Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.6 (thromboplastin)
 13,278 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The vascular endothelium has long been considered to have very little or no active function in inflammatory reactions and hemostasis. However, it has been recently discovered that endothelial cells can dramatically change their functional competence in response to the mononuclear phagocyte products interleukin-1 (IL-1) and tumor necrosis factor (TNF). IL-1 induces synthesis of prostacyclin, platelet activating factor, thromboplastin and plasminogen activator inhibitor. Both IL-1 and TNF cause leukocyte adhesion to the endothelium. On the other hand endothelial cells can themselves initiate the immune response through synthesis and release of IL-1. TNF, released in tissues may act as a chemoattractant and further promote interaction of leukocytes with the vascular lining. IL-1 and TNF can therefore act as a communications signal between circulating cells and the vessel wall and play an important role in the inflammatory and coagulation disorders.
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PMID:The recruitment of leukocytes and their interaction with the vessel wall: the role of interleukin-1 and tumor necrosis factor. 350 9

The prolonged partial thromboplastin time observed in the plasma of a 36 year old asymptomatic man was related to the reduced prekallikrein activities (coagulant; antigenic; and amidolytic) and the absence of coagulant and immunologic activities of high molecular weight kininogen (HMWKg). The patient's plasma also exhibited impaired surface-mediated fibrinolysis and impaired generation of kallikrein. The coagulation defect was identified as the "Fitzgerald trait". The levels of CH50, C2, C4 and C-1 inactivator were normal. Venous occlusion in the patient gave rise to a normal release of extrinsic plasminogen activator from the vascular endothelium. The administration of DDAVP led to a FVIII/VWF response which was similar to that obtained in healthy subjects. No alteration could be observed in the contact phase proteins after DDAVP administration.
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PMID:New congenital deficiency of high molecular weight kininogen and prekallikrein (Fitzgerald trait). Study of response to DDAVP and venous occlusion. 363 67

Formation of a hemostatic plug represents one of the earliest responses to vessel wall injury. Platelets react to any discontinuity in the vascular endothelium through initial contact, spreading, and formation of a thrombus (or aggregate). This development of a primary hemostatic plug requires platelet membrane receptors through which the adhesive macromolecules, von Willebrand factor (vWF) and fibrinogen, anchor platelets to the vessel wall and link them to each other. There are two receptor pathways--classic and alternative--for the binding of vWF to platelets; the latter induced by thrombin, and adenosine diphosphate (ADP) is shared with fibrinogen. Synthetic peptides, patterned after known binding domains of adhesive molecules, have been designed to inhibit their interactions with platelet receptors. A secondary hemostatic plug, composed of platelets enmeshed in fibrin, results from the action of thrombin, which is not only essential for formation of fibrin but also for exposure of platelet receptors for adhesive molecules and for "activation" of factors V and VIII. Thrombin generation is greatly enhanced through the activity of the prothrombinase complex formed on the surface of platelets, perturbed endothelial cells, and leukocytes. A pivotal event is activation of factor X through the intrinsic and extrinsic coagulation pathways. Binding of factors IXa and VIIa to the vascular endothelium represents a localized mechanism for factor Xa generation. Formation of a platelet and fibrin thrombus is controlled by regulatory mechanism: prostacyclin, endogenous heparin-antithrombin III complex, thrombomodulin-protein C-protein S system, and the fibrinolytic system. The balance of all components--vessel wall, platelets, adhesive and coagulation proteins, regulatory mechanisms--determines the effectiveness of the hemostatic plug in maintaining the structural and functional integrity of the circulatory system. An approach to detection of hemostatic derangements in patients at risk evolves from a full understanding of inherited and acquired deficiencies affecting each step of hemostatic plug formation and from selective use of laboratory tests.
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PMID:Formation and regulation of platelet and fibrin hemostatic plug. 380 19

An outline has been given of the major abnormalities of coagulation which can occur secondary to diseases in previously normal individuals. First, the disorders due to deficiency of the vitamin K-dependent clotting factors are described. Vitamin K deficiency can occur in the newborn, or at later stages in life when there is intestinal malabsorption. The malabsorption disorders, such as coeliac disease, together with major abdominal surgery or prolonged use of broad-spectrum antibiotics can give rise to vitamin K deficiency. Additionally, in obstructive jaundice the lack of secretion of bile salts into the upper intestine causes vitamin K malabsorption. The use of oral anticoagulants is associated with haemorrhage in a small proportion of patients. These patients usually have an excessively prolonged prothrombin time, due to overdosage with anticoagulants, but occasionally haemorrhage can occur from a localized bleeding site, such as a duodenal ulcer, in patients under good anticoagulant control. The large number of drugs which can interact with anticoagulants are listed, from which it can be seen that careful monitoring of all patients on oral anticoagulants must be carried out. The haemostatic defects associated with liver disease are then tabulated. In this situation abnormalities may be due to deficient synthesis of coagulation factors in hepatocellular failure, by failure of vitamin K absorption, and also by disseminated intravascular coagulation (DIC). DIC occurs in hepatocellular failure, because the liver cells are normally responsible for clearing activated products of the coagulation and fibrinolytic enzyme systems. The presence of clinical haemorrhage and haemostatic breakdown in hepatic disease usually indicates a serious prognosis, but appropriate replacement therapy is indicated in this situation. Disseminated intravascular coagulation embraces a large number of clinical haemorrhagic syndromes, where intravascular activation of the coagulation system takes place accompanied by compensatory fibrinolytic activity. DIC can be initiated by intravascular release of procoagulant substances, such as tissue thromboplastin, or by damage to vascular endothelium and platelets. The main clinical conditions associated with DIC comprise the severe infections and septicaemias, obstetric accidents, shock and trauma, neoplasia and snake-bite envenoming. In all instances, the pathophysiological disorder of haemostasis is managed by treating the underlying disease.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Acquired coagulation disorders. 389 41

