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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The presence of nineteen blood coagulation factors and fibrinolysis factors was immunohistochemically evaluated in human lymph node germinal centers (GCs). Twelve of these factors were detected within lymphoid GCs. The predominant pattern was dendritic with occasional crescent-shaped, ring-shaped or 'moth-eaten' appearance. Immunostains of factor VIII-related antigen, factor I, protein C, tetranectin, antithrombin III, type 2-plasminogen activator inhibitor, and alpha 2-plasmin inhibitor were almost entirely absent from GCs, although they reacted in vascular wall and lumen, respectively. The immunostaining to high molecular weight kininogen, kallikrein, factors XII, X, V, II, XIIIa, XIIIs, plasminogen, tissue-plasminogen activator, and type 1-plasminogen activator inhibitor more frequently revealed a positive dendritic pattern. Immuno-electron microscopy demonstrated factor X and factor XIIIa attached to the cell surfaces of lymphocytes, macrophages, and follicular dendritic cells (FDCs); and in the intercellular space within GCs, especially attached to the labyrinthine-like structure of FDCs. No reaction products were observed in the perinuclear cisternae and rough endoplasmic reticulum in either lymphocytes or FDCs. Our data demonstrate that human lymphoid GCs really contain some of the proteins related to the blood coagulation and fibrinolysis cascades.
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PMID:Localization of blood coagulation factors and fibrinolysis factors within lymphoid germinal centers in human lymph nodes. 168 Aug 35

A broad-based, dynamic model of intrinsic coagulation is described. Non-anticoagulated whole blood was perfused through polyethylene tubing under standard conditions, and coagulation (cessation of flow) was monitored by pressure changes. The dynamic coagulation test (DCT) is a sequel to the shear-induced haemostasis, a platelet function test routinely performed prior to coagulation. DCT has two important advantages over stagnant overall clotting tests: i./DCT reflects platelet coagulant activities; selective activation by adenosine diphosphate or shear-stress or inhibition of platelets by prostacyclin greatly enhanced or prolonged dynamic coagulation, respectively. Furthermore, activation of platelets by plasminogen activators (streptokinase, t-PA) was manifested in a significantly shortened coagulation. ii./ DCT allows the rapid assessment of fibrin crosslinking, the mechanical stability of the clot formed. Antibody against factor XIIIa greatly prolonged the time until completion of clotting. In patients taking oral anticoagulant (n = 54), strong correlations were observed between DCT, the prothrombin time (INR) and the thrombelastograph measurements. It is concluded that this simple assay could be useful in the overall screening for coagulation abnormalities.
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PMID:Coagulation of flowing native blood: advantages over stagnant (tube) clotting tests. 180 65

The effect of inhibition of factor XIIIa with 2-(l-acetonylthio)-5-methylthiazolo[2,3-b]1,3,4-thiadiazo lium perchlorate (L-722,151) on coronary thrombolysis and reocclusion was studied in an acute dog model of electrically induced coronary thrombosis. L-722,151 (0.1 mg/kg/min intravenously [IV] or placebo was administered 15 minutes before current initiation (150 microA) and for the duration of the experiment (270 minutes). Fifteen minutes after thrombus formation, heparin (300 U/kg, IV) was administered, followed 45 minutes later by recombinant tissue-type plasminogen activator (tPA) (10 micrograms/kg/min, IV for 90 minutes). Placebo-treated animals thrombosed at 48.9 +/- 8.1 minutes (mean +/- SEM) and reperfused in response to tPA at 49.1 +/- 9.3 minutes. L-722,151 pretreated animals thrombosed at 44.4 +/- 9.7 minutes and reperfused in response to tPA at 16.4 +/- 2.8 minutes (P less than .05 v vehicle). Furthermore, residual thrombus mass was reduced by L-722,151 from 6.9 +/- 1.9 mg in placebo-treated animals to 1.7 +/- 0.6 mg (P less than .05 v vehicle). Acute reocclusion occurred in 86% of placebo and in 75% of L-722,151-treated animals. The incidence of tPA-induced reperfusion in L-722,151-treated dogs was 100% (8 of 8), whereas only 70% (7 of 10) of placebo-treated dogs reperfused. These results demonstrate that pretreatment with L-722,151 hastens reperfusion time threefold and reduces residual thrombus mass. These effects occurred with no change in systemic blood pressure in response to L-722,151. When L-722,151 was administered 15 minutes after thrombus formation in a separate group of dogs (n = 5), no beneficial effect on thrombolysis time or thrombus mass was observed. Thus, the specific factor XIIIa catalyzed crosslinking reaction(s), which may determine(s) resistance to plasmin-mediated fibrin degradation, occur(s) rapidly. Inhibition of this crosslinking by pretreatment with L-722,151 promotes tPA-induced thrombolysis.
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PMID:Inhibition of factor XIIIa in a canine model of coronary thrombosis: effect on reperfusion and acute reocclusion after recombinant tissue-type plasminogen activator. 196 93

