Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.69 (APC)
 16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Procoagulant, anticoagulant, and fibrinolytic activities are associated with endothelial cells and involve the production, secretion, and receptor mediated binding of proteins involved in these processes. The procoagulant aspect of endothelial cells function involves the production and release of von Willebrand Factor(vWF), the production of tissue factor, and the presence of Factor IX/IXa receptors on the cell surface. Secretion of vWf will promote the initial steps in thrombus formation by supporting platelet-platelet interaction and platelet-subendothelial matrix adhesion. Tissue factor which is undetectable in resting cells appears after exposure to various cytokines and initiates factor VIIa activation of factors IX and X. Receptors of Factor IX/IXa are also present and mediate the assembly of the prothrombinase complex on the endothelial cell surface. The anticoagulant pathway involves the cell surface protein thrombomodulin, protein C and its cofactor protein S. Thrombomodulin binds thrombin which activates protein C which in the presence of protein S cleaves and inactivates Factors V and VIII. Inactivation of these two coagulation cofactors halts the coagulation. Finally, endothelial cells also play a pivotal role in the fibrinolytic system. Production and regulated secretion of tissue plasminogen activator creates a profibrinolytic state in the endothelial cell environment. In addition, receptors for plasminogen and urokinase are also present, constituting a cell surface mediated fibrinolytic pathway. Plasminogen activator inhibitor type I, the primary inhibitor of tPA, is also produced by endothelial cells. Thus endothelial cells can promote and inhibit fibrinolysis, depending on the prevailing environmental conditions.
 ...
PMID:[Endothelial cells and vascular hemostasis]. 131 12

Selected coagulation and fibrinolytic parameters were assessed in 40 insulin dependent diabetes mellitus patients with varying degrees of metabolic control; 30 healthy subjects matched for age and sex formed the control group. Activated Partial Thromboplastin Time, Prothrombin Time, Fibrinogen, Factor VII, Antithrombin III, Protein C, Plasminogen, alpha 2-Plasmin Inhibitor, Plasminogen Activator Inhibitor-1, tissue-Plasminogen Activator were functionally evaluated. Antigenic levels of tissue-Plasminogen Activator, Thrombin-Antithrombin complexes and fibrinolytic specific product B beta 15-42 were also determined. Compared to the control group diabetic patients displayed significantly higher levels of Fibrinogen (p < 0.01), Factor VII (p < 0.01), Thrombin-Antithrombin complexes (p < 0.01) and Plasminogen Activator Inhibitor-1 activity (p < 0.01). Regardless of the normal level of the tissue-Plasminogen Activator-related antigen, diabetic patients had tissue-Plasminogen Activator activity lower than the control group (p < 0.05). Coagulation Factor VII and Thrombin-Antithrombin complexes were increased only in the patients with poor metabolic control (p < 0.01). Activated Partial Thromboplastin Time, Prothrombin Time, Antithrombin III, Protein C, Plasminogen, alpha 2-Plasmin Inhibitor, B beta 15-42 fibrin peptide were found to be in the normal range. Fibrinogen correlated positively with fasting blood glucose (p < 0.05) and Thrombin-Antithrombin complexes with glycosylated haemoglobin (p < 0.05), whereas Factor VII was positively correlated with glycemia (p < 0.01) and glycosylated haemoglobin (p < 0.05). Higher levels of Fibrinogen were found in patients affected by nephropathy (p < 0.005) or neuropathy (p < 0.05). These results demonstrate an impairment of the haemostatic balance in diabetic patients, that is a possible hypercoagulable state, which represents an important factor in the pathogenesis of atherosclerotic complications.
 ...
PMID:Coagulation and fibrinolytic system impairment in insulin dependent diabetes mellitus. 144 May 30

