thromboxane-b2 and Blood-Coagulation-Disorders

Glucocorticoids (GCs) target several components of the integrated system that preserves vascular integrity and free blood flow. Cohort studies on Cushing's syndrome (CS) have revealed increased thromboembolism, but the pathogenesis remains unclear. Lessons from epidemiological data and post-treatment normalisation time suggest a bimodal action with a rapid and reversible effect on coagulation factors and an indirect sustained effect on the vessel wall. The redundancy of the steps that are potentially involved requires a systematic comparison of data from patients with endogenous or exogenous hypercortisolism in the context of either inflammatory or non-inflammatory disorders. A predominant alteration in the intrinsic pathway that includes a remarkable rise in factor VIII and von Willebrand factor (vWF) levels and a reduction in activated partial thromboplastin time appears in the majority of studies on endogenous CS. There may also be a rise in platelets, thromboxane B2, thrombin-antithrombin complexes and fibrinogen (FBG) levels and, above all, impaired fibrinolytic capacity. The increased activation of coagulation inhibitors seems to be compensatory in order to counteract disseminated coagulation, but there remains a net change towards an increased risk of venous thromboembolism (VTE). Conversely, GC administered in the presence of inflammation lowers vWF and FBG, but fibrinolytic activity is also reduced. As a result, the overall risk of VTE is increased in long-term users. Finally, no studies have assessed haemostatic abnormalities in patients with Addison's disease, although these may present as a consequence of bilateral adrenal haemorrhage, especially in the presence of antiphospholipid antibodies or anticoagulant treatments. The present review aimed to provide a comprehensive overview of the complex alterations produced by GCs in order to develop better screening and prevention strategies against bleeding and thrombosis.

Topics: Blood Coagulation Disorders; Cushing Syndrome; Factor VIII; Fibrinogen; Glucocorticoids; Humans; Thrombocytosis; Thromboxane B2; Venous Thromboembolism; von Willebrand Factor

Our previous study demonstrated the types of platelet dysfunction varied at early stage (∼3 h) in trauma-induced coagulopathy (TIC) caused by different types of injuries. And arachidonic acid (AA)-dependent pathway inhibition in platelet seemed to be specific for TIC caused by multiple injury (MI). The aim of this research was to further study AA-dependent pathway inhibition in platelets in a rat model of TIC caused by MI and to explore its potential mechanisms.. Sprague-Dawley rat model of TIC caused by MI was established. We used thrombelastography with platelet mapping as a measure of platelet function to assess the inhibitory extent of AA-dependent activation pathway. Flow cytometry was used to determine the expression of activation-dependent granular protein P-selectin (CD62P). In addition, the plasma levels of 6-Keto-prostaglandin F1 alpha (6-Keto-PGF1α), Prostaglandin E2, and Thromboxane B2 were assessed by enzyme-linked immuno sorbent assay.. The inhibition rate of AA-dependent pathway after injury was significantly higher than that of control. The maximum amplitude decreased in the MI group, compared with that of control. The percentage of CD62P expression in the MI group was remarkably lower than that of control after AA treatment. The plasma concentrations of 6-Keto-PGF1α and PGE2 increased in the MI group.. Platelets inhibition was observed in TIC caused by MI at early stage after injury, which might be partially attributed to AA-dependent activation pathway dysfunction. The increase of plasma Prostacyclin and PGE2 levels may contribute to the inhibition process.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Blood Coagulation Disorders; Blood Platelets; Dinoprostone; Disease Models, Animal; Epoprostenol; Male; Multiple Trauma; P-Selectin; Platelet Activation; Platelet Function Tests; Rats; Rats, Sprague-Dawley; Thrombelastography; Thromboxane B2

