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Low frequency of elevated prothrombin times in patients with lupus anticoagulants when using a recombinant thromboplastin reagent: implications for dosing and monitoring of oral anticoagulant therapy.

Many patients with lupus anticoagulants (LA) are treated with oral anticoagulation and monitored using the international normalised ratio (INR) derived from the prothrombin time (PT). Recent reports have produced conflicting conclusions about the extent to which LA interferes with PT determination. The degree of anticoagulation may be overestimated in a patient whose LA affects the PT. A number of reports conclude that specific thromboplastin reagents containing recombinant tissue factor are sensitive to the presence of LAs and should not be used to monitor oral anticoagulant therapy in these patients. These studies were performed on orally anticoagulated patients. The present retrospective study on 400 patients with LAs who were not receiving therapeutic anticoagulation was performed to ascertain the frequency of prolonged PT in these patients when using Innovin recombinant thromboplastin. Only 17 (4.3%) out of 400 had prolonged PT in the presence of LA. As this is a low prevalence, and not all patients with LAs will require anticoagulant therapy, it is concluded that baseline INR determination should be used to highlight the need to monitor individual patients with LA-insensitive reagents. As the use of moderate-intensity oral anticoagulation for patients with LAs and previous thrombosis is receiving wider acceptance, an informed approach to anticoagulant monitoring will reduce the possibility of under-anticoagulating patients receiving this therapy.

Administration, Oral↗

Variations of prothrombin time, factor VII and protein C with a single daily dose of acenocoumarol. Preliminary results.

In 11 patients on steady anticoagulation with a daily dose of acenocoumarol, prothrombin time, factor VII and protein C were measured 2 and 16 h after the daily intake of acenoumarol. Prothrombin time (expressed as International Normalised Ratio) increases significantly, factor VII and protein C decrease between the two samples. These results suggest that a daily dose of acenoumarol is associated with fluctuation of the anticoagulant effect.

Acenocoumarol↗

[A case of celiac disease with late diagnosis by very long prothrombin and activated partial prothrombin times].

Coeliac disease is usually revealed by intestinal symptoms, but less frequently by deficiency symptoms. Early screening is very important to avoid with appropriate diet an intestinal lymphoma or epidermoid cancer. We report here the case of a 68-year old woman where coeliac disease was pointed out by very long Prothrombin Time (PT) and Activated Partial Thromboplastin Time (APTT). Clinical examination was strictly normal except for leanness, a small height, and several diarrhoea episodes 3 or 4 times a year. Other blood tests showed a macrocytic anemia, a fibrinogen level slightly above the upper limit, a decreased proteinaemia and albuminaemia, and a sideraemia at the lower normal limit. Liver tests pointed to a cytolysis. Vitamin K-dependent factors were decreased. A perfusion of vitamin-K allowed getting a normal PT. Duodenofiberscopy with biopsy allowed the diagnosis of coeliac disease. Neither lymphoma nor epidermoid cancer were detected. A gluten-free diet allowed the disappearing of digestive symptoms, weight rising and return to a normal PT. Searching for a coeliac disease is therefore relevant in aged patients even when very faint clinical or biological symptoms of malabsorption appear, particularly when PT is longer than the control with decreased vitamin-K dependant factors.

Aged↗

Prothrombin time.

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Prothrombin Time↗

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↗

[Prothrombin time, activated partial thromboplastin time, plasma fibrinogen determination. Comparison of two automated coagulation systems: Koagulab 40-A and ACL-100].

In this study the authors compare two automated coagulation instruments: the koagulab-40A (Orthodiagnostics Systems) and l'ACL-100 (Instrumentation Laboratory) using two different methods of detection, photo-optical and nephelemetric respectively. The three parameters studied are: prothrombin time (PT) (82 samples), activated partial thromboplastin time (APTT) (86 samples) and fibrinogenemia (FIB) (109 samples). For each test, they use two reagents of different origins. Samples come from people without any haemostatic disorder and from patients showing abnormal levels of these parameters (heparins or antivitamins K treatments, hypo or hyperfibrinogenemias). For the tree parameters examined, they obtain coefficients of correlation: 0.94 to 0.99 between the two instruments. These values are not noticeably modified by reagent substitution. For fibrinogenemia, the coefficient of variation (CV) is about 4%. Finally, in comparison with the photooptical classical method, the ACL-100 is more rapid, more economical (reduced volumes of reagents) and more feasible (dilutions of plasmas and tubulure changing are not necessary for fibrinogen).

