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PubMed1995

Evaluation of a prothrombin time optimized for the dog on plasmas with defined coagulation factor deficiency due to coumarin intoxication.

The sensitivity of the standard prothrombin time (PT) was low when measured on 56 plasmas with a reduced activity of the coagulation factors mainly of the prothrombin complex (factors II, VII and/or X) taken from eight dogs at different times of vitamin K1 therapy after coumarin intoxication. This was demonstrable by use of three different Ca-thromboplastins. With the standard test only plasmas with an excessive decrease of coagulation factor activity (sum of activity decrease of the single factors in relation to the respective reference range [SAD] > 100%) were detectable with sufficient reliability. In contrast, by using a method optimized for dogs (1:20 sample predilution, fibrinogen substitution) and respecting the species specific features of coagulation physiology, pathological PT-values were measured in up to 70% of the samples (dependent on the Ca-thromboplastin) with slight reductions of single factor activity (SAD: 11-25%). Significant differences concerning the sensitivity were seen additionally between the different Ca-thromboplastins. Human placenta thromboplastin in particular, but also rabbit brain thromboplastin, were more sensitive than a preparation of recombinant human tissue factor. The correlation between the PT and the SAD was closer when using the optimized method (r = 0.919-0.954) compared to the standard test (r = 0.771-0.862). In contrast to the standard test, the PT optimized for dogs is, therefore, a reliable screening test to recognize a slight reduction in prothrombin complex. It is especially suitable for monitoring of vitamin K1 therapy after coumarin intoxication.

Animals↗
PubMed1994

Prothrombin fragment 1 + 2 and antithrombin III-thrombin complex in microalbuminuric type 2 diabetic patients.

In microalbuminuria there is an increased cardiovascular risk not fully explained by the excess of conventional risk factors. To investigate whether or not microalbuminuria is associated with haemostatic abnormalities in Type 2 diabetic patients, we measured the prothrombin fragment 1 + 2, a marker of thrombin generation, and the thrombin-antithrombin complex, a marker of thrombin neutralization. Plasma levels of prothrombin fragment 1 + 2 and thrombin-antithrombin complex were assayed in 17 microalbuminuric patients (albumin excretion rate, AER 20-200 micrograms min-1) and in 17 comparable normoalbuminuric (AER < 20 micrograms min-1) Type 2 diabetic patients. Plasma prothrombin fragment 1 + 2 was significantly higher in microalbuminuric than in normoalbuminuric patients (1.09 +/- 0.06 vs 0.86 +/- 0.04 nM, p = 0.003). Individual values of F1 + 2 were above the upper limit of the normal range in 8/17 microalbuminuric and in none of the normoalbuminuric Type 2 diabetic patients. Plasma thrombin-antithrombin complex values were not significantly different in the two groups and were not correlated with AER. These results suggest that microalbuminuria is associated with a prethrombotic state and a relatively defective thrombin neutralization. Coagulation abnormalities might be part of the cardiovascular risk in microalbuminuric patients.

Aged↗
PubMed2000

Prothrombin 20210 G-->A, MTHFR C677T mutations in women with venous thromboembolism associated with pregnancy.

Over 50 unselected women with maternal venous thromboembolism were screened for the prothrombin 20210 G-->A and MTHFR C677T mutations, in addition to screening for other thrombophilias. The prevalence of thrombophilia in these women was compared with its prevalence in the general population in our area. The prothrombin (OR 4.4; 95% CI 1.2-16) and factor V Leiden (OR 4.5; 95% CI 2.1-14.5) mutations were more common in our patients, compared with the general population, whereas women homozygous for the C677T mutation in the methylene tetrahydrofolate reductase gene (OR 0.45; 95% CI 0.13-1.58) were not. It is recommended that women with a personal or strong family history of venous thromboembolism should be screened for the prothrombin mutation either before or early in pregnancy, in addition to screening for other thrombophilias. Screening for the MTHFR mutation does not appear to identify women at increased risk of maternal venous thrombosis.

Cohort Studies↗
PubMed2001

Factor V Leiden and G20210A prothrombin mutations are risk factors for very early recurrent miscarriage.

