Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.7 (plasmin)
 9,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In general toxicological studies, prothrombin time and activated partial thromboplastin time are routinely measured to assess blood coagulation. Special (problem-driven) tests for blood coagulation are of significance to detect abnormalities and investigate the mechanism of toxicity in detail. In this review, we compiled widely scattered information on blood coagulation testing from different fields in the biological area, and reviewed the methods available and their significance in toxicological studies. The relevant literature cited here reports large species differences in platelet aggregation, coagulation factors or fibrinolysis, and technical limitations. However, the following tests are basically applicable to laboratory animals; (1) assays for individual coagulation factors and protein induced by vitamin K absence or antagonists (PIVKA) to investigate coagulation factor abnormalities; (2) platelet aggregation-, platelet adhesion-, platelet release-tests and von Willebrand factor assay to screen and/or investigate platelet dysfunction; (3) fibrin/fibrinogen degradation products (FDP), D-dimer and thromboelastogram to detect fibrinolitic abnormalities, and assays for plasminogen, plasmin and their activator/inhibitor to investigate fibrinolysis in detail; and (4) bleeding-time to grossly evaluate blood coagulation capability in vivo. An appropriate battery of these tests provides significant information for risk assessment of drugs.
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PMID:Blood coagulation tests in toxicological studies--review of methods and their significance for drug safety assessment. 1501 51

We recently reported that the serum level of macrophage colony-stimulating factor (M-CSF) was elevated in patients with cerebral infarction. In the present study, we measured serum M-CSF level, as well as coagulo-fibrinolytic markers and general laboratory tests in adult healthy subjects of various ages, and investigated the relationship between age and M-CSF level. M-CSF in aged subjects (>or=65 years of age) was significantly higher than that in the younger subjects (<65 years of age), and a significant positive correlation between age and M-CSF was found. Significant positive correlations between M-CSF, and plasma levels of thrombomodulin (TM), von Willebrand factor antigen (vWF), thrombin-antithrombin III complex (TAT), prothrombin fragment 1+2 (F1+2), d-dimer products cross-linked fibrin degradation products (d-dimer) and plasmin-antiplasmin complex (PAP) were also found. Among the general laboratory tests, there was only a significant correlation between M-CSF and serum creatinine; however, no significant correlation was found between M-CSF and other tests including blood cell counts. From these results, age-related elevation of serum M-CSF level was confirmed, and was suggested not to indicate the alteration of hemopoietic condition in aged subjects but to be related to thrombotic state or systemic damaged blood vessel in the apparently healthy aged people.
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PMID:Age related elevation of serum macrophage colony stimulating factor (M-CSF) level. 1537 73

The multimeric size and the function of circulating von Willebrand factor are modulated via its proteolytic cleavage by the plasma metalloproteinase, ADAMTS13. It is unclear how ADAMTS13 activity is regulated within the vascular system. In the absence of a regulatory mechanism, ADAMTS13 activity might compromise platelet adhesion at sites of vascular injury. We hypothesized that at sites of vascular injury, ADAMTS13 activity could be regulated locally by coagulation proteinases. Initiation of coagulation in human plasma resulted in the disappearance of added full-length recombinant ADAMTS13. This loss was inhibited by hirudin. Using purified proteins, we showed that ADAMTS13 is proteolyzed at several cleavage sites by thrombin in a time- and concentration-dependent manner. Furthermore, this proteolysis ablated ADAMTS13 activity against purified von Willebrand factor. Preincubation of thrombin with soluble thrombomodulin, but not heparin, inhibited the proteolysis of ADAMTS13, suggesting the involvement of thrombin exosite I (and not exosite II) in ADAMTS13 recognition. Plasmin also cleaved ADAMTS13 into similar fragments, resulting in the loss of ADAMTS13 activity. This study demonstrates the susceptibility of ADAMTS13 to proteolytic inactivation and suggests possible roles for thrombin and plasmin at sites of vascular injury.
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PMID:Proteolytic inactivation of ADAMTS13 by thrombin and plasmin. 1538 80

