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PubMed2007

A second case of prothrombin Puerto Rico I in the United States.

Prothrombin deficiency is a very rare autosomal recessive bleeding disorder associated with mild to severe bleeding symptoms. We identified this bleeding disorder in a US-born patient as due to prothrombin Puerto Rico I. Unlike other prothrombin deficiencies, prothrombin Puerto Rico I is a series of concordant polymorphisms found in people of Puerto Rican descent with a much higher frequency than those prothrombin deficiencies found in the general population. This case underscores the importance of family history in identifying rare bleeding disorders.

Female↗
PubMed2000

Should we include anti-prothrombin antibodies in the screening for the antiphospholipid syndrome?

Anti-prothrombin antibodies belong to the family of the antiphospholipid antibodies. Their prevalence ranges from 50 to 90% of antiphospholipid-positive patients, depending on the laboratory methodology employed for their detection. ELISA techniques are the most commonly used methods for their measurements, which allow a quick determination of their titer and isotype(s). Unfortunately, no well standardized assays are yet commercially available. The clinical relevance of anti-prothrombin antibodies as risk factors for thromboembolic events has been investigated by a number of retrospective and case-control studies. We reviewed 11 studies: data on 1,440 patients and 371 sex- and age-matched controls were available. Seven studies reported a significant association between anti-prothrombin antibodies and thrombosis by univariate analysis. Multivariate analysis was performed in five studies: only two of them confirmed the association. The sensitivity and specificity of anti-prothrombin antibodies for thrombosis were analysed according to the antibody isotype and to the arterial and/or venous site of thrombosis. The sensitivities are disappointingly low, particularly when the M isotype and arterial thrombosis are considered, whereas the specificities are somewhat better, even though they range widely. These data do not allow to recommend the measurement of anti-prothrombin antibodies in the routine laboratory workout of antiphospholipid-positive patients in order to define their thrombotic risk.

Antibodies, Antiphospholipid↗
PubMed1996

Immobilized hirudin and hirudin-based peptides used for the purification of recombinant human thrombin prepared from recombinant human prothrombin.

A simple and efficient activation-affinity purification system was developed to obtain thrombin from recombinant CHO cells expressing human prothrombin. In this method, a controllable process for the activation of recombinant prothrombin is directly coupled with a purification strategy for the recombinant thrombin generated. At a constant flow rate and with a contact time limited to few seconds, recombinant prothrombin was filtered through immobilized trypsin. In a closed flow system, the recombinant thrombin generated was filtered through newly designed thrombin-specific affinity gels. Hirudin, the most specific thrombin inhibitor, and hirudin-based peptides were covalently immobilized to Sepharose, thus creating thrombin-specific affinity gels that immediately absorb the thrombin generated from the activation mixture. Prothrombin and incompletely activated molecules did not bind to the affinity gel and were recirculated for a further activation cycle. Due to the specificity of the affinity gels for thrombin and the elimination of thrombin from the activation mixture, proteolytic degradation and autocatalytic inactivation of the recombinant thrombin was prevented. Recombinant thrombin was isolated from the hirudin-based affinity gels by chaotrope salt elution, resulting in high yields of highly pure, active thrombin. Affinity purification of thrombin was not deleteriously affected by contamination of the starting material with other proteins. Activation and affinity purification were equally effective for recombinant and human plasma-derived prothrombin as well as for human and recombinant thrombin.

Amino Acid Sequence↗
PubMed1980

An immunological study of prothrombin in liver cirrhosis.

Prothrombin was assayed in 24 patients with liver cirrhosis both as activity and as antigen. Prothrombin was found to be decreased by all methods and a good correlation was found among the three methods used. The serum prothrombin assay by means of the electroimmunoassay showed levels comparable to those observed in plasma, as expected. In the bidimensional electrophoresis system, plasma prothrombin appeared decreased but showed a normal mobility. Serum prothrombin in the same system showed the presence of three normal albeit reduced peaks or precipitates.

Antigens↗
PubMed2004

Factor V Leiden and the prothrombin 20210A gene mutation and osteonecrosis of the knee.

