thromboxane-a2 and Thrombocytopenia

A severe case of preeclampsia with Hellp Syndrome is reported. Clinical findings, laboratory abnormalities and pathogenesis, were discussed. We concluded that severe preeclampsia and Hellp Syndrome are not different diseases, but the natural course of preeclampsia per se.

Topics: Adult; Anemia, Hemolytic; Anticonvulsants; Antihypertensive Agents; Cesarean Section; Combined Modality Therapy; Epoprostenol; Female; Humans; Incidence; Liver Diseases; Pre-Eclampsia; Pregnancy; Syndrome; Thrombocytopenia; Thromboxane A2; Vasoconstriction

Several selective and potent thromboxane synthetase inhibitors have now been described. In this paper I shall summarize their effects on platelet aggregation, endotoxin- and thrombin-induced pulmonary hypertension, the Forssman reaction-induced thrombocytopenia, and the rat tail vein bleeding time. Although any clinical utility of thromboxane synthetase inhibition remains to be demonstrated, it may be useful in conditions where vasoconstriction or vasospasm are involved, particularly where platelet activation is a contributing factor.

Topics: Animals; Bleeding Time; Blood Platelets; Hypertension, Pulmonary; Imidazoles; Platelet Aggregation; Prostaglandin Endoperoxides; Structure-Activity Relationship; Thrombocytopenia; Thromboxane A2; Thromboxane-A Synthase; Vasoconstriction

Topics: Animals; Arachidonic Acids; Blood Coagulation Disorders; Fibrinolysis; Hemostasis; Humans; Mice; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Neoplastic Cells, Circulating; Platelet Aggregation; Thrombocytopenia; Thromboxane A2

1. The lack of a general agreement on the definition of PE makes the interpretation of laboratory findings in different series of these patients difficult. 2. Thrombocytopenia is the most common hemostatic abnormality in patients with PE and is caused by platelet consumption. 3. There is little concrete evidence that thrombin mediates the thrombocytopenia in most of these patients. 4. Immune mechanisms or severe vasospasm with resultant endothelial damage may contribute to the thrombocytopenia in some patients.

Topics: Anemia, Hemolytic; Disseminated Intravascular Coagulation; Eclampsia; Epoprostenol; Factor VIII; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Fibrinopeptide A; Humans; Hypertension; Platelet Count; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Hematologic; Thrombin; Thrombocytopenia; Thromboxane A2

Collagen-induced platelet activation is a key step in the development of arterial thrombosis via its interaction with the receptors glycoprotein (GP)VI and integrin α(2) β(1) . Adhesion and degranulation-promoting adapter protein (ADAP) regulates α(IIb) β(3) in platelets and α(L) β(2) in T cells, and is phosphorylated in GPVI-deficient platelets activated by collagen.. To determine whether ADAP plays a role in collagen-induced platelet activation and in the regulation and function of α(2) β(1).. Using ADAP(-/-) mice and synthetic collagen peptides, we investigated the role of ADAP in platelet aggregation, adhesion, spreading, thromboxane synthesis, and tyrosine phosphorylation.. Platelet aggregation and phosphorylation of phospholipase Cγ2 induced by collagen were attenuated in ADAP(-/-) platelets. However, aggregation and signaling induced by collagen-related peptide (CRP), a GPVI-selective agonist, were largely unaffected. Platelet adhesion to CRP was also unaffected by ADAP deficiency. Adhesion to the α(2) β(1) -selective ligand GFOGER and to a peptide (III-04), which supports adhesion that is dependent on both GPVI and α(2) β(1), was reduced in ADAP(-/-) platelets. An impedance-based label-free detection technique, which measures adhesion and spreading of platelets, indicated that, in the absence of ADAP, spreading on GFOGER was also reduced. This was confirmed with non-fluorescent differential-interference contrast microscopy, which revealed reduced filpodia formation in ADAP(-/-) platelets adherent to GFOGER. This indicates that ADAP plays a role in mediating platelet activation via the collagen-binding integrin α(2) β(1). In addition, we found that ADAP(-/-) mice, which are mildly thrombocytopenic, have enlarged spleens as compared with wild-type animals. This may reflect increased removal of platelets from the circulation.

