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PubMed1980

[Study of present possibilities of interlaboratory standardisation of the prothrombin time (author's transl)].

The graphs or tables proposed by the manufacturer of reagents, the Thivolle straight lines suggested by Raby or, since 1977, Loeliger's procedure, are three possibilities offered to biologists to transform the prothrombin time into prothrombin concentrations expressed as a percentage. We have studied the possibility of interlaboratory standardisation in the case of patients treated with coumarin derivatives: firstly with the same thromboplastin under various conditions of use; secondly with five different thromboplastins under identical conditions (choosing arbitrarily one of the reagents as reference). Loeliger's procedure is the one which permits the best standardisation, but its practical application seems difficult. It seems to us that before carrying out this standardisation between laboratories, one should indicate, with the result found for the patient, the area of therapeutic activity of the thromboplastin used, as suggested by Ducker and Marbet in 1977 (these authors determined this area of therapeutic activity for 13 different reagents used in Switzerland).

Coumarins↗
PubMed1994

Effects of flupirtine coadministration on phenprocoumon plasma concentrations and prothrombin time.

The influence of flupirtine, a non-opioid, centrally acting analgesic agent on phenprocoumon plasma levels and protein binding as well as prolongation of prothrombin time has been investigated in 12 healthy male volunteers. Subjects received phenprocoumon 1.5 mg od over 28 days. From day 15 to 28 oral flupirtine 100mg tid was added. Phenprocoumon plasma levels and prothrombin time (Quick time), measured at trough before the morning drug intake, were chosen as primary pharmacokinetic and pharmacodynamic variables. In addition, phenprocoumon protein binding and the eudismic ratio of phenprocoumon were determined. The mean values from data obtained on day 12 to 15 (i.e. measurements under phenprocoumon alone) and the mean values from those data obtained from day 25 to 28 (i.e. under comedication with flupirtine) were subject to subsequent statistical procedures. Phenprocoumon plasma concentrations came to 1.38 +/- 0.28 micrograms/ml on day 12 to 15 and were not significantly altered under flupirtine coadministration with 1.48 +/- 0.36 micrograms/ml on day 25 to 28 (95% confidence interval: 1.02-1.11, point estimator: 1.06). The average Quick time came to 68 +/- 10% on day 12-15 and 73 +/- 15% on day 25-28. The nonparametric 95%-confidence interval for the ratio ranged between 0.96 and 1.14, the point estimator was determined to 1.04. Protein binding of phenprocoumon was determined to 88.8% +/- 0.5 on day 14 and to 88.9 +/- 0.5% on day 28. The ratio of S/R-phenprocoumon was 1:0.84 on day 14 and 1:0.84 on day 28. These results do not provide any evidence for a pharmacokinetic and/or pharmacodynamic interaction between flupirtine and phenprocoumon.

Administration, Oral↗
PubMed1995

International normalized ratio for prothrombin times in patients taking oral anticoagulants: critical difference and probability of significant change in consecutive measurements.

To determine when a change in serial measurements of prothrombin time in patients receiving oral anticoagulant therapy (ACT) is a statistically significant biological change necessitating dose adjustment, one must know the size of the "critical difference" in statistical terms (i.e., probabilities). In a cohort of 32 ACT patients at pharmacological steady-state, we studied the within-subject total variation of prothrombin time, expressed as International Normalized Ratio (INR), over 6 months. The total within-subject variation (CV) of INR was 10.1%. The corresponding critical differences required for significance of change in serial INR results was 0.7 at a therapeutic target of 2.5 INR and 1.0 at a therapeutic target of 3.5 INR. The data presented allow generation of objective criteria for monitoring ACT patients and deciding dose adjustments. We recommend that estimations of critical differences for significant change of INR in ACT patients should be based on results obtained in the specific clinic investigated to mirror the routine total variation of INR measurements they obtain.

Aged↗
PubMed1993

Risk factors of bleeding diathesis secondary to low prothrombin complex level in infants: a preliminary report.

