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PubMed1980

[Proteolysis of prothrombin by beta/gamma thrombin].

beta/gamma-thrombin containing 25% of beta-form and 75% of gamma-form was obtained from alpha-thrombin by limited trypsin proteolysis. As compared to the parent alpha-thrombin, these preparations preserved less than 0.02% of fibrinogen-clotting activity, the entire esterase activity and 27% of the amidolytic activity toward N-benzoyl-Phe-Val-Arg-p-nitroanilide. Like alpha-thrombin, beta/gamma-thrombin splits prothrombin to prethrombin I (Mr 58000) and fragment I of prothrombin (Mr 25000) possessing antithrombin activity. Kinetics of prothrombin hydrolysis was studied by different concentrations of enzymes. It was shown that alpha-form is more specific than beta/gamma-form that preserved approximately 5% of prothrombinolytic activity of alpha-thrombin. It is emphasized that beta/gamma-form devoid of clotting activity retains regulatory functions.

Amidohydrolases↗
PubMed1995

Acarboxy prothrombin (PIVKA II) as a tumour marker for hepatocellular carcinoma and other liver diseases.

The clinical usefulness of plasma abnormal prothrombin, defined as protein induced by vitamin K absence or antagonist II: (PIVKA II) as a tumour marker for hepatocellular carcinoma (HCC) and other liver diseases has been evaluated. PIVKA II concentrations were determined using an enzyme-linked immunosorbent assay (ELISA) with monoclonal antibody that reacts with PIVKA II but does not cross-react with normal prothrombin. Seventy four patients (74%) out of 100 with HCC had abnormal PIVKA II levels above 0.5 AU/ml (median = 3.4 AU/ml). The level was above 1.0 AU/ml in 66 (66%) of the patients. In contrast the level of PIVKA II was low in patients with bilharzial periportal fibrosis (median = 0.09 AU/ml), patients with liver cirrhosis (median = 0.13 AU/ml), patients with hepatitis (median = 0.025 AU/ml), and essentially undetectable in all the 34 controls. The diagnostic ability of serum alphafoetoprotein (AFP) was also evaluated in these patients. AFP alone can diagnose 51% of the HCC cases. Of the remaining patients with low or negative AFP levels (65%) can be diagnosed using PIVKA II. Abnormal prothrombin is a potential marker for the laboratory diagnosis of hepatocellular carcinoma.

Adult↗
PubMed1994

[Congenital blood coagulation factor X deficiency. Successful result of the use prothrombin concentrated complex in the control of ++cesarean section hemorrhage in 2 pregnancies].

There is little experience in the prevention of the severe hemorrhagic diathesis of factor X coagulation factor deficiency, before surgical procedures. A female with congenital deficiency of factor X that received prothrombin complex concentrates that contained 1.000 IU of factor X (16.7 U/l Kg BW) immediately prior to a cesarean section in two occasions, is reported. Factor X concentration rose from 1 to 25% in the first occasion and from 10 to 63% in the second. In both episodes, factor X decreased in the first 24 h of the postoperative period and required new infusions of prothrombin complex concentrates. No episodes of abnormal bleeding were observed. It is concluded that the infusion of prothrombin complex concentrates prevents the hemorrhagic diathesis of factor X deficiency, despite its modest increase in plasma. A initial infusion of 1.000 UI of factor X (16-20 IU/Kg BW), followed by 500 IU (8-10 IU/Kg) every 24 hours is suggested for an adequate management of this condition.

Adult↗
PubMed1993

Monoclonal antibodies specific for prothrombin fragment 1.2 and their use in a quantitative enzyme-linked immunosorbent assay.

Prothrombin fragment 1.2 (F1.2) is an activation peptide generated during a critical event of blood coagulation, the conversion of prothrombin to thrombin. As a marker of thrombin generation, F1.2 has clinical potential in assessing thrombotic risk and monitoring anticoagulant therapy. In developing a highly specific, monoclonal antibody-based immunoassay of human plasma F1.2, we generated six murine anti-F1.2 monoclonal antibodies, using as immunogen a synthetic peptide (sequence: CGSD-RAIEGR) similar to the unique carboxyl terminus of F1.2. Each antibody bound F1.2 but not prothrombin. Epitope mapping studies with one antibody (5-3B) showed that optimum binding required six to eight amino acids plus a terminal arginine to emulate the F1.2 carboxyl terminus. A quantitative sandwich ELISA for human plasma F1.2 was configured with monoclonal antibody 5-3B as the capture antibody and peroxidase-labeled polyclonal antibodies to the F1.2 amino-terminal region as detector antibodies. Calibrators were prepared by adding purified F1.2, 0-10 nmol/L, to F1.2-depleted plasma. Assay characteristics included the following: mean (+/- SD) analytical recovery of 98% +/- 13%; no interference from lipemia, hemolysis, icterus, or thrombolytic agents; 0.08 nmol/L sensitivity; and mean intra- and interassay imprecision (three lots) < 12% at both low and high concentrations of F1.2.