This study aimed to investigate the endothelial function in a canine model of burn injury combined with seawater immersion. The model of burn injury was established. The dogs were randomly divided into four groups including dogs with burn injury (B group), or burn injury combined with seawater immersion (BI group), or only immersion in seawater (I group), or control animals with no injury or immersion (C group). The circulating endothelial cell (CEC) count and coagulation-fibrinolysis parameters were measured. The CEC count in B group increased at 4 h, 7 h, and 10 h after injury and then reduced, whereas it continuously increased to a greater extent in BI group (P < 0.05). The von Willebrand factor (vWF) activity, plasminogen activator inhibitor (PAI-1), and the ratio of thromboxane B2 (TXB2) to 6-keto-prostaglandin F1α (6-K-PGF1α ) in BI group had a marked increase after injury, and the tissue-type plasminogen activator (tPA) in the BI group decreased. Microscope observations revealed thrombus formation in lungs of the animals in BI group, but not in C, I, or B groups. Burn injury causes endothelial dysfunction, and seawater immersion lastingly aggravates this injury, leading to a higher risk of developing thrombosis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Coagulation; Blood Coagulation Disorders; Burns; Disease Models, Animal; Dogs; Endothelial Cells; Humans; Immersion; Lung; Plasminogen Activator Inhibitor 1; Seawater; Thromboxane B2; Tissue Plasminogen Activator; von Willebrand Factor

Effects of the effective components group of Xiaoshuantongluo formula (XECG) on rat acute blood stasis model were studied under the guidance of the concept of effective components group. Rat acute blood stasis model was induced by subcutaneous injection of epinephrine combined with ice water bath. Hemorheology indices such as whole blood viscosity, plasma viscosity, erythrocyte aggregation index and platelet aggregation rate; coagulation parameters including PT, APTT, TT and FIB; 6-keto-PGF1alpha, TXB2 and D-dimer levels were determined to evaluate the effects of XECG. The results showed that XECG significantly reduced ADP-induced platelet aggregation, but showed little influence on the whole blood viscosity, plasma viscosity and erythrocyte aggregation rate. XECG extended PT and TT slightly, but had no effects on APTT and FIB content. D-dimer levels significantly decreased after administration of XECG with a little decrease of TXB2, but the content of 6-keto-PGF1alpha did not change significantly. The results suggest that the role of XECG of anti-aggregation is more prominent.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Coagulation; Blood Coagulation Disorders; Blood Viscosity; Drug Combinations; Drugs, Chinese Herbal; Erythrocyte Aggregation; Fibrin Fibrinogen Degradation Products; Hemorheology; Male; Partial Thromboplastin Time; Plants, Medicinal; Platelet Aggregation; Prothrombin Time; Random Allocation; Rats; Rats, Sprague-Dawley; Thrombin Time; Thromboxane B2

Thromboxane A2 (TXA2), synthesized in platelets, is a powerful aggregating agent and vasoconstrictor. To induce platelet aggregation, the platelets' enzyme, prostaglandin endoperoxide H synthase-1 (PGHS-1), first converts arachidonic acid (AA) into prostaglandin H2 (PGH2). PGH2 is then converted by the enzyme thromboxane synthase into TXA2. Finally, TXA2 is secreted and can activate the TXA2 receptor on the platelet surface. The importance of TXA2 in haemostasis has been demonstrated by the presence of a bleeding tendency in patients showing an inherited defect in the TXA2 production pathway. We studied an 18-year-old woman with a lifelong bleeding disorder, moderate thrombocytopenia (55-71 x 109/l) and a prolonged bleeding time (12.5 min). Her platelets aggregated in the presence of both PGH2 and a stable TXA2 analogue, but did not aggregate in the presence of AA. The activity of PGHS-1 in platelets, measured using thin-layer chromatography and radioactive counting of TXA2 formation from [14C]-AA, was reduced to 13% of the activity measured in control subjects. PGHS-1 protein levels, measured using Western blot analysis, were also markedly reduced to 10% of control values. Such levels of PGHS-1 enzyme were too low to sustain platelet aggregation in the patient, even if the enzyme was active. The PGHS-1 protein level was also reduced in the patient's immortalized B lymphocytes, suggesting a systemic expression defect. Northern blot analysis was then carried out with poly (A)+ RNA extracted from the patient's immortalized B lymphocytes. PGHS-1 mRNA was detected as a 2.8-kb band in both the patient and control. The intensity of the band representing the patient's PGHS-1 mRNA was similar to that of the control subject. The Northern blot result suggests a normal transcriptional rate of the PGHS-1 gene for the patient. Therefore, the defect responsible for the reduced levels of PGHS-1 protein is probably post-transcriptional.

