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PubMed2003

Concomitant heterozygous factor V Leiden mutation and homozygous prothrombin gene variant (G20210A) in patient with cerebral venous thrombosis.

BACKGROUND: Factor V Leiden mutation represents the most common genetic risk factor of venous thrombosis in Caucasian population. A common mutation in prothrombin gene, which is due to G-->A transition at position 20210, is also associated with elevated prothrombin concentration and thrombosis. Both this mutations may constitute concomitant risk factors for deep venous thrombosis. CASE REPORT: A 29-years old woman was admitted in the Emergency Department because of severe headache with vomiting that she suffered for a few days without any neurological deficits. In the Emergency she presented first in her life tonic-clonic seizures followed by right hemiparesis and aphasia and than was admitted to hospital. CT and MR scan showed a large lesion in the left fronto-parietal region with extent edema, which was first diagnosed as tumor. Following MR showed more lesions and typical signs of sinus thrombosis. She improved quickly after stroke without any anticoagulant treatment. Genetic study revealed factor V Leiden mutation and homozygous mutation G20210A in prothrombin gene. CONCLUSIONS: Both mutations found in this case, alone, are not a high risk factors for venous thrombosis but together may increase 5-10 fold risk of venous thrombosis. Venous stroke must be considered always in acute neurological events with organic brain lesions, especially in young

Adult↗

PubMed2003

Prevalence of the G20210A prothrombin gene mutation in Northwestern Greece and association with venous thromboembolism.

AIM: The G20210A mutation of the prothrombin gene is a genetic risk factor for venous thromboembolism (VTE). Variability exists in the mutation prevalence in both normal individuals and VTE patients. The aim of this study was to determine the mutation prevalence in Northwestern Greece and evaluate its association with VTE. METHODS: Presence of the G20210A mutation was investigated using DNA analysis in 176 consecutive patients with a history of venous thrombosis or pulmonary embolism and in 300 healthy controls, all Caucasian residents of Northwestern Greece. RESULTS: The mutation was present 12 patients (6.8%) and 8 controls (2.7%). The odds ratio for presence of the mutation versus the normal genotype in VTE was 2.7 (95% CI: 1.1 to 6.7), which was statistically significant. The prevalence of the G20210A prothrombin gene mutation in Northwestern Greece is 2.7% (95% CI: 0.8% to 4.4%) with an allele frequency of 1.3% (95% CI: 0.4% to 2.3%). CONCLUSION: The G20210A mutation of the prothrombin gene is associated with VTE in the Caucasian residents of this geographic region.

Case-Control Studies↗

PubMed1992

Des-gamma-carboxy prothrombin (PIVKA-II) and alpha-fetoprotein-producing IIc-type early gastric cancer.

We describe the case of a 56-yr-old man with primary gastric adenocarcinoma, who had an extremely high plasma level of des-gamma-carboxy prothrombin (2.45 AU/ml) and of serum alpha-fetoprotein (2810 ng/ml). Histopathologically, the gastric cancer was a IIc type of early cancer which consisted of a combination of a poorly differentiated adenocarcinoma and a well-differentiated tubular adenocarcinoma. The association of a hepatic tumor including hepatocellular carcinoma or liver metastasis was ruled out by ultrasonography, computed tomography, radiocolloid liver scan, magnetic resonance imaging, and angiography. Foci strongly resembling hepatocellular carcinoma (hepatoid differentiation) were noted in the gastric tumor. Localization of des-gamma-carboxy prothrombin and alpha-fetoprotein within the tumor cells, especially within the hepatoid differentiated foci, was demonstrated by the immunohistochemical staining of tissue obtained at biopsy and the resected specimen. This case seems to be the first case reported in which des-gamma-carboxy prothrombin was produced by the gastric cancer. This finding supports the theory of hepatoid differentiation of a gastric cancer.

