Fructose-1,6-bisphosphate inhibits in vitro and ex vivo platelet aggregation induced by ADP and ameliorates coagulation alterations in experimental sepsis in rats

Abstract

Sepsis is a systemic response to an infection that leads to a generalized inflammatory reaction. There is an intimate relationship between procoagulant and proinflammatory activities, and coagulation abnormalities are common in septic patients. Pharmaceutical studies have focused to the development of substances that act on coagulation abnormalities and on the link between coagulation and inflammation. Fructose-1,6-bisphosphate (FBP) is a high-energy glycolitic metabolite that in the past two decades has been shown therapeutic effects in great number of pathological situations, including sepsis. The aims of this study were to assess the effects of FBP on platelet aggregation in vitro and ex vivo in healthy and septic rats and evaluate the use of FBP as a treatment for thrombocytopenia and coagulation abnormalities in abdominal sepsis in rat. FBP inhibited platelet aggregation (P < 0.001) in vitro in healthy rats from the smallest dose tested, 2.5 mM, in a dose-dependent manner. The mean effective dose calculated was 10.6 mM. The highest dose tested, 40 mM, completely inhibited platelet aggregation (P < 0.001) induced by ADP. Platelet aggregation in plasma from septic rats was inhibited only with higher doses of FBP, starting from 20 mM (P < 0.001). The calculated mean effective dose was 19.3 mM. Ex vivo platelet aggregation in septic rats was significantly lower (P < 0.05) than healthy rats and the treatment with FBP, at the dose of 2 g/kg, diminished the platelet aggregation at the extension of 27% (P < 0.001), suggesting that FBP is a potent platelet aggregation inhibitor in vivo. Moreover, treatment with FBP 2 g/kg prevented thrombocytopenia (P < 0.001), prolongation of prothrombin and partial thromboplastin time (P < 0.001), but not fibrinogen, in septic rats. The most important findings in this study are that FBP is a potent platelet aggregation inhibitor, in vitro and ex vivo. It presents protective effects on coagulation abnormalities, which can represent a treatment against DIC. The mechanisms for these effects remain under investigation.

Effect of N-Acetylcysteine and Fructose-1,6-Bisphosphate in the Treatment of Experimental Sepsis

“…Another important hematological finding is that FBP prevents the septic-induced platelet decrease, indicating that FBP can act as an important platelet aggregation inhibitor, as previously demonstrated by Oliveira et al [47]. The inhibition of the platelet aggregation can to be very important, since this can improve the tissue perfusion, that is harmed in the septic shock for the formation of clots [47]. In order explain the survival curve results, creatinine and urea serum levels were measured and a significantly elevated urea level was demonstrated in all septic groups (treated and untreated) when compared to the control group.…”

“…These results also confirm the sepsis induction, as established by the International Sepsis Definitions Conference [46], and suggest that the animal's survival is not due to the bacterial infection decrease or due to the lymphocyte defenses increase. Another important hematological finding is that FBP prevents the septic-induced platelet decrease, indicating that FBP can act as an important platelet aggregation inhibitor, as previously demonstrated by Oliveira et al [47]. The inhibition of the platelet aggregation can to be very important, since this can improve the tissue perfusion, that is harmed in the septic shock for the formation of clots [47].…”

The effects of fructose diphosphate on routine coagulation tests in vitro

“…It has been reported in the literature that FDP resists platelet aggregation by inhibiting a variety of platelet aggregation inducers, including ADP. The role of platelet procoagulation mainly involves platelet factor 3 (PF3) in platelet phospholipids, which is exposed to the platelet coat after platelet aggregation activation and completes the activation of coagulation factor X and prothrombin on the surface of PF3 10 . We therefore hypothesized that the possible inhibition of platelet aggregation by FDP would affect the conversion of prothrombin to thrombin, thereby prolonging PT, APTT and TT.…”

Fructose-1,6-Bisphosphate Reduces the Mortality in Candida albicans Bloodstream Infection and Prevents the Septic-Induced Platelet Decrease

“…The role of FBP on platelets has been recently reported, being an important platelet aggregation inhibitor [22]. The inhibition of the platelet aggregation can be very important since this can improve the tissue perfusion that is harmed in the septic shock for the formation of clots [23].…”