Effects of subacute oral warfarin administration on peripheral blood granulocytes in rats

Belij, Sandra; Miljković, Djordje; Popov, Aleksandra; Subota, Vesna; Timotijević, Gordana; Slavić, Marija; Mirkov, Ivana; Kataranovski, Dragan; Kataranovski, Milena

doi:10.1016/j.fct.2012.01.049

Cited by 29 publications

(23 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, using previously validated conformational-specific antibodies [16, 30, 31, 33, 34, 36], we were able to show that γ-carboxylated GRP and MGP are produced by these immune cells. Nevertheless, controversial data has been reported concerning the effect of warfarin on the immune system, described to act as an anti-inflammatory, pro-inflammatory, or not related agent [27, 50, 51]. Altogether, these data clearly emphasize the need for additional molecular studies to unveil the activity of GRP in the inflammatory process and further evaluate the modulating potential of its γ- carboxylation status.…”

Section: Discussionmentioning

confidence: 99%

Gla-rich protein function as an anti-inflammatory agent in monocytes/macrophages: Implications for calcification-related chronic inflammatory diseases

et al. 2017

View full text Add to dashboard Cite

Calcification-related chronic inflammatory diseases are multifactorial pathological processes, involving a complex interplay between inflammation and calcification events in a positive feed-back loop driving disease progression. Gla-rich protein (GRP) is a vitamin K dependent protein (VKDP) shown to function as a calcification inhibitor in cardiovascular and articular tissues, and proposed as an anti-inflammatory agent in chondrocytes and synoviocytes, acting as a new crosstalk factor between these two interconnected events in osteoarthritis. However, a possible function of GRP in the immune system has never been studied. Here we focused our investigation in the involvement of GRP in the cell inflammatory response mechanisms, using a combination of freshly isolated human leucocytes and undifferentiated/differentiated THP-1 cell line. Our results demonstrate that VKDPs such as GRP and matrix gla protein (MGP) are synthesized and γ-carboxylated in the majority of human immune system cells either involved in innate or adaptive immune responses. Stimulation of THP-1 monocytes/macrophages with LPS or hydroxyapatite (HA) up-regulated GRP expression, and treatments with GRP or GRP-coated basic calcium phosphate crystals resulted in the down-regulation of mediators of inflammation and inflammatory cytokines, independently of the protein γ-carboxylation status. Moreover, overexpression of GRP in THP-1 cells rescued the inflammation induced by LPS and HA, by down-regulation of the proinflammatory cytokines TNFα, IL-1β and NFkB. Interestingly, GRP was detected at protein and mRNA levels in extracellular vesicles released by macrophages, which may act as vehicles for extracellular trafficking and release. Our data indicate GRP as an endogenous mediator of inflammatory responses acting as an anti-inflammatory agent in monocytes/macrophages. We propose that in a context of chronic inflammation and calcification-related pathologies, GRP might act as a novel molecular mediator linking inflammation and calcification events, with potential therapeutic application.

show abstract

Section: Discussionmentioning

confidence: 99%

Gla-rich protein function as an anti-inflammatory agent in monocytes/macrophages: Implications for calcification-related chronic inflammatory diseases

et al. 2017

View full text Add to dashboard Cite

show abstract

“…It is also possibly that the bromine group is ionized to a bromide ion that is released after the BDF absorption in the gastrointestinal tract (Schema 1), since conversion of bromide ion to nitrous bromide or hypobromous acid can occur, and is known to affect mitochondrial functions, resulting in increased oxidative stress [17]. It has been demonstrated that warfarin interacts with polymorphonuclear leukocyte (PMN) myeloperoxidase [18], which may induce hemolysis. It is possible that BDF also may interact with PMN's and thereby induces oxidative stress and subsequent rapid temporal hemolysis.…”

Section: Discussionmentioning

confidence: 99%

Brodifacoum Induces Early Hemoglobinuria and Late Hematuria in Rats: Novel Rapid Biomarkers of Poisoning

