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PubMed1996

Prothrombin-related antigens in human aortic intima.

Most plasma proteins are present in both normal and atherosclerotic intima, and their concentrations in intimal interstitial fluid are directly related to plasma concentration and molecular size. All intimal samples also contain soluble fibrin-fibrinogen-related antigens, consisting of variable mixtures of fibrinogen and fibrinogen and fibrin degradation products; the extracted washed tissue contains insoluble fibrin. It appears that the fibrinogen is subjected both to degradation and to conversion to fibrin, which in turn undergoes lysis. Biochemically, insoluble "fibrin" can be detected by incubating the washed tissue with plasmin, and assaying the fibrin degradation products that are released; they are released from all samples, including small amounts from normal intima. The fibrin could arise by incorporation of a mural fibrin clot and/or clotting of the fibrinogen within the intima, which contains a "cocktail" of clotting-related factors including prothrombin/thrombin-related antigens, antithrombin III (AT III), and other protease inhibitors: in recent experiments stripped intima was immediately treated with ethylenediaminetetraacetic acid, minced, extracted with Tris-buffered saline, and the extracts analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting with antisera to prothrombin and AT III. Surprisingly, all blots treated with antiprothrombin antisera showed large bands migrating with free thrombin (36 to 37 kDa) and prothrombin (74 kDa) and four intermediate bands. In addition, in all 10 samples examined a band of high molecular mass (170 kDa) but variable intensity was present. This 170-kDa band comigrated with the major band reacting with anti-serum to AT III. The theoretical 1:1 thrombin:AT III complex (98 kDa) was not detected. Thus active thrombin appears to be present in intima, and this may be a highly atherogenic factor, both causing fibrin deposition and acting as a potent mitogen for arterial smooth muscle cells.

Antigens↗
PubMed1993

[Measurement of prothrombin fragment F1+2 for monitoring the anticoagulant effect of phenprocoumon].

It was the aim of this study to ascertain whether the plasma level of prothrombin fragment F1+2 is a suitable indicator of the anticoagulant effect of coumarin derivatives. The F1+2 levels were measured in 164 patients (100 women, 64 men; mean age 63.3 [34-83] years) in whom stable anticoagulation had been achieved with phenprocoumon, comparing the results with those obtained in healthy subjects (28 women, 19 men; mean age 54.6 [25-72] years) without anticoagulation. There was a significant reduction (P < 0.0005) in F1+2 plasma levels with oral anticoagulation (0.45 + 0.23 vs. 0.67 + 0.32 nmol/l). Even on a low degree of anticoagulation (international normalized ratio [INR] < 2.0) the F1+2 value was reduced to within the normal range (0.32-1.2 nmol/l). These results indicate that changes in the plasma level of prothrombin fragment F1+2 are directly dependent on the degree of oral anticoagulation and that this measure seems suitable for the monitoring of the anticoagulant effect. This is also true for oral anticoagulation of mild degree (INR < 2.0) in which the effect cannot be satisfactorily measured by the thromboplastin time (Quick test).

Administration, Oral↗
PubMed1993

Effect of laboratory variation in the prothrombin-time ratio on the results of oral anticoagulant therapy.

BACKGROUND: Patients receiving long-term anticoagulant therapy may be subject to unnecessary risks of bleeding or thromboembolism because of variability in the commercial thromboplastins used to determine prothrombin time and consequent uncertainty about the actual intensity of anticoagulation. METHODS: We explored the effect of this uncertainty on the benefits and risks of anticoagulation in patients with prosthetic heart valves, using models of thromboembolic and hemorrhagic complications as a function of the intensity of anticoagulation, with quality-adjusted life expectancy and average variable costs used to describe outcomes. RESULTS: Anticoagulation provides a striking benefit for patients whose treatment is conducted within the recommended range of the international normalized ratio (INR)--i.e., 2.5 to 3.5--but if uncertainty about the laboratory results causes the intensity of anticoagulation to fall outside this range, the gain becomes smaller. Uncertainty about the true intensity of anticoagulation may reduce the potential gain in life expectancy, adjusted for quality of life, by more than half and may increase the ratio of costs to effectiveness to almost five times the optimal value. Variability in the intensity of anticoagulation is even greater if older recommendations advocating a higher level of anticoagulation are followed. CONCLUSIONS: Uncertainty about the sensitivities of the commercially available thromboplastins used in the United States can have important clinical and economic effects. This problem could be eliminated if clinical laboratories uniformly reported the intensity of anticoagulation as the INR, by adjusting prothrombin-time ratios for variability in thromboplastins.