Adenocarcinoma↗

PubMed2003

[Occurrence of gene mutations in factor V Leiden, prothrombin and methylenetetrahydrofolate reductase in patients with pre-eclampsia].

OBJECTIVE: The aim of the study was to detect the incidence of thrombophilia FV Leiden, prothrombin G20210A, MTHFR C677T, resistance to activated protein C, and deficiency of protein C and S in pregnant or puerperal women with preeclampsia and control group. DESIGN: Case-control study. SETTING: Department of Obstetrics and Gynecology, Department of Hemato-oncology, Medical Faculty, Palacký University, Olomouc. METHODS: The group of 38 women with confirmed diagnosis of preeclampsia were examined for resistance to activated C protein. (Coatest, APC resistence Chromogenix), levels of C and S protein. For the detection of FV:Q506, prothrombin G20210A and MTHFR C677T allels was done by PCR test. The control group had 50 women, chosen randomly. The statistical evaluation was performed by the STATISTICA program. For the analyzing of the continuous variables the Student's T-test was used. Values below p < 0.01 were considered to be statistically significant. RESULTS: Women who suffered from preeclampsia came to mean age of 32.8 +/- 4.3 (years), mean gestational age 33.6 +/- 2.8 (weeks), mean systolic pressure 163 +/- 21 mmHg, diastolic pressure 108 +/- 8 mmHg. All of the results were rendered to be statistically significant in comparison the control group. On the other hand, the results in observed haematologic parameters were not significant (Preeclampsia/controls). FV Leiden--heterozygous subjects 4/3, prothrombin G20210A 1/0, C677T heterozygous subjects 12P10, C677T 2/0, protein C and S deficiency 2(0. Resistance to activated C protein was found in 14 (37%) patients, in comparison to 6 (12%) in the control group (p = 0.0073). CONCLUSION: We didn't find any difference in the prevalence of genetic mutations in patients with preeclampsia compared to the control group. The prevalence of APC resistance was statistically higher in preeclamptic patients compared to the control group.

Activated Protein C Resistance↗

PubMed1992

Molecular and genetic analysis of a compound heterozygote for dysprothrombinemia of prothrombin Tokushima and hypoprothrombinemia.

The molecular and genetic basis of a compound heterozygote for dys- and hypoprothrombinemia was analyzed. Abnormal nucleotide sequences of the human prothrombin gene were screened by PCR-single-strand conformation polymorphism (PCR-SSCP) with endonuclease digestion and mutated primer-mediated PCR-RFLP. A single nucleotide substitution responsible for dysprothrombinemia of prothrombin Tokushima was detected, as were three polymorphisms. The mutation for hypoprothrombinemia was detected by PCR-single-strand conformation polymorphism (PCR-SSCP) with endonuclease digestion in exon 6, near MboII-RFLP and NcoI-RFLP. Sequencing of PCR-amplified genomic DNA revealed a single base insertion of thymine (T) at position 4177. The resulting frameshift mutation caused both an altered amino acid sequence from codon 114 and a premature termination codon (i.e., TGA) at codon 174 in exon 7. Because exon 7 encodes the kringle 2 domain preceding the thrombin sequence, this frameshift leads to the null prothrombin phenotype. The inheritance of the hypoprothrombinemia gene from the father to the proband was proved by PCR-SSCP with endonuclease digestion and mutated primer-mediated PCR-RFLP.

Amino Acid Sequence↗

PubMed1977

[Determination of the secondary prothrombin structure under different degrees of citraconylation by means of ring dichroism].

A process of spontaneous activation of bovine prothrombin under acylation of cytacone anhydride is studied by means of ring dichroism and disc electrophoresis in sodium dodecylsulphate. Ring dichroism data have shown that native prothrombin contains 14% of alpha-helical structures, 36% of beta-structures and 50% of random coil. Cytraconylation results in a fragmentation of native prothrombin chain and is accompanies by the decrease of alpha-helical regions in the fragments formed. Poly-L-lysine, modified by citracone anydride, does not form alpha-helical regions.

