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PubMed1991

Antibiotic treatment and associated prolonged prothrombin time.

The incidence and type of pathology causing a prolonged prothrombin time and clinical bleeding episodes were assessed in a multicentre study of 1109 patients receiving cefotetan, a N-methyl-thiotetrazole (NMTT), or equivalent antibiotics. There was no significant difference in the incidence of a prolonged prothrombin time (9.9% with cefotetan, 8.0% with comparable antibiotics) of clinical bleeding episodes. However, prothrombin time increases of greater than 12 seconds were significantly (p = 0.002) greater with cefotetan (3.8%) than with comparators (0.8%). In both antibiotic groups increases in prothrombin time were more likely following surgery and in patients who were older, with a high platelet count, low albumin, or higher urea and creatinine concentrations. All antibiotic treatment can be associated with prolonged prothrombin times and new agents should always be assessed in a large multicentre study before the practical, clinical importance of haemostatic defects can be defined.

Adolescent↗
PubMed2000

Photodynamic treatment of pooled coumarin plasma for external quality assessment of the prothrombin time.

AIMS: To determine the conditions of photodynamic inactivation of vesicular stomatitis virus (VSV) added to pooled coumarin plasma and the effects of the photodynamic treatment on the prothrombin times and international normalised ratio (INR) in a Netherlands national external quality assessment scheme. METHODS: Pooled coumarin plasma samples were illuminated with visible light in the presence of 1 microM methylene blue. Inactivation conditions for VSV in pooled coumarin plasma were determined using an end point dilution assay. Plasma illuminated for 20 minutes was mixed with red blood cells and mailed to participants of the Netherlands external quality assessment (EQA) scheme. Prothrombin times and INRs were determined with various thromboplastin reagents. RESULTS: Photodynamic treatment using 1 microM methylene blue and 700 W/m2 caused 4.7 log inactivation of VSV in pooled coumarin plasma. Fibrinogen and coagulation factors II, V, VII, and X were decreased slightly by the treatment. These conditions caused prolongation of the prothrombin time in EQA surveys. The magnitude of the effect was different for various thromboplastin reagents. The increase of the INR was negligible when measured with the Thrombotest reagent. With other reagents, an approximately 5-16% increase of the INR was observed. Interlaboratory variation of the INR was not affected by photodynamic treatment. CONCLUSIONS: Photodynamic treatment of pooled coumarin plasma is very effective for the inactivation of some enveloped viruses such as VSV, but has only a limited effect on the prothrombin time and INR. Photodynamic treatment can be used to improve the viral safety of coumarin plasma for EQA of the prothrombin time and INR.

Coumarins↗
PubMedDate not supplied

Isolation and some properties of 11- and 9-Gla prothrombins from normal plasma.

The relationship of prothrombin structure to function with respect to gamma-carboxyglutamic acid (Gla) residues can be effectively evaluated by characterizing the behavior of prothrombin isomers differing in Gla content. In addition to the isolation of a whole spectrum of Gla-deficient, 0- to 9-Gla isomers from dicoumarol-treated plasma, prothrombin isomers containing 11 (10.90) and 9 (8.85) Gla residues have now been isolated from normal bovine plasma. The isomers were isolated by barium citrate adsorption, elution, and finally by heparin-agarose, DEAE-cellulose, and immuno-affinity chromatographies. Each of the purified isomers showed a single component by agar gel and sodium dodecyl sulfate - polyacrylamide gel electrophoresis. By agar gel electrophoresis, the 11-Gla prothrombin isomer moved the fastest, followed by the 10-, and lastly the 9-Gla isomer, independent of Ca2+. The corresponding 9-, 10-, and 11-Gla prothrombin fragments 1 exhibited similar migration tendencies. By gel electrofocusing, 11- and 9-Gla fragments 1, respectively, focused anodal and cathodal to 10-Gla fragment 1. The Ca2+-induced decrease in the intrinsic fluorescence in 11-, 10-, and 9-Gla fragments 1 was 48, 40, and 45%, respectively. This metal-induced structural change did not correlate with the functional, thrombin-generating property of the isomers, as the 9-Gla variant exhibited 75%, and the 11-Gla 110-115%, of normal coagulant activity.