OBJECTIVE: To determine whether there is an association between early recurrent miscarriage (before 10 weeks of pregnancy) and Factor V Leiden and G20210A prothrombin mutations. DESIGN: A prospective study. SETTING: Department of Gynaecology and Obstetrics, Saint Antoine Hospital, Paris, France. POPULATION: Two groups of women: those with early unexplained recurrent miscarriage before 10 weeks of pregnancy (n = 260) and control healthy women without a previous history of thromboembolism (n = 240). METHODS: Screening for defects in the protein C anticoagulant pathway was performed using the anticoagulant response to agkistrodon confortrix venom (ACV test). Protein C and Factor V Leiden mutation testing was performed for each low ACV level. Each sample was tested for the G20210A prothrombin mutation. RESULTS: Factor V Leiden and G20210A mutations were found to be associated with early recurrent spontaneous miscarriage before 10 weeks of pregnancy, the odds ratios being 2.4 (95% CI 1-5) and 2.7 (95% CI 1-7), respectively. Similar results were found whether or not women had had a previous live birth. CONCLUSIONS: Early recurrent miscarriage before 10 weeks of pregnancy is significantly associated with Factor V or G20210A prothrombin mutations. These results indicate a possible role for anticoagulant prevention in these early miscarriages.

Abortion, Habitual↗
PubMed2005

The G20210A prothrombin-gene mutation and the plasminogen activator inhibitor (PAI-1) 5G/5G genotype are associated with early onset of severe preeclampsia.

Hereditary risk determinants of venous thrombosis have been reported to be associated with severe preeclampsia. So far there are no data to support whether these risk determinants are related to the time of onset of severe preeclampsia. We used a case-control design, studying 97 women with severe preeclampsia in previous pregnancies and 277 normal women, to assess hereditary risk factors of venous thrombosis as risk determinants for severe preeclampsia. A case-only design comprising solely the 97 women with a history of preeclampsia was used to evaluate these risk factors as risk determinants for early onset of severe preeclampsia. Using the case-control design, there was no significant risk association of the hereditary risk factors with severe preeclampsia [factor V Leiden, odds ratio (OR) 0.9, 95% confidence interval (CI) 0.4, 2.2; prothrombin mutation, OR 1.9, 95% CI 0.5, 7.0; methylentetrahydrofolate reductase 677TT genotype, OR 0.8, 95% CI 0.4, 1.8; plasminogen activator inhibitor (PAI-1) 4G/4G genotype, OR 1.2, 95% CI 0.7, 2.1; PAI-1 5G/5G genotype, OR 1.0, 95% CI 0.5, 1.8]. However, the onset of severe preeclampsia was significantly earlier in women with the G20210A prothrombin gene mutation (24.5 weeks vs. 30.1 weeks, P = 0.046) and in women with the PAI-1 5G/5G genotype (25.7 weeks vs. 30.8 weeks, P = 0.024). Hereditary risk factors for venous thrombosis do not predispose for severe preeclampsia. However, women who are carriers of the G20210A prothrombin gene mutation and the PAI-1 5G/5G genotype are at risk for early onset of severe preeclampsia. It appears that these risk factors do not induce the pathomechanism but accelerate the course of preeclampsia.

Adolescent↗
PubMed2005

The factor V Leiden and the G20210A prothrombin gene mutations are rare in women with fetal death.

PROBLEM: To determine if there is an association between two commonly inherited thrombophilias, the factor V Leiden and the G20210A prothrombin mutations, and fetal death. METHOD OF STUDY: We used a case-control study design to compare the frequencies of these mutations in women with fetal death and controls. Fetal death was the intrauterine death of the conceptus > or =10 weeks gestation. Controls had one live birth, no miscarriages, and no fetal death. Results were compared using chi square analysis. RESULTS: One hundred and seventy-five cases and controls were identified. There were 4.6% of cases and 3.8% of controls heterozygous for the factor V Leiden mutation (NS), and 1.3% of cases and 1.7% of controls heterozygous for the prothrombin mutation (NS). CONCLUSION: In our population, neither the factor V Leiden nor the G20210A prothrombin mutations are associated with fetal death. Further evidence is required before routine screening for these mutations can be recommended.

Adolescent↗
PubMed2005

Intraventricular haemorrhage in very-low-birthweight preterm infants: association with low prothrombin activity at birth.