Topics: Adaptor Proteins, Signal Transducing; Animals; Blood Platelets; Carrier Proteins; CD36 Antigens; Collagen; Immunoglobulin Variable Region; Integrin alpha2beta1; Mice; Mice, Inbred C57BL; Mice, Knockout; Peptides; Phospholipase C gamma; Phosphorylation; Platelet Activation; Platelet Adhesiveness; Platelet Aggregation; Platelet Glycoprotein GPIIb-IIIa Complex; Pseudopodia; Splenomegaly; Thrombocytopenia; Thromboxane A2; Thromboxane B2; Time Factors; Tyrosine

We report a family with inherited macrothrombocytopenia and characteristic large membrane complexes in the platelets. Two affected subjects had platelet counts of 40 and 65 x 10(9)/L respectively as assessed by contrast phase microscopy. Ultrastructural studies revealed giant spheroid platelets with characteristic large membrane complexes and/or giant vacuoles containing platelet organelles. Immunohistochemical studies of actin and tubulin showed a disorganization of the microtubule and actin systems. These abnormalities were absent in leukocytes, indicating a platelet-specific cytoskeleton disorder. Platelet autoantibodies were repeatedly absent. Nevertheless, in the peripheral blood we observed several figures of platelet phagocytosis by macrophages and neutrophils. The in vitro aggregometric response of platelets to ADP, collagen, thrombin, ristocetin was present, but shape change was absent. The urinary excretion of thromboxane A2 metabolites of the affected subjects were approximately 2 standard deviations above control values, in spite of a reduced maximal biosynthetic capacity of thromboxane from giant platelets assessed in vitro during whole blood clotting. This inherited platelet disorder shows structural and functional features which allow to distinguish it from other syndromes associated with giant platelets. We also propose to include ultrastructural and cytoskeletal studies in the diagnosis as well as in the classification of inherited giant platelet disorders.

Topics: Blood Platelets; Cytoskeleton; Female; Humans; Male; Middle Aged; Phagocytosis; Thrombocytopenia; Thromboxane A2

Thrombocytopenia frequently occurs early in the course of Gram-negative bacterial infections. Triflavin, an Arg-Gly-Asp-containing disintegrin, has been suggested to interfere with the interaction of fibrinogen with the glycoprotein IIb/IIIa complex. The present study was undertaken to determine whether triflavin could prevent thrombocytopenia in lipopolysaccharide (LPS)-treated rats.. In this study, 51Cr-labeled platelets were used to assess blood and tissue platelet accumulation after LPS challenge. The administration of LPS (4 mg/kg IV bolus) for 4 hours induced a reduction in radiolabeled platelets in blood and an obvious accumulation of platelets in liver. Triflavin (500 microg/kg) but not GRGDS (20 mg/kg) significantly prevented the alteration of radiolabeled platelet distribution in blood and liver when induced by LPS. Furthermore, triflavin but not GRGDS markedly suppressed the elevation in plasma thromboxane B2 concentration within the 4-hour period of LPS administration. In LPS-treated rats, the 5-hydroxytryptamine level was lower in the blood and higher in the liver compared with levels in normal saline-treated rats. Pretreatment with triflavin (500 microg/kg) significantly reversed the 5-hydroxytryptamine concentration in blood and liver of LPS-treated rats. In histological examinations and platelet adhesion assay, triflavin markedly inhibited the adhesion of platelets to subendothelial matrixes in vivo and in vitro.. The results indicate that triflavin effectively prevents thrombocytopenia, possibly through the following 2 mechanisms: (1) Triflavin markedly inhibits platelet aggregation, resulting in decreased thromboxane A2 formation. (2) It inhibits the adhesion of platelets to subendothelial matrixes, thereby leading to a reversal in the distribution of platelets in blood and liver in LPS-treated rats.