In normal pregnancy, there is a marked increase in the procoagulant activity in maternal blood characterized by elevation of factors VII, X, VIII, fibrinogen and von Willebrand factor, which is maximal around term. This is associated with an increase in prothrombin fragments (PF1+2) and thrombin-antithrombin complexes. There is a decrease in physiological anticoagulants manifested by a significant reduction in protein S activity and by acquired activated protein C (APC) resistance. The overall fibrinolytic activity is impaired during pregnancy, but returns rapidly to normal following delivery. This is largely due to placental derived plasminogen activator inhibitor type 2 (PAI-2), which is present in substantial quantities during pregnancy. D-dimer, a specific marker of fibrinolysis resulting from breakdown of cross-linked fibrin polymer by plasmin, increases as pregnancy progresses. Overall, there is a 4- to 10-fold increased thrombotic risk throughout gestation and the postpartum period. Local haemostasis at the placental throphoblast level is characterized by increased tissue factor (TF) expression and low expression of the inhibitor TFPI. Microparticles derived from maternal endothelial cells and platelets, and from placental throphoblasts may contribute to the procoagulant effect. Local anticoagulant mechanisms on placental throphoblasts are important for counterbalance of the procoagulant milieu. Disruption of anticoagulant mechanisms, for example, autoantibodies, to annexin V may increase pregnancy complications in patients with antiphospholipid antibodies (APLA).
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PMID:Haemostatic changes in pregnancy. 1550 71

Fibrinogen is a large, complex, fibrous glycoprotein with three pairs of polypeptide chains linked together by 29 disulfide bonds. It is 45 nm in length, with globular domains at each end and in the middle connected by alpha-helical coiled-coil rods. Both strongly and weakly bound calcium ions are important for maintenance of fibrinogen's structure and functions. The fibrinopeptides, which are in the central region, are cleaved by thrombin to convert soluble fibrinogen to insoluble fibrin polymer, via intermolecular interactions of the "knobs" exposed by fibrinopeptide removal with "holes" always exposed at the ends of the molecules. Fibrin monomers polymerize via these specific and tightly controlled binding interactions to make half-staggered oligomers that lengthen into protofibrils. The protofibrils aggregate laterally to make fibers, which then branch to yield a three-dimensional network-the fibrin clot-essential for hemostasis. X-ray crystallographic structures of portions of fibrinogen have provided some details on how these interactions occur. Finally, the transglutaminase, Factor XIIIa, covalently binds specific glutamine residues in one fibrin molecule to lysine residues in another via isopeptide bonds, stabilizing the clot against mechanical, chemical, and proteolytic insults. The gene regulation of fibrinogen synthesis and its assembly into multichain complexes proceed via a series of well-defined steps. Alternate splicing of two of the chains yields common variant molecular isoforms. The mechanical properties of clots, which can be quite variable, are essential to fibrin's functions in hemostasis and wound healing. The fibrinolytic system, with the zymogen plasminogen binding to fibrin together with tissue-type plasminogen activator to promote activation to the active enzyme plasmin, results in digestion of fibrin at specific lysine residues. Fibrin(ogen) also specifically binds a variety of other proteins, including fibronectin, albumin, thrombospondin, von Willebrand factor, fibulin, fibroblast growth factor-2, vascular endothelial growth factor, and interleukin-1. Studies of naturally occurring dysfibrinogenemias and variant molecules have increased our understanding of fibrinogen's functions. Fibrinogen binds to activated alphaIIbbeta3 integrin on the platelet surface, forming bridges responsible for platelet aggregation in hemostasis, and also has important adhesive and inflammatory functions through specific interactions with other cells. Fibrinogen-like domains originated early in evolution, and it is likely that their specific and tightly controlled intermolecular interactions are involved in other aspects of cellular function and developmental biology.
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PMID:Fibrinogen and fibrin. 1583 18

