Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0012739 (disseminated intravascular coagulation)
 8,673 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Beta2-glycoprotein I (beta2GPI) is a plasma glycoprotein with unknown physiological function(s). In in vitro experiments it has been demonstrated that beta2GPI has both anticoagulant properties, such as the inhibition of factor X and prothrombin activation and procoagulant properties, such as the inhibition of the anticoagulant activity of activated protein C. Besides this, beta2GPI bound to cardiolipin is recognized by antiphospholipid antibodies (aPL). In this study we demonstrate that beta2GPI is very sensitive for cleavage between Lys317 and Thr318 by plasmin, resulting in two immunologically different cleaved forms. In vitro experiments show that these plasmin cleaved forms of beta2GPI bind to negatively charged phospholipids with much lower affinity compared to intact beta2GPI. Similar to plasmin, trypsin and elastase can also induce this proteolytical cleavage in beta2GPI, whereas thrombin and factor Xa do not cleave beta2GPI. The in vivo occurrence of the proteolytical cleavage was demonstrated by the finding that in plasmas of patients with disseminated intravascular coagulation (DIC) and in plasmas of patients treated with streptokinase, significant amounts of cleaved beta2GPI (up to 12 microg/ml) are present. During the development of DIC, the increase in levels of cleaved beta2GPI is accompanied by a 70% decrease in the levels of intact beta2GPI, whereas in streptokinase treated patients levels of intact beta2GPI stay within the normal range. This study demonstrates for the first time that during in vivo activation of fibrinolysis beta2GPI is cleaved. which results in the formation of a form of beta2GPI with much lower affinity for negatively charged phospholipids. Plasmin is most likely responsible for this modification.
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PMID:Beta2-glycoprotein I is proteolytically cleaved in vivo upon activation of fibrinolysis. 1034 17

Important mechanisms underlying immediate xenograft loss by hyperacute rejection (HAR), in the pig-to-primate combination, have been recently delineated. There are now several proposed therapies that deal with the problem of complement activation and xenoreactive natural antibody (XNA) binding to the vasculature that have been shown to prevent HAR. However, vascularized xenografts are still lost, typically within days, by delayed xenograft rejection (DXR), alternatively known as acute vascular rejection (AVR). This process is characterized by endothelial cell (EC) perturbation, localization of XNA within the graft vasculature, host NK cell and monocyte activation with platelet sequestration and vascular thrombosis. Alternative immunosuppressive strategies, additive anti-complement therapies with the control of any resulting EC activation processes and induction of protective responses have been proposed to ameliorate this pathological process. In addition, several potentially important molecular incompatibilities between activated human coagulation factors and the natural anticoagulants expressed on porcine EC have been noted. Such incompatibilities may be analogous to cross-species alterations in the function of complement regulatory proteins important in HAR. Disordered thromboregulation is potentially relevant to the progression of inflammatory events in DXR and the disseminated intravascular coagulation seen in primate recipients of porcine renal xenografts. We have recently demonstrated the inability of porcine tissue factor pathway inhibitor (TFPI) to adequately neutralize human factor Xa (FXa), the aberrant activation of both human prothrombin and FXa by porcine EC and the failure of the porcine natural anticoagulant, thrombomodulin to bind human thrombin and hence activate human protein C. The enhanced potential of porcine von Willebrand factor to associate with human platelet GPIb has been demonstrated to be dependent upon the isolated A1 domain of von Willebrand factor. In addition, the loss of TFPI and vascular ATPDase/CD39 activity following EC activation responses would potentiate any procoagulant changes within the xenograft. These developments could exacerbate vascular damage from whatever cause and enhance the activation of platelets and coagulation pathways within xenografts resulting in graft infarction and loss. Analysis of these and the other putative factors underlying DXR should lead to the development and testing of genetic approaches that, in conjunction with selected pharmacological means, may further prolong xenograft survival to a clinically relevant extent.
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PMID:Factors in xenograft rejection. 1041 73

