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PubMed2006

Urgent reversal of warfarin with prothrombin complex concentrate.

BACKGROUND: When life-threatening bleeding occurs in patients on warfarin, timely reversal becomes imperative. In the USA, warfarin effect is commonly reversed with fresh frozen plasma (FFP). The use of FFP is complicated by delays in correction, volume overload and often, inadequate correction. OBJECTIVE: Evaluate the feasibility and efficacy of a protocol for rapid administration of prothrombin complex concentrate (PCC) in the setting of the urgent need for reversal of warfarin. METHODS/PATIENTS: We instituted a policy for rapid delivery and administration of PCC. Appropriate patients received 25-50 U kg(-1) of PCC. The prothrombin time (PT)/International Normalized Ratios (INR) was recorded before and immediately after dosing, and 24 h postdosing. Patients requiring surgical interventions were cleared for the operating room (OR) immediately. Fifty-eight patients were treated, with a median age of 75.5 years (range 26-92). RESULTS: The median INR on presentation was 3.8 (1.4-52.8). Immediately following PCC administration the median INR was 1.3 (0.9-5.7), only two patients with INRs exceeding 2.0. The benefit was maintained at 24 h with a median INR of 1.5 (1.1-3.4). Four patients experienced thrombotic events during their hospitalization, (two deep vein thrombosis, two non-q-wave myocardial infarction) although none was attributed to PPC therapy. CONCLUSIONS: PCC administration is an effective treatment modality for the correction of warfarin anticoagulation in the urgent setting. Advantages over FFP include more timely correction, absence of volume overload and potentially more complete correction. Broader use of PCC in this setting appears to be appropriate.

Adult↗
PubMed2006

The prothrombin 20209 C-->T mutation in Jewish-Moroccan Caucasians: molecular analysis of gain-of-function of 3' end processing.

BACKGROUND: Mutations of the 3' end mRNA-processing signal of the prothrombin (F2) gene have been reported to cause elevated F2 plasma concentrations, thrombosis, and complications of pregnancy. Whereas the common F2 20210*A mutation is almost exclusively found in Caucasians, the F2 20209*T mutation has been reported in Afro-Americans and Afro-Caribbeans only. PATIENTS AND METHODS: Using LightCycler technology, three unrelated Jewish-Moroccan patients tested for obstetric complications were found to be carriers of the F2 20209*T allele. A detailed molecular analysis was performed to identify the functional impact of this mutation. RESULTS: We report three unrelated women of Jewish-Moroccan origin with a F2 20209*T mutation and fetal loss or infertility. The functional analysis revealed that the F2 20209*T mutation stimulates 3' end processing and up-regulates prothrombin protein expression as assessed by a highly sensitive luminescence-based reporter system. CONCLUSIONS: This is the first report of 20209*T in Caucasians, and functional analysis demonstrates that F2 20209*T falls into a general category of mutations of the F2 gene, which may possibly contribute to thrombophilia and complications of pregnancy by interfering with a tightly balanced architecture of non-canonical F2 3' end formation signals.

Adult↗
PubMed2005

Association of prothrombin gene mutation with sepsis in a preterm with multiple intracardiac thrombi.

We report for the first time, a premature infant with multiple intracardiac thrombi and sepsis, who was heterozygous for the G20210A prothrombin gene variant. Anticoagulant treatment with low molecular weight heparin resulted in the complete disappearance of the thrombi. It may be suggested that prothrombin gene variant associated with sepsis, respiratory distress syndrome, and perinatal asphyxia, as well as other thrombophilic disorders, could be a risk factor for the development of neonatal thrombus.

Disease Progression↗
PubMed1980

Delirium tremens: some clinico-chemical features. A study of alanine-aminotransferase, alcaline phosphatase, prothrombine and enolase.

The relationship between variables reflecting liver disease (serum-alanine-aminotransferase (SGPT), serum alcaline phosphatase and plasma prothrombine) and the clinical signs and symptoms during delirium tremens (DT; grade 3) and related clinical states (grade 2) was studied. Furthermore, it was investigated whether the two isoenzymes of enolase which predominante in brain tissue were present in plasma or cerebrospinal fluid (CSF) in DT patients. A correlation between SGPT and clinical state was not observed, which indicates that a causal relationship does not exist between acute liver cell damage and clinical state during DT of grade 3 or 2. In grade 2 patients, but not in grade 3 patients, both SGPT and serum alcaline phosphatase decreased between admission and recovery. This difference between the groups may be due to a higher alcohol consumption and a shorter interval between last drink and admission in grade 3. The difference in recent drinking history may also account for the finding of a higher plasma prothrombine index in grade 3 compared with grade 2, because chronic ethanol intoxication may be accompanied by enhanced hepatic protein synthesis. "Brain-enolase" was not present in detectable amounts in blood or CSF during DT thus suggesting that brain cell damage resulting in leakage of this enzyme from the cells did not prevail during DT.

