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PubMed1995

Changes in the prothrombin time, haematology and serum proteins during experimental aflatoxicosis in hens and broiler chickens.

Two groups of 32 laying hens and two groups of 32, 23-day-old broiler chickens were given 2.5 and 5 mg kg-1 of aflatoxin in their diet for four, eight, 16 and 32 days; 16 hens and 32 broiler chicks served as control groups. In the laying hens, aflatoxicosis was characterised mainly by an increase in prothrombin time, and decreases in total plasma proteins and albumin levels; there were increases in red blood cell (RBC) counts and haematocrit which were greater in the group fed 5 mg kg-1. There was a decrease in beta-globulins and an increase in gamma-globulins. In the broiler chickens, there was only a slight increase in prothrombin time and a decrease in RBC counts. This data proves the good sensitivity and utility of prothrombin time values as an indicator of aflatoxicosis in birds.

Aflatoxins↗
PubMed1983

The role of platelet factor V in prothrombin conversion.

The contribution of platelet factor V to prothrombin conversion was studied in a purified two-stage system designed to measure the ability of factor V to accelerate prothrombin conversion. When unstimulated gel-filtered platelets (GFP) were substituted for both factor V and phospholipid, thrombin evolution was linear following a long lag time. Gel filtration resulted in considerable phospholipid availability with minimal factor V release. Incubating platelets with collagen in increasing concentrations resulted in marked shortening of the lag time, an increase in the initial rate of thrombin formation, and release of platelet factor V. The inhibition of thrombin formation by preincubation of the platelets with metabolic inhibitors is consistent with previous observations that factor V is released from alpha-granules by collagen in a process requiring metabolic energy. Released platelet factor V added to metabolically inhibited platelets reproduces the acceleration of prothrombin conversion demonstrated in GFP incubated with collagen. Furthermore no acceleration of the clotting time at collagen concentrations used in this study was demonstrated in an assay designed to measure available platelet phospholipid in the presence of excess factor V. The rate of increased thrombin generation produced by collagen stimulation is primarily due to released platelet factor V in the system employed.

Animals↗
PubMed1987

Enhancement of prothrombin activation on platelets by endothelial cells and mechanism of activation of factor V.

Factor Xa-catalyzed prothrombin activation occurs on cellular surfaces, including those of vascular endothelial cells. In a reconstituted model, endothelial cells and platelets acted synergistically to maximally activate prothrombin in the presence of Factor Xa. Synergism was observed at platelet concentrations less than 1 X 10(8)/ml. Thrombin formation was required for optimal prothrombin activation by endothelial cells and Factor Xa, with thrombin serving as an activator of Factor V. These data provide additional support for the hypothesis that vascular endothelium is a physiologic surface for hemostasis.

Animals↗
PubMed1989

Prothrombin times and clottable fibrinogen determination on an automated coagulation laboratory (ACL-810).

Our laboratory evaluated an Automated Coagulation Laboratory (ACL-810) by Instrumentation Laboratory. Prothrombin times and fibrinogen levels from the ACL-810 were compared to results from a Fibrometer and another automated coagulation instrument - either the Coag-A-Mate (prothrombin times) or the Multistat III centrifugal analyzer (fibrinogen). The performance of different thromboplastins on the ACL-810 was also evaluated. Correlation studies revealed excellent performance characteristics and precisions for both the prothrombin time and fibrinogen not only with different instruments, but also with different thromboplastins on the ACL-810. Overall, we found the instrument to be quick, efficient, and easy to operate.

Autoanalysis↗
PubMed1990

A new method for the determination of prothrombin in human plasma.

A two stage method for the determination of prothrombin is described in which the potent synthetic thrombin-inhibitor MD805 is used to suppress the inactivation process of thrombin by antithrombins in plasma. In the activation stage, prothrombin was activated almost instantaneously after the addition of tissue thromboplastin in 20-times diluted plasma and then the generated thrombin was inactivated progressively. Addition of MD805 suppressed the inactivation process of thrombin in a dose-dependent manner, while it hardly affected the complete activation of prothrombin. Thus, the generated thrombin was maintained stable in the presence of 50 microM MD805, and was measured by using 0.5 mM S-2238 as substrate. The method exhibited a linear relationship to the dilution of plasma. The decreased level of the other extrinsic coagulation factors such as FVII, FV, FX and tissue thromboplastin did not cause any significant changes until their activities were decreased to 3, 12, 12 and 20% of their controls. In addition, the method is very simple and easy for standardization.