Cost-Benefit Analysis↗
PubMed1997

Increased tissue factor-initiated prothrombin activation as a result of the Arg506 --> Gln mutation in factor VLEIDEN.

The effect of the Arg506 --> Gln mutation in factor VLEIDEN on thrombin generation was evaluated in a reconstituted system using the purified components of the tissue factor (TF) pathway to thrombin and the components of the protein C pathway. Recombinant full-length tissue factor pathway inhibitor (RTFPI) was included in the system because of a previously observed synergistic inhibitory effect of TFPI and the protein C pathway on TF-initiated thrombin generation. Thrombin generation initiated by 1.25 pM factor VIIa.TF in the absence of the protein C pathway components occurs following an initiation phase, after which prothrombin is quantitatively converted to 1.4 microM thrombin. The factor VLEIDEN mutation did not influence thrombin generation in the reconstituted model in the absence of the protein C pathway. In the presence of 2.5 nM TFPI, 65 nM protein C, and 10 nM recombinant soluble thrombomodulin (Tm), thrombin generation catalyzed by normal factor V was abolished after the initial formation of 25 nM thrombin. In contrast, persistent thrombin generation was observed in the presence of factor VLEIDEN in the same system, although the rate of thrombin generation was slower compared with the reaction without protein C and Tm. The rate of thrombin generation with factor VLEIDEN increased with time and ultimately resulted in quantitative prothrombin activation. When the TFPI concentration was reduced to 1.25 nM, thrombin generation is still curtailed in the presence of normal factor V. In contrast, under similar conditions using factor VLEIDEN, the protein C pathway totally failed to down-regulate thrombin generation. The dramatic effect of a 50% reduction in TFPI concentration on the inhibitory potential of the protein C pathway on thrombin generation catalyzed by factor VLEIDEN suggests that the observed synergy between TFPI and the protein C pathway is directly governed by the TFPI concentration and by cleavage of the factor Va heavy chain at Arg506. This cleavage appears to have a dramatic regulatory effect in the presence of low concentrations of TFPI. Markedly increased thrombin generation in the presence of both 1.25 nM TFPI and factor VLEIDEN was also observed when antithrombin-III was added to the system to complete the natural set of coagulation inhibitors. Protein S (300 nM) had a minimal effect in the model on the inhibition of thrombin generation by protein C, Tm, and TFPI, with either normal factor V or factor VLEIDEN. Protein S also failed to significantly potentiate the action of the protein C pathway in the presence of antithrombin-III in reactions employing normal factor V or factor VLEIDEN. The absence of an effect of protein S in the model, which employs saturating concentrations of phospholipid, suggests that the reported interactions of protein S with coagulation factors are not decisive in the reaction. Altogether the data predict that TFPI levels in the lower range of normal values are a risk factor for thrombosis when combined with the Arg506 --> Gln mutation in factor VLEIDEN.

Animals↗
PubMed1998

A chimeric protein C containing the prothrombin Gla domain exhibits increased anticoagulant activity and altered phospholipid specificity.