1-Carboxyglutamic Acid↗
PubMed2000

Prothrombin G20210A mutation: is it associated with pre-eclampsia?

OBJECTIVE: A strong independent association between the prothrombin G20210A gene mutation and pre-eclampsia has been reported in an Italian population. This result was not confirmed in a subsequent study in a Dutch population. The objective of this study was to further test the hypothesis that the prothrombin G20210A mutation is associated with pre-eclampsia/eclampsia. METHODS: Seventeen eclamptics and 67 pre-eclamptics were recruited from 34 multicase Australian/New Zealand families. An additional 105 unrelated pre-eclamptic/eclamptic women and 119 parous women were recruited as controls. RESULTS: The overall incidence for the prothrombin G20210A gene mutation in the pre-eclamptic group was 3.6% (95% CI 1.2-8.2%) which was not significantly different from the control group 2.5% (95% CI 0.5-7.2%) (p = 0.73, OR 1.44, 95% CI 0.34-6.17). CONCLUSION: This study provides little evidence of a significant relationship between the prothrombin G20210A gene mutation and pre-eclampsia. Based on our results, we do not recommend testing for the prothrombin G20210A mutation in the routine investigation of women with pre-eclampsia.

Adult↗
PubMedDate not supplied

Resistance to activated protein C, factor V leiden and the prothrombin G20210A variant in patients with colorectal cancer.

OBJECTIVE: The aim of our study was to determine the frequency of resistance to activated protein C (APC), factor V Leiden (FVL) and the prothrombin G20210A variant in patients with colorectal cancer. METHODS: 74 patients with colorectal cancer and 192 colonoscopically selected controls were prospectively investigated for the presence of APC resistance, FVL and the prothrombin G20210A variant. APC resistance was measured as the ratio of activated partial thromboplastin times with and without APC (APC sensitivity ratio, APC-SR). The FVL and prothrombin G20210A variant were detected by a polymerase-chain-reaction-based technique. RESULTS: FVL was detected in the heterozygous form in 4 of 74 cancer patients (5.4%) and in 7 of 192 controls (3.6%; p > 0.5, odds ratio: 1.51). After excluding patients and controls with FVL, APC-SR was below 2 in 6 of 70 cancer patients (8.5%) and in 1 of 185 controls (0.5%; p < 0.01, odds ratio: 17.25), and the mean value of APC-SR was significantly lower in cancer patients than the respective level of controls (2.8 vs. 3.7, p < 0.001). The G20210A mutation in the prothrombin gene was found in the heterozygous form in 2 of 74 patients with colorectal cancer (2.7%) and in 5 of 192 colonoscopically control subjects (2.6%; p > 0.5, odds ratio: 1.03). CONCLUSIONS: These findings suggest that patients with colorectal cancer have a high frequency of resistance to APC but no significant differences in the frequency of the FVL or G20210A mutation of the prothrombin gene compared to colonoscopically selected controls.

Activated Protein C Resistance↗
PubMed1986

The prothrombin gene.

Using recombinant DNA techniques, DNA fragments coding for bovine prothrombin mRNA have been cloned and characterized. Structural studies have revealed that prothrombin mRNA encodes a precursor protein having an amino-terminal extension of 43 amino acid residues. Using bovine prothrombin cDNA as a hybridization probe, the genes coding for human and bovine prothrombin have been isolated and partially characterized. The organization of the prothrombin gene is similar, but not identical to the organization of the genes coding for the other vitamin-K-dependent clotting factors.

Amino Acid Sequence↗
PubMed1997

The heterozygous 20210 G/A prothrombin genotype is associated with early venous thrombosis in inherited thrombophilias and is not increased in frequency in artery disease.

