Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation and inactivation of protein C during the clinical course of disseminated intravascular coagulation (DIC) was studied in three patients by qualitative (Western blotting) and quantitative (ELISA) analysis and the intensity of procoagulant activity monitored by the measurement of thrombin and factor Xa antithrombin III complexes. In one patient, inhibitor complexes of APC with protein C inhibitor (PCI) and alpha 1-antitrypsin (alpha 1-AT) were observed and the latter predominated at presentation. Both disappeared during the development of remission but the loss of alpha 1-AT complexes preceded PCI complexes which on Western blotting appeared to increase in intensity prior to disappearance. The two other patients bled to death from uncontrollable haemorrhage. In both cases, APC/inhibitor complexes with alpha 2-macroglobulin (alpha 2-M) in addition to PCI and alpha 1-AT were detected and persisted until death. Although PCI appeared to be the primary inhibitor in all three cases, alpha 1-antitrypsin and particularly alpha 2-macroglobulin appeared to assume greater roles in the two fatal cases. These data are similar to previous findings in an experimental animal model of DIC that suggested that alpha 2-macroglobulin and alpha 1-antitrypsin become more important inhibitors of APC as the primary inhibitor PCI is consumed in the face of a sustained procoagulant challenge.
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PMID:Activation of protein C and its distribution between its inhibitors, protein C inhibitor, alpha 1-antitrypsin and alpha 2-macroglobulin, in patients with disseminated intravascular coagulation. 768 92

Venous thromboembolic diseases are of major importance with respect to morbidity and mortality. Therefore, efficient prophylaxis is essential. Indication for thromboprophylaxis has to be made individually: In high risk situations, especially in orthopedic surgery, every patient should receive medical prophylaxis, e.g. with heparin, in addition to other preventive measures such as the wearing of elastic stockings or physiotherapy until full mobilization. For high-risk patients having a history of recurrent venous thromboembolism or which are suffering from a thrombogenic disease (e.g. myeloproliferative disorder, especially polycythemia vera, paroxysmal nocturnal hemoglobinuria, systemic lupus erythematosus, homocystinuria) or a hereditary thrombophilia (e.g. deficiency of antithrombin III, protein S, protein C or APC resistance), prophylactic measures should be more generally applied. In these patients, risk factors (e.g. oral contraceptive medication) or risk situations (e.g. long-distance travelling by car or airplane) have to be avoided whenever possible. In inevitable risk situations (e.g. perioperative or peripartal period) prophylaxis is mandatory. It is generally limited to the period of elevated thrombogenic risk and is often effected by application of a low molecular weight heparin. Patients with a history of recurrent thromboembolic events despite elimination of all avoidable risk factors should get a lifelong prophylaxis, usually with oral anticoagulants.
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PMID:[Prevention of venous thromboembolism--in whom, when and how?]. 783 22

Resistance to activated protein C (RAPC) has been described recently as a cause of trombophilia; this may justify up to 50% of thromboembolic disease without predisposing cause in patients under 45 years. A 29 years-old male with a previous deep venous thrombosis (DVT) in the lower left limb three years earlier, developed a DVT in the right lower limb after a trauma of the knee that required immobilization, was associated to pulmonary thromboembolism diagnosed by gammagraphic methods. The phlebographic study showed femoro-iliaco-caval venous thrombosis. The proband's father and a younger brother had a previous history of thrombotic episodes. The following tests, were performed in the proband and relatives: prothrombin time, aPTT, thrombin time, fibrinogen, (Von Clauss), antithrombin III (chromogenic), protein C and protein S (coagulometry and ELISA), plasminogen (chromogenic) and lupus anticoagulant (ITT, dRVVT, aCL). RAPC was evaluated in two different samples. The proband study was performed under oral anticoagulation treatment (OAT). Control groups were: 21 blood donors and 12 OAT patients. The results showed a decreased response to APC in the proband (ratio 1.5) and relatives: father (1.4), brothers (1.5 and 1.5), while the mother was within the normal range (> or = 2). In normal controls and OAT patients the ratio was over 2. No other abnormalities were detected in the assays performed. It is concluded that RAPC is the cause of this familial trombophilia. RAPC should be included in the evaluation study of trombophilia.
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PMID:[Familial thrombophilia due to resistance to activated protein C]. 798 58