Arginine↗
PubMed1992

Activation of human prothrombin by the venom of Lonomia achelous (Cramer) caterpillars.

In this paper, we demonstrated that the procoagulant action of Lonomia achelous (Cramer) is due in part to a component that activates prothrombin. The activation by crude venom and Fractions obtained by gel filtration on Sephadex G-75 is not dependent of phospholipid, Ca++ or Factor V. The activation of prothrombin by Fraction I is greatly stimulated by Factor V in the presence of phospholipid and Ca++; in presence of SBTI, we found that the Fraction I and Factor Xa act in a similar manner. These results suggest that the Fraction I is a Factor Xa - like prothrombin activator.

Animals↗
PubMed1995

Prothrombin conversion intermediate effectively neutralizes toxic levels of hirudin.

Meizothrombin, the stable intermediate product of ecarin-induced prothrombin conversion, was investigated for its ability to bind hirudin in blood. After in vitro pre-incubation of rat plasma with ecarin, the prolongation of the thrombin time caused by hirudin was reduced. The extent of hirudin neutralization was found to be dependent on the duration of incubation with ecarin. In vivo, after bilateral nephrectomy in Wistar rats and following administration of hirudin at a dose of 1 or 5 mg/kg, the blood level of hirudin remained constant after 2 h. After infusion of ecarin following hirudin administration, the hirudin blood level dropped sharply, reaching significantly reduced values, and bleeding stopped. Platelet count and fibrinogen level in plasma remained unchanged in the experiments using ecarin-induced prothrombin conversion intermediate generation. It is concluded that meizothrombin, a naturally occurring prothrombin conversion intermediate, provides an effective agent to neutralize toxic blood levels of hirudin.

Animals↗
PubMed1982

Radiation-induced changes in purified prothrombin and thrombin.

The effect of gamma-irradiation on purified prothrombin and thrombin in aqueous solution has been assessed with reference to bifunctional activities, e.g., clotting and esterase functions, physico-chemical changes in structure, and kinetics. The inactivation curves indicated that the clotting activity was more susceptible to gamma-radiation than the esterolytic function in both the proteins. Prothrombin was comparatively more sensitive to radiation than thrombin. The irradiation of prothrombin (100 kR) caused modifications in the protein resulting in reduced formation of thrombin after activation by Factor Xa. The modifications caused by irradiation were assessed in these proteins by changes in spectral characteristics, levels of tryptophan and disulphides, electrophoretic mobility and amino acid composition. Radiation-induced changes in thrombin were reflected in its kinetic behaviour. The clotting activity of thrombin was almost completely lost at 100 kR, while esterolysis was relatively less affected. The modification of tyrosine and tryptophan residues in thrombin influenced the clotting activity, while these were not involved for esterolysis. Histidine had involvement in both these activities.

Amino Acids↗
PubMed1987

Fibrinogen-sepharose interaction with prothrombin, prethrombin 1, prethrombin 2 and thrombin.

Binding of prothrombin, prethrombin 1, prethrombin 2 and thrombin to fibrinogen-Sepharose was studied. Thrombin and prethrombin 2 bound to fibrinogen-Sepharose, while prethrombin 1 and prothrombin did not. Bound thrombin and prethrombin 2 were recovered from the column by eluting with 0.1 M NaCl/0.05 M Tris-HCl buffer (pH 7.4). The affinity of thrombin and prethrombin 2 to fibrinogen-Sepharose depended on ionic strength and reached a maximum at 50 mm concentration. Prethrombin 2 interacts with fibrinogen as well as thrombin; and prothrombin fragment 1.2 is not important in the formation of this complex. Thus, prethrombin 2, which is a precursor of thrombin without measurable enzymatic activity and which lacks the single cleavage at Arg-322-Ile-323 present in thrombin, has the same or very similar structural conformation as thrombin and has the same macromolecular substrate recognition site. These results confirm the earlier results that active center is not necessary in fibrinogen-thrombin interaction.

Amino Acid Sequence↗
PubMed1978

Treatment and prothrombin responses during warfarin toxicosis in rats and mice.