AIM: To determine the occurrence of intraventricular haemorrhage (IVH) and its association with coagulation factors at birth in preterm neonates born before 30 wk gestation. METHODS: 38 neonates (median gestational age 27 wk, range 24-29 wk; median birthweight (BW) 933 g, range 515-1760 g) admitted to the neonatal intensive care unit were studied. Blood samples for coagulation factors were taken within 2 h after birth. The first cranial ultrasonographic examination was performed within the first 3 d. The occurrence of IVH was tested statistically by the Mann-Whitney U-test for association with the activity of coagulation factors and clinical variables. RESULTS: Thirteen IVHs occurred within the first 3 d of life. IVH was associated with BW <1000 g (p=0.012), low mean blood pressure within the first 2 d (p=0.026), gestational age <27 wk (p=0.054), low Apgar scores (<7) at 1 min (p=0.078) and intrauterine growth restriction (p=0.072). At birth (samples drawn with a median of first 36 min of life), infants with subsequent IVH had statistically significantly lower prothrombin (factor II) activity (p=0.024) than infants without IVH. CONCLUSION: The measured low prothrombin may have been affected by a prior bleeding event. Nevertheless, preterm infants with low prothrombin activity may be susceptible to IVH, or to the progression of it, if left undiagnosed.

Cerebral Hemorrhage↗
PubMed1986

The prothrombin gene and serine proteinase evolution.

The gene coding for human prothrombin has been isolated from two human genomic DNA libraries using a human prothrombin cDNA. Present evidence indicates that the gene is approximately 24 kb in length with about 90% of the DNA representing intervening sequence. Thirteen intervening sequences were found to interrupt the region coding for the mRNA into 14 exons. These intervening sequences vary greatly in size and contain at least 11 copies of Alu repetitive DNA. The positions where several of the intervening sequences interrupt the coding region appear to separate functional and structural domains of the protein. A similar placement of intervening sequences in genes coding for proteins homologous to prothrombin has been observed and provides additional evidence that these proteins have evolved from a common ancestor.

Amino Acid Sequence↗
PubMed1960

Polycythaemia vera and Christmas disease with slightly prolonged prothrombin time.

A family is reported in which Christmas disease in one member and polycythaemia in another were associated with prolongations of the one-stage prothrombin time of the factor-VII deficiency type. Changes in the prothrombin time were present in the siblings of the case of Christmas disease and in a number of unrelated cases of polycythaemia vera. The use of "mixing procedures" did not reveal any significant mutual correction of the changes in prothrombin time.

Hemophilia A↗
PubMed1979

A new chromogenic assay for the specific determination of prothrombin.

A new method for the specific assay of prothrombin is described which utilises Taipan snake venom and the chromogenic substrate Tos-Gly-Pro-Arg-pNA (Chromozym TH). The method is sensitive and reproducible and shows good correlation with a conventional specific assay for prothrombin. The reaction is dependent on calcium ions and phospholipid, and is therefore sensitive to the coumarin-induced prothrombin defect. The assay is rapid and well suited for use in the routine coagulation laboratory.

Aniline Compounds↗
PubMed2005

The effect of glycosaminoglycans with acetaldehyde on the activation of prothrombin.

Heparin17-19k, (25, 50, and 100 ng), heparin6k (50 and 100 ng), heparin3k (50, 100, and 200 microg), chondroitin sulfates B (dermatan sulfate) (0.25, 0.5, and 1.0 microg), C (1 and 10 microg), and A (1 and 10 microg) each prolong the activated partial thromboplastin time (APTT) when preincubated with prothrombin to a greater extent than when preincubated with Factor II-deficient plasma prior to their mixing and subsequent additions of APTT reagent and Ca2+. In all cases statistical significance (p < or = 0.05) was observed except with the 2 lower levels of heparin3k. These results suggest that the glycosaminoglycans (GAGs) may exert a direct effect upon prothrombin (FII) in their anticoagulant activity. Pre mix tures of [(FII/25 ng H17-19k) + 447 mmol acetaldehyde (AcH)/L] as well as [(AcH/H) + FII] and [(FII/AcH) + H] each exert a synergistic anticoagulant effect upon APTT. At low AcH concentrations (44.7 mmol/L), neither a synergistic nor an additive effect is seen. H6k and H3k, on premixing with 447 mmol AcH/L, exhibit an additive effect on APTT prolongation but no synergism. Similarly, premixtures of CSB/447 mmol AcH/L/FII show a greater anticoagulant effect than do [(CSB/AcH) + FII] or [(FII/AcH) + CSB] premixtures. CSC-AcH and CSA-AcH patterns are analogous to those of CSB (DS). These data suggest the possibility that AcH, the primary product of ethanol metabolism, may serve as a crosslinking adduct with proteins, in this case, prothrombin, as well as GAGs. Thus ternary complexes between the zymogen form of coagulation factors, GAGs, and AcH are possible, further influencing coagulopathy.

