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PubMed2004

A C677T methylenetetrahydrofolate reductase (MTHFR) polymorphism and G20210A mutation in the prothrombin gene of sickle cell anemia patients from Northeast Brazil.

The C677T methylenetetrahydrofolate reductase (MTHFR) gene polymorphism and the G20210A mutation at the 3' untranslated region (3'UTR) of the prothrombin gene may be considered to be genetic risk factors that contribute to the clinical heterogeneity in sickle cell disease. The current study investigated a group of sickle cell (SS) patients from Salvador-Bahia, Northeast Brazil in order to determine the prevalence of these polymorphisms, using the polymerase chain reaction (PCR) and restriction fragment length polymorphim (RFLP) techniques. Out of 69 SS patients diagnosed with the C677T MTHFR gene polymorphism, 13 (18.6%) were heterozygous and four (5.7%) homozygous. The G20210A mutation was not found in 50 SS patients investigated. These results became important once the C677T MTHFR gene polymorphism was found to be an independent risk factor for vascular disease, a common clinical event in sickle cell disease.

3' Untranslated Regions↗
PubMed2002

Rapid automated simultaneous screening of (G1691A) Factor V, (G20210A) prothrombin, and (C677T) methylenetetrahydrofolate reductase variants by multiplex PCR using fluorescence scanning technology.

The Factor V Leiden mutation (G1691A), and mutations in the prothrombin (G20210A) and 5,10-methylenetetrahydrofolate reductase (C677T) genes are common hereditary risk factors associated with venous thrombosis. The aim of this study was to develop an automated, PCR-based genotyping assay for rapid simultaneous screening of these three mutations. We adapted multiplex PCR, using primer modifications to introduce cleavage sites for restriction endonucleases into the fragments bearing each of the mutations. The three mutations were analyzed in a single tube by fluorescence scanning. An internal digestion control was introduced to prevent false-negative results due to incomplete digestion or a total lack of digestion. DNA fragment analysis was carried out using an automated capillary electrophoresis instrument (ABI310). This reliable, efficient, easy-to-use assay can be applied to specimens from large clinical trials and epidemiological surveys.

Factor V↗
PubMed2003

Homocysteine and prothrombin fragment 1+2 levels in patients with veno-occlusive disease after stem cell transplantation.

Veno-occlusive disease (VOD) of the liver remains a major complication after hematopoietic stem cell transplantation (SCT). VOD is thought to develop after hepatic endothelial cells are damaged by high-dose chemotherapy or radiation, causing microthrombosis in hepatic venules. However, the precise mechanisms leading to VOD are not well defined, and a diagnosis is often difficult to establish. It is also difficult to predict which patients are most likely to develop VOD. Elevated levels of homocysteine (HC) have been associated with thrombosis, and prothrombin fragment 1 + 2 (F1 + 2) is a measurable marker for coagulation. Therefore, we performed a prospective cohort study to determine if HC or F1 + 2 levels could be used to predict the development of VOD prior to SCT, or to help establish a diagnosis of VOD in association with other clinical parameters. Plasma levels of these factors were measured before conditioning and serially for 21 days after SCT in 42 consecutive patients undergoing SCT. Eleven of 26 allogeneic SCT recipients developed VOD, whereas no autologous SCT recipient (n = 16) developed VOD (p = 0.008). In patients who developed VOD, HC levels were consistently higher than those seen in non-VOD patients after day 7 of SCT. Patients with VOD also had higher levels of F1 + 2 after SCT, although this marker was less consistently elevated over time. A logistic regression model that evaluated all serial measures of HC and F1 + 2 showed a moderate sensitivity and specificity in diagnosing VOD in allogeneic SCT patients, but neither marker was useful to predict development of VOD when tested prior to SCT.

Adult↗
PubMed2005

A potent inhibitor of prothrombin gene expression as a result of standardized target site selection and design of antisense oligonucleotides.

The development of antisense oligonucleotides (AS-ODN) always had the limitation that because of complex mRNA secondary structures, not every designed AS-ODN inhibited the expression of its target. There have been many investigations to overcome this problem in the last few years. This produced a great deal of theoretical and empirical findings about characteristics of effective AS-ODNs in respect to their target regions but no standardized selection procedure of AS-ODN target regions within a given mRNA or standardized design of AS-ODNs against a specific target region. We present here a standardized method based on secondary structure prediction for target site selection and AS-ODN design, followed by validation of the antisense effect caused by our predicted AS-ODNs in cell culture. The combination of theoretical design and experimental selection procedure led to an AS-ODN that efficiently and specifically reduces prothrombin mRNA and antigen.