Alanine Transaminase↗
PubMed2005

Prothrombin and intraventricular haemorrhage.

UNLABELLED: In the study by Salonvaara et al., low prothrombin activity in preterm infants was associated with intraventricular haemorrhage (IVH). The interesting research question-do preterm infants who develop IVH have underlying coagulation disturbance?-could not be answered in this study. CONCLUSION: The association needs further investigation. The role of prothrombin in perinatal brain damage in the development of IVH and of white matter damage has to be further elucidated.

Cerebral Hemorrhage↗
PubMed1980

The biosynthesis of bovine fibrinogen, prothrombin, and albumin in a cell-free system.

Preparative amounts of poly A-containing mRNA were isolated from bovine liver. In the presence of a cell-free system from rabbit reticulocytes, this mRNA stimulated the synthesis of a number of plasma proteins including albumin, fibrinogen, prothrombin, and antithrombin III. Automatic Edman degradation of immunoprecipitated albumin showed that this protein was synthesized as preproalbumin containing an NH2-terminal extension of 18 amino acid residues. Prothrombin is also synthesized as a precursor (preprothrombin), and the signal sequence for this protein is also rich in hydrophobic amino acids. The three chains of fibrinogen are synthesized from individual mRNAs, which are then linked by disulfide bonds to form the mature protein.

Amino Acid Sequence↗
PubMed1980

Prothrombin activation by a metalloprotease from Staphylococcus aureus.

Formation of thrombin during incubation of purified bovine prothrombin with purified staphylococcal metalloprotease has been investigated. Thrombin activity was estimated by examination of clotting time and by digestion of a synthetic substrate, Chromozym TH. The metalloprotease caused direct activation of prothrombin which was inhibited by the addition of ethylenediaminetetraacetic acid. Metalloprotease produced by some strains of Staphylococcus aureus may simulate staphylocoagulase activity.

Animals↗
PubMed2004

G20210A prothrombin gene polymorphism and coronary ischaemic syndromes: a phenotype-specific meta-analysis of 12 034 subjects.

OBJECTIVE: To investigate the possible link between the G20210A prothrombin gene variant and different forms of ischaemic heart disease. DESIGN: Phenotype-specific meta-analysis of 19 studies published within March 2002, globally including 4944 patients and 7090 controls. Sample size, inclusion criteria, geographical location, clinical presentation, age, cardiovascular risk factors, and angiographic extent of disease were extracted from each study. Analyses were done according to Mantel-Haenszel. RESULTS: Overall, the odds ratio (OR) for unspecified ischaemic heart disease associated with the 20210A allele was 1.21 (95% confidence interval (CI) 0.99 to 1.59, n = 12 034). Similar findings were seen for acute coronary syndromes (unstable angina and myocardial infarction) and for myocardial infarction without age limits (OR 1.24, 95% CI 0.98 to 1.63, n = 10 240; and OR 1.19, 95% CI 0.93 to 1.58, n = 9765). The effects were similar in male and female subjects. In the 1931 subjects < 55 years of age, the OR for myocardial infarction increased to 1.77 (95% CI 1.16 to 3.42) and in the 1359 subjects < 45 years to 2.30 (95% CI 1.27 to 4.59). No significant association was found between the 20210A allele and the presence of angiographically documented coronary disease (OR 1.08, 95% CI 0.70 to 1.64, n = 3444). However, patients with 0/1 vessel disease at angiography showed a greater prevalence of the A allele than those with multivessel disease (relative risk 2.0, 95% CI 1.2 to 3.1, n = 2376). CONCLUSIONS: G20210A prothrombin gene polymorphism may represent a modest but significant risk factor for myocardial infarction at young ages and favour the expression of ischaemic heart disease among individuals who have a limited extent of coronary atherosclerosis at angiography.

Adult↗
PubMed1970

Estimation of prothrombin in liver disease.

Prothrombin, both by a one- and a two-stage method, and progressive antithrombin were determined on the same plasma samples from 47 patients with cirrhosis and 27 patients with acute hepatitis. In the first group prothrombin estimated by the two-stage method was significantly higher than by the one-stage method. The values were often within the normal range and were not correlated with the indices of protein synthesis. Since progressive antithrombin was also depressed, the unduly high levels measured by the two-stage method are probably related to the influence exerted by antithrombin on the two-stage method. The opposite pattern was observed in patients with acute hepatitis, ie, the one-stage assay gave higher values than the two-stage assay. The one-stage method correlated better with the indices of protein synthesis. It is suggested that a one-stage assay should be used in patients with liver failure to evaluate the haemostatic balance before liver biopsy or surgery.

Antithrombins↗
PubMed1977

Comparison of anticoagulants for the preservation of prothrombin time specimens.