A genetic variation in the 3'-untranslated region of the prothrombin mRNA (20210 G/A) has recently been reported to be associated with elevated plasma prothrombin levels and with an increased incidence of venous thrombosis. We determined the frequency of this mutation, the detection of which was improved by allele-specific amplification of exon 14 and by denaturing gradients (denaturing gradient gel electrophoresis), in cohorts of patients affected by venous thrombosis (n = 132) or by coronary or cerebrovascular diseases (n = 195) and in normal subjects from various populations. An overlapping frequency of the heterozygous genotype (4%) was found in normal subjects from Italy and Cyprus, and no carrier was detected in 40 subjects of Indian or Somali origin. The 20210 GA heterozygous genotype was not increased in frequency in patients with arterial disease. In contrast, the GA genotype was associated (P = .007) with venous thrombosis both in simple heterozygotes (16%) with a family history of thrombosis as well as in double heterozygotes (14%) for other known thrombophilic defects. A synergic interaction between the prothrombin 20210 GA genotype and the factor V Leiden mutation, both potentially affecting the prothrombinase complex, was suggested by the early onset of thrombosis (median age 22 years) in doubly heterozygous patients. The association of the 20210 A allele with higher prothrombin levels was confirmed in the Italian population. However, the prothrombin assay does not allow an efficient preselection of patients for the DNA analysis.

Adolescent↗
PubMed1998

Prothrombin gene G20210-->A transition is a risk factor for cerebral venous thrombosis.

BACKGROUND AND PURPOSE: It has been recently reported that a G-->A transition at nucleotide position 20210 in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increased risk of deep venous thrombosis. To date, it is unknown whether this polymorphism also represents a risk factor for cerebral venous thrombosis (CVT). METHODS: Venous blood samples were collected from 45 patients with CVT and from 354 healthy blood donors as controls. A second control group consisted of 131 subjects with acute ischemic stroke or transient ischemic attack (TIA). Genomic DNA was isolated from peripheral blood leukocytes. Amplification of DNA was performed by polymerase chain reaction (PCR). The G-->A transition at nucleotide position 20210 of the prothrombin gene was detected by allele-specific restriction digestion. RESULTS: The G20210-->A transition in the prothrombin gene was found in a heterozygous form in 4 of 45 patients with CVT (8.9%) and in 8 of 354 healthy control subjects (2.3%). This difference was statistically significant (P=0.010). The G20210-->A transition increased the relative risk for CVT approximately 5-fold (age-adjusted odds ratio 5.7; 95% CI 1.5 to 21.5). In contrast, in the group of patients with acute cerebral ischemia, only 3 of 131 subjects (2.3%) were heterozygous for the G20210-->A transition, which corresponded to the prevalence in the group of healthy blood donors. CONCLUSIONS: The recently described G20210-->A transition in the 3'-untranslated region of the prothrombin gene is an inherited risk factor for CVT but obviously not for acute ischemic stroke or TIA.

Adolescent↗
PubMed2002

Effect of Abciximab on prothrombin activation and thrombin generation in acute coronary syndromes without ST-segment elevation: Global Utilization of Strategies to Open Occluded Coronary Arteries Trial IV in Acute Coronary Syndromes (GUSTO IV ACS) Italian Hematologic Substudy.

BACKGROUND: Abciximab is very effective in reducing major cardiac events in patients undergoing interventional procedures. Its antithrombotic effect is primarily attributable to the blocking of platelet glycoprotein IIb/IIIa receptors, but recent evidence suggests that it may have a direct antithrombin effect. No data are available concerning the effect of abciximab on the in vivo markers of prothrombin activation and thrombin generation in patients with acute coronary syndromes without ST elevation. METHODS AND RESULTS: We measured the plasma levels of prothrombin fragment 1+2 (a marker of prothrombin activation) and the thrombin/antithrombin complex (a marker of thrombin generation) in 167 patients with acute coronary syndromes without ST elevation enrolled in the GUSTO IV ACS trial who were randomized to receive abciximab for 24 hours (52 patients), abciximab for 48 hours (59 patients), or placebo (56 patients) in addition to heparin. Blood samples were obtained at baseline (before any treatment), after 24 and 48 hours (before study drug discontinuation), and 1 month later. There was a significant increase in the plasma levels of prothrombin fragment 1+2 after 48 hours and after 1 month in all 3 groups, placebo (P=0.0001), 24-hour abciximab (P=0.0002), and 48-hour abciximab (P=0.0001). The plasma thrombin/antithrombin complex levels were similar in the 3 groups at all time points and did not change during the study drug infusions. CONCLUSIONS: Abciximab does not decrease prothrombin activation and thrombin generation in patients with acute coronary syndromes without ST elevation not undergoing interventional procedures.