Cell Line, Tumor↗
PubMed1981

Effect of vitamin E on prothrombin levels in warfarin-induced vitamin K deficiency.

Rats rendered lightly vitamin K deficient with warfarin (0.01 mg/100 g, IP) and given the equivalent of 1000 units of vitamin E/kg IM for 7 days, showed a marked reduction in functional factor II activity, but normal factor II levels using Echis venom on coagulation analysis. In 12 humans receiving warfarin, vitamin E was administered in doses of 100 or 400 units/day orally for 4 wk. The results in these patients showed no significant change in the prothrombin time, factor II coagulant activity, or factor II antigen (by electroimmunoassay). However, by using a ratio of factor II coagulant activity to immunoreactive protein, significant reduction was observed when compared to pretreatment ratios. These data suggest that vitamin E acts at the step mediated by vitamin K and not in the synthesis of the factor II precursor. Although the administration of high doses of vitamin E in animals, and possibly humans, with vitamin K deficiency potentiates the vitamin K deficiency, this effect is not clinically obvious with 400 IU/day or less.

Adult↗
PubMed1993

Paradoxic effect of multiple mild coagulation factor deficiencies on the prothrombin time and activated partial thromboplastin time.

Single coagulation factor deficiencies predictably prolong the prothrombin time (PT) and activated partial thromboplastin time (APTT) at levels below 35% of normal activity. Acquired coagulopathies generally are characterized by multiple coagulation factor deficiencies. The effect was studied of such combined deficiencies on the PT/APTT using plasma from patients congenitally deficient in specific factors and pooled normal plasma. The PT begins to lengthen when individual factor levels fall below 25%. The APTT becomes prolonged when the levels of Factor V fall below 45%; the levels of Factors II and XI fall below 40%; and the levels of Factors I, V, VII, VIII, IX, and XII fall below 25% of normal. When plasma samples containing 50% activity of a single factor and 100% of all other factors were prepared by mixing the congenitally deficient plasma samples with the normal pool, the resulting mixtures had normal PT and APTT values. However, when two of these 50% factor-deficient plasmas were combined so that the mixture contained 75% activity of two coagulation factors and 100% of all other factors, the resulting PT and APTT were prolonged over the clotting times of either 50% factor-deficient plasma. Similar findings were obtained in patients with mild factor reductions caused by warfarin treatment. These data indicate that prolongations of the PT and APTT in disorders of coagulation affecting multiple factors represent less of a reduction in factor levels than is generally appreciated. This may explain the poor clinical correlation between abnormalities in these test results and clinical bleeding in acquired disorders of hemostasis.

Blood Coagulation Factors↗
PubMed1994

Use of lyophilized calibration plasmas and control blood for international normalized ratio calculation in external quality assessment of the prothrombin time.

In the Netherlands, most anticoagulant clinics (thrombosis centers) use the reagent Thrombotest with citrated venous blood for laboratory control of oral anticoagulant therapy. In a national external quality assessment scheme, artificial control blood samples were mailed to 160 participants. Each participant returned prothrombin times and international normalized ratio (INR) values for these blood samples. The author investigated whether local calibration with lyophilized plasmas could reduce the interlaboratory variation of the INR. Five lyophilized plasmas were mailed along with the control blood samples. Using a local calibration line determined with the lyophilized plasmas, the interlaboratory variation of INRs determined routinely could be reduced slightly from 5.8% to 7% coefficient of variation (CV) to 5.3% to 6.5% CV. In contrast, when a local calibration line was determined with four similar control blood samples, the interlaboratory variation of the INR was reduced substantially to 2.5% CV.

Calibration↗
PubMed1994

The influence of the reference mean prothrombin time on the international normalized ratio.

