thromboxane-b2 and Disseminated-Intravascular-Coagulation

The physiological inhibitor of thrombin, antithrombin III (ATIII, Kybernin P) was investigated for its antiinflammatory and anticoagulant effects in a pig model of septic shock. Pigs were infused with a dose of 0.25 microgram. kg-1. h-1 of lipopolysaccharide (LPS) over a period of 3 hours. Animals developed systemic inflammation, disseminated intravascular coagulation (DIC), organ failure and cardiovascular abnormalities, namely pulmonary hypertension and systemic hypotension. Twenty septic pigs were allocated to 2 study groups, treated either with ATIII (n=10) or placebo (n=10). ATIII was administered as a 250-U/kg IV bolus infusion for 30 minutes (-60 to -30 minutes) followed by a single IV bolus of 125 U/kg (t=0) and a second 30-minute infusion of 250 U/kg (120 to 150 minutes). ATIII significantly prevented the development of a DIC; the increase in fibrin monomers (placebo, 11.4+/-9.1 reciprocal titers, at 6 hours) was completely overcome by ATIII (P<0. 05). ATIII significantly prevented the increase in thromboxane (TXB2) levels, which were 809+/-287 pg/mL in the placebo and 420+/-174 pg/mL in the verum group after 6 hours (P<0.02). On the other hand, ATIII had no influence on TNF levels. In a lethal study with an increased dose of LPS (0.5 microgram. kg-1. h-1). A significant reduction in mortality was observed in the ATIII group (0 of 7) compared with the placebo group (4 of 6) (P<0.05, chi2 test) a significant reduction of pulmonary hypertension (placebo, 42.0+/-11. 1 mm Hg; ATIII, 23.6+/-7.5 mm Hg, P<0.05), but no effect on systemic hypotension, was noted in the ATIII group. It was thus concluded that modulation of the procoagulatory state by substitution of ATIII results in a late beneficial antiinflammatory effect in this model of septic shock.

Topics: Animals; Antithrombin III; Blood Coagulation; Disseminated Intravascular Coagulation; Inflammation; Male; Shock, Septic; Swine; Thromboxane B2

Artifactual formation of thromboxane (TX) B2 during blood collection falsifies real value of TXB2 in plasma. A part (29.3%) of TXB2 is metabolized to 11-dehydro (DH)-TXB2 in several organs. 11-DH-TXB2 was not generated during blood collection or during serum formation. The peak amount of 11-DH-TXB2 after intravenous injection of TXB2 to rabbits was lower than that of TXB2, but the level of 11-DH-TXB2 was kept 2-3 times higher than that of TXB2 even after more than 5 min. A half life of 11-DH-TXB2 is 45-60 min in the human. Large species differences were found. In human urine, 11-DH-TXB2 was excreted 1.5-5.8 times more than 2,3-dinor-TXB2. Patients with ARDS and DIC, who received platelet transfusion, excreted increased amounts of 2,3-dinor-TXB2 and 11-DH-TXB2 in urine. 11-DH-TXB2 may be a useful parameter of TXA2 formation in pathological states.

Topics: Animals; Disseminated Intravascular Coagulation; Female; Humans; Infant, Newborn; Male; Platelet Aggregation; Respiratory Distress Syndrome; Thromboxane A2; Thromboxane B2

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

In order to evaluate TEI-4120 (3-benzoyl-N-beta-ethoxyisopropyl-2-methylindole), as a possible therapheutic compound to disseminated intravascular coagulation (DIC), DIC model in rats was induced by the treatment of lambda-carrageenan according to the method of Sugiyama et al. with minor modification. Two hours after intraperitoneal injection of lambda-carrageenan, plasma fibrinogen decreased and platelet count, prothrombin time, serial thrombin time and plasma TXB2 prolonged or increased. By use of this model, the activities of TEI-4120, new antithrombotic compound, was evaluated compared with three other compounds, aspirin, warfarin and heparin. As a result, TEI-4120 is effective in this model. Combination therapy of TEI-4120 and warfarin is more effective than single administration of TEI-4120. The effect of combination therapy of TEI-4120 and warfarin is consistent with that of heparin. The above result suggests that TEI-4120 seems to be a promising compound to the therapy of DIC.

Topics: Animals; Aspirin; Bleeding Time; Carrageenan; Disseminated Intravascular Coagulation; Fibrinolytic Agents; Hemodynamics; Heparin; Indoles; Male; Rats; Rats, Inbred Strains; Thromboxane B2; Warfarin