Adult↗
PubMed1993

Prothrombin synthesis in rat hepatoma H4IIEC3 cells: response to the proposed "coagulopoietin factor".

Based on studies in intact animals, the presence of humoral factors, "coagulopoietins", which regulate the synthesis of vitamin K-dependent plasma proteins has been proposed. These proposed factors are produced in response to vitamin K deficiency, coumarin treatment, or specific antibody depletion of vitamin K-dependent clotting factors. The production of prothrombin by rat hepatoma H4IIEC3 cells has now been shown to be dependent on the source of bovine serum in the media. Cells grown in serum from cows treated with dicoumarol produce about 20% more prothrombin in 24 h than those cells grown in control serum. The humoral factor causing this response is present early in the course of dicoumarol treatment, and the increase in prothrombin production is dependent on the amount of serum from a dicoumarol-treated cow in the media. Based on membrane filtration studies, the factor appears to be associated with the protein fraction of serum.

Animals↗
PubMed1994

Human endothelial cells suppress prothrombin activation in nonanticoagulated whole blood in vitro.

Human endothelial cells cultivated on polystyrene microcarrier beads were used to study endothelial anticoagulant activity in vitro. Spontaneous whole blood coagulation was inhibited by endothelial cells on microcarriers at a surface to volume ratio of 16 cm2/ml blood. Thrombin activity generated in nonanticoagulated whole blood during 1 hour and assessed by its fibrinogen clotting effect was reduced by 87% in the presence of endothelial cells. Consistent with this observation, prothrombin fragment1+2, fibrinopeptide A, and thrombin-antithrombin III-complex release during the same period of time were inhibited by 81%, 47%, and 88%, respectively. Immunoblotting analysis of cell-free supernatants derived from the same samples demonstrated that prothrombin activation was strongly suppressed in the presence of endothelial cells. Furthermore, the incubation of nonanticoagulated whole blood with endothelialized beads for only 5 minutes after venipuncture was sufficient to prevent subsequent prothrombin activation in the cell-free supernatants of the same whole blood sample after centrifugation. These findings suggest that interruption of the coagulation cascade is probably one major mechanism of endothelial anticoagulant activity in vivo.

Antithrombin III↗
PubMed1994

Activation-induced exposure of the thrombin anion-binding exosite. Interactions of recombinant mutant prothrombins with thrombomodulin and a thrombin exosite-specific antibody.

The activation of serine protease zymogens involves conformational changes that increase the affinity of substrate binding and the activity of the catalytic center. The activation of prothrombin is particularly complex and requires several cleavages in the proenzyme region in addition to the conserved activation cleavage after Arg320. To understand how these cleavages lead to the exposure of the thrombin anion-binding exosite, a major macromolecular recognition site, interactions of recombinant human prothrombin derivatives with thrombomodulin, and an exosite-specific antibody were studied by competition binding and immunoprecipitation. By either method, the anion-binding exosite is not functional on prethrombin 2, which is cleaved after Arg271 and lacks fragment 1.2, nor on meizothrombin, which is cleaved only after Arg320. In contrast, the exosite is fully exposed on meizothrombin des-F1, which is cleaved after both Arg320 and Arg155 and therefore lacks amino-terminal fragment 1 (F1). Thus, two events are required to create the exosite. First, cleavage after Arg320 causes conformational changes that are much more extensive than those accompanying the activation of trypsinogen. Second, removal of amino-terminal F1 is necessary, perhaps to relieve steric hindrance. These results indicate that the F1 fragment regulates access to the thrombin exosite. The properties of meizothrombin des-F1 suggest that this prothrombin derivative could have a biological function.

Amino Acid Sequence↗
PubMed1993

Antiphospholipid antibodies directed against a combination of phospholipids with prothrombin, protein C, or protein S: an explanation for their pathogenic mechanism?