Haemostatic changes in 16 patients with Crohn's disease were studied from active disease into clinical remission and beyond. Elevated concentrations of fibrinopeptide A (FpA) and prothrombin fragments F1 + 2 (F1 + 2) were found at times of both active (FpA median 3.2, range [0.3-40] ng/ml and F1 + 2 median 2.3, range [0.3-18] nm/l) and inactive disease (FpA median 2, range [0.4-40] ng/ml and F1 + 2 median 1.3, range [0.2-20) nm/l]. We also measured the physiological inhibitors of coagulation and fibrinolysis; there was no significant difference in the levels of antithrombin III, protein C or the Exner ratio between active and inactive disease. Free protein S levels were significantly lower in active disease (median 34, range 9-54 U/dl) than in remission (median 40, range 12-65 U/dl). Plasminogen activator inhibitor type 1 (PAI-1) was significantly raised in remission (median 11, range 3-32 ng/ml) when compared to active disease (median 7, range 3-42 ng/ml). The D-dimer correlated significantly with fibrinopeptide A (P < 0.001), suggesting reactive fibrinolysis in some patients. Most (35/52, 67%) samples showed evidence of persistent haemostatic activation (elevated FpA and/or F1 + 2) during phases of apparent clinical remission in Crohn's disease, a factor that is not reflected by clinical activity scores. This study supports the hypothesis that coagulation is activated in the mesenteric vasculature of patients with Crohn's disease.
 ...
PMID:Evidence for activation of coagulation in Crohn's disease. 148 98

Widespread intravascular coagulation is common in patients with sepsis. Coagulation abnormalities may result from exposure to endotoxin, from tumor necrosis factor alpha or interleukin 1 release, or from the actions of a more specific mediator, such as vascular permeability factor. The result is marked activation of the contact and coagulation systems; simultaneously, there is decreased fibrinolysis and depressed levels of the inhibitors of the contact and coagulation systems. Multiple agents are being studied to correct these abnormalities. Antithrombin III holds promise because it inhibits a number of factors important in contact and coagulation activation, not just thrombin. Plasminogen activators may prove helpful in increasing fibrinolysis during sepsis; because they have been associated with rebound thrombin generation, however, plasminogen activators may be most effective if used in conjunction with hirudin or a synthetic hirudin analogue. Bradykinin may offset hypotension in sepsis. Protein C may inhibit thrombin formation and also complex with plasminogen activator inhibitor 1, thereby promoting fibrinolysis. Other agents that may prove effective include alpha 1-antitrypsin Pittsburgh, C1-esterase inhibitor, monoclonal antibodies to contact factors, soybean trypsin inhibitors, thrombomodulin, prostaglandin I2, and aprotinin. There are no data to support the use of heparin or fibronectin, except in limited circumstances.
 ...
PMID:Modulators of coagulation. A critical appraisal of their role in sepsis. 162 18

Forty-six patients with refractory malignant lymphoma (Hodgkin's and non-Hodgkin's) admitted for autologous marrow or peripheral blood stem cell transplantation (ASCT) were evaluated for the presence of hemostatic abnormalities known to be associated with a hypercoagulable state in other patient populations. All patients had received numerous chemotherapeutic agents in the past and often radiation therapy as well. Hemostatic abnormalities were found to be common in these patients. The most frequent finding was hyperfibrinogenemia, present in 35% of patients. Decreased protein C activity was present in 32% of patients. Protein C antigen was low in only one individual and protein S was normal or increased in all patients. Low levels of antithrombin III were present in 16%. Plasminogen activator inhibitor was elevated in 20%. Anticardiolipin antibodies were present in 29% of patients; other evidence of a lupus anticoagulant was present in only eight patients. The frequency of each hemostatic abnormality was similar for patients with Hodgkin's disease (HD) and those with non-Hodgkin's lymphoma (NHL) despite the fact that significantly more patients with HD had received irradiation and/or previous splenectomy than patients with NHL. We conclude that multiple prothrombotic abnormalities of hemostasis are present in patients with refractory lymphoma referred for ASCT. Whether these are the result of lymphoma or the result of therapy cannot be determined from this study.
 ...
PMID:Prothrombotic hemostatic abnormalities in patients with refractory malignant lymphoma presenting for autologous stem cell transplantation. 187 94