Twenty infants aged 2 weeks to 3 months with the diagnosis of bleeding disorder secondary to low prothrombin complex level were studied. Sixty children of the control group were matched to the cases by age +/- 2 weeks, sex and race. The ratio of boys to girls was 2.3:1. The median, mean, and range of age of the cases and controls were 43.5 days, 43.7 days, 21-73 days and 43.5 days, 46.8 days, 26-28 days respectively. Most of them were pale with a mean hematocrit of 23.55%. The partial thromboplastin time and prothrombin time were markedly prolonged. The means of vitamin K dependent coagulation factors II, VII, IX and X were 1.10%, 5.87%, 2.86%, and 4.47% of adult activity, respectively. The clinical manifestations related to the bleeding of the cases were drowsiness and convulsion (95%), pallor (85%), and apparent bleeding (10%). The sites of the bleeding were demonstrated in the cranial cavity (95%), gastrointestinal tract and oral cavity (15%), and skin (5%). Nineteen patients with intracranial hemorrhage had bleeding in the subdural space (79%), intracerebral (42%), intraventricular (32%), and subarachnoid space (5.2%). The mortality rate and permanent brain damage occurred in 10% and 45%, respectively. Only 45% of the cases recovered normally. The permanent neurological sequelaes were hemiparesis (44.4%), microcephaly (33.3%), convulsive disorder (33.3%), mental retardation (33.3%), spasticity (22.2%), and hydrocephalus (11.1%). Breast feeding alone up to the day of study (OR = 7.0, p < 0.005) was found to be a significant risk factor for bleeding in these infants.(ABSTRACT TRUNCATED AT 250 WORDS)

Breast Feeding↗
PubMed1975

Amino acid sequence of a vitamin K-dependent Ca2+-binding peptide from bovine prothrombin.

The amino acid sequence of a 31-residue peptide from bovine prothrombin has been determined. This peptide has been shown to contain the vitamin K-dependent modification required for Ca2+ binding (Nelsestuen, G. L., and Suttie, J. W. (1973) Proc. Natl. Acad. Sci. U. S. A. 70, 3366-3370) and the modified amino acid, gamma-carboxyglutamic acid (Nelsestuen, G. L., Zytkovicz, T., and Howard, J. B. (1974) J. Biol. Chem. 249, 6347-6350). The peptide was shown to correspond to residues 12 to 42 of prothrombin.

Amino Acid Sequence↗
PubMed1993

Thrombin production, inactivation and expression during open heart surgery measured by assays for activation fragments including a new ELISA for prothrombin fragment F1 + 2.

Activation of coagulation was studied during the peri-operative period in patients undergoing cardiopulmonary bypass (CPB) surgery using activation markers which have recently become available: prothrombin fragment F1 + 2 (F1 + 2), which is a measure of total thrombin generation, and thrombin-antithrombin complex, which is a measure of inactivation of free thrombin by antithrombin. Levels of the specific marker of fibrin breakdown, D-dimer, were also determined. F1 + 2 levels were assessed using a newly developed ELISA described herein which employs a neoantigen-specific capture antibody raised using a synthetic peptide; the latter antibody has been pre-adsorbed against prothrombin to ensure high specificity for F1 + 2. Increased generation of thrombin during surgery was clearly demonstrated despite maintenance of a high concentration of heparin during the period of extracorporeal blood circulation. There was a close association (r = 0.882) between the generation of thrombin (F1 + 2 levels) and its inhibition (TAT levels). Differences were noted, however, between the information provided by F1 + 2 and TAT, which are interpreted with regard to the different in vivo fates of F1 + 2 and thrombin. The enhanced activation and inhibition of coagulation observed during CPB was suppressed once physiological blood circulation was restored, with F1 + 2 returning to pre-surgical levels within 24 h after surgery. During the post-operative period D-dimer levels, which rose in concert with F1 + 2 and TAT levels, remained highly elevated, suggesting that not all of the generated thrombin was inactivated by antithrombin.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1993

Evaluation of a new chromogenic substrate assay for the measurement of the prothrombin time.