Topics: Adult; Arachidonic Acid; Autoradiography; B-Lymphocytes; Blood Coagulation Disorders; Blood Platelets; Blotting, Northern; Blotting, Western; Case-Control Studies; Cell Line; Female; Humans; Male; Middle Aged; Platelet Aggregation; Prostaglandin-Endoperoxide Synthases; RNA, Messenger; Thromboxane A2; Thromboxane B2

Endothelial injury in vivo induced by Rickettsia Conorii, the etiologic agent of Mediterranean Spotted Fever (MSF) has been recently demonstrated. We sought to determine whether platelet and/or coagulative activation in vivo can be demonstrated in the acute phase of MSF, through measurements of a major metabolite of thromboxane (TX) in the urine (11-dehydro-TXB2) and of plasma prothrombin fragment 1 + 2, whose levels reflect activation of prothrombin to thrombin. Moreover, we measured plasma endothelin-1 as marker of endothelial dysfunction. Our results provide biochemical evidence for the occurrence of TXA2-dependent platelet activation and thrombin generation in vivo, together with endothelial dysfunction. These phenomena could account for clinical manifestations of MSF, such as vasculitis and focal microthrombus formation. These results could also provide a rationale for testing the efficacy of aspirin or heparin in reducing the prothrombotic status of Rickettsiae diseases.

Topics: Acute Disease; Adult; Aged; Anticoagulants; Blood Coagulation Disorders; Boutonneuse Fever; Endothelium, Vascular; Female; Humans; Male; Middle Aged; Peptide Fragments; Platelet Activation; Prothrombin; Rickettsia; Thromboxane B2; Vasculitis

Topics: Adult; Aldosterone; beta-Thromboglobulin; Blood Coagulation Disorders; Blood Pressure; Female; Hemostasis; Humans; Hyperaldosteronism; Male; Thromboxane B2; von Willebrand Factor

Willebrand-factor antigen level and structure analysis, ristomycin-cofactor assay, beta-thromboglobulin and thromboxane metabolite estimations were performed in 22 patients with mixed connective tissue disease to evaluate the incidence and the possible role of haemostatic alterations in the complications occurring during the course of the disease. High levels of Willebrand-factor antigen and ristomycin-cofactor activity were detected in patients with thrombocytopenia, previous thrombotic event, pulmonary vascular lesions and usually in the presence of circulating anti-endothelial antibodies. Increased platelet activation could have been found in antibody positive cases and in patients with thrombocytopenia as well. The documented alterations of endothelial and platelet functions may play important role in the vascular complications of mixed connective tissue disease.

Topics: Adult; Autoantibodies; Autoimmune Diseases; beta-Thromboglobulin; Blood Coagulation Disorders; Blood Platelets; Endothelium, Vascular; Female; Hemostasis; Humans; Incidence; Male; Mixed Connective Tissue Disease; Thromboxane B2; von Willebrand Factor

In order to provide an overview of the relative contribution of platelet, von Willebrand factor, and other abnormalities to patients with clinical bleeding difficulties, we performed a retrospective survey of coagulation studies on 569 individuals referred to the University of Manitoba coagulation laboratory because they, or a closely related family member, showed clinical evidence of a bleeding disorder. There was a highly significant (p less than 0.001) negative correlation between the bleeding time and each of the following parameters: the platelet count; the hematocrit; the percent aggregation to collagen, epinephrine, ADP, and arachidonic acid; and the logarithm of von Willebrand factor antigen and a measure of its activity (ristocetin cofactor). A significant and independent inverse relationship between the length of the bleeding time and the extent of platelet adhesion to glass beads, patient age, and prothrombin consumption were also observed. Multivariate analysis of the ability of all parameters to predict the bleeding time showed an r2 of only 0.33. Bleeding time thromboxane B2, in a second smaller study of 70 patients, showed a negative correlation with the length of the bleeding time (p = 0.0001), and, when used together with the above parameters, significantly enhanced the ability to predict the length of the bleeding time (r2 = 0.55). Defects in platelet function, as measured in vitro, and significant enough to have an effect on the bleeding time, occurred with greater frequency than defects in von Willebrand factor in the Manitoba patients evaluated.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Bleeding Time; Blood Coagulation Disorders; Child; Child, Preschool; Female; Hematocrit; Humans; Male; Middle Aged; Platelet Function Tests; Thromboxane B2; von Willebrand Factor