The pathogenesis of experimental adrenal hemorrhagic necrosis produced by acrylonitrile in the rat was investigated by various morphologic, biochemical, and pharmacologic methods. One dose of this chemical injected intravenously caused 100 per cent incidence of adrenal hemorrhage and necrosis in 90 to 120 minutes. Electron microscopy, histochemistry, and light microscopy combined with colloidal carbon labeling suggested an early damage (30 minutes after administration of acrylonitrile) to the vascular endothelium in the adrenal cortex, prominent at 60 minutes, when lesion to the parenchymal cells was not visible. The use of extracellular diffusion tracer horseradish peroxidase further indicated that parenchymal cell injury was a late event. Damage to the vascular endothelium in the adrenal cortex was associated with retrograde embolization of medullary cells and cell fragments into the cortical capillaries. The ultrastructurally demonstrated platelet aggregation and fibrin precipitation at the sites of discontinuous vascular endothelium were accompanied by a decrease in circulating platelets and fibrinogen as well as prolongation of prothrombin, partial thromboplastin, and thrombin time. The concentration of dopamine, unlike that of noradrenaline, in the adrenals but not in the brain of rats injected with acrylonitrile showed a time-dependent elevation. Pretreatment with phenoxybenzamine (alpha-adrenergic antagonist) or labetalol (alpha- and beta-adrenergic blocker) or metyrapone (11-beta-hydroxylase inhibitor) and the depletion of catecholamines by reserpine or prior medullectomy prevented the chemically induced adrenal necrosis. These results indicate that the presence of a functional adrenal cortex is necessary for the development of cortical damage which is associated with early vascular lesion caused and/or modulated by vasoactive amines from the medulla and/or (metabolites of) acrylonitrile.
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PMID:Pathogenesis of experimental adrenal hemorrhagic necrosis ("apoplexy"): ultrastructural, biochemical, neuropharmacologic, and blood coagulation studies with acrylonitrile in the rat. 610 78

Four groups of 6 pigs each were given 5 x 10(5) to 3 x 10(6) sporocysts of a Georgia isolate of Sarcocystis suicanis. Only the 6 pigs given 3 x 10(6) sporocysts became acutely ill at postinoculation days (PID) 12 to 15, and 3 of the 6 diet at PIG 14 or 15. Clinical signs included purpura of the skin of the ear, snout, and buttocks and dyspnea, muscle tremors, and severe locomotor difficulties. Clinical abnormalities were accompanied by laboratory findings of pyrexia, severe anemia, leukopenia, thrombocytopenia, megathrombocytosis, prolonged prothrombin time and activated partial thromboplastin time, and hypofibrinogenemia. Seemingly, excessive intravascular coagulation may be involved in the pathogenesis of this disease in swine. Pigs given 5 x 10(5) to 1 x 10(6) sporocysts did not exhibit clinical signs; however, leukopenia and thrombocytopenia were demonstrated in the pigs at all dosage levels. Growth rates were impaired in surviving pigs. Second-generation schizonts containing merozoites were found in vascular endothelium of pigs dying on PID 14 or 15. Nonsuppurative myocarditis and hepatitis were present. Numerous developing cysts were in the musculature of pigs enthanatized on PIG 35 to 52. Cyst dissolution and resorption occurred concomitantly, indicating that swine may be able to clear the infection.
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PMID:Experimental Sarcocystis suicanis infections: disease in growing pigs. 680 76

Low molecular weight heparins (LMWHs) are now considered to be the drugs of choice for prophylaxis against deep venous thrombosis (DVT) in post operative patients undergoing both general and orthopaedic surgical procedures. Despite extensive research, the exact mechanism of the antithrombotic activity of LMWHs remains unclear. These agents have been shown to activate the fibrinolytic system and to directly inhibit both the activity and the generation of factor Xa and thrombin. New evidence suggests that LMWHs also stimulate the release of endogenous tissue factor pathway inhibitor (TFPI) from the vascular endothelium. This study was designed to investigate the role of TFPI in mediating the antithrombotic activity of LMWHs. We measured the plasma levels of TFPI in a group of post orthopaedic surgery patients treated with daily subcutaneous injections of LMWH and a group of patients treated with placebo. In the placebo group (n = 25), the plasma TFPI levels were slightly elevated immediately after surgery but returned to their baseline value by the fifth post operative day. In contrast, in the group of patients treated with LMWH (n = 34), the plasma levels of TFPI increased significantly and remained elevated for up to 7 days following surgery. However, the TFPI levels in both groups showed wide patient to patient variability. These results indicate that LMWHs stimulate the release of TFPI into the bloodstream of post surgical patients. This suggests the importance of TFPI in mediating the antithrombotic activity of LMWHs.
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PMID:Role of tissue factor pathway inhibitor in post surgical deep venous thrombosis (DVT) prophylaxis in patients treated with low molecular weight heparin. 802 8