Chemical Phenomena↗

PubMed1992

High level expression of active human prothrombin in a vaccinia virus expression system.

We have worked out an efficient and time saving procedure for the expression of recombinant human prothrombin. The glycoprotein was expressed in the vaccinia virus expression system in several mammalian cell lines. The kidney cell lines Vero and BHK and the human cell line Hela were found to efficiently secrete prothrombin. Expression level of 3-4 micrograms of factor II per 10(6) cells per day corresponding to 18-23 mU per 10(6) cells per day were achieved. Since the expression levels obtained with the vaccinia virus/Vero cell system were comparable to those obtained in amplified transformed CHO cells it provides an alternative system for the efficient expression of human prothrombin and may allow to further elucidate structure-function relationships of (pro)thrombin and its various effectors.

Amino Acid Sequence↗

PubMed2004

The contribution of factor V Leiden and prothrombin G20210A mutation to the risk of central venous catheter-related thrombosis.

BACKGROUND AND OBJECTIVES: The purpose of this study was to assess the incidence of central venous catheter (CVC)-related thrombosis and the contribution of two common inherited coagulation disorders (factor V Leiden, prothrombin G20210A mutation) to this complication in a large hospital population. DESIGN AND METHODS: In a prospective setting, patients were assessed daily for signs and symptoms suggestive of thrombosis. Routine Doppler-ultrasound was performed weekly in all patients until CVC removal. Doppler-ultrasound examinations were stored on videotape and assessed by two blinded observers. In the case of clinically suspected thrombosis the physicians followed routine diagnostic and therapeutic procedures. The presence of factor V Leiden and prothrombin G20210A mutation and other potential risk factors were assessed in all patients. RESULTS: In 252 consecutive patients the cumulative incidence of-CVC related thrombosis was 30% (clinically manifested thrombosis: 7%). The relative risk of factor V Leiden or prothrombin G20210A mutation for thrombosis was 2.7 (CI95% 1.9 to 3.8). In addition, a personal history of venous thrombosis was associated with CVC-related thrombosis, whereas the severity of thrombosis was affected by the absence of anticoagulants and the presence of cancer. INTERPRETATION AND CONCLUSIONS: Thrombosis is frequently observed after central venous catheterization. Common inherited abnormalities in blood coagulation contribute substantially to CVC-related thrombosis. In view of physicians' reluctance to prescribe prophylactic anticoagulant treatment in vulnerable patients, a priori determination of common inherited and acquired risk factors may form a basis to guide these treatment decisions.

5' Untranslated Regions↗

PubMedDate not supplied

[Cerebral venous thrombosis associated to subacute De Quervain's thyroiditis in a carrier for the G20210A mutation of the prothrombin gene].

INTRODUCTION: Recently, thyrotoxicosis has been described as a risk factor for cerebral venous thrombosis (CVT) in some reported cases. We present a case of CVT associated to a subacute De Quervain's thyroiditis in a young female who was an heterozygous carrier for the G20210A mutation of the prothrombin gene. CASE REPORT: A 42-year-old female with irrelevant past medical history developed a thrombosis of the superior sagital and right transverse sinus in the initial phase of a subacute thyroiditis. Diagnosis was made by thyroid radioactive iodine uptake, and cerebral computerized tomography scan, magnetic resonance imaging, and magnetic resonance angiography. Treatment with aspirin and corticosteroids was started until thyroid function was normalized. When CVT diagnosis was made, the patient was treated with anticoagulation. Two months later, magnetic resonance imaging showed resolution of the CVT. The patient was diagnosed as an heterozygous carrier for the G20210A mutation of the prothrombin gene by genetic studies. CONCLUSIONS: Subacute thyroiditis might act as a risk factor for CVT, increasing the thrombotic risk in the presence of other acquired or hereditary prothrombotic factors, such as the G20210A mutation of the prothrombin gene in our patient.