Efficacy of whole blood, vitamin K-3 and vitamin K-1 treatment during warfarin feeding was investigated in rats and mice. Prolonged prothrombin times were observed in mice after 9--12 h of warfarin feeding. Prothrombin times greater than 300 sec were consistently observed in mice on continuous warfarin feeding and receiving whole blood or vitamin K-3 treatment. Withdrawal of warfarin resulted in normal prothrombin times after 96 h in mice receiving no treatment, 48--72 h on whole blood and 48 h in mice treated with 72 mg vitamin K-3/kg of body wt./day. Marked protection against warfarin induced hypoprothrombinemia and mortality occurred in mice treated with 5 mg vitamin K-1/kg/day. Treatment with 72 mg vitamin K-1/kg/day resulted in rapid alleviation of hypoprothrombinemia and prolonged protection against warfarin toxicosis. Intraperitoneal administration of 72 mg/kg/day of vitamin K-1 or vitamin K-3 were not toxic to mice. Mortality was consistently higher in mice given warfarin continually and in those receiving the greater number of treatments. Frequent handling appears to aggrevate warfarin toxicosis.

Animals↗
PubMed1991

Prothrombin mRNA is expressed by cells of the nervous system.

Thrombin, a serine protease of the blood coagulation system, has additional effects on cells in vitro. It is mitogenic for fibroblasts and astrocytes and contributes to the regulation of neurite outgrowth and astrocyte stellation. Until now the expression of thrombin or its precursor prothrombin in tissues other than liver has not been demonstrated conclusively because of difficulty in avoiding serum contamination. Using sensitive mRNA detection methods, we show here that prothrombin is expressed not only in the liver, but also in the brain throughout development. Polymerase chain reaction, Northern, and in situ hybridization studies demonstrate the presence of prothrombin transcripts in the olfactory bulb, the cortex, the cerebellum, and other regions of the rat and human nervous system, as well as in neural cell lines. These results support an involvement of (pro)thrombin in the regulation of cellular events in the nervous system.

Animals↗
PubMed2006

Prevalence of factor V Leiden, prothrombin and methylene tetrahydrofolate reductase mutations in women with adverse pregnancy outcomes in Lebanon.

OBJECTIVE: The purpose of this study was to determine the prevalence of factor V Leiden, prothrombin, and methylene tetrahydrofolate reductase gene mutations in women with adverse pregnancy outcome compared with women who had uneventful pregnancies. STUDY DESIGN: Between 2003 and 2005, pregnant women with > or = 1 unexplained second trimester abortion, > or = 1 intrauterine fetal death, severe preeclampsia, or severe intrauterine growth restriction (study subjects) were compared with control subjects (uneventful pregnancy) for the frequency of the mutations. RESULTS: The cases of 91 patients in each arm were analyzed. Obstetric complications were second trimester abortions (16.5%), intrauterine fetal death (53.8%), preeclampsia (8.8%), and severe intrauterine growth restriction (20.9%). Study subjects were more likely to be older and multiparous compared with control subjects. The 2 groups showed no difference in the incidence of smoking or family history of thrombosis, but study subjects were more likely to have a positive family history of obstetric complications. The prevalence of factor V Leiden (12.1% vs 18.7%; P = .304), prothrombin (7.7% vs 5.5%; P = .765), methylene tetrahydrofolate reductase gene mutations (53.8% vs 65.9%; P = .130), and > 1 mutation (11.0% vs 17.6%; P = .290) was not significantly different between study subjects and control subjects. CONCLUSION: Factor V Leiden, prothrombin, and methylene tetrahydrofolate reductase gene mutations did not seem to play a significant role in adverse pregnancy outcome in our population.

Adult↗
PubMed2005

Hypercoagulability markers in young asymptomatic heterozygous carriers of factor V Leiden (G1691A) or prothrombin (G20210A) variant.

BACKGROUND: Mutations in factor V (factor V Leiden-G1691A) and prothrombin (G20210A) genes are important risk factors for thrombophilia due to their high incidence in patients with thromboembolic events, especially among the young. However, it is not clear if levels of hypercoagulability markers are significantly altered in asymptomatic young carriers of factor V Leiden or prothrombin G20210A. METHODS: Hemostatic status of 32 asymptomatic young individuals carrying these mutations and of 18 normal control individuals was investigated through the determination of plasma thrombomodulin (TM), prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complex (TAT) and D-dimer. RESULTS: No significant differences were observed in these hemostatic markers when comparing groups of individuals carrying mutations and the control group. CONCLUSION: Analysis of these results leads to the conclusion that the presence of these mutations, in the absence of acquired risk factors, does not constantly predispose these young carriers to a state of hypercoagulability.