The International Normalized Ratio (INR) is a mathematical transformation of the prothrombin time (PT). The transformation requires a laboratory to compute the geometric mean of its own reference population. In this paper, the authors examine how the reference mean PT influences the INR accuracy and precision using a validated probabilistic model. The variance of the geometric mean of reference populations in three laboratory settings was determined. Because the variance of an individual laboratory geometric mean is not directly determinable by simple parametric equations, its variance is estimated using bootstrap analysis. The geometric mean is compared to the computationally simpler arithmetic mean for effects on accuracy and precision of the resulting INR. The study shows mathematically and empirically that using the arithmetic mean biases INR determinations so that patients tend to be over-anticoagulated. However, in the laboratory settings examined, the amount of bias was both statistically and clinically insignificant. An analysis of the effect on the INR of errors in estimating the geometric mean reference PT also is performed. For large biases in estimating the reference mean, the INR can be significantly affected and can trigger inappropriate clinical actions in patients. The authors demonstrate empirically and mathematically that biases in the geometric mean reference PT do not affect the INR coefficient of variation. However, they produce significant differences in confidence intervals for INR determinations. Laboratories must exercise care in determining specific reference means to ensure that biases do not occur in geometric mean reference PT determinations. This can be achieved by circumspection in the selection of normal subjects for the reference population, carefully reviewing the data, and performing the proper calculations on the data.

Female↗
PubMed1997

Prothrombin time and activated partial thromboplastin time can be performed on the first tube.

The current practice standard for coagulation studies on venous blood specifies the use of the second (or subsequent) tube for testing. Unless other tests are ordered, the first tube is discarded. This practice, derived from early experience using nondisposable materials, gained support from a report based on modern phlebotomy methods but inexperienced phlebotomists. For our study, paired blood specimens were collected by experienced phlebotomists from 175 outpatients whose physicians had ordered coagulation tests. Prothrombin time (PT) and activated partial thromboplastin time (APTT) were performed on the first and second tubes. Similar values were obtained for PT and APTT. (PT: n = 174; mean = 15.36 seconds; mean difference = 0.10 seconds; y = 1.02x - 0.28; t = 0.24; P>.81; r = 0.995; APTT: n = 160; mean = 38.25 seconds; mean difference = 0.48 seconds; y = 1.03x - 0.71; t = 0.25; P=.80; r = 0.993.) For coagulation tests on specimens collected by experienced phlebotomists, the first tube yields accurate results and need not be discarded.

Blood Coagulation Tests↗
PubMed1998

Prolonged prothrombin time and activated partial thromboplastin time due to underfilled specimen tubes with 109 mmol/L (3.2%) citrate anticoagulant.

Underfilling of specimen tubes containing 129 mmol/L (3.8%) buffered citrate prolongs prothrombin time (PT) and activated partial thromboplastin time (APTT) values. We studied this phenomenon by using 109 mmol/L (3.2%) buffered citrate as the anticoagulant, anticipating some increase in tolerance to underfilling. Venous blood drawn from 12 healthy subjects and 30 patients receiving long-term oral warfarin therapy was mixed with 109 mmol/L buffered citrate solution in proportions equivalent to filling the collection tubes from 52% to 100% of capacity. Accurate PT values were obtained from normal specimens if the tubes were filled to 65% or more of capacity. Accurate PT results in the therapeutic range were obtained only with filling to 80% or more of capacity (using a "moderately sensitive" thromboplastin reagent, International Sensitivity Index [ISI] = 2.06) or 90% or more of capacity (using a "highly sensitive" thromboplastin reagent, ISI = 1.01). In contrast, APTT was much less tolerant to underfilling, with prolonged values observed in most specimens filled to less than 90% of capacity. No false low values were observed. Specimen tubes should be filled to at least 90% of capacity to avoid falsely elevated PT or APTT results, but values within the reference range may be acceptable even from underfilled tubes.

Adult↗
PubMed1982

Prothrombin antigen evaluation by means of laser nephelometry in health and disease.

Prothrombin antigen concentration was evaluated by means of laser nephelometry in 10 patients on coumarin therapy, in 17 patients with cirrhosis of the liver, and in four patients with congenital hypo- or dysprothrombinemias. The average values obtained were 46.4, 37.7, and 35.6%, respectively, for anticoagulated, cirrhotic, and congenitally abnormal patients. These values correlated well with those obtained by means of electroimmunoassay (Laurell) and immunodiffusion (Mancini) methods. Similarly, satisfactory results were obtained in eight normal subjects. Multiple evaluations at different incubation times, also allowed the authors to construct kinetic curves of the interaction between antigen and antibody. However, an abnormal kinetic curve was demonstrated only for coumarin-treated patients.