Acetaldehyde↗
PubMed1977

Estrogen and prothrombin synthesis: effect of estrogen on absorption of vitamin K1.

Intact male and female albino rats fed a vitamin K-deficient diet develop a plasma prothrombin-proconvertin deficiency. Male rats respond with a precipitous drop to approximately 20-30% of normal plasma levels within 2-5 days, whereas female rats respond at a slower rate. Ethynylestradiol, 5-10 mug/day, or castration, reduces the progressive decline of plasma prothrombin-proconvertin seen in nonsupplemented intact male rats. The response of castrate females differs little from the response of intact females. Ethynylestradiol, 5-10 mug/day, affects both castrate males and females similarly, limiting the prothrombin-proconvertin decrease to about 13% below control value after 14 days. Intestinal absorption of vitamin K1 measured in the thoracic duct lymph of pentobarbital-anesthetized castrate male and female rats was shown to increase significantly after estrogen treatment. Estrogen-treated castrate male and female rats absorbed 25.8 mug and 11.8 mug vitamin K1, respectively. Nontreated control castrate male and female rats absorbed 0.0 mug and 1.2 mug, respectively, during a 240-min collection period. Use of radioactive vitamin K1 in similar experiments confirmed these results. Estrogen-treated castrate males absorbed vitamin K1 at the rate of 30-40 mug/g lymph whereas nontreated control males absorbed only about 6 mug/g lymph.

Animals↗
PubMed1977

Turnover of fibrinogen, plasminogen, and prothrombin during exercise in man.

The turnover of biologically intact high-purity 125I- and 131I-labeled fibrinogen, plasminogen, and/or prothrombin was studied in 16 untrained healthy subjects before and during strenuous physical exercise on a bicycle ergometer (repeated 4 times/day for 2 days). The exertion resulted in the well-known changes in the coagulation and fibrinolytic tests but did not induce changes in the concentration of fibrinogen, plasminogen, or prothrombin in the plasma. A significantly increased catabolism of fibrinogen and plasminogen but not of prothrombin was observed. The extent of Aalpha-chain degradation of fibrinogen in the plasma was quantitated before and 2 h after exercise, and a significant increase in degraded Aalpha chains was found in the postexercise samples. Immunochemical estimation of plasmin-antiplasmin complex in four subjects revealed a small increase after exercise in three of them. All these data support the concept that plasminogen activation and plasmin-induced fibrinogen degradation occur to some extent in man following strenuous physical exercise.

Adult↗
PubMedDate not supplied

Comparative study of a portable monitor for prothrombin time determination, Coaguchek, with three systems for control of oral anticoagulant treatment.

Self-testing of oral anticoagulation is a new possibility related to the development of portable capillary whole blood prothrombin time monitors. The aim of this study was to evaluate one of this monitors, Coaguchek, with respect to its comparability with our routine prothrombin time determination system, as well as with the reference manual technique and two thromboplastins of high sensitivity, Manchester Reagent and one manufactured in our center, Thromboplastin Bilbao, in a group of patients on oral anticoagulant treatment. Although a correlation of r = 0.9271 was found between international normalized ratio (INR) values of Coaguchek and our routine method, Neoplastine/STA analyzer, the difference of the INR scatter increased with the magnitude of measurement, being lowest for INR between the portable monitor and Manchester Reagent and Thromboplastin Bilbao, with a similar coefficient of correlation, r = 0.8948 and r = 0.8905, respectively. A test was performed showing a 65.6% agreement with the INR values of the STA analyzer, 66.4% with Manchester Reagent and 73.4% with Thromboplastin Bilbao. On the basis of this correspondence with laboratory prothrombin time results Coaguchek may be considered as a possible option for monitoring anticoagulated patients even though patients should be given instructions and advice as regards the management and interpretation of the results.