The activation of platelets and the coagulation mechanism was studied by collecting blood from a standard bleeding time incision at 30-second intervals and measuring the plasma concentrations of fibrinopeptide A (FPA), platelet factor 4 (PF4), and thromboxane B2 (TxB2). FPA was observed in the first samples (30 to 60 seconds) obtained, increased progressively until cessation of bleeding, and was markedly diminished after heparin administration, thus indicating that thrombin formation occurs early in incisional blood. PF4 increased monotonically throughout blood sampling, whereas the major increase in TxB2 appeared near the cessation of bleeding. The initial increase in FPA content occurred normally in patients with deficiencies of either factor IX or VIII, was markedly diminished in patients with factor X or V deficiency, and was delayed in patients with factor VII deficiency. These studies suggest that tissue factor activation of the classic (activation of factor X) extrinsic coagulation mechanism occurs as an early event during the arrest of bleeding from bleeding time incisions. The relation of the aforementioned to platelet activation is less clear because there was no consistent correlation between decreased FPA formation and impaired PF4 secretion or TxB2 production. In fact, the latter were normal in some subjects with the most impaired FPA formation, which suggests that both collagen and thrombin, perhaps synergistically, may contribute to platelet activation during the primary arrest of bleeding.

Topics: Biomechanical Phenomena; Bleeding Time; Blood Coagulation; Blood Coagulation Disorders; Blood Specimen Collection; Fibrinopeptide A; Humans; Platelet Factor 4; Reference Values; Thromboplastin; Thromboxane B2

In an attempt to elucidate the nature of the bleeding tendency in uremia, some in vitro functions of platelets from eight patients undergoing long-term hemodialysis were studied. None of the patients had diabetes. All had bleeding times longer than eight minutes. Threshold aggregating concentrations for collagen, adenosine diphosphate, and epinephrine, when used singly or in pairs, were two to three times higher than normal in platelet-rich plasmas from these patients. In contrast, those for arachidonic acid and U-46619, a cyclic endoperoxide/thromboxane A2 analogue, were within the normal ranges. Thromboxane B2 formation was normal in response to arachidonic acid (0.2 to 1 mM), whereas it was decreased by 30 to 50 percent in response to thrombin (0.5 to 10 units/ml), collagen (0.5 to 10 micrograms/ml), and the combination of collagen with adenosine diphosphate or epinephrine. There was a partial (about 35 percent) reduction of the platelet granular content of adenosine diphosphate. Secretion of adenosine triphosphate by 5 units/ml of thrombin was 25 to 50 percent less than in normal subjects. Thus, there was a storage pool defect as well. Similar but less severe defects were found in platelets from uremic patients who had never undergone hemodialysis. Partial correction of aggregation and thromboxane B2 formation was seen after dialysis, although platelet adenosine diphosphate content did not increase. It is concluded that the platelet dysfunction in uremia is multifaceted. There appears to be an aggregation and secretion defect related to impaired arachidonic acid release from platelet phospholipids as well as a storage pool defect. The first is improved with dialysis; the second is not.

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Adult; Arachidonic Acid; Arachidonic Acids; Blood Coagulation Disorders; Blood Platelets; Collagen; Epinephrine; Humans; Platelet Aggregation; Renal Dialysis; Thromboxane B2; Uremia

A 62-year-old man with clinical and biochemical findings consistent with homozygous Tangier disease is presented. Widespread atherosclerosis was present. Bile lipid analysis showed a low molar percentage of cholesterol with a low saturation index. The data suggest that high density lipoprotein cholesterol may act as a preferential precursor of biliary cholesterol. Coagulation and platelet studies indicated that the patient's platelets were hyper-responsive to aggregating agents and produced an increased amount of thromboxane B2. A platelet storage pool deficiency was also found.

Topics: Aged; Apolipoprotein A-I; Apolipoproteins; Bile; Bile Acids and Salts; Blood Coagulation Disorders; Blood Platelet Disorders; Cholesterol; Cholesterol, HDL; Humans; Hypolipoproteinemias; Lipids; Lipoproteins, HDL; Male; Middle Aged; Serotonin; Tangier Disease; Thromboxane B2