The pharmacologic characteristics of low-molecular-weight (LMW) heparins and unfractionated heparin are reviewed, and clinical trials comparing LMW heparins with unfractionated heparin for the initial treatment of deep-vein thrombosis (DVT) are described. LMW heparins are derived from native heparin and range in mass from 3000 to 8000 daltons. All LMW heparins contain the antithrombin III-specific pentasaccharide unit found on unfractionated heparin. LMW heparins are stronger inhibitors of factor Xa than unfractionated heparin, but their mechanisms of action, like that of unfractionated heparin, is predominantly the inhibition of thrombin. The efficacy of LMW heparins in the prophylaxis of DVT is not correlated with activated partial thromboplastin time (APTT); monitoring of APTT or anti-factor Xa may not be necessary. Compared with unfractionated heparin, LMW heparins have a lower affinity for heparin cofactor II, platelet factor 4, von Willebrand factor, and vascular epithelium. Subcutaneously administered LMW heparins are more bioavailable than s.c. unfractionated heparin. In clinical trials in patients with DVT, LMW heparins (dalteparin, enoxaparin, nadroparin, and tinzaparin) have resulted in venography scores similar to those obtained with unfractionated heparin. Frequencies of recurrent thromboembolism and bleeding complications were also similar. Dalteparin and logiparin were effective when administered in single daily subcutaneous doses; this could lead to lower treatment costs. Additional studies are needed to compare LMW heparins and unfractionated heparin with respect to efficacy, bleeding complications, mortality, and cost. LMW heparins may be valuable alternatives to unfractionated heparin for the treatment of DVT.
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PMID:Low-molecular-weight heparins for the treatment of deep-vein thrombosis. 813 6

Twenty newborn Holstein calves were allotted at random to 4 groups: group A received 0.9% sterile saline solution; group B received phenylbutazone (5 mg/kg of body weight, IV) and 0.9% sterile saline solution; group C received progressively increasing doses of endotoxin (0.1 to 15 micrograms/kg); and group D received phenylbutazone and endotoxin similarly as did calves of groups B and C, respectively. Phenylbutazone was given once daily and saline solution or endotoxin were given every 8 hours for 5 days. Clinical variables--PCV, plasma total protein and fibrinogen concentrations, platelet count, prothrombin time, activated partial thromboplastin time, and fibrin degradation products concentration were measured at 24-hour intervals. Necropsy was performed on each calf. Phenylbutazone suppressed the clinical response to endotoxin challenge until large doses (7.5 to 15 micrograms/kg) were administered. Calves of groups C and D remained stable until they abruptly developed severe dyspnea necessitating euthanasia. Thrombocytopenia and leukopenia developed after the initial endotoxin dose. Prothrombin time was prolonged and PCV suddenly decreased at 96 hours. Necropsy revealed consistent lesions in the vascular endothelium and lungs. Phenylbutazone administration did not enhance or ameliorate endotoxin-induced hemostatic alterations or pathologic lesions.
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PMID:Effect of phenylbutazone and repeated endotoxin administration on hemostasis in neonatal calves. 821 7

A recirculating Langendorff heart preparation is used to characterize the endogenous antithrombin associated reversibly with murine vascular endothelium. Rat hearts are perfused clear of blood and then recirculated with a physiological salt solution. Addition of heparin educes antithrombin activity continuously into the perfusate during 6 min of recirculation. This process contrasts with a more rapid equilibration of the system as assessed by displacement of [125I]thrombin with hirudin or with a heparin-antithrombin mixture. Perfusion of washed hearts with [125I]factor Xa, which evidences no significant binding to the coronary endothelium, identifies a minor fraction of the endogenous antithrombin that reacts immediately with factor Xa, i.e., at a rate indicative of heparin enhancement. This rapid-reacting antithrombin is not reproducibly detected with [125I]thrombin, which binds preferentially to thrombomodulin in this system. The amount of antithrombin reacting rapidly with factor Xa is too low to detect as a burst of antithrombin activity eluted into the perfusate when the hearts are perfused with heparin. It is concluded that the murine myocardial microvasculature harbors at least two pools of antithrombin, the minor of which is in an activated configuration characteristic of association with heparin. The major pool is in a more slowly accessible compartment or configuration.
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PMID:Endogenous antithrombin associated with microvascular endothelium. Quantitative analysis in perfused rat hearts. 829 10


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