Administration, Oral↗
PubMedDate not supplied

Influence of fibrinogen degradation products on thrombin time, activated partial thromboplastin time and prothrombin time of canine plasma.

To investigate how thrombin time, activated partial thromboplastin time (APTT) and prothrombin time are influenced by fibrinogen degradation products (FDP), different concentrations (0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.8 and 1.0 mg/ml) of the purified FDP X, Y, D and E were added to the plasma of healthy dogs. If fragment Y was added to the plasma a considerable inhibitory effect could be demonstrated for all three test systems. A significant prolongation (p < 0.05) was found for concentrations of > or =0.1 mg/ml (thrombin time, APTT) and > or =0.2 mg/ml (prothrombin time). With FDP Y concentrations from >0.185 mg/ml (prothrombin time) to >0.24 mg/ml (APTT) coagulation time was prolonged beyond the respective reference range. As regards the other fragments, a comparable inhibitory effect could only be shown for fragment X added to the thrombin time test system. This effect can most probably be explained by the competition of the FDP X and fibrinogen for the fibrinogen binding sites of thrombin, rather than by a fibrin polymerization disorder. The results demonstrate that for plasma with normal fibrinogen concentration the group tests are only prolonged beyond the reference range at FDP concentrations very rarely found in spontaneous hyperfibrinolysis.

Animals↗
PubMed1998

Prevalence of the G20210A polymorphism in the 3'-untranslated region of the prothrombin gene in different human populations.

Recently a novel polymorphism in the 3'-untranslated region of the prothrombin gene (a G to A transition at position 20210) was discovered, and an association with venous thrombosis and cardiovascular disease was found. The prevalence of the polymorphic allele in different human populations is unknown. We investigated the prevalence of the A 20210 allele of the prothrombin gene in 420 unrelated individuals (840 chromosomes) who belong to four different ethnic groups: Whites, African and Brazilian Blacks, Asians and Amerindians. PCR amplification followed by HindIII digestion was employed. The polymorphism was found in heterozygosity in 2 out of 120 Whites or a prevalence of 1.6% (allele frequency 0.8%), similar to that observed for other Caucasian populations. The A allele was absent among the other ethnic groups analyzed. Our data indicate that in non-Caucasians the prevalence of the 20210 G-->A mutation in the prothrombin gene, if any, must be extremely low. The absence of this novel genetic risk factor for venous and arterial thrombotic disease among non-Caucasians may contribute to explaining geographical and ethnic differences in the risk of vascular disease.

Alleles↗
PubMed2005

Gene structures of trocarin D and coagulation factor X, two functionally diverse prothrombin activators from Australian rough scaled snake.

Activation of prothrombin to thrombin is the key reaction in blood coagulation cascade. We have recently shown that Australian rough scaled snake, Tropidechis carinatus, possesses two parallel prothrombin activator systems. Trocarin D, a venom prothrombin activator produced in the venom gland, plays an offensive role as a toxin, whereas factor X is produced in the liver and plays a role in the hemostatic mechanism. These two proteins are structurally similar and have identical domain architecture. Because of the differences in their physiological roles, and tissue-specific expression, we determined the gene structure of these closely related proteins. Both the genes have eight exons similar to all mammalian factor X genes. All the exon-intron boundaries of these two genes are at the same position and the splice junctions are almost identical. Partial sequencing of the introns shows that they share a very high degree of sequence identity indicating that the gene duplication is a recent event. Further studies on the characterization of these two genes particularly the promoter regions are in progress.

Animals↗
PubMed1996

Computational studies of human prothrombin fragment 1, the Gla domain of factor IX and several biological interesting mutants.

We have employed molecular dynamics simulations to understand the properties of the gamma-carboxyglutamic acid (Gla) domains of human prothrombin fragment 1 (residues 1-144) and factor IX (residues 1-47). The simulations are based on (1) the crystal structure of bovine prothrombin fragment 1 in the presence of calcium and (2) our subsequent simulation of the solution structure for which we found accommodation of the long range ionic forces critical. In addition, we have estimated the solution structures for key mutant proteins [prothrombin (Gla6 to Asp and Gla16 to Asp) and factor IX (Gly12 to Ala)]. The simulations for the latter two mutants do not stabilize, a result in concert with the known biological data.

1-Carboxyglutamic Acid↗