The chromogenic prothrombin time assay Nycotest Chrom was evaluated and compared with another chromogenic assay (Chromoquick) and with the well-known coagulometric Thrombotest. The intra-assay variation of the test was satisfying both in the normal range (CV = 3.6%) and in the therapeutical range of oral anticoagulation (CV = 3.5%). These values were somewhat higher than those of the Chromoquick test (1.3% and 1.1%) and those of the Thrombotest (2.3% and 2.5%). The inter-assay variation coefficient amounted to 3.3% in the normal range and in the therapeutical oral anticoagulation range to 4.4%. The respective values for the Chromoquick test were somewhat lower (2.2% and 3.9%), those of the Thrombotest in the normal range were also lower (2.1%), and in the therapeutical range they were much higher (9.2%). The coefficients of correlation of the Nycotest Chrom test in the therapeutical range were highest when comparing them with those for the Chromoquick test (r = 0.97; p < 0.0001) and somewhat lower in comparison with the Thrombotest (r = 0.95; p < 0.0001). The results of the three methods paralleled also in the starting phase of oral anticoagulation treatment. Storage at 4 degrees C and at 25 degrees C showed good stability of the Nycotest Chrom reagent for up to 24h. We conclude that the Nycotest Chrom assay is well suited for the measurement with a centrifugal fast analyser, which is attractive on behalf of the usually large series of request for prothrombin time measurements when monitoring oral anticoagulation therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1993

International standardization of laboratory control of oral anticoagulant therapy: a survey of thromboplastin reagents used for prothrombin time testing.

The prothrombin time (PT) test is the primary measurement in the laboratory control of oral anticoagulant treatment. The traditional expression of PT test results, either as percentage prothrombin activity or PT ratio, is inadequate for international communication and comparison because the values depend on the nature of the thromboplastin test system used. The WHO recommended universal scale of reporting PT results is based on calibration of local thromboplastin systems against an international reference preparation. This scale is the International Normalized Ratio (INR). Application of the INR scale in clinical practice should be encouraged by External Quality Assessment (EQA) schemes, which improve its precision. Many physicians are insufficiently aware of the different sensitivities of rabbit thromboplastins, which result in different anticoagulation intensities being employed in different clinics. Improvement in the situation can only be achieved by continuous education. The more widespread use of the INR scale should facilitate international comparison of anticoagulation results and eventually consensus on optimal target values. The introduction of the INR to countries not already using it, particularly the USA, should be strongly encouraged by all physicians with an interest in anticoagulation and especially those undertaking the long-term management of patients with prosthetic heart valves.

Animals↗
PubMed1977

The activation of prothrombin complex concentrates by calcium in vitro.

The activation of prothrombin concentrate mixtures incubated "in vitro" was investigated. "Activation" was assessed by the correcting effect of suct mixtures on the APTT of a test plasma containing a factor VIII inhibitor and also by the generation of free thrombin. Thrombin itself was found to have insignificant activating effect. Prothrombin concentrates incubated with near-physiological levels of calcium appeared to correct the abnormal APTT to an increasing degree as the calcium concentration was increased. Free thrombin was generated with calcium cencentrations greater than those required for APTT correction. The activation process could be stopped at any stage by adding citrate which removed ionized calcium from the incubation mixture.

Blood Coagulation Tests↗
PubMed1996

Determination of prothrombin activation fragments in young patients with inflammatory bowel disease.