Despite many studies on the pathophysiology of antiphospholipid antibodies (aPL), the mechanism by which aPL causes thrombosis has not been established. We have tried to elucidate the paradox between the prolongation of the clotting time of phospholipid-dependent coagulation tests in vitro and the occurrence of thrombosis in vivo. The effect on endothelial cell-mediated prothrombinase activity of 30 IgG fractions, of which 22 prolong the aPTT of normal plasma, was investigated. Only 4 of 22 fractions (18%) inhibited prothrombinase activity when tested on this more physiologic phospholipid surface, indicating that in most patients with aPL the prolongation of clotting tests is predominantly as in vitro phenomenon. It was recently reported that in detection methods for aPL, two plasma proteins, beta 2-glycoprotein I and prothrombin, enhance the binding of aPL to phospholipids. We have studied the specificity of the 4 IgG fractions that inhibit the prothrombinase activity and found that they were directed against a combination of phospholipids and prothrombin. However, the involvement of prothrombin in binding of aPL leading to impaired thrombin generation could still result in both a bleeding and a thrombotic tendency. Therefore, we proposed a new thrombogenic mechanism for aPL in which aPL bind to complexes of phospholipids and coagulation proteins, thereby interfering in different coagulation reactions. We tested this new hypothesis by investigating the effect of IgG from the same 30 patients on the activated protein C (APC)-mediated factor Va inactivation in the absence and presence of protein S. Three IgGs that inhibited APC-mediated factor Va inactivation independent of protein S and 4 additional IgGs that inhibited in the presence of protein S were found. Furthermore, we could specifically adsorb the inhibitory IgG with cardiolipin vesicles to which APC with or without protein S was bound. In conclusion, these results suggest that subpopulations of aPL exist that are directed to complexes of phospholipids and different plasma proteins. The identity of the plasma proteins involved in the binding of aPL might determine which pathogenic mechanism causes thrombosis.

Adult↗
PubMedDate not supplied

[Interaction of prothrombin with erythrocytes and alveolar macrophages].

A study was made of porcine 125I-prothrombin interaction with red cells and alveolar macrophages in the presence of CaCl2 or EDTA. Prothrombin binding with red cells was similar to that to alveolar macrophages (Kd = 3.7 x 10(-6) M and 1.9 x 10(-6) M, respectively). These parameters did not depend on the presence of Ca2+ ions in the medium. Red cell hemolysis led to diminished affinity of prothrombin to blood ghost surfaces.

Animals↗
PubMed1994

The response of Quick's prothrombin time test to oral anticoagulation. Influence of thromboplastin source and calcium chloride concentration.

The response of the prothrombin time to oral anticoagulant treatment depends on the thromboplastin reagent and method of testing. A prothrombin time assay system may be characterized by its international sensitivity index (ISI) with which a coumarin-treated patient's international normalized ratio can be calculated. Both the anticoagulant (sodium oxalate or sodium citrate) and calcium chloride concentrations influenced the ISI. An ISI of 2.0 was obtained for Quick's prothrombin time assay using rabbit brain thromboplastin. Replacing rabbit brain by human brain thromboplastin (Aggeler's method) resulted in an ISI of 1.3. The results described herein are mainly of historical interest and may assist in the interpretation of anticoagulation intensity in early American recommendations.

Administration, Oral↗
PubMed1993

Specific contribution of different phospholipid surfaces to the activation of prothrombin by the fully assembled prothrombinase.

This paper addresses, in thermodynamic and kinetic terms, the reasons for the acidic lipid specificity of the human prothrombinase complex. We obtained, from the measured lipid titrations of the initial rates of prothrombin activation, the empirical binding constants for prothrombinase assembly on different membranes. These favored assembly on phosphatidylserine (PS)- as opposed to phosphatidylglycerol (PG)-containing membranes. In addition, we have used full time courses of prothrombin activation, in conjunction with a calculation of the equilibrium distribution of factor Xa between four enzymatic forms, to obtain the intrinsic kinetic constants of the prothrombinase assembled on PS- or PG-containing membranes. The resulting values of kcat, Km, and kcat/Km increased as acidic lipid content increased, and kcat/Km reached a plateau at 12 mol % PS and 50 mol % PG. Using the measured assembly and kinetic constants, the observed shapes of the phospholipid titration curves of human prothrombin activation were interpreted. We conclude that the difference in activity of prothrombinase assembled on PS- versus PG-containing membranes results both from the different binding properties of factors Xa and Va to these surfaces and from the different intrinsic activities of the prothrombinase when assembled on different membranes.