Adult↗

PubMed2004

Factor V Leiden, prothrombin G20210A and MTHFR gene mutations in inflammatory bowel disease.

BACKGROUND/AIMS: Thromboembolic events are more common in patients with inflammatory bowel disease than in the normal population; however, the reason for the increased prevalence is not clear. The aim of this study was to evaluate the prevalence of factor V Leiden, prothrombin G20210A and methylene tetrahydrofolate reductase (MTHFR) gene mutations in IBD patients followed in our outpatient clinic. METHODS: Thirty-four patients with ulcerative colitis and 28 patients with Crohn's disease and 80 healthy controls were included in the study. No patient had a history of previous thromboembolism. Factor V Leiden, prothrombin G20210A and MTHFR gene mutations were studied. RESULTS: Heterozygote factor V Leiden mutation was found in five (6.25%) control patients and in two (3.2%) IBD patients. Heterozygote MTHFR mutation was obtained in seven (11.3%) IBD patients and in five (6.25%) controls. Heterozygote prothrombin G20210A mutation was found in two (2.5%) and homozygote MTHFR mutation in one (1.25%) control patient. There was no statistical difference between the IBD group and healthy controls. CONCLUSIONS: Genetic mutations that could increase the thrombosis risk were not found to be different in IBD versus the normal population in our study.

Adult↗

PubMed2007

Vibrio extracellular protease with prothrombin activation and fibrinolytic activities.

A 36 kDa extracellular metalloprotease (designated to as vEP-MO6) was purified and characterized from Vibrio vulnificus sp. strain MO6 24/0. vEP-MO6 cleaved azocasein and a few other proteins such as prothrombin, plasminogen, fibrinogen and Factor Xa, which are associated with the blood coagulation pathway. The enzyme activity of vEP-MO6 was inhibited by EDTA, which was reversed by the addition of excess divalent cations. vEP-MO6 showed little or no activity toward various chromogenic substrates that are specific for other proteases. The cleavage of prothrombin by vEP-MO6 produced active thrombin, as revealed by an activity assay with thrombin-specific chromogenic substrate and Western blot analysis with anti-thrombin antibody. The enzyme also actively hydrolyzed fibrin polymer as well as the cross-linked fibrin. These results suggest that vEP-MO6 is a prothrombin-activating and cross-linked fibrin-degrading enzyme belonging to the metalloprotease family.

Amino Acid Sequence↗

PubMed1991

Characterization of a novel liver-specific enhancer in the human prothrombin gene.

The 5'-flanking sequence of the human prothrombin gene was isolated by screening a human liver phage library with a human prothrombin cDNA as a hybridization probe. A phage was identified that contained 3 kilobase pairs of DNA upstream of the initiator methionine codon. Primer extension studies showed that the major transcription initiation sites were located 23 and 36 base pairs upstream of the initiator codon. DNA sequences in the 5'-flanking region of the human prothrombin gene were then analyzed for cis-activating transcriptional activity by a transient expression system using the human growth hormone gene as the reporter gene. The chimeric expression vector was introduced into HepG2 cells, and secreted human growth hormone was monitored by using a radio-immunoassay. These studies showed that the 3-kilo-base pair fragment contained sequences that were sufficient for the initiation of transcription in HepG2 cells. Subsequent deletion studies showed that the 3-kilobase pair fragment contained two elements: a weak promoter in the region immediately upstream of the mRNA coding sequence and an enhancer located between nucleotides -860 and -940. The enhancer element was active at a distance and in either orientation. In addition, the enhancer was liver cell-specific and acted on heterologous promoters including the herpes simplex virus thymidine kinase promoter and the mouse metallothionein I promoter. Comparison of the nucleotide sequence of the enhancer with a DNA sequence data base showed the enhancer sequence to be unique. The enhancer sequence is flanked by an inverted repeat 5' CCTCCC 3' and contains a putative binding site for hepatic nuclear factor 1. Deoxyribonuclease I footprint analysis and linker scanning mutagenesis showed that the enhancer contains multiple protein binding motifs. Mutagenesis of the 3' boundary CCTCCC sequence eliminated the enhancer activity. Comparison with other liver genes showed the presence of the CCTCCC sequence in the hepatitis B virus enhancer, the alpha 1-antitrypsin promoter, and the fibrinogen beta-chain promoter, suggesting a functional role for this motif.