OBJECTIVE: To assess coagulation cascade activation as a potential index of thromboembolic risk in inflammatory bowel disease (IBD). STUDY DESIGN: Fifty plasma samples were obtained during consecutive outpatient encounters with 29 patients (male:female = 20:9) with either Crohn's disease (CD) (n = 23) or ulcerative colitis (UC) (n = 6). Disease activity for CD was determined using the Pediatric Crohn's Disease Activity Index (PCDAI) and for UC using signs/symptoms and mucosal histology. Patients were grouped as active, recently active (not currently active but had been active within the previous 2 months), or inactive. Prothrombin fragment 1.2 (F1.2) was determined by enzyme-linked immunosorbent assay on plasma samples. Lab parameters were compared using the Kruskal-Wallis test with pairwise comparisons made using Wilcoxian rank sum test. RESULTS: Forty-three percent of samples taken during active phases of disease (13 of 30) had elevated prothrombin cleavage byproduct F1.2. Similarly, five of eight encounters (63%) with recently active IBD had elevated F1.2 values. In contrast, none of the patients with inactive disease exhibited F1.2 elevation. Median F1.2 levels in both the active (0.85 nM/L) and recently active (1.4 nM/L) patient groups were greater than that of the inactive group (0.6 nM/L; p < 0.05). CONCLUSIONS: Evidence of coagulation cascade activation in patients with active and recently active IBD suggests an increased risk of thrombogenesis during active disease that extends for a period of time after commencement of medications to induce remission in their disease process. It may be prudent to counsel patients to avoid risk factors associated with thrombotic phenomenon around the time of active IBD.

Adolescent↗
PubMed1996

Antibodies to prothrombin imply a risk of myocardial infarction in middle-aged men.

Antiphospholipid antibodies in patients with "antiphospholipid syndrome" may be directed at least in part against plasma phospholipid-binding proteins, such as beta 2-glycoprotein I or prothrombin, which are involved in the control of thrombosis and haemostasis. IgG-class antibodies against prothrombin and beta 2-glycoprotein I were measured by enzyme-linked immunoassay in initially healthy middle-aged dyslipidaemic men (non-high-density lipoprotein > 5.2 mml/l). Serum samples had been drawn at entry to a 5-year coronary primary-prevention trial with gemfibrozil from 106 subjects who experienced either a non-fatal myocardial infarction or cardiac death during the follow-up and from 106 subjects without coronary episodes, matched for treatment group (gemfibrozil/placebo) and geographical area. The antiprothrombin antibody level, as expressed in optical density units, was significantly higher in patients than in controls (0.26 +/- 0.17 versus 0.22 +/- 0.09; p < 0.02). A high level of antiprothrombin antibodies (highest tertile of distribution) predicted a 2.5-fold increase in the risk (95% confidence interval 1.2-5.3) of myocardial infarction or cardiac death. The distribution of IgG-class antibodies against beta 2-glycoprotein I did not differ significantly between cases and controls. The joint effect of antiprothrombin antibodies and other factors associated with hypercoagulative state: triglyceride level, lipoprotein(a) and smoking, was multiplicative for the risk. Antiprothrombin antibodies are a new immunological predictor of myocardial infarction and the effect of these antibodies may be mediated by hypercoagulative mechanisms.

Apolipoproteins↗
PubMed1997

Impaired prothrombin consumption in Bernard-Soulier syndrome is corrected in vitro by human factor VIII.

The Bernard-Soulier syndrome (BSS) is characterized by thrombocytopenia with giant platelets, a prolonged bleeding time with defective platelet adhesion to the subendothelium related to a defect in platelet membrane glycoprotein Ib (GPIb) and a decreased prothrombin consumption. The mechanism of the latter abnormality remains unknown. In this study, we showed that this defect was corrected by the addition of purified human factor VIII (FVIII) to blood from four patients with BSS. The correction of prothrombin consumption was almost complete at concentrations between 1.5 and 3 IU/ml of FVIII procoagulant activity (VIII:C) and partially abolished by a monoclonal antibody which neutralizes VIII:C. This correction was specific for FVIII and was not observed after addition of purified human FIX. It was obtained, in the same magnitude range, with FVIII complexed to von Willebrand factor (vWF) but not with free vWF. These data provide a new insight into the knowledge of the physiological interaction between the platelet membrane and the vWF-FVIII complex facilitating plasma coagulation activation and may lead to helpful therapeutic advances.

Antibodies, Monoclonal↗
PubMed1997

Effect of fixed minidose warfarin, conventional dose warfarin and aspirin on INR and prothrombin fragment 1 + 2 in patients with atrial fibrillation.