Arginine↗
PubMed1977

Mechanism of action of anticoagulants: correlation between the inhibition of prothrombin synthesis and the regeneration of vitamin K1 from vitamin K1 epoxide.

It has been proposed that coumarin and indandione anticoagulants inhibit clotting protein synthesis by preventing the regeneration of vitamin K1 from its 2,3-epoxide metabolic. To test this hypothesis, the effects of nine coumarin and indandiones on prothrombin synthesis and the conversion of vitamin K1 epoxide to vitamin K1 were measured. There was a good correlation between the inhibition of prothrombin synthesis and the epoxide-K1 conversion both in vivo and in vitro. Diphenadione (2-diphenyl acetyl-1,3-indandione) caused a delayed inhibition of prothrombin synthesis which correlated with a delayed inhibition of the epoxide-K1 conversion in vivo. These results provide strong evidence for the proposed mechanism of action of coumarin and indandione anticoagulants.

Animals↗
PubMedDate not supplied

Membrane-based, dry-reagent prothrombin time tests.

The authors describe a prototype membrane-based, dry-reagent prothrombin time assay for whole blood. This system uses an asymmetric polysulfone membrane to separate plasma from red blood cells, and works with samples as small as 10 microliters. The membrane contains calcium and thromboplastin, and permits the reactions of the complete extrinsic pathway to occur with minimal distortion from membrane surface interactions. Thrombin generation is monitored optically using a rhodamine-110-based fluorescent thrombin substrate. Fluorescence kinetics are analyzed to produce a prothrombin-time--equivalent parameter that can be converted to an international normalized ratio (INR) value. The system provides results that correlate well with conventional liquid phase prothrombin time assays (R2 = 0.96).

Anticoagulants↗
PubMed1997

High antibody levels to prothrombin imply a risk of deep venous thrombosis and pulmonary embolism in middle-aged men--a nested case-control study.

Antibodies against phospholipid-binding plasma proteins, such as beta2-glycoprotein I (beta2-GPI) and prothrombin, are associated with thromboembolic events in patients with systemic lupus erythematosus and also in subjects with no evident underlying diseases. We wanted to examine whether increased levels of antibodies to negatively-charged phospholipids (cardiolipin), to phospholipid-binding plasma proteins beta2-GPI and prothrombin and to oxidised low-density lipoprotein (LDL) were associated with risk of deep venous thrombosis or pulmonary embolism in subjects with no previous thrombosis. The antibodies were measured in stored serum samples from 265 cases of deep venous thrombosis of the lower extremity or pulmonary embolism occurring during a median follow-up of about 7 years and from 265 individually matched controls. The study subjects were middle-aged men participating in a cancer prevention trial of alpha-tocopherol and beta-carotene and the cases of thromboembolic events were identified from nationwide Hospital Discharge Register. The risk for thrombotic events was significantly increased only in relation to antiprothrombin antibodies. As adjusted for body mass index, number of daily cigarettes and history of chronic bronchitis, myocardial infarction and heart failure at baseline, the odds ratio per one unit of antibody was 6.56 (95% confidence interval 1.73-25.0). The seven highest individual optical density-unit values of antiprothrombin antibodies were all confined to subjects with thromboembolic episodes. In conclusion, the present nested case-control study showed that high autoantibody levels against prothrombin implied a risk of deep venous thrombosis and pulmonary embolism and could be involved in the development of the thrombotic processes.

Aged↗
PubMed1997

Prevalence of the prothrombin gene variant (nt20210A) in venous thrombosis and arterial disease.

The prothrombin gene variant resulting form a G-->A transition at position 20210 has been described as a common genetic risk factor for venous thrombosis. However, the risk for developing arterial disease is unknown. In this investigation, we studied 116 patients with venous thrombosis and 71 with arterial disease, all of whom were compared with 295 controls. Additionally, we also investigated the distribution of the prothrombin alleles among African descendents and Amazonian Indians from Brazil. The prevalence of 0.7% for 20210A allele in the control group increased to 4.3% (P = 0.021) among patients with venous thrombosis. There was also a high prevalence of the mutated allele in a selected arterial disease group (5.7%) without hyperlipoproteinemia, hypertension, and diabetes mellitus when compared to the controls (P = 0.013). Heterozygotes for the allele 20210A were common among individuals of African descent (2%) and rare among Indians. These data support the hypothesis that the prothrombin variant is a risk factor for venous thrombosis and suggest that it may also be a risk factor for arterial disease.