The value of different anticoagulants as preservatives of specimens for prothrombin time ratios is evaluated and discussed. An increase in the ratio was demonstrated with all anti-coagulants after 24 hours and this was significant when coagulometer error was taken into account. Both solid and liquid sodium citrate were superior to sodium oxalate as preservatives at 24 hours after taking off samples, but differences were slight and were not significant when coagulometer error was considered. It was concluded that for routine clinical practice, where a range of the prothrombin time ratio of 1.8/1 to 2.5/1 is allowable, there would be no significant advantage in any of the anticoagulants considered.

Anticoagulants↗
PubMed1981

Comparison of liquid and dried sodium citrate as the anticoagulant for Thrombotest and prothrombin time estimations.

Samples which are taken for the Quick one-stage prothrombin time estimation for the control of patients receiving oral anticoagulant treatment are by convention taken into liquid sodium citrate anticoagulant. Dried sodium citrate has been rejected on the grounds that excessive haemolysis causes activation of clotting factors and therefore falsely short clotting times. Tests were performed with both liquid and dried sodium citrate as an anticoagulant for prothrombin time and Thrombotest. No clinically significant difference between the values given by the two anticoagulants was observed.

Anticoagulants↗
PubMed1989

Effect of automation on prothrombin time test in NEQAS surveys.

The performance of coagulometers in the National Quality Assessment Scheme (NEQAS) surveys of the prothrombin time conducted between 1986 and 1987 was reviewed. There were sufficient data for analysis for eight types of coagulometer used with a single type of thromboplastin reagent and one instrument with an alternative reagent. The overall reliability efficacy of each instrument was evaluated by determining the orthogonal regression slope parameters for prothrombin time (PT) and international normalised ratios (INR) using the manual technique as the reference method. Seven of the eight types of coagulometer tended to overestimate the INR. A pattern frequently observed with coagulometers, and difficult to regulate, was a trend to underestimate INR below 3.0 and overestimate higher INR. Overestimation of INR values over 3.0 was particularly pronounced with three types of instrument (Fibrintimer, Lancer, KC4/10). The KC4/10 was used by a sufficient number of participants to permit analysis of the performance of individual instruments. Within instrument differences were similar to those produced by different types of coagulometers. Thromboplastin reagents affected the INR values obtained with coagulometers. The study indicates that each local reagent-instrument combination must be calibrated by the participant to obtain reliable INR values. The use of a general correction factor for a local PT system seems to be invalid owing to the considerable variation in performance of individual coagulometers. The two best guides to the choice of coagulometer may be the deviation from the manual result and precision estimated by the coefficient of variation of the INR.

Blood Coagulation Tests↗
PubMed1990

Automation and prothrombin time: a United Kingdom field study of two widely used coagulometers.

Current performance in the prothrombin time (PT) of the two main United Kingdom coagulometer/thromboplastin systems was assessed in a field survey. Twenty abnormal samples covering a wide spectrum of International Normalised Ratio (INR) were distributed to users of the KC4/KC10 and Coag-a-Mate instruments. Coagulometer results were compared with those of the manual method. A substantial minority with each system showed good agreement with the manual reference values. There was, however, a considerable variation between instruments, meaningful in clinical terms, evidenced by varying regression slopes and local system International Sensitivity Indices (ISI). For intense anticoagulation (3.0 to 4.5 INR) a larger dose of warfarin is needed with the Coag-a-Mate than with the KC instruments. With a manual INR of 4.0 the KC instruments tended to give longer PT (mean INR + 0.3); the Coag-a-Mate PT was generally shorter (mean INR -0.1). With both systems the mean normal PT were shorter than the manual but the degree of shortening did not parallel that of the abnormal samples. This effect undermines the use of a simple prothrombin ratio and of an INR value derived from it, based on a manual ISI. The use of a system related ISI cannot, however, be recommended until local instrument variables are controlled.

Blood Coagulation Tests↗
PubMed1998

Screening INR deviation of local prothrombin time systems.

AIM: To assess the reliability of local international normalised ratios (INR) using a set of three international reference preparation (IRP) certified freeze dried plasmas. METHODS: 55 centres in the United Kingdom and the Republic of Ireland participated; 36 centres employed coagulometers and 19 a manual prothrombin time technique, all with the same batch of routine commercial thromboplastin. The plasmas had certified INR with the manual technique using a thromboplastin IRP, and results were provided graphically to participants for self assessment. An INR deviation of more than +/- 10% from the certified INR with any of the screening plasmas was regarded as unsatisfactory and clinically significant. Sets of 20 freeze dried plasmas were provided for local ISI calibrations and sets of seven freeze dried normals were provided for supplementary exercises where screening results were unsatisfactory. RESULTS: 15 of 38 coagulometers, but only three of the 19 manual prothrombin time test techniques, gave unsatisfactory results. With 10 of the 15 unsatisfactory coagulometer results the problem was resolved by local ISI calibrations with plasma calibrant sets provided. Unsatisfactory results with manual technique in all four instances were corrected by substitution of the mean result with freeze dried normal plasmas provided. CONCLUSIONS: The freeze dried plasma screening set was useful in detecting incorrect INR in a high proportion of coagulometer users and a smaller number of participants using the manual technique.