Interaction of tissue plasminogen activator (t-PA) with fibrin plays a key role in regulation of plasminogen activation and clot dissolution. Previous investigations of t-PA-fibrin interaction, using incorporation of t-PA into polymerizing fibrin clots, have suggested that no significant differences exist in the binding of one-chain or two-chain t-PA to non-cross-linked or cross-linked fibrin. In the present study, binding of 125I-labeled and affinity-purified one-chain and two-chain forms of t-PA to preformed non-cross-linked or cross-linked, sonicated suspension of fibrin was investigated. Interaction of one-chain t-PA with cross-linked fibrin involved a single type of binding site with dissociation constant (kd) of 0.58 mumol/L and a stoichiometry (n) of 1.5. Interaction of one-chain t-PA with non-cross-linked fibrin, however, involved two classes of binding sites with dissociation constants of 0.32 and 1.5 mumol/L and corresponding number of binding sites equal to 0.57 and 2.0, respectively. In contrast to the binding of one-chain t-PA to cross-linked fibrin by a limited number of sites, two-chain t-PA appeared to involve a considerably greater number of sites (minimum six) whose dissociation constant was 3.2 mumol/L. Interaction of two-chain t-PA with non-cross-linked fibrin also showed the presence of many binding sites (minimum seven) with approximate dissociation constant of 6.4 mumol/L, as well as a few (n = 0.012) high-affinity sites with a kd of 0.011 mumol/L epsilon-Aminocaproic acid did not completely reverse the binding of either one-chain t-PA or two-chain t-PA to fibrin. The present findings suggest that the fibrin-binding properties of t-PA undergo considerable changes on proteolytic conversion from one-chain to two-chain t-PA, catalyzed under physiologic conditions by plasmin. The cleavage of one-chain t-PA to two-chain t-PA allows to bind to a large number of low-affinity binding sites on fibrin. Cross-linking of fibrin by factor XIIIa results in masking of high-affinity binding sites that are present in non-cross-linked fibrin. We propose that both plasmin and factor XIIIa play an important regulatory role in dissolution of blood clots by modulating t-PA-fibrin interaction.
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PMID:Differences between binding of one-chain and two-chain tissue plasminogen activators to non-cross-linked and cross-linked fibrin clots. 250 9

The effect of a selective thrombin inhibitor, (2R, 4R)-4-methyl-1-[N2-[(3-methyl-1,2,3,4-tetrahydro-8-quinolinyl)sulfonyl]- L-arginyl]-2-piperidinecarboxylic acid (MCI-9038), on the fibrinolysis induced by t-PA and u-PA was studied in vitro and in vivo. MCI-9038 remarkably reduced the lysis time of the plasma clot generated by the addition of calcium chloride to the plasma at the concentration ranging from 0.01 to 0.3 microM. Heparin also reduced the plasma clot lysis time with a lower effect than MCI-9038. The fibrin crosslinkage in the plasma clot was inhibited by MCI-9038 or heparin. MCI-9038 potently inhibited the factor XIIIa generation from factor XIII by thrombin. The effect on the in vivo thrombolysis was studied on the arterial thrombosis generated by the endothelial cell injury of the rabbit carotid artery by acetic acid. t-PA dissolved the thrombi with the infusion at 0.96 mg/kg over 2 h without a significant activation of a systemic fibrinolysis. u-PA dissolved the thrombi with the infusion at 180,000 and 360,000 IU/kg over 2 h. At a dose of 0.48 mg/kg t-PA or 90,000 IU/kg u-PA, the thrombi were not dissolved, but the combined use of MCI-9038 at 1.2 mg/kg over 2 h effectively dissolved the thrombi. Thus, combination of MCI-9038 with plasminogen activators accelerated thrombolysis of an experimental thrombosis in rabbits.
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PMID:Effect of a selective thrombin inhibitor MCI-9038 on fibrinolysis in vitro and in vivo. 287 8