Abciximab↗
PubMed2006

Prevalence of prothrombin gene mutation (G-A 20210 A) in general population: a pilot study.

The objective of this study was to determine the prevalence of prothrombin gene mutation in a sample population from Pakistan. Two hundred apparently healthy unrelated adults (older than 18 years) were included in the study. The sample population comprised 100 Punjabis (male 50, female 50) and 100 Pathans (male 50, female 50). Patients with a history of previous thromboembolism were excluded from the study. Five milliliters (5 mL) of whole blood was drawn in an EDTA bottle. The DNA was extracted by the standard phenol-chloroform method. The DNA was amplified between exon number 14 and the 3'-untranslated region of the prothrombin gene by a polymerase chain reaction in a thermal cycler. Amplified products were digested overnight with HindIII at 37 degrees C. The digested products were electrophoresed on 6% polyacrylamide gel. The fragments were visualized by silver nitrate staining. A heterozygous wild type and an uncut amplified product were included in the electrophoresis strip for quality control. The wild type of DNA ran as a 350-bp fragment and internal control was cut as 550- and 150-bp fragments. The abnormal prothrombin gene was cut into 350-, 322-, and 28-bp fragments. Only two cases of heterozygous prothrombin gene mutation G-A 20210A were found in the sample studied, giving an overall carrier rate of 01% (95% CI 0.4-2.4%) in the target population. Prothrombin gene mutation is present in our population but at a lower frequency than in the white population.

Adult↗
PubMed2002

The G20210A mutation does not affect the stability of prothrombin mRNA in vivo.

The activated form of prothrombin plays pivotal roles in the regulation of crucial coagulation, fibrinolytic, and cellular processes. Among several congenital genetic defects affecting the prothrombin gene, a G-->A mutation at position 20210--the accepted polyadenylation site--has been linked to hyperprothrombinemia and a corresponding increase in venous and arterial thrombotic risk. The current study substantiates the hypothesis that the 20210A mutation effects posttranscriptional dysregulation of the prothrombin messenger RNA (mRNA). Moreover, data from experiments carried out in fresh liver tissue indicate that the 20210A mutation does not affect prothrombin mRNA stability but, rather, effects a change in the location of the 3'-cleavage/polyadenylation reaction. Based upon this evidence, we propose an alternate model for the dysregulated expression of the prothrombin 20210A gene that does not require a change in the stability of its mRNA.

Heterozygote↗
PubMed2003

Hyperprothrombinemia associated with prothrombin G20210A mutation inhibits plasma fibrinolysis through a TAFI-mediated mechanism.

The prothrombin gene mutation G20210A is a common risk factor for thrombosis and is associated with increased prothrombin levels. However, the mechanism whereby hyperprothrombinemia predisposes to thrombosis remains unclear. Because thrombin is the physiologic activator of TAFI (thrombin activatable fibrinolysis inhibitor), the precursor of an antifibrinolytic carboxypeptidase (TAFIa), we evaluated the influence of hyperprothrombinemia on fibrinolysis. Thirty-two heterozygous carriers of the G20210A mutation and 30 noncarriers were studied. Plasma fibrinolytic factors and TAFI levels were similar in the 2 groups. Mean lysis time of tissue factor-induced plasma clots exposed to 25 ng/mL exogenous tissue-type plasminogen activator (t-PA) was significantly longer in 20210A carriers than in control donors. This difference disappeared on addition of a specific inhibitor of TAFIa. Determination of thrombin and TAFIa activity, generated during clot lysis, revealed that G20210A mutation was associated with a significant enhancement of late thrombin formation and an increase in TAFI activation. Plasma prothrombin level was highly significantly correlated with both clot lysis time and TAFI activation. The addition of purified prothrombin, but not of factors X or VIIa, to normal plasma caused a concentration-dependent, TAFI-mediated inhibition of fibrinolysis. These findings provide a new mechanism that might contribute to the thrombotic risk in prothrombin 20210A carriers.