INTRODUCTION: The pathogenesis behind osteonecrosis of the knee is still unknown. Circulatory impairment of the bone secondary to thrombosis in the microcirculation has been suggested as a mechanism. The purpose of this study was to examine the association between osteonecrosis of the knee and abnormalities in the thrombotic pathway in the form of factor V Leiden and the prothrombin 20210A gene mutation. MATERIALS AND METHODS: Thirty-eight consecutive patients (13 men and 25 women) with osteonecrosis of the knee without a history of knee trauma or surgery to the knee were enrolled in this study. Assays for the detection of factor V Leiden and the prothrombin 20210A gene mutation were performed, and the results were compared with those from 282 healthy volunteers. RESULTS: Six patients were diagnosed with secondary osteonecrosis, four corticosteroid-induced and two alcohol-induced. In 32 patients, no aetiological factor was found, and these patients were diagnosed with primary osteonecrosis of the knee. Twelve patients had 14 gene mutations, 11 factor V Leiden and 3 prothrombin 20210A gene mutations. Factor V Leiden and the prothrombin 20210A gene mutation occurred significantly (p=0.006) more frequently in patients with osteonecrosis than in a population of 282 healthy volunteers (odds ratio 3.1, 95%CI 1.4-6.6). CONCLUSION: The results of this study suggest that coagulation abnormalities in the form of factor V Leiden and the prothrombin 20210A gene mutation might play a role in osteonecrosis of the knee.

Adult↗
PubMed2005

Prothrombin G20210A mutation in cases with recurrent miscarriage: a study of the mediterranean population.

BACKGROUND: Thrombophilic predisposition may be one of the underlying causes of recurrent miscariage (RM). The purpose of this study was to evaluate the Prothrombin G20210A mutation in cases with history of RM. MATERIAL AND METHODS: A total of 104 cases, 55 with diagnosis of RM and 49 control cases, were included in this controlled study. In all cases, in addition to full examination tests, Prothrombin 20210A mutation analysis was carried out by means of Polymerase Chain Reaction (PCR). RESULTS: Mean number of the abortion was 3.51 +/- 0.74 in the RM group and 0.08 +/- 0.27 in the control group (p < 0.05). As a consequence of comprehensive examinations, in 24 (43.6%) of 55 RM cases at least one etiologic factor was put forth. Prothrombin G20210A mutation was observed in six (10.9%) cases of the RM group and one (2.04%) in the control group (p < 0.05). Four of the six cases (66.7%) of Prothrombin G20210A mutation had a subsequent pregnancy. Among these four pregnancies, there was one spontaneous loss at 14 weeks of gestation and one severe pre-eclampsia. CONCLUSION: Our data together with literature suggest that Prothrombin G20210A mutation may be associated with RM. We recommend this genetic testing as a screening tool for women with history of RM.

Abortion, Habitual↗
PubMed1985

Tryptase from rat mast cells converts bovine prothrombin to thrombin.

The effect of tryptase purified from rat peritoneal mast cells on bovine prothrombin was examined. Tryptase activated prothrombin, as evidenced by the increase in thrombin activity with a synthetic substrate, t-butyloxy-carbonyl-Val-Pro-Arg-4-methylcoumaryl-7-amide. The apparent Km value toward bovine prothrombin and the kcat value were 2.3 microM and 46.3 s-1, respectively. Studies on the time course of prothrombin activation by tryptase and by activated factor X (Xa), and analysis of the activation products on sodium dodecyl sulfate gel electrophoresis showed that the process of activation of prothrombin by tryptase was similar to that by Xa except that an intermediate of 67,000 daltons was formed.

Alpha-Globulins↗
PubMed1995

Changes in plasma warfarin levels and variations in steady-state prothrombin times.

