Heparin Blunts Endotoxin-Induced Coagulation Activation

Abstract

Background-Lipopolysaccharide (LPS) is a major trigger of sepsis-induced disseminated intravascular coagulation (DIC) via the tissue factor (TF)/factor VIIa-dependent pathway of coagulation. Experimental endotoxemia has been used repeatedly to explore this complex pathophysiology, but little is known about the effects of clinically used anticoagulants in this setting. Therefore, we compared with placebo the effects of unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) on LPS-induced coagulation. Methods and Results-In a randomized, double-blind, placebo-controlled trial, 30 healthy male volunteers received LPS 2 ng/kg IV followed by a bolus-primed continuous infusion of UFH, LMWH, or placebo. In the placebo group, activation of coagulation caused marked increases in plasma levels of prothrombin fragment F 1ϩ2 (PϽ0.01) and polymerized soluble fibrin, termed thrombus precursor protein (TpP; PϽ0.01); TF-positive monocytes doubled in response to LPS, whereas levels of activated factor VII slightly decreased and levels of TF pathway inhibitor remained unchanged. UFH and LMWH markedly decreased activation of coagulation caused by LPS, as F 1ϩ2 and TpP levels only slightly increased; TF expression on monocytes was also markedly reduced by UFH. TF pathway inhibitor values increased after either heparin infusion (PϽ0.01). Concomitantly, factor VIIa levels dropped by Ͼ50% at 50 minutes after initiation of either heparin infusion (PϽ0.01). Conclusions-This

High Doses of Vitamin C Reverse Escherichia coli Endotoxin–Induced Hyporeactivity to Acetylcholine in the Human Forearm

“…10 -12 Serum concentrations of antioxidants are low in patients with cardiovascular disease, 10 and high local concentrations of antioxidants such as vitamin C have been shown to restore endothelial function in patients with cardiovascular risk factors, including diabetes, hypertension, hypercholesterolemia, and smoking. 13 The purpose of the present study was to test the hypothesis that systemic concentrations of the antioxidant vitamin C are decreased during acute inflammation secondary to Escherichia coli endotoxin (LPS) and that endotoxin-associated endothelial dysfunction can be restored by high doses of vitamin C. The administration of low doses of LPS is an established model for generation of an acute systemic inflammatory response in humans, 5,14,15 and forearm vascular function was studied using strain-gauge plethysmography.…”

Factor V Leiden mutation enhances fibrin formation and dissolution in vivo in a human endotoxemia model

“…19 Injection of endotoxin similarly causes formation of large amounts of plasmin, with a maximum PPIC concentration after 2 hours. 20 In contrast to ancrod, endotoxin also stimulates tPA release from the endothelium. 20,21 The profibrinolytic response is subsequently terminated by increasing levels of PAI-1, 20,21 resulting in a rapid drop in PPIC concentration.…”

“…This may be a consequence of the increased amount of soluble fibrin acting as cofactor in tPA-induced plasminogen activation and possibly shielding tPA from inactivation by PAI-1. Pernerstorfer at al 20 showed that maximal thrombin generation occurs 4 to 6 hours after endotoxin infusion. Levels of prothrombin fragment F1.2 and thrombinantithrombin complexes, as well as soluble fibrin, return to baseline within 24 hours.…”

“…Levels of prothrombin fragment F1.2 and thrombinantithrombin complexes, as well as soluble fibrin, return to baseline within 24 hours. 20 In patients with FVL, thrombin formation and formation of soluble fibrin follow different kinetics, with elevated levels also after 24 hours.…”

“…The participants had not been treated with anticoagulant or antiplatelet drugs for at least 2 months before inclusion in the trial. The human endotoxemia model described in detail by Pernestorfer et al 11 was used. After overnight fasting, an infusion of 5% glucose was started and continued for 8.5 hours at 3 mL/kg of body weight per hour.…”