Patients with acute myeloid leukemia have multiple hemostatic and thrombotic complications, which may or may not result from disseminated intravascular coagulation. Previous studies incorporating routine coagulation analyses failed to detect any clinically useful information in most of these patients. In this study, the first comprehensive evaluation of the various aspects of the hemostatic system in a population of patients with acute myeloid leukemia was performed. Eighteen patients (23-71 years of age) were studied at either diagnosis or relapse. Hemostatic studies were performed at onset and on days 3, 7, and 30 after initiation of therapy. The bone marrow blast counts ranged from 8% to 98%; prothrombin time and activated partial thromboplastin time showed only minor prolongations in a few of these patients. However, in all patients measurement of platelet-associated markers revealed elevated platelet factor 4 and thromboxane B2 and normal 6-keto-prostaglandin F1 alpha levels. Fibrinolytic markers showed an increase in D-dimer and tissue plasminogen activator and a decrease in alpha 2-antiplasmin levels. Plasminogen, plasminogen activator inhibitor, and fibrinogen levels were normal. Coagulation markers demonstrated a decrease in protein C and antithrombin III levels and an elevation of the thrombin-antithrombin complex. The pretreatment values for all hemostatic markers studied were similar to the values obtained on days 3, 7, and 30 during treatment. This investigation demonstrated a subclinical activation of the components of the hemostatic system possibly leading to a hypercoagulable state. Although only six patients (33%) experienced hemorrhagic complications, the risk of bleeding and/or thrombosis was strongly evident in all patients. The significance of finding abnormal levels of specific molecular markers of hemostasis will be established in the future application of such markers in clinical evaluations of leukemic patients known to be at risk for coagulation disorders.
 ...
PMID:Global and molecular hemostatic markers in acute myeloid leukemia. 222 Jun 67

Parameters of the fibrinolytic system were studied in a primate model where the generation of thrombin was promoted in vivo. The procoagulant stimulus used was a combination of human factor Xa in combination with phosphatidylcholine/phosphatidylserine lipid vesicles (PCPS) as the source of coagulant active phospholipid. The dosage of each component was formulated to provide a gradation of thrombin generating potential assessed prior to in vivo study in an in vitro clotting assay. These ranged from 25.25-36.60 pMole/kg (factor Xa) and 18.85-56.30 nMole/kg (PCPS). In each case, the ratio of the dose of factor Xa/PCPS was maintained at 0.65 (pMole factor Xa/nMole PCPS). Individual dosage combinations producing recalcification clotting times in vitro of 15, 20, 25 and 30 s were used in detailed in vivo studies. Previous studies in dogs had confirmed the thrombin generating potential of factor Xa/PCPS infusions and demonstrated an associated activation of protein C and increased fibrinolytic activity. This has now been extensively characterized in the chimpanzee as follows: 10 min after the infusion of the highest dose (36.6 pMole factor Xa/56.3 nMole PCPS kg bodyweight), the level of circulating t-PA had risen to 900 ng/ml (antigen), 885 IU/ml (functional). Dosage was observed with the lowest dose of 12.25 pMole factor Xa and 18.85 nMole PCPS being associated with relatively minor increases in circulating t-PA activity. There were no changes in u-PA at any dosage during the full time course of the experimental period (90 min). Plasminogen activation was also apparent with alpha-2 antiplasmin levels falling to 30-40% of pre-infusion levels at the highest dosages.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:The fibrinolytic potential of the normal primate following the generation of thrombin in vivo. 240 50

We report a prospective study in nine consecutive adult patients with acute promyelocytic leukaemia (APL). The study objective was to assess the prevalence of activation of blood coagulation and/or activation of fibrinolysis in APL. Coagulation and fibrinolytic parameters relevant to the objective included antithrombin III, plasminogen, fibrin/fibrinogen degradation products and alpha-2 antiplasmin activity and antigen levels. The results of this study revealed consistently normal antithrombin III levels, both before and in the course of antileukaemic treatment. Plasminogen levels were slightly decreased or normal. However, a distinct alpha-2 antiplasmin activity deficiency in all patients was observed with levels even reaching zero in three patients, during chemotherapy. Alpha-2 antiplasmin activity levels were consistently lower than the alpha-2 antiplasmin antigen levels. The in vitro binding of alpha-2 antiplasmin activity to fibrin clots was severely reduced which appeared to be due to the reduced alpha-2 antiplasmin plasma levels. Upon crossed-immunoelectrophoresis against alpha-2 antiplasmin antiserum two alpha-2 antiplasmin antigen peaks were observed in the plasma of all nine patients. All abnormalities were reversible 4 d after completion of chemotherapy. In a second series of 12 consecutive APL patients we confirmed the consistency of the alpha-2 antiplasmin activity deficiency and normal antithrombin III plasma levels. In addition Protein C activity and antigen levels were normal or near normal in 10 and reduced in two patients. Thrombin-antithrombin III complexes were increased in 10 and normal in two patients. We conclude that some activation of blood coagulation is present in APL (increased thrombin-antithrombin III complex levels) but its contribution to the coagulopathy seems to be minor (normal antithrombin III and only slightly reduced protein C levels). The observed reduced alpha-2 antiplasmin content of the fibrin clot in vitro may result in vivo in a fibrin clot that is highly susceptible to fibrin degradation, thus aggravating the coagulopathy in APL.
 ...
PMID:Acquired alpha-2-antiplasmin deficiency in acute promyelocytic leukaemia. 246 Jan 26