Antigens↗
PubMed1984

Inhibition of the cold activation of Factor VII and the prothrombin time.

Normal whole blood, collected and stored in borosilicate or commercial siliconized borosilicate tubes at 4 degrees C, undergoes a time-dependent activation of Factor VII and a shortening of the prothrombin time (PT). Addition of inhibitors to Factor XII fragments (corn Hageman factor inhibitor, CHFI) or to activated Factor XII (Cytochrome-C) inhibited in a concentration-dependent way the cold-promoted activation of Factor VII and the shortening of the PT. When celite was added to whole blood in polypropylene tubes at 4 degrees C, Factor VII was activated and the PT shortened. Preincubation of celite with CHFI or Cytochrome-C prevented the activation of Factor XII and the subsequent activation of Factor VII and the PT. These studies demonstrate the importance of Factor XII in the cold activation of Factor VII and shortening of the PT and indicate that inhibitors to activated Factor XII or XII fragments are useful in inhibiting in vitro shortening of the PT. These findings suggest that the development of a collection tube that prevents contact activation also would inhibit adequately the cold-promoted activation of the PT and Factor VII.

Aprotinin↗
PubMed1986

A comprehensive evaluation of the performance of duplicate prothrombin time and activated partial thromboplastin time assays.

An evaluation of the performance of duplicate prothrombin time (PT) and activated partial thromboplastin time (aPTT) assays was undertaken to develop analytical duplicate performance criteria in order to quantitate the risks associated with singlet versus duplicate procedures. Data were retrospectively collected from two hospital laboratories using two different coagulation systems. Included in the study were 6,391 patient samples; 3,047 PT, 3,334 aPTT, for a total of 12,782 data points. If a difference between duplicates of 5% or less is deemed analytically (or clinically) insignificant for PT, then fewer than 1% of the samples analyzed by either laboratory would require duplicates. If a difference between duplicates of 15% or less is deemed analytically (or clinically) insignificant for aPTT, then fewer than 2% of samples would exceed this limit for laboratory A, but 6.0% of samples from laboratory B exceeded this limit.

Blood Coagulation Tests↗
PubMed1987

A novel whole blood capillary technic for measuring the prothrombin time.

The prothrombin time (PT) is frequently performed to monitor anticoagulant therapy. Although relatively simple to perform, it requires venipuncture and laboratory resources for sample handling and analysis. A recently developed capillary whole blood device that uses fingerstick samples was evaluated. Paired capillary whole blood and reference plasma PTs were performed in 858 samples from 732 subjects. The PT for normal volunteers (n = 193) was 11.8 +/- 0.9 seconds with the use of the new instrument and 12.1 +/- 0.5 seconds with the use of the reference method. In samples from 539 patients receiving anticoagulants, the correlation coefficient between the two methods was 0.96. Venous whole blood without anticoagulant and capillary whole blood gave equivalent results, which suggests that the fingersticks do not effect the quality of the specimen. Variation in hematocrit between 23.4% (0.34) and 53.8% (0.538) did not alter the performance of the instrument. The new instrument is easy to use and may allow testing by nonlaboratory personnel and patients. It obviates the need for venipuncture, provides immediate results, and appears to be comparable in accuracy to current reference methods.

Anticoagulants↗
PubMed1989

Special report: a simple system for the derivation of International Normalized Ratios for the reporting of prothrombin time results with North American thromboplastin reagents.

The World Health Organization international scale of reporting prothrombin time results is based on the calibration of thromboplastins against an international reference preparation to derive an International Sensitivity Index (ISI). Once the ISI has been assigned to an individual thromboplastin reagent, the derivation of International Normalised Ratios (INRs) for reporting results depends on mathematic formulae requiring a special calculator or mathematic tables. This causes difficulties and errors. A simplified system for interpretation of INRs with the range of thromboplastins widely used in North America is therefore presented, which obviates the need for mathematic procedures for the derivation of INR equivalents. It should thus facilitate the application of the INR system and of safer therapeutic ranges.

Calibration↗
PubMed1989

Comparison of two automated coagulometers and the manual tilt-tube method for the determination of prothrombin time.