Autoanalysis↗

The effect of fluorescent humic substances existing in the well water of Blackfoot disease endemic areas in Taiwan on prothrombin time and activated partial thromboplastin time in vitro.

Fluorescent humic substances (FHS) in well water of Blackfoot disease endemic areas were purified and fractionated by Sephadex G-25 column chromatography. Four fractions of the purified FHS were isolated. The purified FHS and their fractions were then added to normal human pool plasma in vitro separately to detect the abilities of the effects on prothrombin time (PT) and activated thromboplastin time (APTT). Results showed that all of the four fractions of the purified FHS prolonged both PT and APTT in the higher concentration ranges (10 mg/ml - 20 mg/ml), but shortened both PT and APTT in the lower concentration ranges (0.5 mg/ml - 5 mg/ml). Among the four fractions of the FHS, the fraction 1, the humic substance with the highest molecular weight among all the four FHS, showed the most obvious effects. Owing to the effects of the FHS on PT and APTT values, we supposed that there is a close relationship between the FHS and the cause of Blackfoot disease.

Arsenic↗

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↗

Mathematical model for the blood coagulation prothrombin time test.

A mathematical model for the prothrombin time test is proposed. The time course of clotting factor activation during coagulation was calculated, and the sensitivity of the test to a decrease in the concentrations of coagulation proteins or their activities was studied. The model predicts that only severe coagulation disorders connected with a more than five-fold decrease in the concentrations or activities of the blood coagulation factors can be revealed by the test.

Blood Coagulation Factors↗

Fructose-1,6-diphosphatase deficiency: a rare cause of prolonged prothrombin time.

A 20-year-old woman presented with severe life-threatening metabolic acidosis and hypoglycemia. In addition, her blood tests revealed elevated hepatic enzymes and a prolonged prothrombin time, with a reduction in factor VII activity. After treatment with a glucose and bicarbonate-containing intravenous infusion, there was a dramatic clinical improvement and normalization of the prothrombin time within 2 days. The patient was found to have fructose-1,6-diphosphatase deficiency, a rare metabolic disorder which has not been described previously as causing coagulation defects.

Acidosis↗

Arsenic as a promoter in the effect of humic substances on plasma prothrombin time in vitro.

Protocatechuic acid can be oxidized and polymerized to from humic substances (humic acid and fulvic acid). Should AS2O3 occur in the process of oxidative polymerization, humic acid output can increase by 1.5 - 2.3 times and, in the case of fulvic acid, at least 10 times. After protocatechuic acid is oxidized and polymerized, the resultant humic and fulvic acids both exhibit the ability to shorten the prothrombin time of human pool plasma in vitro. This ability becomes more apparent when AS2O3 serves as a promoter in the course of oxidative polymerization as described above. However, AS2O3 or protocatechuic acid alone is unable to shorten the prothrombin time of human pool plasma.

Arsenic↗

Surface plasmon resonance (SPR) analysis of coagulation in whole blood with application in prothrombin time assay.

It is previously shown that surface plasmon resonance (SPR) can be used to study blood plasma coagulation. This work explores the use of this technique for the analysis of tissue factor induced coagulation, i.e. prothrombin time (PT) analysis, of whole blood and plasma. The reference method was nephelometry. The prothrombin time analysis by SPR was performed by mixing two volumes of blood/plasma, one volume of thromboplastin, and one volume of CaCl2 solution directly on a sensor surface. The measurements show good agreement between nephelometry and SPR plasma analysis and also between SPR plasma and whole blood analysis. The effect of anticoagulant treatment on the clotting times was significant both quantitatively and qualitatively. The impact on the SPR signal of different physiological events in the coagulation process is discussed, and tentative interpretations of the sensorgram features are given. The major advantage of the SPR method compared to nephelometry is the possibility to perform analysis on whole blood instead of plasma. In conclusion, SPR is a promising method for whole blood coagulation analysis.

Anticoagulants↗

Which coagulation factors interfere with the one-stage prothrombin time?

Coagulation factors that interfere with the one-stage prothrombin time (PT) were investigated. PT responded with identical activities (adequately) against coagulation factors VII or X, only half as expected against factor IX, less than expected and nonlinearly against factor II. In multiple coagulation factor deficiencies PT did not differ from factor VII, which was the most reduced coagulation factor in warfarin therapy or liver disease. PT may also be influenced by factor VII at high activities.

Blood Coagulation↗

[Modified capillary blood prothrombin-time test for the calculation of an international normalized ratio].