Carboxypeptidase B2↗
PubMed2004

A recombinant murine meizothrombin precursor, prothrombin R157A/R268A, inhibits thrombosis in a model of acute carotid artery injury.

Mutations in human prothrombin that generate a stable form of meizothrombin or meizothrombin(desF1) cause dysprothrombinemia in both the homozygous and heterozygous state, suggesting that meizothrombin has dominant anticoagulant effects in vivo. The enzymatic characterization of recombinant mouse meizothrombin, meizothrombin(desF1), and thrombin indicates that all 3 enzymes have similar activity toward the chromogenic substrate S-2238, that meizothrombin and meizothrombin(desF1) have less than 10% of the fibrinogen-clotting activity of thrombin, and that meizothrombin is more active than thrombin or meizothrombin(desF1) for thrombomodulin-dependent protein C activation. Thus, activated mouse prothrombin R157A/R268A is similar to human meizothrombin in activity toward S-2238, fibrinogen, and protein C. The time to occlusion after FeCl(3)-induced carotid artery injury was delayed (11.8 +/- 3.6 minutes, n = 5) in Cf2(+/-) mice infused with prothrombin R157A/R268A compared with control mice infused with wild-type prothrombin (5.3 +/- 1.5 minutes, n = 3; P =.006). In this model, prothrombin R157A/R268A has anticoagulant activity that reflects its decreased fibrinogen-clotting activity and preserved protein C-activating activity and is consistent with dominant inhibition of fibrinogen clotting.

Acute Disease↗
PubMed2001

Autoantibody against prothrombin aberrantly alters the proenzyme to facilitate formation of a complex with its physiological inhibitor antithrombin III without thrombin conversion.

Acquired coagulation factor inhibitors include pathologic immunoglobulins that specifically bind to coagulation factors and either neutralize their procoagulant activity, accelerate their clearance from the circulation, or have proteolytic activity to degrade them into inactive polypeptides. Here, an autoantibody against prothrombin is described in a patient with serious hemorrhagic diatheses. The autoantibody exerts its influence by a previously unknown mechanism in which it inhibits coagulation through aberrant activation of the proenzyme in a catalytic manner. The antibody-bound prothrombin formed a stable stoichiometric complex with antithrombin III, consisting of intact prothrombin and an antithrombin III molecule cleaved at the (393)Arg-(394)Ser bond. The antibody dissociated from prothrombin after the complex formation with antithrombin III. Although the bound antibody elicited protease activity from prothrombin, the complex was not able to convert fibrinogen to fibrin or to activate protein C. Thus, this is the first description of an autoantibody that induces protease-like activity from a human proenzyme, permitting subsequent neutralization by its physiological inhibitor. (Blood. 2001;97:3783-3789)

Amino Acid Sequence↗
PubMed2000

Association of the prothrombin G20210A mutation with factor V Leiden in a midwestern American population.