Tissue factor pathway inhibitor (TFPI), a Kunitz-type protease inhibitor with three tandem inhibitory domains (K1, K2 and K3), inhibits the initial reactions of the extrinsic blood coagulation pathway through its K1 and K2 domains. We prepared and characterized a monoclonal antibody (Mab8-1) against TFPI-factor Xa (TFPI-Xa) complex. The reactivities of Mab8-1 toward TFPI-Xa complex, TFPI without C-terminal (TFPI-C)-Xa complex, K1K2-Xa complex and K2K3-Xa complex were examined using a surface plasmon resonance analysis (Biacore). The Biacore system allowed a quantitative analysis of antibody-antigen interaction, in real time, from which the association and dissociation rate constants could readily be obtained. The bindings of Mab8-1 to TFPI-Xa complex, TFPI-C-Xa complex and K2K3-Xa complex were each concentration-dependent. However, no binding of Mab8-1 to the K1K2-Xa complex was observed. The binding of Mab8-1 to TFPI or Xa was also not observed. These results suggested that the epitope for Mab8-1 was exposed in the K3 domain of TFPI, which was generated by the conformational change after the formation of TFPI-Xa complex. We then developed an enzyme-linked immunosorbent assay method specific for TFPI-Xa complex using Mab8-1, and we used this assay to measure plasma levels of TFPI-Xa. The normal range assessed from analyses of plasma from 30 normal healthy volunteers was 17.7-66.7 with a mean of 35.5 +/- 11.7 pmol/l. In order to asses the clinical implication of TFPI-Xa complex in the plasma of patients with thrombotic disorders, plasma concentrations were measured in 37 patients with disseminated intravascular coagulation (DIC) caused by a variety of underlying diseases. The TFPI-Xa antigen levels were significantly higher in the patients with DIC (51.9 +/- 21.6 pmol/l) and the 36 patients with pre-DIC (55.1 +/- 20.2 pmol/l) than in the 137 non-DIC patients (37.9 +/- 13.1 pmol/l). In the patients with DIC or pre-DIC, there was no significant correlation between TFPI-Xa complex and the elevated levels of thrombin-antithrombin complex, plasmin-alpha2 plasmin inhibitor complex, D-dimer, soluble fibrin monomer, soluble thrombomodulin or tissue factor. These data indicate that the plasma level of TFPI-Xa seems to be a novel independent molecular marker of DIC and pre-DIC.
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PMID:Monoclonal antibody specific for tissue factor pathway inhibitor-factor Xa complex: its characterization and application to plasmas from patients with disseminated intravascular coagulation and pre-disseminated intravascular coagulation. 1049 12

Tissue factor pathway inhibitor (TFPI), the major downregulator of the procoagulant activity of tissue factor (TF), is synthesised by endothelial cells (EC) and acutely released in vitro after thrombin stimulation. Expression of TF on EC and subsequent thrombin generation occurs in vivo during sepsis or malignancy, inducing disseminated intravascular coagulation (DIC). The present study investigates the changes in plasma TFPI in relation to markers of in vivo thrombin generation induced by injection of factor Xa (FXa)/phospholipids in baboons at dosages leading to partial (48%) or complete fibrinogen depletion. The plasma concentrations of thrombin-antithrombin III (TAT) and fibrinopeptide A (FpA), as markers of in vivo generation of thrombin, were strongly enhanced after injection of FXa/phospholipids. TFPI levels, whether measured as antigen or activity, increased significantly in both treatment groups within few minutes, and were dependent on the dose of FXa/phospholipids. Significant positive correlations between plasma levels of TFPI and of TAT or FpA were observed. Altogether, our results indicate that experimentally induced in vivo generation of thrombin causes the acute release of TFPI, high-lighting a possible novel function of thrombin in downregulation of the coagulation process, potentially relevant for the outcome of DIC.
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PMID:Acute release of tissue factor pathway inhibitor after in vivo thrombin generation in baboons. 1061 51