Two automatic coagulometers--ACL 810 (Instrumentation Laboratory), a laser-nephelometric centrifugal analyzer, and KoaguLab 40 A (Ortho Diagnostics), an optical automatic coagulometer--were compared with the manual tilt-tube method for the performance of prothrombin time (PT). Seven ISI- (International Sensitivity Index) calibrated commercial thromboplastin reagents were used for duplicate determinations in 30 normal subjects, 30 patients with liver disease, and 30 patients receiving stabilized oral anticoagulation. Clotting times were longer with the manual method than with ACL 810 and, to a lesser extent, with KoaguLab 40 A. Average imprecision of duplicate determinations (CV) was less than 1% with ACL 810; KoaguLab 40 A and the manual method had similarly higher imprecisions (2.8% and 2.7%). Differences in origin and slope of the regression curves of clotting times obtained with the coagulometers over the tilt-tube method were observed with all the reagents tested. Transformation of clotting times to PT ratios did not eliminate the bias resulting from the different clot-detection methods. A higher percentage of patients with liver disease had abnormal PT ratios when their plasma was tested with the coagulometers than with the manual method. Transformation of PT ratios to International Normalized Ratios effectively eliminated the bias resulting from the different thromboplastin reagents but had no effect on the bias resulting from the different clot-detection methods. A significant proportion of patients appeared excessively anticoagulated (INR greater than 4.5) with the coagulometers but not with the manual method. These results highlight the need for standardization of both instrumentations and reagents to improve monitoring of oral anticoagulant treatment.

Anticoagulants↗
PubMed2006

Effect of Factor V Leiden and prothrombin G20210-->A mutations on thromboembolic risk in the national surgical adjuvant breast and bowel project breast cancer prevention trial.

BACKGROUND: In the National Surgical Adjuvant Breast and Bowel Project's Breast Cancer Prevention Project (BCPT), tamoxifen use was associated with an increased relative risk for venous thromboembolic events, including deep vein thrombosis and pulmonary emboli, compared with placebo. However, the involvement of hypercoagulability factors in this association is unclear. METHODS: To examine possible associations among the risk of venous thromboembolic events, tamoxifen use, and Factor V Leiden (FVL) and prothrombin G20210-->A (PT20210) mutations, which are involved in promoting blood coagulation, we used a nested, matched, case-control (1 : 4) design and compared women in the BCPT who had experienced venous thromboembolic events (n = 76) with women who did not (n = 295). FVL and PT20210 mutations were detected in genomic DNA that was isolated from blood samples collected at trial enrollment. RESULTS: Venous thromboembolic events occurred in 28 women (deep vein thrombosis in 22 and pulmonary emboli in six) who were taking placebo and in 53 women (deep vein thrombosis in 35 and pulmonary emboli in 18) who were taking tamoxifen (relative risk = 1.90, 95% confidence interval = 1.18 to 3.12). Excessive risk for venous thromboembolic events was observed only in the first 36 months of therapy. There were no differences in age, smoking, and race between the groups, but women with venous thromboembolic events had a higher body mass index than women without (mean +/- standard deviation, 30 kg/m(2) +/- 7.7 versus 27.1 +/- 5.6; P<.001). FVL and/or PT20210 mutations were found in nine women (four on tamoxifen and five on placebo) with venous thromboembolic events and in 20 control subjects (nine on tamoxifen and 11 on placebo). No associations were found between risk of venous thromboembolic events and mutation status in either treatment group. CONCLUSIONS: Venous thromboembolic disease in the BCPT women is associated with tamoxifen use and body mass index, but not with FVL and PT20210 mutations. Screening women at risk for breast cancer for FVL and/or PT20210 appears to offer no benefit in determining the risk of tamoxifen-associated thromboembolic events.

Adenine↗
PubMed1979

A new method for purification of staphylocoagulase by a bovine prothrombin-Sepharose column.

Staphylocoagulase was isolated from a culture filtrate of Staphylococcus aureus, strain st-213, by a two step purification procedure of chromatography on a bovine prothrombin-Sepharose 4B affinity column and gel filtration on Sephadex G-25. The yield of the coagulase activity ranged from 75--83% and the purified preparation gave a single precipitin line in immunodiffusion tests against anti-crude and anti-purified staphylocoagulase sera. However, the final product was shown to contain one major and two minor components by sodium dodecyl sulfate polyacrylamide gel electrophoresis. Chemical analysis of the material indicated that it does not contain any cystine residues and that its NH2-terminal residue is a single isoleucine.

Amino Acids↗