Choline or CDP-choline attenuates coagulation abnormalities and prevents the development of acute disseminated intravascular coagulation in dogs during endotoxemia

Abstract

Sepsis/endotoxemia causes platelet dysfunctions, abnormalities in coagulation and hemostatic mechanisms leading to organ dysfunctions and mortality. Choline prevents organ injury and improves survival during endotoxemia. The main objective of the present study was to determine the effects of choline or cytidine-5'-diphosphocholine (CDP-choline) on endotoxin-induced activation of coagulation and development of disseminated intravascular coagulation (DIC). Dogs were treated intravenously (i.v.) with saline, choline (20 mg/kg), or CDP-choline (70 mg/kg) three times with 4-h intervals starting 5 min before i.v. injection of endotoxin (1 mg/kg). Platelet counts and functions, prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, coagulation factors, D-dimer and antithrombin (AT) were measured before and at 0.5-96 h after endotoxin. Circulating platelet, fibrinogen, coagulation factors and AT were decreased, whereas PT and aPTT were prolonged and serum D-dimer levels were elevated after endotoxin. Endotoxin-induced reductions in platelet counts and functions, fibrinogen, coagulation factors and AT were attenuated or blocked by choline or CDP-choline. Choline or CDP-choline blocked endotoxin-induced prolongation in PT and aPTT and enhancement in D-dimer. Elevated DIC scores were attenuated by choline and blocked by CDP-choline. Choline administration increased serum choline concentrations and caused bradycardia. Choline also increased choline and acetylcholine contents of circulating mononuclear cells and inhibited radioligand binding to their cholinergic receptors. These data show that choline administration, as choline chloride or CDP-choline, restores the abnormalities in the primary, secondary, and tertiary hemostasis and prevents the development of DIC during experimental endotoxemia in dogs probably by increasing both neuronal and non-neuronal cholinergic activity.

Protective effects of S-adenosylmethionine (SAMe) and silybin on hepatorenal and hemostatic functions in dogs with endotoxemia

“…In this study, endotoxemia was characterized by pyrexia, tachycardia, tachypnea (Table 1), leukopenia, and thrombocytopenia (Table 2), as well as organ damage (Table 3) within 1 h after LPS administration in dogs, as reported in our previous experiments (3)(4)(5)9,21). These observations after LPS administration were likely due to activation of the initial endocrine-metabolic stress response, defined as acute-phase reaction (24), in which TNF-α is one of the major cytokines to regulate host immunologic reaction against LPS (8,16,19).…”

“…Based on our study design, it is not possible to discriminate whether one of them (SAMe or silybin) is better to create these positive effects than the other. LPS-associated cytokine increases (TNF-α and interleukins) lead to production and release of hepatic acute-phase proteins into circulation, and this process results in hepatic injury and coagulation disorders (5,8,16). The presence of hemostasis abnormalities was shown by the prolonged global clotting times (PT and aPTT) in natural cases of dogs with sepsis (8,23).…”

“…Endotoxin entry into circulation from gram-negative bacteria, which are most commonly isolated in sepsis, gives rise to multiple organ failure, severe sepsis, and endotoxemia (1). Thus, experimental intravenous administrations of endotoxin (lipopolysaccharide, LPS) in humans (2), dogs (3)(4)(5), ovines (6), and calves (7) have been done to emulate sepsis (7,8). Hepatorenal injury and coagulation abnormalities such as disseminated intravascular coagulation (DIC) are the most common complications during sepsis (5,8,9).…”

“…Thus, experimental intravenous administrations of endotoxin (lipopolysaccharide, LPS) in humans (2), dogs (3)(4)(5), ovines (6), and calves (7) have been done to emulate sepsis (7,8). Hepatorenal injury and coagulation abnormalities such as disseminated intravascular coagulation (DIC) are the most common complications during sepsis (5,8,9). Thromboelastography (TEG), a point-of-care hemostatic analyzer, evaluates the changes in the viscoelastic properties of whole blood from initial clot formation through fibrinolysis, thereby providing global assessment of the hemostatic process.…”

Investigation of the dose-dependency of citicoline effects on nerve regeneration and functional recovery in a rat model of sciatic nerve injury

“…Therefore, it might be suggested that citicoline increases axonal recovery by preventing the activation of PLA2, which triggers Wallerian degeneration in the peripheral nerve damage, and thereby, the destruction of axon and myelin, by increasing the level Citicoline is the drug form of CDP-choline, a metabolic intermediate in membrane phospholipid biosynthesis (21). Citicoline administration was shown to exhibit cardiovascular (12,34) and neuroendocrine (10,11,18,19) effects, and provide benefit in endotoxemia (20,40) in experimental studies. Citicoline has been suggested to reduce brain injury in both experimental and clinical studies (2).…”