Disseminated intravascular coagulation (DIC) is an acquired syndrome characterized by intravascular fibrin formation occurring in the course of a variety of severe diseases. In gram-negative sepsis, endotoxin is the bacterial component eliciting a cascade of tissue factor dependent hypercoagulable reactions mediated by cytokines, including tumor necrosis factor-alpha and interleukin-6. Fibrinolysis is activated in this process by the action of tumor necrosis factor-alpha, but its activity is impaired by the predominant inhibitory effect of plasminogen activator inhibitor-1. Natural inhibitory mechanisms include antithrombin, the protein C system, and tissue factor pathway inhibitor. Each of these defense systems counteracts the harmful effects of DIC, and its acquired deficiency is associated with increased mortality in observational studies. The generation of several proteases in DIC, including factor Xa and thrombin, has potential interactions with inflammatory pathways that may potentiate the systemic inflammatory syndrome that often accompanies DIC. Experimental studies support the notion that defects in the protein C pathway modulate the inflammatory response, and illustrate that coagulation and inflammation are coupled systems in DIC.
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PMID:Pathophysiology of disseminated intravascular coagulation in sepsis. 1100 90

Plasma levels of tissue factor pathway inhibitor (TFPI)-activated factor Xa (FXa) complex were measured in patients with disseminated intravascular coagulation (DIC), pre-DIC, and DIC. Plasma levels of plasmin-plasmin inhibitor complex (PPIC), D-dimer, and soluble fibrin monomer (SFM) were significantly higher in patients with DIC than in those with pre-DIC or non-DIC; the levels of these hemostatic markers were significantly higher in patients with pre-DIC than in those with non-DIC. Plasma levels of thrombin-antithrombin complex (TAT) were significantly higher in patients with DIC or pre-DIC than in those with non-DIC. Plasma levels of tissue factor (TF), total TFPI, free TFPI, and TFPI-Xa complex were significantly higher in patients with DIC than in those with non-DIC. Plasma levels of TFPI-Xa complex were significantly increased in patients with pre-DIC as compared to those with non-DIC; however, plasma free TFPI levels were significantly decreased in patients with pre-DIC as compared to those with non-DIC. These findings suggest that free TFPI might be consumed in the pre-DIC state, thereby confirming the activation of the extrinsic pathway. Plasma levels of TFPI-Xa complex were significantly correlated with TF, free TFPI, and total TFPI. Increased plasma TFPI-Xa complex levels might be useful for the diagnosis of DIC or pre-DIC, particularly that occurring by activation of the extrinsic pathway of blood coagulation.
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PMID:Increased plasma levels of tissue factor pathway inhibitor-activated factor X complex in patients with disseminated intravascular coagulation. 1107 37

In 1967 we reported for the first time five cases of an acquired bleeding disorder in humans which developed after contact with saturnidae caterpillars. Since that time, other cases have been reported in Brazil, French Guyana, Peru, Paraguay and Argentina. The caterpillars have been identified as Lonomia achelous (LA) in Venezuela and northern Brazil and as Lonomia obliqua (LO) in southern Brazil. All patients present pain and a burning sensation at the site of contact. Within a few hours hematomas and hematuria are seen in combination with intracerebral and intraperitoneal hemorrhage (in some cases also renal failure). Hematological tests show: mild anemia with leucocytosis; prolonged PT, PTT and ThT; decreased fibrinogen, factor V, factor XIII, plasminogen and alpha2-antiplasmin levels; increased factor VIII:c, von Willebrand factor, and FDPs/D-dimers levels with normal ATIII and platelets. Factor VII, factor II and PC levels varied. Several activities similar to or directed against blood clotting factors have been identified in LA: fibrinolytic enzymes, which degrade fibrinogen producing abnormal FDPs; prothrombin activators: one direct and one factor Xa-like; a thermostable factor V activator; a thermolabile factor V inhibitor; a factor XIII proteolytic/urokinase-like activity; and a kallikrein-like activitiy. In LO three activities have been described: a prothrombin activator called 'Lonomia obliqua prothrombin activator protease' (LOPAP); a factor X activator; and a phospholipase A(2)-like activity called Lonomiatoxin. No fibrinolytic activity has been described in LO. Subcutaneous injection of crude hemolymph and some chromatographic fractions of LA induce a decrease in fibrinogen, plasminogen and factor XIII. Intravenous injection of factor XIII proteolytic/urokinase-like activity induce a dose-dependent thrombolysis with a decrease in plasmatic factor XIII without hemorrhagic manifestations. Intradermal injection of LO bristle extracts in rats and rabbits produce incoagulability whereas intravenous injection of LOPAP induced DIC in mice.
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PMID:Lonomia genus caterpillar toxins: biochemical aspects. 1108 23