The efficacy of conventional dose adjusted oral anticoagulation for stroke prevention in patients with non-valvular atrial fibrillation is well-documented but not considered ideal as primary antithrombotic treatment in elderly patients. The antithrombotic effect of fixed minidose warfarin 1.25 mg/day alone or in combination with aspirin 300 mg/day, of conventional dose adjusted warfarin (INR 2.0-3.0), and of aspirin 300 mg/day have been investigated in outpatients with chronic nonvalvular atrial fibrillation in the second Copenhagen Atrial Fibrillation, Aspirin and Anticoagulant Therapy Study (AFASAK 2). In order to investigate the effect on the coagulation system of the treatments, the International Normalized Ratio of the prothrombin time (INR) and prothrombin fragment 1 + 2 (F1 + 2) were monitored at baseline and after three months of treatment in 100 patients consecutively included in the trial. At baseline no differences in INR and F1 + 2 between the four treatment groups were present. After three months of therapy the level of INR increased significantly from baseline in patients receiving warfarin in any dose and the level of F1 + 2 decreased significantly by combined minidose warfarin-aspirin and by dose adjusted warfarin. When comparing the changes over time in F1 + 2 (three-month value minus baseline value) during therapy with fixed minidose warfarin, combined minidose warfarin-aspirin and aspirin alone no significant difference between the groups was found. In conclusion, INR was changed by all three warfarin regimens but only dose adjusted warfarin (INR 2.0-3.0) had a marked effect on F1 + 2.

Aged↗
PubMed1998

The European Concerted Action on Anticoagulation (ECAA) evaluation of a set of lyophilized normal plasmas to establish the normal prothrombin time for coagulometer systems.

Establishing the mean normal prothrombin time (MNPT) from fresh samples for prothrombin ratios and INR often presents difficulty in selection and collection of donors. A set of seven lyophilized normal plasmas has therefore been prepared at the ECAA Central Facility and studied at 143 laboratories in sixteen European states using coagulometers in serial field exercises. All centres tested either the high ISI ECAA rabbit or low ISI ECAA human reference thromboplastin. The MNPT of fresh plasmas and means of the lyophilized samples were closely comparable with most routine rabbit thromboplastins. Using human thromboplastins means with the lyophilized normals were marginally but significantly longer and with the bovine Thrombotest significantly shorter than the MNPT of fresh plasmas causing alterations in INR. There was no appreciable effect on INR of 2.5 and 3.5 when lyophilized normals were substituted for fresh normals with the rabbit reagents.

Animals↗
PubMed1998

Lonomia obliqua caterpillar spicules trigger human blood coagulation via activation of factor X and prothrombin.

In southern Brazil, envenomation by larvae of the moth Lonomia obliqua (Walker) may result in blood clotting factor depletion, leading to disseminated intravascular coagulation with subsequent haemorrhage and acute renal failure which may prove fatal. We have examined the effect of a crude extract of spicules from these caterpillars on in vitro hemostasis. The extract alone did not aggregate platelets and had no detectable effect on purified fibrinogen, suggesting that extract induces clot formation by triggering activation of the clotting cascade. In agreement with the presence of thrombin-mediated activity, hirudin prevented clot formation. The extract was found to activate both prothrombin and factor X, suggesting that the depletion of blood clotting factors results from the steady activation of factor X and prothrombin. Heating and diisopropylfluorophosphate abolished the procoagulant activity of the extract, indicating that the active component involved is a protein that may belong to the serine protease family of enzymes. The ability of hirudin to inhibit this coagulant activity suggests that this inhibitor could be beneficial in the treatment of patients envenomed by L. obliqua caterpillars.

Animals↗
PubMed1998

[Evaluation of the quality of prothrombin time technique in the Basque Country].