OBJECTIVE: To determine the relative contribution of changes in the plasma warfarin level to variation in the serial steady-state prothrombin times. METHODS: This was a prospective observational cohort study performed at two outpatient anticoagulation clinics. Serial prothrombin times and paired plasma total warfarin levels were determined in a convenience sample of otherwise healthy patients who required long-term oral anticoagulation therapy with warfarin. RESULTS: Serial measurements were obtained from 129 patients, 60 of whom provided three or more serial samples. Analysis of covariance showed a highly significant (p = 0.0001) relationship between the anticoagulant effect and the logarithm of the warfarin concentration (R2 = 0.75), with 15.3% of the total variance attributable to the effect of warfarin and 31.1% attributable to individual variation in sensitivity to warfarin. In an analysis of the subjects who had three or more serial measurements, the mean weighted correlation coefficient for the relationship between the logarithm of the warfarin concentration and the anticoagulant response varied widely, from strongly negative to strongly positive, and as the range of observed prothrombin times increased, stronger positive correlation was observed. CONCLUSIONS: In this cohort, the plasma warfarin level was a strong predictor of observed changes in serial prothrombin time measurements. However, the correlation between clotting times and warfarin levels varied widely among subjects, particularly when the range of observed prothrombin times was moderate. This suggests that in these subjects, other factors, such as measurement error or pharmacodynamic changes, played a major role.

Adult↗
PubMed1982

Heparin with low affinity to antithrombin III inhibits the activation of prothrombin in normal plasma.

Standard unfractionated heparin is known to have two actions on blood clotting. Unfractionated heparin enhances the rates at which antithrombin III inactivates activated clotting factors, and inhibits the activation of both Factor X and prothrombin by disrupting the calcium and phospholipid dependent assembly of the Factor X and prothrombin activator complexes. This latter inhibitory action of heparin occurs independently of antithrombin III. A heparin fraction with low affinity to antithrombin III was prepared from standard heparin by affinity chromatography on antithrombin-III-Sepharose and its properties compared with unfractionated heparin. The low affinity heparin fraction and the unfractionated heparin had equivalent inhibitory effects on prothrombin activation in antithrombin III depleted plasma. In normal plasma, the low affinity fraction inhibited the activation of prothrombin. Unlike the unfractionated heparin, however, the fraction of heparin with low affinity to antithrombin III did not enhance the inactivation of either Factor Xa or thrombin. This antithrombin III independent inhibition of the activation of prothrombin was also evident when activated platelets were used as the source of the procoagulant phospholipids. The antithrombin III independent effect of heparin is unlikely to be important therapeutically, however, if this property of heparin is shared by other naturally occurring glycosaminoglycans, it could be important in maintaining the fluidity of blood under physiological conditions.

Animals↗
PubMed1986

Proteolysis of bovine and human prothrombin and of bovine factor X by rat mast cell proteinase.

The alpha-chymotrypsin-like proteinase from rat peritoneal mast cells (RMCP I) rapidly destroyed the normal clotting activity of purified, calcium-free, bovine prothrombin, human prothrombin and bovine factor X and simultaneously removed similar N-terminal peptides (Mr approximately 5,000) from both prothrombin and the 'light' chain of factor X. The amino acid composition of the peptides agreed with the known composition of the regions of the respective parent molecules where gamma-carboxyglutamic acid residues are situated. Ca2+ ions protected each of the proteins from proteolysis and loss of procoagulant activity. Prolonged incubation in the standard physiological assay medium used for prothrombin or treatment with Echis carinatus venom indicated that the thrombogenic portion of prothrombin survived proteolysis by RMCP I. This restricted proteolysis was confirmed by electrophoretic analysis.

Amino Acids↗
PubMed1990

Prothrombin-antibody coexistent with lupus anticoagulant (LA): clinical study and immunochemical characterization.

The patient is a 23 y.o. man with acute nephritis and bleeding at presentation. Laboratory data consistent with the diagnosis of systemic lupus erythematosus. A lupus anticoagulant was found: tissue thromboplastin inhibition test (TTIT) ratio 3.4; diluted Russell viper venom (DRVV) ratio 2.6. Hypoprothrombinemia (FII:C less than 1%; FIIR:Ag 5%) was present; prothrombin survival time (FII concentrate infusion 60 U/kg): t1/2 approximately to 9 hours. A prothrombin antibody was identified: it is not neutralizing but forms an immunecomplex with prothrombin. The antibody was characterized as IgG2, IgA, k, lambda. The prothrombin survival time indicates that the hypoprothrombinemia is due to the clearance of the prothrombin-antiprothrombin complex in vivo.