Fawn-hooded (FH) rats possess a hereditary bleeding diathesis and platelet function defect, which is presumably the result of a storage pool deficiency. In this study, we have investigated the prostaglandin synthesis capacity of platelets and aorta from FH rats as compared to Sprague Dawley (SD) rats, after 2 months on a normal or 1% cholesterol diet. No difference was found in thromboxane B2 (TXB2) production by platelets of FH as compared to SD rats. Cholesterol-feeding resulted in an increased TXB2 production by SD platelets, but not FH platelets. FH rat aorta was found to convert significantly less arachidonic acid (AA) to 6-keto-prostaglandin-F1 alpha (PGF1 alpha) and cholesterol-feeding stimulated this reduced capacity. In contrast, cholesterol-feeding in the SD rat reduced aortic 6-keto-PGF1a production. Aggregation of platelet-rich plasma by AA was enhanced in the cholesterol-fed FH rat. This result suggests the possibility of an influence of platelet aggregability on aortic prostacyclin production.

Topics: Alprostadil; Animals; Aorta, Thoracic; Blood Coagulation Disorders; Blood Platelets; Cholesterol; Cholesterol, Dietary; Platelet Aggregation; Prostaglandins; Prostaglandins E; Rats; Rats, Inbred Strains; Thromboxane B2

Three family members from three successive generations presented with a moderate bleeding tendency and a functional platelet defect. They had absent aggregation with arachidonic acid (0.6--3 microM), reversible aggregation with ADP (4 microgram) and cyclic endoperoxide analogues, single wave aggregation only with adrenaline (5.4 microgram) and a prolonged template bleeding time (> min). Malondialdehyde formation was reduced after N-ethylmaleimide stimulation (2--6 nmol/10(9) platelets; control values 8--12 nmol) and serum thromboxane B2 values were reduced (33--101 ng/ml; control values 200--700 ng/ml). When the platelets were incubated with [3H]arachidonic acid the final metabolite of the lipoxygenase pathway (HETE) was produced in normal amounts but the production of thromboxane B2 and HHT was decreased whereas prostaglandin F2a, and E2 and probably D2 were increased. Evidence for enhanced production of prostaglandin D2 was also provided by the rise in the patient's platelet cyclic AMP levels following stimulation with arachidonic acid. The patient's washed platelets stimulated the production of 6-keto PGF 1a by aspirin-pretreated cultured bovine endothelial cells. The plasma levels of 6-keto PGF1a (439--703 pg/ml; normal 181 +/- 46 pg/ml) were raised. The decreased production of thromboxane B2, HHT and malondialdehyde and increased formation of prostaglandin F2a, E2, D2 and of 6-keto PGF1a are compatible with a partial platelet thromboxane synthetase deficiency and reorientation of cyclic endoperoxide metabolism. The markedly prolonged bleeding time would result not only from reduced formation of thromboxane A2 but also from increased production of the aggregation inhibiting prostaglandins PGI2 and PGD2.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Adult; Arachidonic Acids; Blood Coagulation Disorders; Child, Preschool; Cyclic AMP; Fatty Acids, Unsaturated; Humans; Hydroxy Acids; Male; Malondialdehyde; Middle Aged; Oxidoreductases; Pedigree; Platelet Aggregation; Prostaglandin Endoperoxides; Prostaglandins F; Thromboxane B2; Thromboxane-A Synthase

An IgG antiplatelet antibody found in a multitransfused patient with Bernard-Soulier syndrome (BSS), reacted with a normal platelet surface antigen of 150 000 daltons which was similar to the glycoprotein missing from BSS platelets. The BSS platelet antibody (BSS-Pab) aggregated all control platelets which then released ADP and 5-HT and synthesized thromboxane. When mixed with the antibody, BSS platelets did not aggregate, did not release ADP and 5-HT and failed to synthesize thromboxane. The BSS-Pab was not inactivated by incubation with BSS platelet stroma. While the antibody did not aggregate thrombasthenic platelets, its aggregating activity was lost after incubation with their stroma. The BSS-Pab did not provoke ADP or 5-HT release or thromboxane synthesis in thrombasthenic platelets or in the platelets of a patient with platelet cyclooxygenase deficiency or in normal platelets treated with indomethacin. The aggregating, release and synthetic responses of platelets after binding of BSS-Pab to its membrane antigen (probably glycoprotein I) requires the presence of glycoprotein IIb and/or IIa and the normal metabolism of arachidonic acid.

Topics: Antibodies; Blood Coagulation Disorders; Blood Platelet Disorders; Blood Platelets; Glycoproteins; Humans; Platelet Aggregation; Syndrome; Thromboxane B2