Prothrombin time (PT) is usually measured in citrated venous blood. This test is undesirable in pediatric practice and in patients taking anticoagulants due to frequent venepunctures. Capillary blood PT test has no adverse impact. The authors have developed a standardized modified method for PT measurement in capillary blood. The adequacy of the test is due to the fact that analyzed test packed cell volumes are kept in mind. The modified test has shown that the values of normal plasma PT may be used to calculate an international normalized ratio (INR). It makes it possible to determine capillary blood PT in the range of packed cell volumes from 0.15 to 0.7 in the examinees and to monitor anticoagulant therapy. The results of the modified test closely correlated with those when determining PT and INR in venous plasma (r = 0.99) and applying the CoaguChek test (r = 0.97).

Anticoagulants↗

European concerted action on anticoagulation. Minimum numbers of lyophilized plasma samples for ISI calibration of CoaguChek and TAS point-of-care whole blood prothrombin time monitors.

International sensitivity index (ISI) calibration of whole blood prothrombin time (PT) monitors is too complex. We previously simplified the method by using European Concerted Action on Anticoagulation (ECAA) lyophilized plasma samples with the TAS PT-NC (Bayer AG, Leverkusen, Germany) and the CoaguChek Mini (Roche Diagnostics, Mannheim, Germany) whole blood PT monitoring systems. The TAS PT-NC required a correction derived from the line of equivalence. Monte Carlo bootstrap analysis of reducing numbers of test samples was performed with both systems. Plasma samples from patients receiving coumarin (coumarin samples), healthy subjects (normal samples), and plasma samples artificially depleted of coagulation factors were used. With the TAS PT-NC, 20 coumarin samples or 20 artificially depleted samples with 7 normal samples gave reliable ISI and international normalized ratio and satisfactory precision. With the CoaguChek Mini, 30 coumarin and 10 normal samples were required. Simplification of ISI calibration of the 2 monitoring systems is possible using fewer ECAA lyophilized plasma samples than the 80 required according to the World Health Organization guidelines for conventional PT systems and previously recommended for fresh plasma samples tested on the same 2 monitoring systems.

Animals↗

External quality assessment of prothrombin time: the split-sample model compared with external quality assessment with commercial control material.

OBJECTIVE: CoaguChek S is a point-of-care, whole-blood, prothrombin time monitor. The purpose of this study was to compare two different methods for external quality assessments of CoaguChek S. MATERIAL AND METHODS: In the traditional external quality assessment scheme, commercial control material was sent to office laboratories and the results were compared with a method-specific target value. In the alternative external quality assessment (the split-sample survey) patient samples were analyzed on CoaguChek S at office laboratories, and venous blood samples from the same patients were analyzed at a hospital laboratory using an assigned comparison method. To obtain comparable performance criteria for the two methods, the limits for "good", "acceptable" and "poor" performance evaluation in the split-sample survey had to be expanded because of uncertainties in preanalytical factors and the comparison method. RESULTS: In the traditional external quality assessment the total imprecision (between-office and within-office) was 8.0% at the low level (1.6 INR (International Normalized Ratio)) and 10.5% at the therapeutic level (3.4 INR). In the split-sample survey the total imprecision was 12.3% at the low level (2.1 INR) and 10.7 % at the high level (3.0 INR). Seventy-five percent of the participating office laboratories were characterized as "good" with the traditional external quality assessments, whereas the corresponding number was 73% using the split-sample model. CONCLUSIONS: Available commercial control material for CoaguChek S is different from patient samples. This study demonstrates that split-sample survey is achievable, and is an acceptable alternative to traditional external quality assessment for point-of-care prothrombin time monitors where appropriate control material is difficult to obtain.

International Normalized Ratio↗

Prothrombin time proficiency testing: a robust grading method.

A robust two-way analysis of variance technique was applied to determine simultaneously the effects of method and thromboplastin on prothrombin time. A new approach to outlier detection for two-way analysis of variance was used. Focusing on the underlying error structure improved the uniformity of the grading procedure in the hematology proficiency testing program of the New York State Department of Health. The logarithm-transformed scale produced constancy of error variance and resulted in uniformity of the acceptable spread of data. The common variance was lower than that obtained by previous methods and allowed for a narrower acceptable range of reported prothrombin times by reducing the inflated standard deviation, thus improving the efficiency of the grading procedure. For proficiency testing, no advantage was found in the use of either a common thromboplastin or freeze-dried, coumadinized patient plasmas rather than artificially depleted commercial plasmas, except for special purposes.

Automation↗