ADAMTS13, a reprolysin-like metalloprotease, limits platelet-rich thrombus formation in the small arteries by cleaving von Willebrand factor (vWF) at the Tyr1605-Met1606 peptide bond. Deficiency of plasma ADAMTS13 activity, due to either an inherited or an acquired etiology, may lead to a potentially lethal syndrome, thrombotic thrombocytopenic purpura (TTP). Molecular cloning and characterization of the ADAMTS13 gene have provided further insight into the structure-function relationships, biosynthesis, and regulation of the ADAMTS13 protease, in addition to understanding the pathogenesis of TTP and perhaps other thrombotic disorders. ADAMTS13 consists of a short propeptide, a typical reprolysin-like metalloprotease domain, followed by a disintegrin-like domain, first thrombospondin type 1 (TSP1) repeat, Cys-rich domain, and spacer domain. The carboxyl terminus of ADAMTS13 has seven more TSP1 repeats and two CUB domains. ADAMTS13 is synthesized mainly in hepatic stellate cells, but also in vascular endothelial cells. Recognition and cleavage of vWF require the proximal carboxyl terminal domains, but not the middle and distal carboxyl terminal domains. Cleavage of vWF appears to be modulated by shear force, binding to platelet or platelet glycoprotein-1balpha, heparin, inflammatory cytokine (interleukin-6), and chloride ion. At the site of thrombus formation, the ADAMTS13 may be inactivated by thrombin, plasmin, and factor Xa. Having a sensitive and specific assay for ADAMTS13 activity is not only critical to understand the basic biology of ADAMTS13 protease, but also to facilitate a more timely and accurate clinical diagnosis of TTP, and to initiate potentially life-saving plasma exchange therapy. Although many assays have been developed and tested for clinical applications, the fluorescent resonance energy transfer-vWF73 assay appears to be the simplest and most promising assay to date.
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PMID:Molecular biology of ADAMTS13 and diagnostic utility of ADAMTS13 proteolytic activity and inhibitor assays. 1638 17

When the continuity of the vascular endothelium is disrupted, platelets and fibrin seal off the defect. Haemostatic processes are classified as primary (mainly involving platelets) and secondary (mainly related to fibrin formation or blood coagulation). When the blood clot is no longer required for haemostasis, the fibrinolytic system will dissolve it. The pivotal ligand for initial platelet recruitment to injured vessel wall components is von Willebrand factor (vWF), a multimeric protein present in the subendothelium and in plasma, where it is conformationally activated by shear forces. Adhering activated platelets recruit additional platelets, which are in turn activated and form a platelet aggregate. Coagulation is initiated by a reaction, activating factors IX and X. Once critical amounts of factor Xa are generated, thrombin generation is initiated and soluble fibrinogen is converted into insoluble fibrin. Excessive thrombin generation is prevented via inhibition by antithrombin and also via downregulation of its further generation by activation of the protein C pathway. Activation of the fibrinolytic system results from conversion of the proenzyme plasminogen into the active serine proteinase plasmin by tissue-type or urokinase-type plasminogen activators. Plasmin digests the fibrin component of a blood clot. Inhibition of the fibrinolytic system occurs at the level of the plasminogen activator (by plasminogen activator inhibitors) or at the level of plasmin (by alpha2-antiplasmin). Together, these physiological processes act to maintain normal functioning blood vessels and a non-thrombotic state.
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PMID:Haemostasis. 1700 71

Plasmin not only functions as a key enzyme in the fibrinolytic system but also directly inactivates factor VIII and other clotting factors such as factor V. However, the mechanisms of plasmin-catalyzed factor VIII inactivation are poorly understood. In this study, levels of factor VIII activity increased approximately 2-fold within 3 min in the presence of plasmin, and subsequently decreased to undetectable levels within 45 min. This time-dependent reaction was not affected by von Willebrand factor and phospholipid. The rate constant of plasmin-catalyzed factor VIIIa inactivation was approximately 12- and approximately 3.7-fold greater than those mediated by factor Xa and activated protein C, respectively. SDS-PAGE analysis showed that plasmin cleaved the heavy chain of factor VIII into two terminal products, A1(37-336) and A2 subunits, by limited proteolysis at Lys(36), Arg(336), Arg(372), and Arg(740). The 80-kDa light chain was converted into a 67-kDa subunit by cleavage at Arg(1689) and Arg(1721), identical to the pattern induced by factor Xa. Plasmin-catalyzed cleavage at Arg(336) proceeded faster than that at Arg(372), in contrast to proteolysis by factor Xa. Furthermore, breakdown was faster than that in the presence of activated protein C, consistent with rapid inactivation of factor VIII. The cleavages at Arg(336) and Lys(36) occurred rapidly in the presence of A2 and A3-C1-C2 subunits, respectively. These results strongly indicated that cleavage at Arg(336) was a central mechanism of plasmin-catalyzed factor VIII inactivation. Furthermore, the cleavages at Arg(336) and Lys(36) appeared to be selectively regulated by the A2 and A3-C1-C2 domains, respectively, interacting with plasmin.
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PMID:Mechanisms of plasmin-catalyzed inactivation of factor VIII: a crucial role for proteolytic cleavage at Arg336 responsible for plasmin-catalyzed factor VIII inactivation. 1718 54