Pediatric patients with acute lymphoblastic leukemia (ALL) are at an increased risk of thromboembolic events. Potential responsible mechanisms include the disease process itself, treatment with chemotherapeutic agents (particularly L-Asparaginase [ASP]), or a combination of the disease and treatment. We studied thrombin regulation in 26 consecutive children with ALL and 14 healthy age-matched controls by: (1) plasma concentrations of prothrombin; (2) plasma inhibition of 125I-alpha-thrombin; and (3) four biochemical markers of in vivo thrombin activation (thrombin complexed to its inhibitor antithrombin III [ATIII; TAT], prothrombin fragment 1.2 (F1.2), activated protein C complexed to the inhibitors alpha 1 antitrypsin [APCAT]), and protein C inhibitor (APC-PCI). Measurements were made at presentation before treatment, after treatment with ASP alone, and during combination chemotherapy with and without ASP. At presentation, the capacity to generate thrombin (reflected by plasma prothrombin concentrations) and the capacity to inhibit thrombin (125I-alpha-thrombin--inhibitor complex formation) were similar in children with ALL compared with that for healthy children. After ASP alone or as part of combination chemotherapy, prothrombin levels were preserved, whereas plasma inhibition of 125I-alpha-thrombin decreased significantly because of a decrease in plasma concentrations of inhibitors, most importantly ATIII. After combination chemotherapy without ASP, plasma concentrations of ATIII and the capacity to inhibit 125I-alpha-thrombin returned to normal values, whereas prothrombin levels increased above control values. Thrombin generation in vivo also differed from healthy controls. At presentation, plasma concentrations of three of four markers of in vivo thrombin activity (TAT, F1.2, APCAT, but not APC-PCI) were increased in children with ALL. Neither ASP alone nor combination chemotherapy with or without ASP significantly altered values of these three markers. In summary, although the in vitro capacity to generate thrombin was preserved, the in vitro capacity to inhibit 125I-alpha-thrombin decreased after ASP therapy. Evidence for increased endogenous thrombin generation was documented in children with ALL at presentation and throughout treatment. We speculate that poor regulation of this thrombin may contribute to thrombotic complications in children with ALL.
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PMID:Increased endogenous thrombin generation in children with acute lymphoblastic leukemia: risk of thrombotic complications in L'Asparaginase-induced antithrombin III deficiency. 828 39

Although patients with thromboembolic disease frequently have family histories of thrombosis, well-defined defects such as inherited deficiencies of anticoagulant proteins are found only in minority of cases. Herein, we present a family study of 42 years old woman with recurrent deep vein thrombosis which occurred first time four years ago during pregnancy, in subclavian vein, in relation to cardiac stimulator implantation because of atrio-ventricular III(0) block. Her laboratory investigation demonstrated normal APTT time, prothrombin time, platelet number, antithrombin III and protein C activity. Plasma antiphospholipid antibodies contents was within the normal range. The result of activated protein C(APC) resistance test was abnormal (R=1.64). Family study revealed similar degree of APC-resistance defect in her DVT symptomatic mother and two healthy young daughters (R=1.73 and 1.54 respectively). Additionally, a slightly reduced total protein S plasma concentration was found in the patient and her two children. The influence of a slightly reduced protein S level on the results of APC-resistance was excluded by evaluation of normalized activated protein C sensitivity ratio (nAPC-SR) as described de Ronde and Bertina.
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PMID:[Thrombophilia in a family with resistance to activated protein C and protein S deficiency]. 861 15

