The Effect of Factor Xa/Phospholipid Infusion on the Acute Phase Response in Baboons

Abstract

SummaryDisseminated intravascular coagulation (DIC) is a frequent complication of septicemia or tissue injury and may be accompanied by elevations of interleukin-6, a mediator of the acute phase response. It is not known whether thrombin or fibrin deposition may directly induce an acute phase response. To study this, we employed a baboon model of in vivo thrombin generation, induced by the administration of purified bovine Factor Xa and phospholipid vesicles. Two Xa/phospholipid dosages were used, a low dosage (2 animals) leading to a rapid 49% decrease in fibrinogen and a high dosage (two injections at 5h interval; 3 animals) leading to complete fibrinogen depletion. Thereafter, fibrinogen levels increased in both treatment groups, reached a maximum of 2.52 ± 0.23 g/1 (mean ± SE, n = 5; p <0.01 with respect to basal levels) at day 2, and returned to normal by day seven. In five control (injection of 0.15% NaCl) baboons no significant changes of fibrinogen were observed (maximal values: 1.88 ± 0.12 g/1). Serum concentrations of C-reactive protein, an acute phase protein, increased from 3.7 ± 0.4 mg/1 to a maximum of 33.0 ± 7.3 at day one, which was five-fold higher (p <0.01) than in control animals at day one (6.2 ± 0.5 mg/1). Transient increases were observed within 6 h for interleukin-6 from basal values of 6.2 ± 1.7 ng/1 to peak plasma levels of 42.9 ±21.4 ng/1, a value threefold higher (p = 0.07) than in control animals (14.8 ± 4.0 ng/1).The preliminary results of this observational study suggest that factor Xa/phospholipid infusion is followed by an acute phase response, leading after one day to significant increases of fibrinogen and of C-reactive protein.

Pharmacokinetics and Pharmacodynamics of the Dual FII/FX Inhibitor BIBT 986 in Endotoxin-induced Coagulation

“…26,27 Further, BIBT 986 infusion significantly and dosedependently reduced the LPS-induced increases in IL-6 and TNF-a in a recent study with rats. Animal studies showed that infusion of factor Xa as well as thrombin infusion increase the production of proinflammatory cytokines such as IL-6.…”

“…Animal studies showed that infusion of factor Xa as well as thrombin infusion increase the production of proinflammatory cytokines such as IL-6. 26,27 Further, BIBT 986 infusion significantly and dosedependently reduced the LPS-induced increases in IL-6 and TNF-a in a recent study with rats. 28 Therefore, we compared the anticoagulant activity of three doses of BIBT 986 on parameters of coagulation, platelet activation, and inflammation with placebo and examined the safety of BIBT 986 in this setting.…”

Tissue factor upregulation drives a thrombosis–inflammation circuit in relation to cardiovascular complications

“…a. j. chu CD18 174 revealing the initiation of inflammation by TF. The direct evidence includes (i) administration with recombinant FVIIa enhances IL-6 and -8 production in healthy human subjects, 175 (ii) FXa/PL infusion increases L-6 and CRP in baboons, 176 and (iii) FIIa with fibrin(ogen) dependency induces macrophage adhesion and the production of IL-6 and MCP-1.…”

Acute Release of Tissue Factor Pathway Inhibitor after In Vivo Thrombin Generation in Baboons

“…The full picture of the clinical tolerance of the injection of FXa/PCPS, as well as the analysis of the parameters illustrating the modifications of the coagulation and fibrinolytic systems in baboons were described in detail previously (3,13,14). No complications were seen after injection of "low dose" FXa/PCPS, but after the first bolus of "high dose" FXa/PCPS all animals presented a transient venous collapse during 30 min which prevented blood collection in this period.…”