Base Composition↗

PubMed1990

Prothrombin time in first week of life with special reference to vitamin K administration.

Prothrombin time was estimated in 100 neonates (80 full term and 20 preterm). Among the full term infants 50 were healthy and 30 sick. Prothrombin time was altered in neonates with birth hypoxia and prematurity (p less than 0.001). Vitamin K administration to anoxic babies resulted in improvement in prothrombin time after 48-72 hours (p less than 0.001). Four newborns has bleeding, 2 had anoxia and 2 were only in preterms who did not receive vitamin K after birth. It is concluded that vitamin K should be given to all preterms and those with difficult deliveries; term, healthy newborns do not need it.

Humans↗

PubMed1990

Prothrombin time in the monitoring of oral anticoagulant: a comparison of results using different thromboplastins.

The objective of this report is to compare the prothrombin time performed with thromboplastin of different tissues and species in patients under oral anticoagulant therapy as well as the way of expressing the results. The results showed that the ISI of the thromboplastin of human and rabbit brain are very close to the IRP BCT/253 (1.2 vs 1.1) and RBT/79 (1.3 vs 1.4), respectively. In contrast, the rabbit lung thromboplastin showed the greatest differences in the ISI values (1.6 vs 1.4) and in the CV (6.1%). The authors found significant statistical differences with the results of the prothrombin time as expressed in activity percentage (p less than 0.001) in three plasma pools of patients under different oral anticoagulant level for all thromboplastins studied. However, if the results are expressed in terms of INR, the values obtained are almost the same. The results here reported would demonstrate that the prothrombin time as INR allows the use of only one scheme for oral anticoagulant control when the thromboplastin reagent is calibrated according to the recommendations of the WHO.

Administration, Oral↗

PubMed1986

A computer assisted method to obtain the prothrombin activation velocity in whole plasma independent of thrombin decay processes.

A method is described that, on the basis of the time course of amidolytic activity after the triggering of thrombin generation in normal plasma, allows the calculation of the velocity of prothrombin conversion independent of thrombin inactivating processes. It is shown how the reaction constants for the alpha 2M-dependent and the alpha 2M-independent thrombin inactivation processes can be obtained in a sample of whole plasma. The method is verified by demonstrating that the experimentally observed time courses of residual prothrombin and of alpha 2M-thrombin complex coincide with those calculated from the time course of amidolytic activity, and by showing that the course of prothrombin conversion in plasma without alpha 2-macroglobulin or AT III is adequately described if the alpha 2M or AT III-dependent breakdown constants are taken zero in the calculations. It appears that the inactivation of thrombin, endogenously generated in whole plasma, is about half as fast as that of exogenous thrombin added to the plasma. A computer program is presented that carries out the relevant calculations.

Brain↗

PubMed1988

Functional characterization of thrombin Salakta: an abnormal thrombin derived from a human prothrombin variant.