Tryptase (EC 3.4.21.59), the major secretory product of human mast cells, has become widely used as a biochemical marker for mast cells and mast cell activation, and is attracting attention as a mediator of allergic disease. However, there is little information available on the properties, or even the presence, of this protease in commonly used species of laboratory animals. We, here, report the demonstration and characterisation of this enzyme in the guinea pig lung. Tryptic activity resistant to alpha 1-proteinase inhibitor and soybean trypsin inhibitor was detected in sections of guinea pig lung tissue with the histochemical substrate Z-Gly-Pro-Arg-MNA. It was localised to mast cells and appeared to be present in all mast cells staining with Alcian Blue. A tryptic protease was purified 2400-fold from whole lung tissue by high salt extraction, cetylpyridinium chloride precipitation, heparin agarose chromatography, and gel filtration. This enzyme was found to be multimeric with a subunit of 38 kDa and a native molecular mass of 860 +/- 100 kDa. Inhibitor studies identified it as a serine protease. Like human tryptase, it was inhibited by leupeptin, benzamidine, and APC 366 (N-(1-hydroxy-2- naphthoyl)-L-arginyl(-L-prolinamide hydrochloride), but not by alpha 1-proteinase inhibitor, soybean trypsin inhibitor, or antithrombin III. Its response to changes in pH and ionic strength was similar to that of human tryptase. Differences between the guinea pig and human enzymes were seen in activity toward a panel fo 10 tryptic p_nitroanilide peptide substrates. Kinetic constants were determined for two of these: with L-Pyr-Pro-Arg-pNA the guinea pig tryptase had a similar Km but a 5-fold lower kcat than human tryptase, and with L-Pyr-Gly-Arg-pNA the guinea pig enzyme had a 10-fold lower Km and a 30% greater kcat than human counterpart. Heparin stabilised guinea pig tryptase, but did not alter its kinetic parameters as it did with human tryptase, decreasing the Km towards both substrates. The presence of a protease with similarities to human tryptase in the mast cells of guinea pigs suggests that this species may be an appropriate model to investigate the actions to tryptase in vivo, provided cognizance is taken of the differences that do exist.
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PMID:Guinea pig lung tryptase. Localisation to mast cells and characterisation of the partially purified enzyme. 869 58

Oral contraceptives increase the natural incidence of venous thromboses of 1-2/10,000 women per year 3-to 4fold. Recent investigations have shown that during intake of desogestrel or gestodene containing formulations the risk is twice that with older low-dose ovulation inhibitors. This difference is larger in first time users than in women who had previously used an oral contraceptive. During pregnancy, the incidence of thromboses rises up to 10/10,000 women-years and post partum up to 40/10,000 women-years. In about 60 % of thromboses no causal explanation can be found. It is suggested that in 40 % of all cases an inherited thrombophilia is present. Among the hereditary types of thrombophilia, the resistance against activated protein C (APC-resistance) represents nearly 50 %, while altogether 15 to 20 % is based on a deficiency of antithrombin III, protein C or protein S. APC-resistance the prevalence of which is 3-5 % in the general population, increases the risk of thrombosis 8fold and in users of oral contraceptives 35fold. Protein C-deficiency (prevalence 0.1-0.5 %) increases the risk of thrombosis 9fold and in users of oral contraceptives 15fold, while antithrombin III-deficiency (prevalence 0.02-0.05 %) enhances the risk in pill-users 8fold. Ovulation inhibitors do not influence risk of thrombosis in women with protein S-deficiency. Antiphospholipid-antibodies the concentration of which may increase during treatment with oral contraceptives, represent a considerably enhanced risk of thrombosis, too. A positive family history (before age of 40 years) indicates an inherent thrombophilia. In these risk groups, the cost/benefit ratio of a selective screening is unfavorable, as at most 70 % of the hereditary thrombophilias can be diagnosed by laboratory analysis, and only very few patients will actually experience a thrombotic event: only 3 of 1000 carriers of APC-resistance will suffer from thrombosis during oral contraception per year. On the other hand, a negative result of laboratory tests does not exclude a hereditary thrombophilic disorder which as yet cannot be substantiated. It is not yet clarified whether a selective screening is superior to a careful assessment of individual and family history. A general screening cannot be justified because of the unfavorable cost/benefit ratio. If the individual or family history or pathological laboratory parameters indicate an enhanced risk of thrombosis, this risk has to be carefully weighed against the consequences of discontinuation of pill use. Those few individuals with risk factors who will experience a thrombosis, cannot be identified in advance. If in patients with thrombophilic disorders and/or other risk factors the use of oral contraceptives represents a particularly high risk, other contraceptive methods should be taken into consideration. If a patient with risk factors decides for the use of oral contraceptives, she has to be informed that in the case of symptoms indicating a thrombosis, the physician has to be consulted immediately. The earlier an appropriate therapy is initiated, the more effectively an acute pulmonary emboli or permanent damages, e.g. the post-thrombotic syndrome, can be prevented.
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PMID:[Significance of hereditary thrombophilia for risk of thrombosis with oral contraceptives]. 870 22