Adult↗
PubMed2004

The effect of phospholipids on the formation of immune complexes between autoantibodies and beta2-glycoprotein I or prothrombin.

In the last decennium, it became clear that antiphospholipid antibodies found in patients with antiphospholipid syndrome (APS) are in fact antibodies against lipid-bound plasma proteins. The most frequently occurring antigens are beta2-glycoprotein I and prothrombin, although several other lipid-bound plasma proteins have been reported as antigen for antiphospholipid antibodies. Both proteins bind to anionic phospholipids, mainly phosphatidylserine, which becomes exposed at the surface of activated platelets, apoptotic cells, or cell-derived microparticles. The binding of beta2-glycoprotein I and prothrombin to these cell surfaces or to artificial lipid vesicles with comparable amounts of anionic phospholipids is rather weak. Antiphospholipid antibodies from patients are predominantly of low affinity regarding their interaction with beta2-glycoprotein I or prothrombin in solution. In the presence of a suitable phospholipid surface, however, this interaction is strongly enhanced. There is now strong evidence that formation of bivalent, trimolecular immune complexes at the lipid membrane essentially contributes to the binding of these intrinsically low affinity patient antibodies. Depending on the affinity, the epitope specificity, and the polyclonality of a particular IgG preparation, multimeric structures of lipid-bound immune complexes may form a lattice with multiple interactions on the lipid (cell) surface. It is hypothesized that the functional activity, that is, the ability of antibodies to interfere with lipid-dependent reactions, not only depends on their affinity for the antigen, but also on their ability to form multiple interconnected bivalent trimolecular complexes at the lipid (or cell) surface. It is further proposed that the rate of desorption of immune complexes may present a better indicator for the functional properties of the antibodies than the amount of adsorbed immune complexes.

Animals↗
PubMed2005

A whole-blood homogeneous assay for the multiplex detection of the factor V G1691A and the prothrombin G20210A mutations.

We describe an assay for the simultaneous detection in DNA or whole blood samples of the G1691A (Leiden) mutation in the factor V allele and the G20210A mutation in the prothrombin allele, both of which predispose humans to thrombosis. The assay uses a dual-probe quenching system in which one probe of a pair is labelled with a fluorophore and the adjacent probe is labelled with a fluorescence quencher. The primer partners were present in unequal amounts, and the genotypes were identified by melt curve analysis, which, together with the PCR, was performed in a Rotor-Gene centrifugal thermal cycler. The performance of the assay was assessed by consistency of melting temperature (Tm) values and height of melt curves from within- and between-run analyses. The stability of the PCR reagents and whole blood was assessed by determining Tm and peak height values after storage at -20, 4 degrees C or room temperature. Concentrations of the reaction reagents were finely adjusted to obtain consistent and clearly distinguishable melt curves that facilitated automatic assignment of 43 genotypes comprising wild-type and mutant alleles. The mean (SD) Tms and peak heights of 31 DNA samples assayed in a single run were 54.85 degrees C (0.07) and 2.33 U (0.15) for factor V and 53.69 degrees C (0.19) and 1.5 0U (0.08) for prothrombin. The Tms and melt peak heights for DNA from wild-type individuals (n=10) when assayed for between- and within-run variability showed SDs of <or=0.17 and <or=0.3 for Tm and peak height values, respectively. When whole blood was used as the sample, the assay performance was comparable to that of purified DNA samples, with whole blood assays (n=30) yielding mean (SD) Tms and peak heights of 53.74 degrees C (0.11) and 2.10 U (0.32) for factor V and 53.27 degrees C (0.12) and 2.15 U (0.18) for prothrombin. Reaction reagents stored for 12 months at room temperature produced satisfactory results, as did whole blood stored frozen for 2 years or in mineral oil at room temperature for at least 1 week. The features of the homogeneous PCR assay described in this article should facilitate the use of such assays in clinical laboratories.