The genetic variant prothrombin Salakta has been described in a patient presenting with a normal level of prothrombin antigen but reduced prothrombin activity. Initial studies indicated that factor Xa-catalyzed cleavages proceed normally but lead to the production of a thrombin molecule with an altered enzymatic activity. To characterize the functional abnormality of thrombin Salakta more precisely, it was purified by chromatography on heparin-Sepharose and diethylaminoethyl-Sephadex. The purified variant does not differ from normal thrombin by size, as judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and is 93.1% +/- 7.6% active by titration with p-nitrophenyl-p'-guanidinobenzoate. Its activity, however, is altered to various extents toward the following substrates: H-D-phenylalanyl-L-pipecolyl-L-arginine paranitroanilide (S 2238), fibrinogen, factor V, protein C, and antithrombin III. The Michaelis constant (Km) of thrombin Salakta for S 2238 is higher (12.2 +/- 3.3 mumol/L) than normal (2.8 +/- 0.7 mumol/L), whereas the turnover number (Kcat) is normal (84.4 +/- 6.6 s-1 v 85.9 +/- 14.0 s-1 for normal thrombin). The interaction of thrombin Salakta with benzamidine is also altered as evidenced by an increased inhibition constant (Ki = 3.5 mmol/L v 0.28 mmol/L for normal thrombin). The inability of fibrinogen to act as a competitor in the inactivation of thrombin Salakta by diisopropylfluorophosphate clearly indicates that fibrinogen binding to the fibrinopeptide groove is drastically impaired. In contrast, interactions involving sites remote from the active site such as those with fibrin and thrombomodulin are only slightly impaired. These results indicate that thrombin Salakta exhibits a specific pattern of functional alterations different from those reported for other variants. The structural defect seems to affect essentially the primary substrate binding site and to a lesser extent recognition site(s) remote from the catalytic site such as those for fibrin and thrombomodulin.

Catalysis↗

PubMed1986

Immunological evidence for prothrombin in human platelets.

An attempt was made to isolate from plasma the platelet surface substrate for thrombin, glycoprotein V (GPV), because a GPV antigen was reported to be present in plasma. Plasma fractionation based on procedures for purification of GPV from platelets revealed a thrombin-sensitive protein with appropriate electrophoretic mobility. The protein was purified; an antiserum against it reacted with detergent-solubilized platelet proteins or secreted proteins in a double diffusion assay, adsorbed a protein from the supernatant solution of activated platelets, and inhibited thrombin-induced platelet activation, but the antiserum did not adsorb labeled GPV. The purified protein was immunochemically related to prothrombin rather than to GPV. Other antibodies against prothrombin were also able to adsorb a protein from platelets. It is concluded that plasma does not contain appreciable amounts of GPV, and platelets contain prothrombin or an immunochemically similar protein.

Blood Platelets↗

PubMed1987

Mg(II) binding by bovine prothrombin fragment 1 via equilibrium dialysis and the relative roles of Mg(II) and Ca(II) in blood coagulation.

The first direct equilibrium dialysis titration of the blood coagulation protein bovine prothrombin fragment 1 with Mg(II) is presented. Fragment 1 has fewer thermodynamic binding sites for Mg(II) than Ca(II), less overall binding affinity, and significantly less cooperativity. Several nonlinear curve fitting models were tested for describing the binding of fragment 1 with Mg(II), Ca(II), and mixed metal binding data. The Mg(II) data is represented by essentially five equivalent, noninteracting sites; for Ca(II), a model with three tight, cooperative sites and four "loose", equal affinity, noninteracting sites provides the best model. Based on the reported equilibrium dialysis data and in conjunction with other experimental data, a model for the binding of Ca(II) and Mg(II) to bovine prothrombin fragment 1 is proposed. The key difference between the binding of these divalent ions is that Ca(II) apparently causes a specific conformational change reflected by the cooperativity observed in the Ca(II) titration. The binding of Ca(II) ions to the three tight, cooperative sites establishes a conformation that is essential for phospholipid X Ca(II) X protein binding. The filling of the loose sites with Ca(II) ions leads to charge reduction and subsequent phospholipid X Ca(II) X protein complex interaction. Binding of Mg(II) to bovine prothrombin fragment 1 does not yield a complex with the necessary phospholipid-binding conformation. However, Mg(II) is apparently capable of stabilizing the Ca(II) conformation as is observed in the mixed metal ion binding data and the synergism in thrombin formation.

Animals↗