Topics: Animals; Aorta, Thoracic; Bacteremia; Crotalid Venoms; Endothelium, Vascular; Escherichia coli; Lipopolysaccharides; Liver; Male; Microscopy, Electron; Nitrates; Peptides; Platelet Adhesiveness; Platelet Aggregation Inhibitors; Rats; Rats, Sprague-Dawley; Serotonin; Thrombocytopenia; Thromboxane A2

LCB 2853 (sodium 4-[[1-[[[(4-chlorophenyl)sulfonyl]amino]methyl]cyclopentyl] methyl]benzeneacetate, CAS 141335-11-7) was demonstrated to be a potent thromboxane A2/prostaglandin H2 (TXA2/PGH2) receptor antagonist in in vitro, ex vivo and in vivo experiments. The specific mechanism of action was studied in [3H]SQ 29548 receptor binding studies (pKi = 7.93) and was shown to be of competitive nature in U 46619-induced platelet aggregation (pA2 = 6.82). TXA2-dependent platelet rich plasma (PRP) aggregation (U 46619, arachidonic acid (AA), collagen, ADP or serotonin second phase) was inhibited in vitro in humans (IC50:0.037-0.65 mumol/l) and different animal species, as well as ex vivo i.v. rat and p.o. guinea-pig AA-induced aggregation (ED50 = 48 and 57 micrograms/kg). The U 46619-induced contractions of aorta, caudal artery and trachea were inhibited in a dose-dependent way (IC50 = 0.07, 0.02 and 0.5 mumol/l respectively). In vivo, both against platelet aggregation and vasoconstriction, LCB 2853 showed an ED50 lower than 1 mg/kg i.v. in rat AA-induced thrombocytopenia or U 46619-induced hypertension (ED50 = 0.25 and 0.16 mg/kg) as well as in AA-induced sudden death in the mouse (ED50 = 0.44 mg/kg). The U 46619-induced bronchoconstriction was blocked after i.v. administration of LCB 2853 (ED50 = 18.4 micrograms/kg). The duration of action observed in different models was 6 h by oral route and between 3 and 5 h by intravenous route. These properties in TXA2-dependent models led to further investigations of the antithrombotic activity of this novel TXA2 antagonist.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Administration, Oral; Animals; Blood Platelets; Blood Pressure; Death, Sudden; Dogs; Female; Guinea Pigs; Humans; In Vitro Techniques; Injections, Intravenous; Male; Mice; Muscle Contraction; Muscle, Smooth; Muscle, Smooth, Vascular; Phenylacetates; Platelet Aggregation Inhibitors; Prostaglandin Endoperoxides, Synthetic; Rabbits; Radioligand Assay; Rats; Rats, Wistar; Receptors, Thromboxane; Sulfonamides; Thrombocytopenia; Thromboxane A2; Vasodilator Agents

When injected i.v. to guinea pigs, the granulocyte secretagog N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP) induces bronchoconstriction (BC), lung platelet sequestration and increased transendothelial albumin exchanges in lungs. We evaluated BC and the variations of the lung contents in radiolabeled platelets, erythrocytes and extravascular albumin, as measurements of platelet lung entrapment, reduction of lung blood volume and increase of transendothelial albumin exchanges, respectively. Trimetoquinol, a thromboxane A2 (TXA2)-endoperoxide receptor antagonist, inhibited BC and platelet entrapment by lungs induced by fMLP, but protection was nonspecific because it also suppressed BC by histamine. The specific TXA2 synthetase inhibitor/endoperoxide receptor antagonist ridogrel suppressed BC and reduced lung platelet entrapment, but failed to prevent the increase of extravascular albumin and the decrease of erythrocyte lung contents due to fMLP. Consequently, the fMLP-induced increase of vascular albumin exchanges and reduction of lung blood volume are TXA2-independent. Aspirin prevented BC, but failed to suppress lung platelet entrapment by fMLP, indicating that in vivo platelet activation is not TXA2-dependent, even though the levels of circulating TXB2, the stable metabolite of TXA2, were increased after fMLP concomitantly with that of 6-keto-prostaglandin (PG)F1 alpha, the stable metabolite of PGI2. The ridogrel-treated animals showed reduced blood level of TXB2 and increased levels of 6-keto-PGF1 alpha after fMLP challenge. Blocking the cyclooxygenase pathway with aspirin prevented ridogrel-induced protection against lung platelet sequestration after fMLP, supporting the concept that rechanneling of arachidonate metabolism toward protective prostaglandins accounts for protection by ridogrel.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Blood Platelets; Bronchoconstriction; Guinea Pigs; Imidazoles; Lung; N-Formylmethionine Leucyl-Phenylalanine; Pentanoic Acids; Platelet Aggregation; Prostaglandin Endoperoxides, Synthetic; Pyridines; Radioimmunoassay; Serum Albumin; Suprofen; Thrombocytopenia; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase; Tretoquinol

