6-ketoprostaglandin-f1-alpha and Disseminated-Intravascular-Coagulation

To clarify whether activated platelets play an important role in the occurrence and exacerbation of disseminated intravascular coagulation (DIC), we investigated the effects of 4 anti-platelet drugs, a PGI2 analog (CS-570), a thromboxane synthetase inhibitor (dazoxiben), a thromboxane receptor antagonist (BM-13177), and ticlopidine, in an experimental DIC model in rats. Experimental DIC was induced by a continuous infusion of lipopolysaccharide (LPS derived from E. coli, 055 B5, 25 mg/kg/hr) for 4 hrs. In the time-course determination of the coagulation parameters and prostanoids, an abrupt increase in TxB2 (a stable metabolite of TxA2) and 6-keto-PGF1 alpha (a stable metabolite of PGI2) was followed by a decrease in platelet count, a prolongation of blood coagulation time, and an increase in fibrinogen/fibrin degradation products (FDP). Four hours after the start of LPS infusion, the rats were considered to be in the state of DIC. The effects of the anti-platelet drugs were investigated 4 hrs after the start of LPS infusion. CS-570 and ticlopidine ameliorated DIC in a dose-dependent manner. CS-570 (10 micrograms/kg/min) improved DIC in the platelet count, prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (Fbg), and FDP, without affecting TxB2 and 6-keto-PGF1 alpha formation. Ticlopidine (200 mg/kg, i.p.) prevented the exacerbation of DIC in such item parameters as platelet count, APTT, and FDP. Both dazoxiben and BM-13177 (30 mg/kg, i.p.) ameliorated DIC in following parameters as platelet count, APTT and FDP. Dazoxiben, but not BM-13177, significantly inhibited the increase in TxB2 concentration at 4 hr. These observations suggest that drugs which inhibit platelet activation by a TxA2-dependent route are effective in improving DIC induced by LPS, and that drugs which inhibit multiple platelet-activating routes improve DIC in more item parameters than drugs which inhibit only the TxA2-dependent activating route. Consequently, it is concluded that activated platelets might play an important role in the occurrence and exacerbation of DIC induced by LPS, and that one of the roles of TxA2 in DIC is to activate platelets.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Coagulation; Disseminated Intravascular Coagulation; Endotoxins; Epoprostenol; Fibrin; Humans; Imidazoles; Kidney Glomerulus; Male; Platelet Activation; Platelet Aggregation Inhibitors; Platelet Count; Prostaglandins, Synthetic; Rats; Rats, Inbred Strains; Sulfonamides; Thromboxane B2; Thromboxane-A Synthase; Ticlopidine

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Disseminated Intravascular Coagulation; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thromboxane B2

Acute disseminated intravascular coagulation (DIC) is a life-threatening condition that may be encountered in many situations, especially in cases of shock with uncontrollable hemorrhage. Anisodamine, an alkaloid extracted from a Chinese herb, is well known for its dramatic therapeutic effect on DIC. Sixty male rabbits were used to establish an acute DIC model. A total of 240 blood samples were taken for laboratory assays of changes in blood coagulation factors, platelet count, platelet adhesion, platelet aggregation, malondialdehyde (MDA), thromboxane B2 (TXB2), and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha). Changes of the microcirculatory status and the rate of the blood flow in the conjunctival capillaries of 60 rabbits were observed with WXS-II microcirculation microscope. Pathological sections of the lungs and kidneys were studied. Our investigation showed the presence of microthrombi in the microvasculature. After treatment with anisodamine, the prothrombin time stayed in the normal range, fibrinogen consumption was lessened, adenosine-diphosphate-induced platelet aggregation was inhibited, thromboxane B2 and malondialdehyde concentrations were significantly lower than in the control group, and the elevated quantity of 6-keto-PGF1 alpha was spared. We concluded that the anti-platelet-aggregating, microcirculation-facilitating, thromboxane-B2-inhibiting, malondialdehyde-inhibiting, and 6-keto-PGF1 alpha-sparing effects of anisodamine are the important mechanisms of its dramatic therapeutic effect on DIC.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Coagulation; Disseminated Intravascular Coagulation; Kidney; Lung; Male; Malondialdehyde; Microcirculation; Platelet Aggregation; Platelet Count; Rabbits; Regional Blood Flow; Solanaceous Alkaloids; Thromboxane B2

Platelet/vascular and plasma elements of hemostasis were investigated in normal subjects and coronary patients under stimulated emotional stress, following the assessment of vascular wall antithrombogenic properties on the basis of evidence from short-term local vascular ischemia (the cuff test). In normal subjects, vascular wall antithrombotic properties remained unchanged, providing a sufficient anticoagulant and thrombolytic support under emotional stress and thereby protecting the body against thrombosis. Coronary patients showed depressed vascular-wall antiaggregant, anticoagulant and fibrinolytic activity and latent disseminated intravascular microcoagulation that tended to progress under mental stress, creating a risk of intravascular thrombosis.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Blood Coagulation; Blood Platelets; Blood Vessels; Coronary Disease; Disseminated Intravascular Coagulation; Hemostasis; Humans; Middle Aged; Nucleotides, Cyclic; Thromboxane B2

During endotoxemia there is increased synthesis of arachidonic-acid-derived metabolites. We investigated the potential deleterious role of the proaggregatory vasoconstrictor, thromboxane A2, an arachidonic acid metabolite, in the endotoxic shocked rat. Plasma levels of thromboxane B2, the stable metabolite of thromboxane A2, 6-keto-PGF1 alpha, the stable metabolite of PGI2, and PGE were measured via radioimmunoassay. We also investigated the therapeutic efficacy of the fatty acid cyclo-oxygenase imidazole and 7(1-imidazolyl)-heptanoic acid (7-IHA), in endotoxic shocked rats. Thirty minutes after intravenous (IV) administration of Salmonella enteritidis endotoxin (20 mg/kg), plasma immunoreactive thromboxane B2 (TxB2) was increased from nondetectable levels (less than 200 pg/ml) in normal nonshocked rats to 2207 +/- 282 pg/ml (N = 16). The 6-keto-PGF1 alpha level was increased from nondetectable levels to 840 +/- 59 pg/ml (N = 8), and prostaglandin E rose from 146 +/- 33 to 2160 +/- 606 pg/ml (N = 5). Ibuprofen (3.75 mg/kg) or indomethacin (10 mg/kg) administered IV 30 min prior to endotoxin (20 mg/kg) improved the survival rate to 81% (N = 15, P less than 0.001) and 78% (N = 17, P less than 0.001), respectively, compared to the 24-hr survival of 8% (N = 26) in the vehicle-treated rats. Ibuprofen also inhibited the endotoxin-induced elevation of TxB2, 6-keto-PGF1 alpha, and fibrinogen/fibrin degradation products. Imidazole (30 mg/kg) or 7-IHA (30 mg/kg), IV, 30 min prior to endotoxin improved survival 65% (N = 11) and 81% (N = 15), respectively. These drugs also inhibited endotoxin-induced elevations in TxB2 and fibrinogen/fibrin degradation products, but did not inhibit endotoxin-induced elevations in plasma PGE. These results are consistent with the suggestion that TxA2 plays a role in the pathogenesis of endotoxic shock.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dinoprost; Disseminated Intravascular Coagulation; Fibrin Fibrinogen Degradation Products; Ibuprofen; Indomethacin; Male; Muridae; Prostaglandins E; Prostaglandins F; Shock, Septic; Thromboxane A2; Thromboxanes