Adult↗
PubMed1991

Prothrombin plasma clearance is not mediated by hepatic asialoglycoprotein receptors.

The hepatic asialoglycoprotein receptor (AGPR) system can efficiently internalize and degrade circulating glycoproteins which lack terminal sialic acids on their carbohydrate chains. Since pro-thrombin is a glycosylated plasma protein, possible involvement of AGPR system in its clearance from circulation was evaluated. The half lives of bovine 125I-prothrombin and 125I-asialoprothrombin, injected intravenously into rats, were 192 and 1.8 minutes, respectively. Asialoprothrombin appeared to be cleared by the hepatic AGPRs since 33% of it accumulated in the liver at 30 minutes and its clearance was competitively blocked by simultaneous administration of increasing amounts of asialofetuin. Only 5% of prothrombin accumulated in the liver at 3 hours and injections asialofetuin in amounts capable of saturating the AGPR for the duration of four asialoprothrombin half lives had no effect on the disappearance of prothrombin. Our observations indicate that, although asialoprothrombin is readily cleared from plasma by the AGPR system, prothrombin is not. Thus these receptors do not appear to be involved in physiological processes that control prothrombin half life.

Animals↗
PubMed1992

Sphingosine inhibits factor Xa-catalyzed prothrombin activation on the surface of cultured calf pulmonary artery endothelium perturbed by hydrogen peroxide.

The effects of hydrogen peroxide on factor Xa-catalyzed prothrombin activation on the surface of vascular endothelial cells, and the inhibitory effect of sphingosine on prothrombin activation were studied in cultured calf pulmonary artery endothelial cells (CPAEC). Hydrogen peroxide enhanced factor Xa-catalyzed prothrombin activation on the cell surface in a time and dose-dependent manner. Sphingosine, a potent inhibitor of protein kinase C and the extrinsic pathway of blood coagulation, showed a partial inhibition of prothrombin activation on the surface of CPAEC. When cells were perturbed by hydrogen peroxide, sphingosine inhibited prothrombin activation and displaced factor Xa bound to the cell surface.

Amino Acid Sequence↗
PubMed1983

Dye binding probes of lipid-binding structures. An investigation of 2-p-toluidinylnaphthylene-6-sulfonate binding to human and bovine prothrombin and fragment 1 in the presence and absence of calcium and magnesium ions.

TNS (2-p-toluidinylnaphthylene-6-sulfonate) binds to human and bovine prothrombin and Fragment 1 in the absence and presence of added Ca2+. The stoichiometry of TNS binding is 1:1 for human and bovine prothrombin and Fragment 1. The Ca2+-dependence of the fluorescence of TNS bound to bovine prothrombin Fragment 1 yields a modified Hill plot slope of 2.7, which is consistent with the slope obtained by monitoring the Ca2+ dependence of protein fluorescence quenching, CD changes and phospholipid binding. Mg2+ has have no effect on the fluorescence of TNS-prothrombin fluorescence. TNS binding to the amino-terminal region of prothrombin is the first relatively simple probe of the subtle and complex relationship which exists between protein structure and phospholipid binding.

Animals↗
PubMed1989

Conformational changes in human prothrombin as detected by antibody populations.

The amino-terminal peptides of human prothrombin corresponding to residues 1-51 and 52-156 have been isolated from a thrombin digest of prothrombin fragment 1. The products of digestion were purified by means of barium citrate and ammonium sulfate precipitations, followed by gel filtration and hydroxyapatite chromatographies. They were identified by their molecular sizes as well as their amino acid compositions. Peptides 1-51 (F1A) and 52-156 (F1B) were used as affinity ligands for the isolation of antibody populations from antisera that were elicited against human prothrombin or prothrombin fragment 1. These antibody populations displayed restricted specificity for the respective ligands as shown by competitive radioimmunoassays. They were used to study the conformational changes in prothrombin and fragment 1. The F1A-specific antibody populations detected a conformational change which is stabilized by calcium ions and which has a transition midpoint at approximately 0.2 mM calcium ion concentration. The F1B-specific antibody populations identified a different conformational change which is destabilized by calcium ions and which has a transition midpoint at approximately 0.5 mM calcium.