Arthritis induced in hyperimmune rabbits by the intra-articular injection of the specific antigen was associated with a fall in circulating platelet number that lasted up to 60 days. Pretreatment of the animals with indomethacin and econazol at doses that significantly decreased thromboxane levels in the synovial fluids reduced the arthritis-related thrombocytopenia in the acute phase of arthritis. A similar inhibition was seen when L-655,240, a specific Thromboxane A2 antagonist, and BN 52021, a Platelet Activating Factor antagonist were used. The results suggest that both thromboxane and PAF are involved in the mechanisms leading to thrombocytopenia in this experimental model of arthritis.

Topics: Animals; Arthritis, Experimental; Diterpenes; Econazole; Female; Ginkgolides; Indoles; Indomethacin; Lactones; Male; Platelet Activating Factor; Rabbits; Synovial Fluid; Thrombocytopenia; Thromboxane A2; Thromboxane B2

A synthetic, tyrosine-sulfated, dodecapeptide (BG8865) modeled on residues 53-64 of hirudin was found to elevate the activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT) of human plasma in a dose-dependent manner. The most sensitive assay was the TT, which was prolonged 2 and 3 times control values at 2.2 and 4.1 micrograms/mL hirudin peptide, respectively. The sulfated dodecapeptide exhibited no dependency on antithrombin III as monitored by the APTT in the presence of sheep anti-human antithrombin III antibodies, and its activity was not neutralized by platelet releasates or platelet factor 4. In studies of thrombin-induced platelet activation, the hirudin peptide was found to block aggregation, serotonin release and thromboxane A2 generation. At thrombin concentrations of 0.25 U/mL, the IC50 (concentration resulting in 50% inhibition) for inhibition of platelet aggregation was 0.72 micrograms/mL peptide. Inhibition of TXA2 generation and serotonin release correlated closely with inhibition of aggregation. Using platelets from patients with clinically documented heparin-induced thrombocytopenia anticoagulant doses of heparin were found to induce platelet aggregation and thromboxane A2 generation. In sharp contrast, anticoagulant-equivalent doses of hirudin peptide had no effect on patient platelets, as evidenced by a lack of platelet aggregation and thromboxane A2 generation. These data provide compelling in vitro evidence that the hirudin peptide has several potential advantages over heparin, namely effective inhibition of thrombin-induced platelet activities, co-factor independence, insensitivity to endogenous heparin-neutralizing factors, and an apparent lack of direct or immune-mediated platelet stimulating properties.

Topics: Amino Acid Sequence; Anticoagulants; Blood Coagulation; Blood Platelets; Heparin; Hirudins; Humans; In Vitro Techniques; Molecular Sequence Data; Oligopeptides; Partial Thromboplastin Time; Peptide Fragments; Platelet Aggregation; Platelet Aggregation Inhibitors; Thrombin; Thrombocytopenia; Thromboxane A2

The effects of S-145, a newly synthesized thromboxane, A2 (TXA2) receptor antagonist, were studied on collagen-induced changes of electrocardiograms (ECG) in rats and thrombocytopenia in rats and mice. Intravenous injection of collagen induced abnormal ECG changes such as elevation or depression of the ST segment, arrhythmia and in severe cases, cardiac arrest. These changes peaked at 3-5 min and lasted for 10 min. S-145 showed remarkable improvement of the ECG changes by both intravenous and oral administration, and the action lasted over 4 hr with 10 mg/kg, p.o. Reference compounds ONO-3708, dazoxiben and aspirin also improved the ECG changes significantly, but ticlopidine was ineffective. S-145 prevented the collagen-induced thrombocytopenia in rats but did not affect the increase in plasma TXB2 levels. S-145 also prevented collagen-induced thrombocytopenia in mice after either intravenous or oral administration in a dose-dependent manner. The efficacy of S-145 was 4-13 times greater than those of the reference compounds, and the duration of action was over 4 hr with 10 mg/kg, p.o. These results indicate that S-145 is a potent, orally, active and long-lasting TXA2 receptor antagonist, which will be promising as a drug for thromboembolism and ischemic heart disease caused by platelet activation.