The prothrombin G20210A mutation has been identified as a risk factor for thrombosis. We studied the relationship between prothrombin G20210A and factor V Leiden mutations in patients with thrombophilia. The first 264 patients for whom these molecular diagnostic studies were requested at our institution were included in the study. For 116 of the 264 patients, additional coagulation test results were available in the laboratory database. The prothrombin G20210A mutation was found in 16 (6.1%) of the patients and the factor V Leiden mutation in 44 (16.7%). Of the 16 patients with the prothrombin G20210A mutation, 8 also carried factor V Leiden; this association was significant. In contrast, only 2 patients of the 116 with additional coagulation testing harbored more than 1 prothrombotic risk factor. These data support the hypothesis that thrombophilia is a multigenic disorder. Among unselected samples from a Midwestern population evaluated for thrombotic risk factors, the prevalence of factor V Leiden and prothrombin G20210A mutations are similar to those found in other populations in the Western world.

Adolescent↗
PubMed2001

Gene targeting in hemostasis. Prothrombin.

There have been extensive studies on the structure and function of prothrombin; a protein critical for the coagulation of blood. The biological functions of prothrombin and its activated form, thrombin are discussed, as well as the structure and functional domains of the protein. Prothrombin is expressed in a tissue-specific manner and its gene structure and regulatory elements have been analyzed in detail. In order to learn more about the functions of prothrombin in an in vivo context, the gene was ablated in mice. Homozygous deletion of prothrombin results in a partial embryonic lethal phenotype. Approximately half of the homozygous mutant mice die during mid-gestation and the remainder die soon after birth. The cause of death of neonates is due to excessive bleeding, while null embryos have a lack of integrity of the yolk sac membrane resulting in bleeding into the yolk sac cavity. These results are discussed in relation to the phenotypes found for other mice lacking specific coagulation factors.

Animals↗
PubMed1975

Investigation and standardization of prothrombin times in chickens.

This investigation was undertaken to standardize the determination of the one-stage prothrombin time for use with chickens. Homologous thromboplastin was essential and the most active thromboplastin was obtained from chickens four-weeks old or younger. Acetone-dried brain powder could be stored for at least 4 months at -15 degrees C. without loss of activity. Extraction of brain powder with 0.025 M CaCl2 at 42 degrees C. gave better thromboplastic activity than the standard extraction with physiological saline at room temperature. Thromboplastin solutions could be stored in ice water for only 6 hours without loss of activity. Citrate concentration had to be increased from the usual 0.10 M to 0.18 M to prevent premature clotting of plasma. Plasma donor age had no effect on the prothrombin times. Freezing and thawing as well as storage of plasma in the frozen state increased the prothrombin times. Using the best conditions, the mean prothrombin time for 1200 birds determined over a 6-month period was 9.4 sec. with an individual range of 7.18-11.4 sec. This represents a significantly lower prothrombin time with lower variability than that reported in the literature.

Age Factors↗
PubMed2006

[Factor V Leiden and prothrombin G20210A among Chilean patients with venous and arterial thrombosis].

BACKGROUND: Factor V Leiden and G20210A mutation of prothrombin gene are two important genetic polymorphisms associated with an increased risk for thrombosis. AIM: To establish the prevalence of factor V Leiden and prothrombin G20210A mutation in the Chilean population and their association to venous and arterial thromboembolism. MATERIAL AND METHODS: A case-control study was conducted where 149 patients with thrombosis (87 with arterial and 62 with venous thrombosis) confirmed by CAT-scan, electrocardiogram and cardiac enzymes or Doppler depending on the case, and 160 healthy blood donors were genetically analyzed for the presence of both polymorphisms. RESULTS: Factor V Leiden mutation was found in 5.4% of patients and in 1.3% of healthy controls (p=0.04). Heterozygosity for G20210A prothrombin mutation was found in 5.4% of patients and in 2.5% of the control group (p=NS). When arterial and venous thrombosis were considered as separate entities, 4.6% of patients with arterial thrombosis and 6.5% with venous thrombosis presented factor V Leiden (p=NS). Likewise, 8.1% of patients with venous thrombosis and 3.5% of patients with arterial thrombosis had G20210A prothrombin mutation (p=NS). CONCLUSIONS: In non selected consecutive Chilean patients with arterial and venous thrombosis the frequency of factor V Leiden and prothrombin G20210A is less than we could expect from their prevalence in the general population.

Case-Control Studies↗