Antibody Affinity↗
PubMed1979

Interactions between heparin and factor Xa. Inhibition of prothrombin activation.

The effects of heparin on prothrombin activation have been examined. Heparin was found to inhibit the rate of prothrombin activation by Factor Xa, calcium and phospholipid. In the absence of phospholipid, heparin had no effect on the rate of prothrombin activation. In contrast, heparin was found to increase the rate of activation of prethrombin-1 and prethrombin-2. Initial velocity studies indicated that heparin blocks lipid stimulation of prothrombin activation. In accord with this, binding studies demonstrated that heparin could displace Factor Xa, and in separate experiments, prothrombin, from phospholipid vesicles.

Animals↗
PubMedDate not supplied

Coagulation protein function. III. Effect of acetaldehyde upon the activation of prothrombin.

When prothrombin is mixed with acetaldehyde (AcH), the primary metabolite of ethanol, at room temperature for 30 min, dialyzed to remove excess AcH, and then activated with Echis carinatus venom (ECV), a prolonged clotting time is observed. Similarly treated prothrombin, however, readily hydrolyzes the synthetic substrate, benzoyl-DL-arginine-beta-naphthylamide (BANA). These results suggest that AcH does not react with the catalytic site of thrombin, which is protected in the prothrombin molecule. However, it does react with susceptible sites on the prothrombin surface which remain alkylated during extensive dialysis to remove excess AcH and subsequent activation of the molecule by ECV. These alkylated sites on the newly formed thrombin molecule may inhibit or prevent the effective/efficient binding of fibrinogen at its binding sites, causing prolonged clotting times. The binding sites for accommodating fibrinogen on the thrombin molecule are apparently quite different from those that bind BANA. These data further suggest that prolonged clotting times that are reported in chronic alcoholics may be due, in part, to ready interaction of acetaldehyde with circulating prothrombin. Fibrinogen, which has been exposed to AcH and subsequently dialyzed to remove excess AcH, also responds with a prolonged clotting time in the presence of added thrombin, signifying that sites on fibrinogen that are essential for its function/conformation are susceptible to AcH.

Acetaldehyde↗
PubMed2004

Characterization of the prothrombin gene expression during nerve differentiation.

The transcriptional regulation of the prothrombin gene expression in neuroblastomas was investigated because of the interest in non-hepatic thrombin expression and function in the nervous system. The data indicated that the murine prothrombin gene was distinctively transcribed in proliferating murine N2a cells and that the transcripts were decreased during the differentiation of N2a cells. The gene transcription in proliferating N2a cells was due to the C-I nuclear complex formation in the promoter region, -248/-140. Mutation analyses indicated that nucleotides from -237 to -231 are the core C-I binding site while the longer sequence -248/-140 is needed for the C-I binding. The C-I binding to the promoter -248/-140 could be inhibited by the presence of competitor probe -187/-166, and the mutation in nucleotides from -186 to -179 significantly diminished not only the formation of C-I binding in the promoter region but also the promoter activity in proliferating neuroblastoma cells. Cyclic AMP response element (CRE) modulator, CREM, appeared to selectively bind to the sequence encompassing -186/-179. Taken together, the results indicate that the prothrombin gene transcription in proliferating N2a cells was critically dependent on the cooperative interaction between the factor(s) binding to the C-1 cis-acting element (-237/-231) and the putative CRE site (-186/-179) in the prothrombin promoter, and that the lack of prothrombin expression that coincided with nerve differentiation was mainly due to the lack of C-I complex formation in the promoter.

Base Sequence↗