PURPOSE: The Programme for Quality Assessment in Anticoagulant Therapy, which was started in the Basque Country in 1984, included the manufacturing of a standard human thromboplastin reagent plus periodical quality controls of the prothrombin time. A rabbit thromboplastin reagent was available in 1994; it was called Thromboplastin Bilbao, or TBi, and had to be used as a pattern reagent. Its stability, sensitivity and composition were plotted against the Manchester Reagent, of similar nature and composition. A new phase of quality quality controls was simultaneously started with this new reagent, a group of hospitals of the Autonomous Community taking part in the programme. The aim was to compare this reagent with the others used by the hospitals and to evaluate the variations with regard to the stages previous to the introduction of the human reagent. MATERIAL AND METHODS: Nine centres joined the study. Controls were performed every fourth month including plasma from patients under anticoagulant treatment, plus the reference reagents. The partaking centres used their usual reagents and routine procedures, as well as the reference reagents and manual technique. RESULTS: The coefficient of variation (CV) of the INR of anticoagulated plasmas used for these studies when following the centres' own methods and thromboplastins was 9.5 +/- 6.40%, versus 9.94 +/- 1.57% when TBi was used. These results are in accordance with those attained with the previously manufactured human reagent, whose CV was 8.75 +/- 2.19% in the quality assurance methods performed in the period 1984-88. Concurrently with the programme, the reagent was sent as a part of the Spanish Programme for Quality Assessment in Anticoagulant Treatment to the 51 centres taking part in the study. The CV of the INR of the two lyophilized plasmas sent was, respectively, 14.97% and 16.5%. The average value for the healthy subjects was 14.77 seconds, with 8% inter-centres variation when using manual methods. CONCLUSIONS: These results suggest that a thromboplastin is now available whose sensitivity and reproducibility make it suitable as the national standard for usage in the quality assessment of prothrombin time.

Animals↗
PubMed1998

Factor V Leiden (G1691A), the prothrombin 3'-untranslated region variant (G20210A) and thermolabile methylenetetrahydrofolate reductase (C677T): a single genetic test genotypes all three loci--determination of frequencies in the S. Wales population of the UK.

Simultaneous genetic diagnosis of factor V (FV) Leiden (G1691A), the prothrombin variant (G20210A) and the thermolabile methylenetetrahydrofolate reductase (MTHFR) variant (C677T) has been achieved using multiplex heteroduplex analysis. All three loci are amplified in a single polymerase chain reaction (PCR) containing test DNA and three heteroduplex generators, respectively detecting the three nucleotide substitutions. After PCR, the products are analysed directly without further manipulation and the resulting heteroduplex profiles permit straightforward interpretation of the respective genotypes. The multiplex test has been used to assess the prevalence and allele frequency of each of the three nucleotide substitutions in 300 individuals (150 males and 150 females) from the local (S. Wales) population. A prevalence of 8% and an allele frequency of 0.040 +/- 0.015 (95% confidence interval) was obtained for FV Leiden; the prothrombin variant showed a prevalence of 1% and an allele frequency of 0.007 +/- 0.006 (95% confidence interval); the MTHFR mutation showed a prevalence of 60% and an allele frequency of 0.377 +/- 0.039 (95% confidence interval). This method is applicable to investigation of large cohorts of patients with arterial or venous thrombotic disease.

Cohort Studies↗
PubMed1998

Autoantibodies to human prothrombin and clinical manifestations in 207 patients with systemic lupus erythematosus.

OBJECTIVE: Prothrombin (factor II) is one of the phospholipid binding proteins with a procoagulant property. Some publications have shown the presence of autoantibodies against prothrombin (aPT) in patients with antiphospholipid antibodies (aPL). We assessed the clinical significance of aPT in thrombotic events in patients with systemic lupus erythematosus (SLE). METHODS: IgG and IgM aPT were tested by ELISA in 207 patients with SLE. RESULTS: Fifty-eight patients (28%) had positive aPT (> mean + 3 SD of 100 controls). Twenty-eight (14%) had IgG alone, 21 (10%) IgM alone, and 9 (4%) had both IgG and IgM. Patients with aPT had a history of thrombosis more frequently than those without aPT [31/58 (53%) vs 47/149 (32%), chi-squared=7.6, p=0.006]. No correlation was found between the presence of aPT and clinical features of SLE. CONCLUSION: aPT are frequently found in patients with SLE, and are a potential marker for thrombosis.

Abortion, Spontaneous↗