Topics: Administration, Oral; Animals; Aspirin; Bridged Bicyclo Compounds; Bridged-Ring Compounds; Collagen; Electrocardiography; Fatty Acids, Monounsaturated; Imidazoles; In Vitro Techniques; Injections, Intravenous; Male; Mice; Mice, Inbred Strains; Prostaglandins; Rats; Receptors, Prostaglandin; Receptors, Thromboxane; Thrombocytopenia; Thromboxane A2

The production of thromboxane A2 (TxA2) and prostacyclin (PGI2) was studied in patients with chronic idiopathic thrombocytopenic purpura (10 patients) compared to central thrombocytopenia (five patients) and healthy subjects (10 subjects). This production was monitored by the assay of urinary 2,3-dinor-TxB2 and 2,3-dinor-6-keto-PGF1 alpha as respective breakdown products of TxA2 and PGI2 by stable isotope dilution assays employing negative ion-chemical gas-chromatography-mass-spectrometry. Evidence is presented for the existence of an enhanced PGI2 and TxA2 urinary excretion in the group of idiopathic thrombocytopenic purpura (ITP) patients. Moreover, production of serum TxB2 per platelet was decreased in ITP group. These results provide arguments for an in vivo platelet cyclooxygenase hyperactivity during chronic ITP.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Epoprostenol; Female; Humans; Male; Middle Aged; Platelet Count; Prospective Studies; Purpura, Thrombocytopenic; Thrombocytopenia; Thromboxane A2; Thromboxane B2

Heparin-induced thrombosis is due to an immune-mediated activation of circulating platelets and has significant clinical implications for patients with vascular disease. The purpose of this article was (1) to define the biochemical mechanisms of heparin-induced platelet activation (HIPA) and (2) to determine the relationship between thromboxane A2 (TxA2) synthesis and platelet granule release. In two patients with confirmed HIPA, heparin (3 U/ml) induced extensive platelet aggregation (61.5%), release of 14C-serotonin (81.5% of releasable 14C-serotonin, a dense granule marker) and platelet factor 4 (63.7% of releasable platelet factor 4, an alpha granule marker) and generation of TxB2, a stable metabolite of TxA2 (100% relative to serum control). In one patient heparin did not induce release of n-acetyl-beta-glucosaminadase (N-AC, a lysosomal granule marker), and aspirin (4 mmol/L), which abolished TxA2 synthesis, prevented aggregation and granule release. In the second patient heparin did induce release of N-AC (39.7% of releasable N-AC) and aspirin, despite abolishing TxA2 synthesis, did not prevent aggregation or granule release. In contrast, by elevating intracellular cyclic adenosine monophosphate, iloprost (0.01 mumol/L), a stable prostacyclin analogue, prevented heparin-induced aggregation, granule release, and TxB2 generation in both patients. Thus we show (1) HIPA can proceed independently of TxA2 synthesis; (2) heparin in certain patients can release lysosomal hydrolases, thus mimicking strong platelet agonists such as thrombin; and (3) iloprost but not aspirin prevents HIPA regardless of the biochemical pathways involved.

Topics: Aged; Cytoplasmic Granules; Female; Heparin; Humans; Platelet Aggregation; Thrombocytopenia; Thromboxane A2; Thromboxane B2