Calibration↗
PubMed1999

Mesenteric infarction due to combined protein C deficiency and prothrombin 20210 defects.

The prothrombin gene mutation, 20210A, a guanine to adenine substitution at nucleotide position 20210, has recently been described as an additional risk factor for venous thromboembolic disease. We describe the case of a patient with combined heterozygous prothrombin 20210A mutation and type 1 protein C deficiency who presented with massive mesenteric venous infarction of his small bowel and survived following the use of protein C concentrate and extensive small bowel resection.

Anticoagulants↗
PubMedDate not supplied

[Portal-splenic-mesenteric venous thrombosis secondary to a mutation of the prothrombin gene].

Thrombosis of the portal-mesenteric axis is an infrequent cause of intestinal ischemia or infarction. In addition to the multiple acquired factors that contribute to the development of this entity, hereditary risk factors, especially the factor V Leiden mutation and the G20210A mutation of the prothrombin gene, have been implicated. The G20210A mutation of the prothrombin gene is found in up to 40% of patients with splenic-portal-mesenteric thrombosis. The present case illustrates the unusual and nonspecific presentation of this mutation in the form of diarrhea and images of thrombosis of the superior mesenteric-portal vein and cavernous transformation of the portal vein. Delayed diagnosis is highly frequent since the clinical signs, laboratory investigations and radiological tests do not suggest the diagnosis. The patient received anticoagulant treatment and showed clinical improvement with complete portal-mesenteric recanalization. Currently the diagnostic technique of choice is magnetic resonance angiography or computerized tomography angiography and treatment consists of indefinite anticoagulation. This case illustrates that an unusual or atypical localization of venous thrombosis may be a manifestation of thrombophilia, emphasizing the importance of genetic screening in these cases.

3' Untranslated Regions↗
PubMed2000

Extensive thrombus formation in the right ventricle due to a rare combination of arrhythmogenic right ventricular cardiomyopathy and heterozygous prothrombin gene mutation G20210 A.

Arrhythmogenic right ventricular cardiomyopathy is a rare heart muscle disease characterized by right and often left ventricular myocardial atrophy and fibrofatty replacement. Heart failure, arrhythmias and sudden death are characteristic complications. We observed a female in whom arrhythmogenic right ventricular cardiomyopathy was diagnosed due to presyncopes and dyspnea on exertion. A left ventricular thrombus was found echocardiographically, which disappeared with oral anticoagulation. Subsequently, however, extensive thrombus formation in the dilated akinetic right ventricle occurred which was resistant to combined treatment with heparin and oral anticoagulation. Thrombophilia screening showed a mutant prothrombin 20210A allele which is an inherited coagulopathy associated with increased plasma levels of prothrombin and increased risks of mainly venous thrombosis. The patient developed endstage biventricular heart failure and underwent heart transplantation within 3 months after thrombus formation in the right ventricle was diagnosed. In the explanted heart, the thrombus in the right ventricle was impressively large and calcified. In patients with unusual thrombus formation in the heart, coagulopathy may be associated and should be excluded.

Adult↗
PubMedDate not supplied

Snake venom prothrombin activators homologous to blood coagulation factor Xa.

We have recently determined the complete amino acid sequence of trocarin, a group D prothrombin activator from the venom of Tropidechis carinatus (Australian rough-scaled snake). This proteinase is both functionally and structurally similar to mammalian blood coagulation factor Xa. It shows approximately 70% homology and possesses the characteristic Gla domain, two EGF domains and serine proteinase domain. To examine structure-function relationships, we generated a molecular model of trocarin based on a human factor Xa des-Gla crystal structure (1xka) as template. Based on known sites of interaction between mammalian factor Xa, factor Va and prothrombin, structure-function relationships of trocarin were explored. Unlike factor Xa, trocarin is glycosylated and has a large carbohydrate moiety at the entrance to its active site pocket. This might contribute to differences observed in the kinetics of hydrolysis of synthetic substrates by trocarin as compared to human factor Xa. A Ca(2+)-binding loop present in the heavy chain of factor Xa also seems to be lost in trocarin. In addition to its role in hemostasis, factor Xa shows other biological effects, including inflammation via its interaction with effector protease receptor-1 (EPR-1). Interestingly, the EPR-1 recognition site is distinctly different in trocarin, the functional consequences of which are being investigated.

Animals↗