Physiologic fibrinolysis is a reparative process that occurs in response to hemostatic plug or thrombus formation. The final enzymatic step, fibrin proteolysis, results from a coordinated interaction of enzymes and inhibitors, which produces effective action at the site of the disease and spares the proteins of the blood or uninvolved parts of the vascular system. The agent of fibrinolysis, the enzyme plasmin, is derived from its zymogen (plasminogen) through limited proteolysis effected by plasminogen activators. They can be grouped according to functional and immunologic properties into the tissue type and urokinase-like plasminogen activators. The ability of alpha 2 antiplasmin to neutralize efficiently free (nonfibrin-bound) plasmin prevents inappropriate systemic activation of fibrinolysis. This control is superseded in certain conditions, such as with the therapeutic administration of plasminogen activators to lyse pathologic thrombi, when plasmin degrades plasma fibrinogen into degradation fragments (X, Y, D, and E). Degradation of cross-linked fibrin results in distinctive products that are characterized by cross-linked (factor XIIIa-induced) derivatives such as D dimer. Disease states resulting from abnormalities in the fibrinolytic system include both hemorrhagic disorders, resulting from excessive fibrinolysis, and thrombosis, as the result of deficient fibrinolysis. Hyperfibrinolysis can result from pharmacologic administration of activators or from defective inhibition produced by alpha 2 antiplasmin deficiency. Hypofibrinolytic thrombosis can result from hereditary defects, for instance of plasminogen or fibrinogen, or from pharmacologic inhibition of fibrinolysis such as with epsilon aminocaproic acid. Laboratory evaluation of fibrinolysis is useful for monitoring fibrinolytic therapy and assessing thrombotic disorders and bleeding; it also includes the specific measurements of plasminogen activator, plasminogen, plasmin, inhibitors and circulating fibrinogen, and cross-linked fibrin degradation products.
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PMID:Physiologic regulation and pathologic disorders of fibrinolysis. 354 75

When blood is clotted, alpha(2)-plasmin inhibitor (alpha(2)PI) is cross-linked to fibrin by activated fibrin-stabilizing factor (activated coagulation Factor XIII, plasma transglutaminase). The amount of cross-linked alpha(2)-PI is proportional to the amount of alpha(2)PI present at the time of clotting. Plasma from a patient with congenital deficiency of alpha(2)PI was supplemented with various amounts of purified alpha(2)PI. Clots were prepared from these plasmas and were suspended in plasma containing a normal concentration of alpha(2)PI, and spontaneous clot lysis was observed. When the clot was formed in the presence of calcium ions and thereby allowing cross-linking to occur, the rate and extent of fibrinolysis were found to be inversely proportional to the concentrations of alpha(2)PI present in the clot at the time of clotting. When the clot was formed in the absence of calcium ions so that no cross-linking occurred, the clot underwent fibrinolysis at similar rates, regardless of the concentrations of alpha(2)PI in the clot. When the clot formed in the presence of calcium ions was squeezed and washed to remove unbound proteins before being suspended in plasma, the extent of fibrinolysis was also inversely proportional to the amount of alpha(2)PI cross-linked to fibrin. Similar results were obtained when the clot was suspended in buffered saline instead of plasma. These observations suggest that spontaneous fibrinolysis is mainly carried out by plasminogen/plasminogen activator bound to fibrin, and this fibrinolysis caused by fibrin-associated activation of plasminogen was mainly inhibited by alpha(2)PI cross-linked to fibrin. To further support this concept, alpha(2)PI treated with activated fibrin-stabilizing factor and that had lost most of its cross-linking capacity was used in similar experiments. This modified alpha(2)PI had the same inhibitory activity on plasmin as the native inhibitor, but gave significantly less inhibition of fibrinolysis in every experiment, particularly when the clot was compacted by platelet-mediated clot retraction or by squeezing. Thus, it was concluded that alpha(2)PI cross-linked to fibrin plays a significant role in inhibition of physiologically occurring fibrinolysis. It is further suggested that the absence of cross-linked alpha(2)PI contributes to accelerated fibrinolysis and hemorrhagic tendency in patients with congenital deficiency of fibrin-stabilizing factor.
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PMID:Significance of cross-linking of alpha 2-plasmin inhibitor to fibrin in inhibition of fibrinolysis and in hemostasis. 719 38