The variations in platelet counts upon intravenous challenge with soluble aggregates of IgG were assessed in normal rats. A time- and dose-dependent thrombocytopenia, followed by recovery to preinfusion values after 30 minutes was observed. Rats injected with immune aggregates showed an increase in plasma levels of immunoreactive thromboxane B2, however, this increase was delayed as compared with the peak level of the thrombocytopenia. Previous treatment of rats with either indomethacin or aspirin, inhibited thromboxane B2 release, but did not affect thrombocytopenia. Pretreatment of the animals with BN 52021, a potent antagonist of platelet-activating factor binding to its receptor, also failed to block thrombocytopenia. Complement depletion by prior treatment with cobra venom factor, caused a significant reduction of the thrombocytopenia, whereas DL-2-mercaptomethyl-3-guanidinoethylthiopropanoic acid, an inhibitor of carboxypeptidase N, potentiated the thrombocytopenia elicited by submaximal doses of either IgG aggregates or a homogeneous preparation of rat anaphylatoxin containing C5a. In addition, rats challenged with doses of IgG aggregates higher than 5 mg/kg showed a massive complement consumption coincident with the onset of thrombocytopenia. "In vitro" aggregation/secretion experiments with rat platelets showed little platelet-stimulating activity either by aggregated IgG through the Fc receptor or through the CR1 receptor. By contrast, a preparation of rat serum anaphylatoxins containing C5a, showed a high platelet-secreting activity. These data suggest that a complement-derived peptide(s), most probably C5a, is one of the effector substances for platelet activation in response to soluble aggregates of IgG.

Topics: Anaphylatoxins; Animals; Antigen-Antibody Complex; Complement C5; Complement C5a; Immunoglobulin G; Peptides; Platelet Count; Rats; Rats, Inbred Strains; Thrombocytopenia; Thromboxane A2; Thromboxane B2

SC 38249 [RS)-1-(2,3-bis-[(4-methoxyphenyl)methoxy]propyl)-1H-imidazole) caused dose-related inhibition of collagen-induced thromboxane A2 formation in human platelet rich plasma (IC50: 9.9 +/- 1.0 microM) accompanied by a dose-dependent increase in plasma PGE2. Broad inhibitory activity was evident against human platelet aggregatory and secretory responses in vitro. IC50 values of 11.9 +/- 1.9 microM (0.64 mM arachidonic acid), 18.3 +/- 3.8 microM (0.5 microgram ml-1 collagen) and 37.6 +/- 6.1 microM (25 nM Paf-acether) were obtained against maximum increase in PRP light transmission achieved by each agonist. Although less potent, SC 38249 retained significant inhibitory activity against PRP responses induced by a higher (3.0 micrograms ml-1) concentration of collagen (IC50: 272.5 +/- 24.6 microM), and against Paf-acether-induced responses in PRP pre-treated with 10 microM indomethacin (I.C.50: 192.0 +/- 16.1 microM). Experimental animal studies confirmed the in vitro anti-aggregatory efficacy of SC 38249, since significant inhibitory activity was observed against Paf-acether and ADP-induced responses in dog PRP ex vivo, anti-Forssman antibody-induced thrombocytopenia in anaesthetized guinea pigs, and collagen-induced intravascular aggregation in anaesthetized rabbits. Thus, SC 38249 is a novel thromboxane synthase inhibitor which possesses interesting anti-aggregatory properties which cannot wholly be attributed to prevention of platelet thromboxane A2 formation.

Topics: Adolescent; Adult; Animals; Arachidonic Acid; Arachidonic Acids; Collagen; Dinoprostone; Dogs; Humans; Imidazoles; In Vitro Techniques; Male; Platelet Aggregation; Prostaglandins E; Rabbits; Thrombocytopenia; Thromboxane A2; Thromboxane-A Synthase

The method of infusion of hardened red blood cells described by Clement et al. (1983) to induce pulmonary hypertension in the minipig has been modified to obtain a model of pulmonary microembolism in the mouse. In this model, the infusion of hardened red blood cells causes the death of about 90% of control animals in 2-5 min, and the efficacy of a given pharmacological treatment can be assessed in terms of the percentage of animals protected from death 15 min after the infusion. Platelets are not apparently involved, since the number of circulating platelets, plasma levels of TxB2, and PF-4 are not modified, and the mortality in thrombocytopenic animals is not different from controls. Furthermore, aspirin and heparin are totally inactive in this model. Preliminary results with some Ca++ channel blockers (nitrendipine and nicardipine) indicate that these compounds may be active. This experimental model offers an easy and relatively inexpensive test for the characterization of compounds to prevent pulmonary microembolism, acting via a platelet-independent mechanism.