The effects of steroids on the outcome of sepsis are dose dependent. Low doses appear to be beneficial, but high doses do not improve outcome for reasons that are insufficiently understood. The effects of steroids on systemic inflammation as a function of dose have not previously been studied in humans. To determine the effects of increasing doses of prednisolone on inflammation and coagulation in humans exposed to LPS, 32 healthy males received prednisolone orally at doses of 0, 3, 10, or 30 mg (n = 8 per group) at 2 h before i.v. injection of Escherichia coli LPS (4 ng/kg). Prednisolone dose-dependently inhibited the LPS-induced release of cytokines (TNF-alpha and IL-6) and chemokines (IL-8 and MCP-1), while enhancing the release of the anti-inflammatory cytokine IL-10. Prednisolone attenuated neutrophil activation (plasma elastase levels) and endothelial cell activation (von Willebrand factor). Most remarkably, prednisolone did not inhibit LPS-induced coagulation activation, measured by plasma concentrations of thrombin-antithrombin complexes, prothrombin fragment F1+2, and soluble tissue factor. In addition, activation of the fibrinolytic pathway (tissue-type plasminogen activator and plasmin-alpha(2)-antiplasmin complexes) was dose-dependently enhanced by prednisolone. These data indicate that prednisolone dose-dependently and differentially influences the systemic activation of different host response pathways during human endotoxemia.
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PMID:Prednisolone dose-dependently influences inflammation and coagulation during human endotoxemia. 1723 35

The purpose of this study was to investigate whether platelet indices [platelet count, mean platelet volume (MPV), platelet-large cell ratio (P-LCR) and platelet distribution width (PDW)] could serve as diagnostic tools to evaluate the potential significance of platelet heterogeneity on thrombus formation in patients with aortic aneurysm (AA). Blood samples were obtained from 54 patients with AA (mean age 73 years; 40 males and 14 females), and from 120 age-matched controls (AC; mean age 74 years; 61 males and 59 females). Blood platelet indices were measured using an automated counter for all AC (n = 120) and AA (n = 54). Plasma thrombin-antithrombin III complex (TAT), alpha(2)-plasmin inhibitor-plasmin complex (PIC), D-dimer, von Willebrand factor antigen (vWF:Ag) and interleukin-6 (IL-6) were also measured in part of AC and AA. In AA patients, TAT, PIC, D-dimer, vWF:Ag and IL-6 levels were significantly (p < or =0.0005) higher than in AC. In the patients, TAT was significantly inversely correlated with platelet count (rho = -0.302, p = 0.038, n = 48), and significantly positively correlated with MPV (rho = 0.329, p = 0.0373, n = 48), P-LCR (rho = 0.361, p = 0.0134, n = 48) and PDW (rho = 0.315, p = 0.0466, n = 48). PIC was negatively correlated with platelet count and inversely correlated with MPV, P-LCR and PDW. vWF:Ag was not correlated with platelet count, and inversely correlated with MPV, P-LCR and PDW in the patients. IL-6 was positively correlated with platelet count, and significantly inversely correlated with MPV, P-LCR and PDW in the patients. In AC, vWF:Ag was inversely correlated with platelet count and significantly positively correlated with MPV, P-LCR and PDW. However, PIC, TAT and IL-6 were not correlated with platelet indices in AC. D-dimer was not at all correlated with platelet indices both in AA and AC. In conclusion, the correlation between platelet indices and plasma hemostatic factor levels, e.g. TAT, PIC, D-dimer, vWF:Ag and IL-6, will be important factors for the understanding of platelet heterogeneity in patients with AA.
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PMID:Relationship between hemostatic markers and platelet indices in patients with aortic aneurysm. 1756 39


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