A new type of gamma Gly-268 (GGA) to Glu (GAA) substitution has been identified in a homozygous dysfibrinogen by analyses of the affected polypeptide and its encoding gene derived from a 58 year-old man manifesting no major bleeding or thrombosis. The functional abnormality was characterized by impaired fibrin assembly most likely due to failure to construct properly aligned double-stranded fibrin protofibrils. This presumption was deduced from the following findings: (1) Factor XIIIa-catalyzed cross-linking of the fibrin gamma-chains progressed in a normal fashion, indicating that the contact between the central E domain of one fibrin monomer and the D domain of another took place normally; (2) Nevertheless, factor XIIIa-catalyzed cross-linking of the fibrinogen gamma-chains was obviously delayed, suggesting that longitudinal association of D domains of different fibrin monomers, ie, D:D association was perturbed; (3) Plasminogen activation catalyzed by tissue-type plasminogen activator was not as efficiently facilitated by polymerizing fibrin monomer derived from the patient as by the normal counterpart. Therefore, gamma Gly-268 would not be involved in the 'a' site residing in the D domain, which functions as a complementary binding site with the thrombin-activated 'A' site in the central E domain, but would be rather involved in the D:D self association sites recently proposed for human fibrinogen. Thus, the gamma Glu-268 substitution newly identified in this homozygous dysfibrinogen seems to impair proper alignment of adjacent D domains of neighboring fibrin molecules in the double-stranded fibrin protofibril, resulting in delayed fibrin gel formation.
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PMID:A gamma Gly-268 to Glu substitution is responsible for impaired fibrin assembly in a homozygous dysfibrinogen Kurashiki I. 863 38

The physiological and pathophysiological state of tissues determines the exudation of plasma proteins, hemostasis, and fibrinolysis, i.e., inflammation, injury, and malignancy. The physiological controls of extravascular fibrinolysis ultimately rest on a balance between generation of the fibrinolytic enzyme(s), i.e., plasmin, elastase, cathepsins, etc., and inhibitors of the fibrinolytic enzyme(s), i.e., plasminogen activator inhibitors, alpha-2 plasmin inhibitor, alpha 1-protease inhibitors, etc. Moreover, it is the structural modification of fibrin that determines its stability toward proteolytic enzymes and physical duress. The structural modification of fibrin involves factor XIIIa-mediated cross-linking of interfibrin chains and alpha 2-plasmin inhibitor to fibrin. In turn, there are a number of agents that influence factor XIIIa catalytic activity (e.g., sulfhydryl agents, albumin, erythrocytes). The two key proenzymes, factor XIII and plasminogen, are tightly bound with the circulating fibrinogen molecules. Such high selective affinity for fibrin(ogen) provides the reaction specificity in a complex tissue fluid milieu and governs the kinetics of fibrinolysis. Any agents that interfere with such binding reactions, e.g., autoantibodies, may also affect the fibrinolytic reactions. Understanding these unique biochemical controls of factors involved in fibrinolysis may provide an insight into the complex regulatory process of extravascular fibrinolysis.
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PMID:Factors that control extravascular fibrinolysis. 912 12

Elevated plasma fibrinogen levels are a major risk factor for thrombosis. This report shows two mechanisms by which fibrinogen can affect the fibrinolysis rate in vitro and thus may lead to thrombosis. First, the lysis rate of fibrin decreases as the initial concentration of fibrinogen increases. Second, a minor variant form of fibrinogen decreases the rate of fibrinolysis. This variant, gammaA/gamma' fibrinogen, has one altered gamma chain and is known to bind to factor XIII zymogen. In a fibrinolysis assay containing purified thrombin, fibrinogen, tissue-type plasminogen activator, and plasminogen, clots from gammaA/gammaA and gammaA/gamma' fibrinogen lysed at similar rates. However, when factor XIII was added, slower lysis was seen in gammaA/gamma' fibrin clots when compared with gammaA/gammaA fibrin clots. A D-dimer agglutination assay showed that the gammaA/gamma' clots were more highly cross-linked than the gammaA/gammaA clots. The lysis rates of gammaA/gamma' clots were similar to gammaA/gammaA clots in the presence of N-ethylmaleimide, a specific inhibitor of factor XIIIa. The gammaA/gamma' fibrin clots made in the presence of factor XIII showed increased proteolytic resistance to both plasmin and trypsin. Clots made from afibrinogenemic plasma reconstituted with gammaA/gamma' fibrinogen also showed significant resistance to lysis compared with gammaA/gammaA fibrinogen. These data demonstrate gammaA/gamma' fibrin is resistant to fibrinolysis, possibly as a result of concentrating factor XIII on the clot. The total fibrinogen concentration and the amount of gammaA/gamma' fibrinogen increase clot stability in vitro and thus may contribute independently to the risk of thrombosis in humans.
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PMID:Resistance of gammaA/gamma' fibrin clots to fibrinolysis. 916 58


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