Plasminogen activator inhibitor (PAI) was purified in active form from porcine platelets under nondenaturing conditions. The purified inhibitor (Mr 47,000) reacts with tissue-type plasminogen activator (t-PA), urokinase (UK), and activated protein C (APC) to yield both SDS-stable complexes and a modified PAI of slightly reduced molecular weight. The second-order rate constants for the inhibition of t-PA and UK by PAI are 3.5 X 10(7) and 3.4 X 10(7) M-1 s-1, respectively. Activated protein C reacts with PAI with a second-order rate constant of 1.1 X 10(4) M-1 s-1. This rate is not accelerated by protein S, phospholipid, and calcium, or heparin. It is concluded that (1) PAI can function as both inhibitor and substrate of its target proteases, (2) if APC promotes fibrinolysis via inactivation of PAI, then APC must be present in concentrations several orders of magnitude greater than t-PA, or the interaction of APC and PAI must be accelerated by presently unknown mechanisms, and (3) in the absence of heparin, platelet PAI is the most rapid inhibitor of APC yet described.
 ...
PMID:Platelet plasminogen activator inhibitor: purification and characterization of interaction with plasminogen activators and activated protein C. 250 42

Plasminogen activator inhibitors (PAIs) play a pivotal role in the control of fibrinolysis. The mechanisms regulating the plasma levels of PAI(s) are still unknown. We report here that the infusion of bovine thrombin (1 U/kg/min, over 60 minutes) in rabbits treated with 0.5 microgram/kg endotoxin (to induce an increase in circulating fast-acting PAI) causes a marked reduction of PAI (50% of preinfusion value), as indicated by functional assay and reverse fibrin autography. Moreover, blood clots prepared from samples obtained after thrombin infusion lysed faster than preinfusion clots when exposed, in vitro, to tissue plasminogen activator. Donor-receiver transfusion experiments showed that the half-life of circulating PAI activity was shorter in thrombin-infused rabbits than in controls (4.1 minutes versus 7.4 minutes), suggesting an accelerated clearance. As expected, thrombin infusion resulted also in activation of protein C (PC). The following observations suggest a close relationship between PC activation and PAI reduction. (1) Infusion of thrombin in rabbits made deficient in vitamin K-dependent plasma proteins by warfarin treatment did not result in modification of PAI activity. (2) Treatment of the latter animals with a barium citrate eluate (PE) of rabbit plasma restored both the anticoagulant and profibrinolytic response to thrombin. (3) Short infusion of thrombin-activated PE (containing activated PC, PCa), but not of unactivated PE, induced both anticoagulation and reduction of PAI activity. In vitro, incubation of PAI-rich rabbit serum with thrombin-activated PE and phospholipids resulted in a progressive disappearance of PAI activity with a t1/2 of 30 minutes. However, this slow inactivation rate does not fully explain the results obtained in vivo. Our data suggest that thrombin infusion in rabbits causes a reduction of circulating PAI activity and that activation of PC is the intermediary mechanism involved in this phenomenon.
 ...
PMID:Thrombin infusion in endotoxin-treated rabbits reduces the plasma levels of plasminogen activator inhibitor: evidence for a protein-C-mediated mechanism. 238 62


1 2 3 4 Next >>