Topics: Animals; Disease Models, Animal; Erythrocytes; Fibrinolytic Agents; Mice; Platelet Count; Platelet Factor 4; Pulmonary Embolism; Thrombocytopenia; Thromboxane A2

Topics: Adult; Arteriosclerosis; Diabetic Angiopathies; Epoprostenol; Female; Humans; Male; Middle Aged; Thrombocytopenia; Thromboxane A2

Topics: Angiotensin II; Blood Platelets; Blood Vessels; Disseminated Intravascular Coagulation; Epoprostenol; Female; Humans; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Hematologic; Thrombocytopenia; Thromboxane A2

KF4939, 2,2'-dithiobis-(N-2-hydroxypropylbenzamide), is a potent inhibitor of platelet aggregation in vitro in rabbit and human PRP. This agent inhibited both cyclooxygenase product-dependent (collagen and arachidonate) and independent (ADP and thrombin)-platelet aggregations. This action carried over to ex vivo situation following intraduodenal dosing as demonstrated in rabbits. KF4939 inhibited experimentally induced thrombocytopenias in rats and pulmonary thrombosis in mice following oral doses in a range of 25-300mg/kg. These results indicate that KF4939 is a new orally active inhibitor of platelet aggregation possessing a different mode of action from cyclooxygenase inhibition.

Topics: Adenosine Diphosphate; Animals; Arachidonic Acid; Arachidonic Acids; Aspirin; Benzamides; Collagen; Dose-Response Relationship, Drug; Fibrinolytic Agents; Humans; In Vitro Techniques; Male; Mice; Papaverine; Platelet Aggregation; Rabbits; Rats; Rats, Inbred Strains; Thrombin; Thrombocytopenia; Thrombosis; Thromboxane A2

Eleven patients in whom thrombocytopenia developed during heparin therapy were studied. Six patient (group 1) had severe thrombocytopenia with delayed onset and five of these patients had thromboembolic complications. A serum factor which induced heparin-dependent thromboxane B2 synthesis, 14C-serotonin release, and platelet aggregation was found in all patients in group 1. The serum factor was shown to be IgG. These findings suggest that the mechanism of the severe thrombocytopenia secondary to heparin therapy is immunological and the associated thromboembolic complications may be attributed to in-vivo activation of the platelet prostaglandin pathway and platelet aggregation induced by the heparin-dependent antibody. The five patients in group 2 had mild symptomless thrombocytopenia with early onset. In this group, the heparin-dependent antibody was not found and the mechanism of the thrombocytopenia is probably a direct action of heparin on platelets.

Topics: Adult; Aged; Female; Heparin; Humans; Immunoglobulin G; Male; Middle Aged; Platelet Aggregation; Serotonin; Thrombocytopenia; Thromboxane A2; Thromboxane B2; Thromboxanes; Time Factors

We investigated a rat fecal peritonitis model of acute intraabdominal sepsis in order to evaluate the potential role of arachidonic acid metabolites in septic shock. Immunoreactive TxB2, the stable metabolite of thromboxane A2, and i6-keto-PGF1 alpha, the stable metabolite of prostacyclin, were measured by radioimmunoassay. Plasma levels of iTxB2 rapidly increased from nondetectable (ND less than 200 pg/ml) to 1,052 +/- 208 pg/ml, one hour after feces injection. iTxB2 then increased to 1,681 +/- 248 pg/ml at four hours and remained unchanged through six hours. Plasma i6-keto-PGF1 alpha increased from ND to 3,848 +/- 489 pg/ml a one hour. Four hours after feces, i6-keto-PGF1 alpha levels rose to 7, 450 +/- 933 pg/ml then continued to rise to 9,465 +/- 792 pg/ml at six hours. Either essential fatty acid deficiency (arachidonic acid depletion) or indomethacin treatment (cyclo-oxygenase inhibition) significantly decreased (P less than 0.01) the elevation of plasma iTxB2 and i6-keto-PGF1 alpha associated with fecal peritonitis. Thrombocytopenia occurred within six hours after injection of feces and was significantly improved (P less than 0.05) by indomethacin. Elevated fibrin degradation products at six hours (18 +/- 3 micrograms/ml) were significantly reduced in essential fatty acid-deficient (7 +/- 2 micrograms/ml; P less than 0.05) and indomethacin-treated (4 +/- 0.7 micrograms/ml; P less than 0.01) rats. Survival time (8.6 +/- 0.2 hours) was significantly enhanced by essential fatty acid-deficiency (10.2 +/- 0.4 hours; P less than 0.01) or indomethacin treatment (13.3 +/- 0.6 hours; P less than 0.01). These studies show that fecal peritonitis is associated with increased synthesis of thromboxane A2 and prostacyclin and suggest that these arachidonic acid metabolites may play a role in the pathophysiology of septic shock.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Epoprostenol; Fatty Acids, Essential; Female; Fibrin Fibrinogen Degradation Products; Indomethacin; Peritonitis; Prostaglandins; Rats; Rats, Inbred Strains; Shock, Septic; Thrombocytopenia; Thromboxane A2; Thromboxanes; Time Factors