Adolescent↗
PubMed1998

The methylenetetrahydrofolate reductase TT677 genotype is associated with venous thrombosis independently of the coexistence of the FV Leiden and the prothrombin A20210 mutation.

A polymorphism, C-->T677, in the methylenetetrahydrofolate reductase (MTHFR) gene has been identified as a cause of mild hyperhomocysteinemia, a risk factor for venous thrombosis. We have investigated the frequency of the TT genotype in 277 consecutive patients with confirmed deep venous thrombosis and 431 healthy subjects. The TT MTHFR genotype was more frequent in patients than in controls (25.6% vs. 18.1%; p = 0.016). The risk of thrombosis among carriers of this genotype was significantly increased [odds ratio: 1.6 (95% CI: 1.1-2.3)]. The estimated risk associated with the TT genotype was 2.0 (95% CI: 1.3-3.1) in subjects with (n = 122), and 1.3 (95% CI: 0.8-2.0) in those without (n = 155) predisposing (hereditary, acquired or circumstantial) risk factors for venous thrombosis. Factor V Leiden and prothrombin G-->A20210 are known risk factors for venous thrombosis. After stratification for FV Leiden and prothrombin A20210 mutations, a significant association was also observed. After adjustment for sex, FV Leiden and prothrombin A20210 mutation, the estimated risk of venous thrombosis among carriers of the TT MTHFR genotype was 1.7 (95% CI: 1.2-2.6). The TT MTHFR genotype is independently associated with venous thrombosis, mainly among individuals with a high risk profile.

Adolescent↗
PubMed1998

Prevalence of 20210 A allele of the prothrombin gene in venous thromboembolism patients.

BACKGROUND: The 20210 A allele variation in the 3' -untranslated region of the prothrombin gene was recently identified as a risk factor as regards deep venous thrombosis. AIM: To assess the frequency of the variation in unselected patients with a proven venous thromboembolism (VTE). METHODS: The presence of the prothrombin variation was determined in all consecutive patients referred from July 1994 to August 1997 for a clinical suspicion of VTE, and in whom the diagnosis was confirmed. A control group consisted of bone marrow volunteer donors. RESULTS: Of the 366 patients included, 17 (4.6%) were carriers of the 20210 A allele (95% CI, 2.4% to 6.7%). The mutation was present in 1.0% of the 400 controls. Odds ratio for having VTE in the presence of the 20210 A allele was 4.8 (95% CI, 1.5 to 19.8). Forty-six (12.5%) patients had the mutation of the factor V gene and five (1.4%) patients shared both mutations. After excluding the carriers of the factor V mutation, odds ratio for having VTE in the presence of the 20210 A allele was 3.7 (95% CI, 1.1 to 13.6). Mean age at admission as well as mean age of the first VTE episode were both significantly higher in patients free from the two mutations studied, as compared to carriers of the 20210 A allele (p = 0.04 and 0.01, respectively). CONCLUSION: Our findings in a large series of patients (1) confirm the 20210 A allele prothrombin gene as a risk factor for VTE. (2) suggest that its association with the factor V Leiden is not uncommon.

Adult↗
PubMed1998

No association between the 20210 G/A prothrombin gene mutation and premature coronary artery disease.

The 20210 G/A prothrombin gene mutation is associated with an increased risk of venous thrombosis but whether there is an association of the mutation with premature coronary artery disease and acute myocardial infarction remains unclear. To further assess the role of the G/A genotype as a risk factor for arterial vascular disease, we performed a case-control study of 644 patients aged less than 50 years with angiographically proven coronary artery disease, 402 of whom had myocardial infarction, and 679 unrelated healthy control subjects aged less than 50 years, randomly selected from the electoral roll. The prevalence of the G/A genotype was 2.5% in patients with coronary artery disease, and 3.2% in control subjects (odds ratio 0.8; 95% confidence interval 0.35 to 1.83). The mutation was not more frequent among patients with a history of myocardial infarction (2.2%, odds ratio 0.7; 95% confidence interval 0.27 to 2.05), and there was no evidence of an interaction between the prothrombin mutation and conventional cardiovascular disease risk factors. There was no association between genotype and extent of angiographic coronary artery disease (p=0.73). We conclude that the 20210 G/A prothrombin gene mutation is not a major risk factor for premature coronary artery disease in our predominantly Caucasian Australian population.

3' Untranslated Regions↗