cDNAs for protein C inhibitor (PCI), prepared from human liver RNA, contained two forms of PCI, designated PCI*A and PCI*B. While PCI*A is identical to the published PCI sequence, PCI*B differs in 4 of 1221 bp and two amino acids, A36V and K86E. Frequencies for the PCI*B allele, determined from genomic DNA, differed among ethnic groups. Frequency distribution and historical migration of modern man suggest that PCI*A arose from the PCI*B allele. Antigen levels in plasma homozygous for PCI*A or PCI*B equalled that of pooled normal plasma. K86E in PCI*B causes a charge alteration in helix D which is likely involved in heparin binding in antithrombin III but not likely involved in glycosaminoglycan binding in PCI. Kinetic studies showed that plasmas homozygous for PCI*A and PCI*B are similar in their APC inhibiting properties and in their heparin sensitivity, consistent with the idea that helix D in PCI is not involved in heparin binding.
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PMID:A two-allele polymorphism in protein C inhibitor with varying frequencies in different ethnic populations. 871 81

Oral contraceptives increase the natural incidence of venous thrombosis of 1-2/10,000 women per year 3- to 4-fold. Recent studies have shown that desogestrel or gestodene containing formulations bear twice the risk of older low-dose ovulation inhibitors. During pregnancy, the incidence of thrombosis rises to 10/10,000 women-years and post partum up to 40/ 10,000. For 60% of thromboses no causal explanation can be found. In approximately 40% of the patients an inherited thrombophilia can be presumed. Among the hereditary types of thrombophilia, a resistance to activated protein C (APC-resistance) represents nearly 50%, while in 15 to 20% a deficiency of antithrombin III, protein C or protein S is found. APC-resistance, with a prevalence of 3-5% in the general population, increases the risk of thrombosis 8-fold and in users of oral contraceptives 35-fold. Antithrombin III-deficiency carries a comparable risk. Protein C-deficiency increases the risk of thrombosis 9-fold and in users of oral contraceptives 15-fold. Ovulation inhibitors do not influence the risk of thrombosis in women with protein S-deficiency. Anti-phospholipid-antibodies increase during treatment with oral contraceptives and represent a considerably enhanced risk of thrombosis. Inherent thrombophilia is suspected in a patient with a positive history or family history of thrombosis, especially with thrombosis before the age of 40 or with atypical localisation. Even in these risk groups, the cost-benefit ratio of selective screening is unfavorable, as today at most 70% of the hereditary thrombophilias can be diagnosed by laboratory analysis, and only very few of the patients will actually experience a thrombotic event: only 3 of 1000 carriers of APC-resistance will suffer from thrombosis during oral contraception. On the other hand, a negative result of laboratory tests does not exclude a hereditary thrombophilic disorder. At present, it is unclear whether a selective screening process is superior to a careful assessment of individual and family history. A general screening, however, cannot be justified because of the unfavorable cost/benefit ratio. If the individual or family history or pathological laboratory parameters indicate an increased risk of thrombosis, this risk has to be carefully weighed against the consequences of discontinuation of pill use. Those few individuals with risk factors who will experience a thrombo-embolic event, cannot be identified in advance. If oral contraceptives represent a particularly high risk in patients with thrombophilic disorders and/or other risk factors, other contraceptive methods should be considered. If a patient with risk factors decides on the use of oral contraceptives, she must be informed that in the case of symptoms indicating a thrombosis, a physician should be consulted immediately. The earlier an appropriate therapy is initiated, the more effectively pulmonary thrombo-embolism and permanent damage, such as the post-phlebitic syndrome, can be prevented.
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PMID:[Risk of thrombosis with oral contraceptives: value of a thrombophilia screening test]. 896 51

A 27 year old woman presented with recurrent cerebrovascular strokes in the setting of an ill defined auto-immune disease responsive to corticosteroid therapy. Investigation for a hypercoagulable state revealed activated protein C resistance in the absence of protein C, protein S, or antithrombin III deficiency or anticardiolipin antibodies. Her parents and sibling did not demonstrate APC resistance. This case suggests that activated protein C resistance may be associated with arterial as well as venous thrombotic events and implies that resistance to activated protein C should also be considered in the evaluation of young adults with strokes.
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PMID:Resistance to activated protein C: arterial thrombosis associated with autoimmune features. 926 89


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