Levels of 6-oxo-prostaglandin F1 alpha (6-oxo-PGF1 alpha), the non-enzymic degradation product of prostacyclin, were measured in arterial blood from anaesthetized rabbits, before and after intravenous (i.v.) administration of endotoxin (Lipopolysaccharine W E. coli 0111:B4, 5 mg/kg). 6-Oxo-PGF1 alpha was assessed by radioimmunoassay after extraction and separation by thin-layer chromatography. The basal concentration of 6-oxo-PGF1 alpha in blood was less than 100 mg/ml in 19 out of 20 rabbits. This indicates that the level of circulating prostacyclin is generally below 100 pg/ml. The administration of endotoxin induced a biphasic hypotension, and increased levels of 6-oxo-PGF1 alpha were found in all endotoxin-treated animals during the secondary hypotension after 60 and 120 min. Pretreatment with indomethacin (2.5 mg/kg) prevented the secondary fall in arterial blood pressure and significantly suppressed the rise in 6-oxo-PGF1 alpha. However, indomethacin failed to alter the endotoxin-induced thrombocytopenia and did not modify the endotoxin-induced platelet aggregation in vitro. It is concluded that prostacyclin contributed to the secondary hypotension which accompanied the i.v. administration of endotoxin. Thromboxane A2 seems not to be of primary importance in the endotoxin-platelet interaction.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Endotoxins; Epoprostenol; Heart Rate; Hypotension; Male; Platelet Aggregation; Prostaglandins F; Rabbits; Thrombocytopenia; Thromboxane A2

Prostacyclin (PGI2), a newly discovered short-acting prostaglandin that inhibits platelet aggregation, was evaluated as an agent for prevention of cardiopulmonary bypass-induced thrombocytopenia. Ten adult, splenectomized greyhounds were divided into three treatment groups prior to beginning 120 minutes of partial cardiopulmonary bypass. Group 1 animals received 300 units of heparin per kilogram of body weight, Group 2 animals received 300 units of heparin per kilogram plus PGI2, 1.5 micrograms per minute, and Group 3 animals received 300 units of heparin per kilogram plus PGI2 3.0 micrograms per minute. Bypass and PGI2 infusion were started simultaneously. Mean platelet counts of each group at 5 minutes were approximately 40% of prebypass levels. Additional platelet loss was seen in Groups 1 and 2 at 30, 60, and 120 minutes. However in Group 3, platelet counts at 30 and 60 minutes were essentially unchanged from prebypass levels. At 30, 60, and 120 minutes of cardiopulmonary bypass, the differences between Groups 1 and 3, and 2 and 3 are highly significant (p less than 0.01). We conclude that PGI2 is an effective agent for preserving platelet levels during experimental cardiopulmonary bypass. Furthermore, it is possible that platelet loss during cardiopulmonary bypass may be caused, in part, by an imbalance between PGI2 and thromboxane A2, which results in excessive platelet adhesion and aggregation.

Topics: Animals; Blood Platelets; Cardiopulmonary Bypass; Dogs; Dose-Response Relationship, Drug; Epoprostenol; Platelet Count; Prostaglandins; Thrombocytopenia; Thromboxane A2

Topics: Animals; Arachidonic Acids; Aspirin; Blood Platelets; Dogs; Drug Interactions; Erythrocytes; Ethanol; Humans; Linoleic Acids; Oxygenases; Platelet Aggregation; Rabbits; Saponins; Thrombocytopenia; Thromboxane A2