Ware

Feinstein²,

Rubinstein³

et al. 2015

Am J Nephrol

View full text Add to dashboard Cite

Introduction: Brodifacoum (BDF) is a superwarfarin that is used primarily as a rodenticide. There have been increasing numbers of reports of human cases of accidental or intentional BDF ingestion with high mortality rate. Its broad availability and high lethality suggest that BDF should be considered a potential chemical threat. Currently, there is no biomarker for early detection of BDF ingestion in humans; patients typically present with severe coagulopathy. Since we demonstrated earlier that warfarin can induce acute kidney injury with hematuria, we tested whether BDF would also lead to change in urinary biomarkers. Material and Methods: BDF was administered to Sprague Dawley rats via oral gavage. N-acetylcysteine (NAC) was given per os in drinking water 24 h prior to BDF. Urinalysis was performed at different times after BDF administration. Anticoagulation and serum creatinine levels were analyzed in the blood. Results: We observed that within a few hours the animals developed BDF-dose-dependent transient hemoglobinuria, which ceased within 24 h. This was accompanied by a transient decrease in hematocrit, gross hemolysis and an increase in free hemoglobin in the serum. At later times, animals developed true hematuria with red blood cells in the urine, which was associated with BDF anticoagulation. NAC prevented early hemoglobinuria, but not late hematuria associated with BDF. Conclusions: We propose that transient early hemoglobinuria (associated with oxidative stress) with consecutive late hematuria (associated with anticoagulation) are novel biomarkers of BDF poisoning, and they can be used in clinical setting or in mass casualty with BDF to identify poisoned patients.

show abstract

“…In fact, warfarin has been shown to raise the plasma levels of interleukin-6 and acute phase proteins, including fibrinogen, implying that it induces a mild inflammatory status in rats. 51 The coagulating activity of BjV was firstly evaluated in plasma pools from animals pretreated with saline and warfarin, as well as in a rat plasma pool that has been adsorbed with BaCl 2 to remove VKDCF; adsorption with barium was used to test if warfarin per se interfered in BjV coagulating activity. The efficiency of BaCl 2 adsorption was tested by assaying PT, which was markedly prolonged (greater than 200 s) in the BaCl 2 -treated plasma pool.…”

Section: Warfarinization Reduces the In Vitro Coagulant Activity Of Bjvmentioning

confidence: 99%

Bothrops jararaca envenomation: Pathogenesis of hemostatic disturbances and intravascular hemolysis

Senise

Yamashita

Santoro

2015

Exp Biol Med (Maywood)

View full text Add to dashboard Cite

To attain fully functional biological activity, vitamin-K dependent coagulation factors (VKDCF) are g-carboxylated prior to secretion from liver. Warfarin impairs the g-carboxylation, and consequently their physiological function. Bothrops jararaca snake venom (BjV) contains several activators of blood coagulation, especially procoagulant enzymes (prothrombin and factor X activators) and thrombin-like enzymes. In order to clarify the relative contribution of prothrombin and factor X activators to the hemostatic disturbances occurring during experimental B. jararaca envenomation, warfarin was used to deplete VKDCF, prior to BjV administration. Male Wistar rats were pretreated with saline (Sal) or warfarin (War) and inoculated subsequently with BjV or saline, thus forming four groups: Sal þ Sal (negative control), Sal þ BjV (positive control), War þ Sal (warfarinization control), and War þ BjV. Three hours after inoculation, prothrombin and factor X levels fell 40% and 50%, respectively; levels of both factors decreased more than 97% in the War þ Sal and War þ BjV groups. Platelet counts dropped 93% and 76% in Sal þ BjV and War þ BjV, respectively, and plasma fibrinogen levels decreased 86% exclusively in Sal þ BjV. After 6 and 24 h, platelet counts and fibrinogen levels increased progressively. A dramatic augmentation in plasma hemoglobin levels and the presence of schizocytes and microcytes in the Sal þ BjV group indicated the development of intravascular hemolysis, which was prevented by warfarin pretreatment. Our findings show that intravascular thrombin generation has the foremost role in the pathogenesis of coagulopathy and intravascular hemolysis, but not in the development of thrombocytopenia, in B. jararaca envenomation in rats; in addition, fibrinogenases (metalloproteinases) may contribute to coagulopathy more than thrombin-like enzymes.

show abstract

Effects of subacute oral warfarin administration on peripheral blood granulocytes in rats

Cited by 29 publications

References 68 publications

Gla-rich protein function as an anti-inflammatory agent in monocytes/macrophages: Implications for calcification-related chronic inflammatory diseases

Gla-rich protein function as an anti-inflammatory agent in monocytes/macrophages: Implications for calcification-related chronic inflammatory diseases

Brodifacoum Induces Early Hemoglobinuria and Late Hematuria in Rats: Novel Rapid Biomarkers of Poisoning

Bothrops jararaca envenomation: Pathogenesis of hemostatic disturbances and intravascular hemolysis

Contact Info

Product

Resources

About