procoagulant activities of histones METHODS: Binding affinities between heparin variants and histone subunits were determined by Bio-layer Interferometry. The ability of heparin variants to diminish the cytotoxic and procoagulant effects of histones was studied by treating endothelial cells or monocytic THP-1 cells with histones ± heparin variants.RESULTSUnfractionated heparin, LMWH, and Vasoflux bind histone subunits with high affinities (K_d <1 pM-66.7 nM) whereas fondaparinux exhibited a low affinity (K_d of 3.06 µM-81.1 mM). UFH, LMWH, and Vasoflux neutralize histone-mediated cytotoxicity as well as monocytic procoagulant activity (as assessed by cell surface tissue factor and phosphatidylserine). In contrast, fondaparinux has no effect on these activities. All four heparin variants reverse histone-mediated impairment of APC generation in a dose-dependent manner.CONCLUSIONSThe ability of heparin to neutralize the cytotoxic and procoagulant effects of histones require heparin fragments >1.7 kDa and is independent of the antithrombin-binding pentasaccharide. In contrast, the ability of heparin to neutralize histone-mediated impairment of APC generation is independent of size and anticoagulant activity. These findings suggest that heparin variants may have differential therapeutic potential in vascular diseases associated with elevated levels of histones.

2021-12-01·Shock2区 · 医学

Mechanistic Studies of DNase I Activity: Impact of Heparin Variants and PAD4

2区 · 医学

Article

作者: Liaw, Patricia C. ; Sohrabipour, Sahar ; Dwivedi, Dhruva J. ; Sharma, Neha ; Muniz, Valdirene S.

ABSTRACTBackground:Excessive production of neutrophil extracellular traps (NETs) in sepsis contributes to vascular occlusion by acting as a scaffold and stimulus for thrombus formation. Removal of extracellular DNA, the major structural component of NETs, by DNase I may reduce host injury.Objectives:Methods:DNA–histone complexes were treated with DNase I ± heparin variants and visualized via agarose gels. We compared the ability of DNase I ± heparin variants to digest NETs released by phorbol 12-myristate 13-acetate-stimulated neutrophils versus DNA–histone complexes released by necrotic HEK293 cells. Plasma DNA and DNase I levels were measured longitudinally in 76 septic patients.Results:Heparin enhances DNase I-mediated digestion of DNA–histone complexes in a size-dependent manner that does not require the antithrombin-binding region. In contrast, DNase I alone was able to degrade the DNA–histone component of NETs presumably due to peptidylarginine deiminase 4 (PAD4)-mediated histone citrullination that weakens DNA–histone interactions. In purified systems, PAD4 treatment of DNA–histone complexes enhanced the ability of DNase I to degrade histone-bound DNA. In septic patients, endogenous DNase I levels remained persistently low over 28 days, and there were no significant correlations between DNA and DNase I levels.Conclusion:Heparin enhances DNA-mediated digestion of DNA–histone complexes in a size-dependent manner that is independent of its anticoagulant properties. Citrullination of histones by PAD4 renders DNA–histone complexes susceptible to DNase I digestion. Endogenous DNase I levels are persistently decreased in septic patients, which supports the potential utility of DNase I as a therapy for sepsis.

2001-08-01·American Heart Journal2区 · 医学

Randomized comparison of a novel anticoagulant, vasoflux, and heparin as adjunctive therapy to streptokinase for acute myocardial infarction: Results of the VITAL study (Vasoflux International Trial for Acute Myocardial Infarction Lysis)

2区 · 医学

Article

作者: Weitz, Jeffrey I. ; Anderson, H. Vernon ; Spickler, William ; Peters, Ron J. G. ; Weaver, W. Douglas ; Gibson, Michael ; Molhoek, Peter G. ; Hirsh, Jack ; Theroux, Pierre ; White, Harvey

BACKGROUNDVasoflux is a low-molecular-weight heparin derivative that inhibits factor IXa activation of factor X and catalyzes fibrin-bound thrombin inactivation by heparin cofactor II. We studied whether vasoflux improves the results of thrombolysis with streptokinase for acute myocardial infarction.METHODS AND RESULTSWe randomized 277 patients with acute myocardial infarction to standard intravenous unfractionated heparin (UFH) or intravenous vasoflux 1, 4, 8, or 16 mg/kg as a bolus followed by 1, 4, 8, or 16 mg/kg per hour infusion, on top of streptokinase and aspirin, until angiography at 90 minutes. Patency and corrected Thrombolysis in Myocardial Infarction (TIMI) frame count were studied at 60 and 90 minutes. Rates of TIMI grade 3 flow with vasoflux at any dose (35% to 42%) were not different from UFH (41%) at either time point, nor was the corrected TIMI frame count. However, there was an excess of bleeding in the patients randomized to vasoflux 8 or 16 mg/kg: 78% and 71%, compared with 53% for UFH (P =.004 and.043, respectively). Major bleeding was observed in 13% and 28% at these vasoflux doses compared with 8% with UFH (P =.558 and.01, respectively).CONCLUSIONAt doses that increase the risk of bleeding, the addition of vasoflux to streptokinase and aspirin did not lead to improved patency rates compared with UFH. Targeting factor IXa and heparin cofactor II may not be a useful adjunct to thrombolysis.

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适应症	最高研发状态	国家/地区	公司	日期
凝血障碍	临床2期	北美洲	-	-
心肌梗塞	临床2期	北美洲	-	-
心肌梗塞	临床2期	-	Inflazyme Pharmaceuticals	-
心肌梗塞	临床2期	全球	-	-
血栓形成	临床2期	北美洲	-	-
血栓形成	临床2期	-	Inflazyme Pharmaceuticals	-