Blood Chemical Analysis↗
PubMed2005

Effect of magnesium contamination in evacuated blood collection tubes on the prothrombin time test and ISI calibration using recombinant human thromboplastin and different types of coagulometer.

UNLABELLED: The purpose of the present study was to assess the effect of two types of evacuated blood collection tube on the prothrombin time and international sensitivity index (ISI) of Recombiplastin, a recombinant human thromboplastin. Vacutainer tubes were compared with Venoject II tubes. Magnesium contamination was detected in the sodium citrate solutions contained in the Vacutainer tubes with concentrations ranging from 1.1 to 1.5 mmol/l. In contrast, magnesium ions could not be detected in the Venoject II tubes. The prothrombin ratio was decreased by contamination with magnesium ions and, hence, the ISI was increased. The magnitude of the effect of magnesium contamination on the ISI was influenced by the type of coagulometer and increased in the order: ACL Advance (3%), ACL-300 (4%), Electra-1000 (6%). The ISI bias is transmitted to the international normalized ratio (INR). In the case of the Electra-1000, the INR bias would be approximately 6% at INR 3.0 if the two types of blood collection tubes would be used without distinction. In a secondary study, the effect of magnesium contamination on the prothrombin time was assessed with the current World Health Organization international reference preparation for recombinant human thromboplastin (rTF/95). Magnesium chloride added to patients' blood (0.2 mmol/l) induced 2.3% reduction of the INR determined with rTF/95 and the manual technique. CONCLUSION: The magnitude of the influence of blood collection tubes contaminated with magnesium on ISI and INR determined with recombinant human thromboplastin depends on the coagulometer.

Anticoagulants↗
PubMed2004

A novel high molecular weight metalloproteinase cleaves fragment F1 of activated human prothrombin.

A hemorrhagic proteinase, jerdohagin, was purified from Trimeresurus jerdonii venom by gel filtration and ion-exchange chromatographies. It was a single chain polypeptide with an apparent molecular weight of 96 kDa as estimated by SDS-PAGE under the non-reducing and reducing conditions. Internal peptide sequencing indicated that it consisted of metalloproteinase, disintegrin-like and cysteine-rich domains and belonged to the class III snake venom metalloproteinases (class P-III SVMPs). Like other typical metalloproteinases, hemorrhagic activities of jerdohagin were completely inhibited by EDTA, but not by PMSF. Jerdohagin preferentially degraded alpha-chain of human fibrinogen. Interestingly, jerdohagin did not activate human prothrombin, whereas it cleaved human prothrombin and fragment F1 of activated human prothrombin.

Amino Acid Sequence↗
PubMed2003

Association between factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations and events of the arterial circulatory system: a meta-analysis of published studies.

BACKGROUND: The association between the inherited gene mutations of factor V, prothrombin, and homocysteine metabolism and venous thromboembolic events is accepted widely; however, their influence on the arterial circulatory system remains controversial. METHODS: We performed a MEDLINE search to identify published case-control and cohort studies correlating the factor V Leiden, prothrombin (PT) G20210A, and methylenetetrahydrofolate reductase (MTHFR) C677T (TT genotype) mutations with myocardial infarction, ischemic stroke, or peripheral vascular disease. Studies were included only when they adhered to specific diagnostic criteria for ischemic events and met the published methodological criteria. Odds ratios (ORs) with accompanying 95% CIs were calculated for each mutation and clinical end points with a random-effects model (DerSimonian and Laird method). RESULTS: The association between inherited gene mutations and arterial ischemic events was modest: factor V Leiden mutation (OR, 1.21; 95% CI, 0.99-1.49), PT G20210A mutation (OR, 1.32; 95% CI, 1.03-1.69), and MTHFR TT mutation (OR, 1.20; 95% CI, 1.02-1.41). Subgroup analyses of younger patients (<55 years old) and of women revealed slightly stronger associations overall. CONCLUSIONS: Genetic abnormalities specific to factor V, prothrombin,and homocysteine metabolism increase the risk for myocardial infarction and ischemic stroke, particularly among younger patients and women. Because the overall association is only modest, screening studies should be limited to carefully selected patient populations. The individual propensity for arterial and venous thrombosis is likely influenced by differing local mechanisms, systemic mechanisms, or both.

Arteries↗