Abstract
BackgroundThe beneficial effects of heparin in the treatment of severe sepsis, septic shock, and sepsis-associated disseminated intravascular coagulation (DIC) have recently been reported. However, the mechanisms underlying the therapeutic benefits of heparin in these conditions have not yet been clearly elucidated. The purpose of this study was to confirm the effect of heparin of neutralizing histone toxicity.MethodsRat models of histone H3-induced organ dysfunction were administered in a low or high dose of unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), or argatroban, and the therapeutic effects of each anticoagulant were examined. In another series, the survival of the histone H3-administered animals was evaluated. Furthermore, the effect of each of the aforementioned anticoagulants on cell death induced by histone H3 was examined in cultured vascular endothelial cells and leukocytes.ResultsAlthough UFH, LMWH, and argatroban significantly suppressed the histone-induced decrease of the WBC and platelet counts in the animal models of organ dysfunction, only UFH and LMWH attenuated hepatic and renal dysfunction. In addition, the mortality was significantly reduced only by high-dose UFH and LMWH. The in vitro study revealed that both vascular endothelial cell death and leukocyte cell death were significantly attenuated by UFH and LMWH but not by argatroban.ConclusionsThe histone-neutralizing effect of heparin may contribute to the beneficial effects of heparins observed in the animal study. The results of the in vitro study further confirmed the above contention and suggested that heparin binds to histones to attenuate the cytotoxic actions of the latter. Since heparin has been demonstrated to protect animals from the organ damage induced by histones and consequently reduce the mortality, administration of heparin could become a treatment of choice for patients suffering from severe sepsis.
Highlights
The beneficial effects of heparin in the treatment of severe sepsis, septic shock, and sepsis-associated disseminated intravascular coagulation (DIC) have recently been reported
The fibrinogen degradation products (FDP) levels were significantly lower in the high-dose groups than in the low-dose groups (p < 0.01 for the unfractionated heparin (UFH) group, and p < 0.05 for the low-molecular-weight heparin (LMWH) and argatroban groups) (Fig. 1)
One of the purposes of this study was to examine the organ- and life-protective effects of UFH and LMWH, and our results indicated that both heparins demonstrated remarkable effects in both the in vitro and in vivo studies
Summary
The beneficial effects of heparin in the treatment of severe sepsis, septic shock, and sepsis-associated disseminated intravascular coagulation (DIC) have recently been reported. Ekaney et al [3] have demonstrated the increased levels of circulating histone in septic patients They reported that histones play important roles in the pathogenesis of sepsis. A randomized controlled trial (RCT) was carried out to examine the effect of low-dose unfractionated heparin (UFH), which inhibits the coagulation system without increasing the bleeding risk, as a complementary treatment for sepsis [5, 9]. These studies failed to yield the expected results, recent systematic reviews have reported a consistent trend of favorable results. The effect of each anticoagulant was examined in animal models of histone-induced organ dysfunction, and in the second experiment, the effects of the anticoagulants were examined in a coagulation factor-free in vitro setting
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