Research on synthetic peptides at the Institute for Drug Research (IDR) is exemplified by an overview of the projects that resulted in significant results. The first synthesis of oxytocin, a pituitary hormone, in 1953 launched the research on synthetic peptides all over the world. This synthesis was reproduced by Bodanszky at the IDR in 1954, then, after some improvements, the process was presented to Richter to produce synthetic oxytocin for therapeutic purposes. Significant result was the first synthesis of the 39-member whole molecule of human ACTH, another pituitary hormone. A short SAR study on luteinizing hormone-releasing hormone (LHRH) led to an interesting analog, Cit-8-LHRH, and somewhat later, to the D-Cit-6-LHRH analogues, of which SB-75 become marketed under the name Cetrorelix. Studies on the brain peptides, enkephalins, resulted in GYKI-14,238, the first analog that showed analgesic activity upon systemic administration and whose human efficacy could also be proven during clinical examination. Significant results were also achieved in the research on anticoagulant peptides. The first highly potent peptide aldehyde inhibitor of thrombin, GYKI-14,166, was identified at the IDR as well as its stable analog, GYKI-14,766. This compound was selected for detailed preclinical study, licensed to Eli Lilly Company, got the generic name efegatran, and entered clinical trials. The first non-covalent peptide inhibitor of thrombin, GYKI-14,525, was also identified at the IDR. Thus IDR really provided the prototype of original thrombin inhibitors in the mid 70's, and analogues were prepared in many laboratories through two decades. IDR's current research program's objective includes a quest for peptide originals that can inhibit both thrombin and factor Xa in solution and also within plasma clots in which these enzymes are entrapped. Structures with such inhibitory profile were identified among the efegatran-related alpha-hydroxy acid and ethoxycarbonyl-amino acid derivatives. The follow-up molecules are even more promising as antithrombotics, and may also be useful for treatment of disseminated intravascular coagulation, an often fatal syndrome, so we continue working on this project.
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PMID:[Research on synthetic peptides of biological interest]. 1176 93

The rejection of xenografts is associated with vascular-based inflammation, thrombocytopenia and the consumption of coagulation factors that may evolve into disseminated intravascular coagulation. Natural regulators of coagulation in porcine xenografts have abnormal physiological interaction with human effectors. We have demonstrated the enhanced potential of porcine von Willebrand factor to associate with human platelet GPlb to be dependent upon the isolated AI domain of von Willebrand factor. The inability of porcine tissue factor pathway inhibitor (TFPI) to adequately neutralize human factor Xa (FXa), the aberrant activation of both human prothrombin and FXa by porcine EC and the failure of the porcine natural anticoagulant, thrombomodulin to bind human thrombin and hence activate human protein C may all be pathogenetic in the DIC following xenograft rejection. In this brief review, molecular incompatibilities of contributors in the physiologically fine tuned system of hemostasis are summarized and brought in context with the disordered thromboregulation, that seems to be invariably associated with delayed xenograft rejection. Possible therapeutic interventions are discussed.
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PMID:Molecular incompatibilities in hemostasis between swine and men--impact on xenografting. 1189 92

Severe consumption coagulopathy has been detected in rats after Lopap (a prothrombin activator from Lonomia obliqua caterpillar bristles) infusion and in humans after accidental contact with L. obliqua bristles. However, platelet count and antithrombin (AT) levels were only modestly affected, suggesting that a different form of blood coagulation activation may be involved in this hemorrhagic syndrome. Here we describe that Lopap had no effect on aggregation of washed human platelets induced by several agonists, suggesting that it might not impair platelet function in vivo. AT was able to inhibit the amidolytic activity of thrombin generated by incubation of Lopap with prothrombin in a purified system, which may be different from that generated by the prothrombinase complex in vivo. The surface expression of both ICAM-1 and E-selectin but not of VCAM-1 was upregulated by Lopap in cultured HUVEC, suggesting that it may behave differently from other mediators, such as thrombin and tumor necrosis factor-alpha.
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PMID:Effects of lopap on human endothelial cells and platelets. 1191 Jan 93


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