To determine the structural basis of phosphatidylethanolamine (PE)-dependent activated protein C (APC) activity, we prepared a chimeric molecule in which the Gla domain and hydrophobic stack of protein C were replaced with the corresponding region of prothrombin. APC inactivation of factor Va was enhanced 10-20-fold by PE. Protein S enhanced inactivation 2-fold and independently of PE. PE and protein S had little effect on the activity of the chimera. Factor Va inactivation by APC was approximately 5-fold less efficient than with the chimera on vesicles lacking PE and slightly more efficient on vesicles containing PE. The cleavage patterns of factor Va by APC and the chimera were similar, and PE enhanced the rate of Arg506 and Arg306 cleavage by APC but not the chimera. APC and the chimera bound to phosphatidylserine:phosphatidylcholine vesicles with similar affinity (Kd approximately 500 nM), and PE increased affinity 2-3-fold. Factor Va and protein S synergistically increased the affinity of APC on vesicles without PE to 140 nM and with PE to 14 nM, but they were less effective in enhancing chimera binding to either vesicle. In a factor Xa one-stage plasma clotting assay, the chimera had approximately 5 times more anticoagulant activity than APC on PE-containing vesicles. Unlike APC, which showed a 10 fold dependence on protein S, the chimera was insensitive to protein S. To map the site of the PE and protein S dependence further, we prepared a chimera in which residues 1-22 were derived from prothrombin and the remainder were derived from protein C. This protein exhibited PE and protein S dependence. Thus, these special properties of the protein C Gla domain are resident outside of the region normally hypothesized to be critical for membrane interaction. We conclude that the protein C Gla domain possesses unique properties allowing synergistic interaction with factor Va and protein S on PE-containing membranes.

Amino Acid Sequence↗
PubMed2003

Mutations in autolytic loop-2 and at Asp554 of human prothrombin that enhance protein C activation by meizothrombin.

Thrombin acts on many protein substrates during the hemostatic process. Its specificity for these substrates is modulated through interactions at regions remote from the active site of the thrombin molecule, designated exosites. Exosite interactions can be with the substrate, cofactors such as thrombomodulin, or fragments from prothrombin. The relative activity of alpha-thrombin for fibrinogen is 10 times greater than that for protein C. However, the relative activity of meizothrombin for protein C is 14 times greater than that for fibrinogen. Modulation of thrombin specificity is linked to its Na(+)-binding site and residues in autolytic loop-2 that interact with the Na(+)-binding site. Recombinant prothrombins that yield recombinant meizothrombin (rMT) and rMT des-fragment 1 (rMT(desF1)) enable comparisons of the effects of mutations at the Na(+)-binding residue (Asp(554)) and deletion of loop-2 (Glu(466)-Thr(469)) on the relative activity of meizothrombin for several substrates. Hydrolysis of t-butoxycarbonyl-VPR-p-nitroanilide by alpha-thrombin, recombinant alpha-thrombin, or rMT(desF1) was almost identical, but that by rMT was only 40% of that by alpha-thrombin. Clotting of fibrinogen by rMT and rMT(desF1) was 12-16% of that by alpha-thrombin, as already known. Strikingly, however, although meizothrombins modified by substitution of Asp(554) with either Ala or Leu or by deletion of loop-2 had 6-8 and <1%, respectively, of the clotting activity of alpha-thrombin, the activity of these meizothrombins for protein C was increased to >10 times that of alpha-thrombin. It is proposed that interactions within thrombin that involve autolytic loop-2 and the Na(+)-binding site primarily enhance thrombin action on fibrinogen, but impair thrombin action on protein C.

Autolysis↗
PubMed2006

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↗
PubMed2004

The association of antibodies to cardiolipin, beta 2-glycoprotein I, prothrombin, and oxidized low-density lipoprotein with thrombosis in 292 patients with familial and sporadic systemic lupus erythematosus.

OBJECTIVE: To determine the prevalence of antibodies to phospholipid-binding plasma proteins (aPL) and to oxidized low-density lipoprotein (OX-LDL), and to study the association of these antibodies with thrombosis and coronary heart disease (CHD) in patients with systemic lupus erythematosus (SLE). METHODS: Clinical data and sera from 89 Finnish patients with familial and 203 with sporadic SLE were available for the study. Enzyme-linked immunosorbent assays (ELISA) were used for antibody determination. RESULTS: The occurrence of thrombosis in our SLE patients was 13.7% (40/292) and of clinically diagnosed CHD was 1.4% (4/292). All antibody assays, except IgM-aCL, were significantly associated with thrombosis. IgG-aCL alone or in combination with anti beta 2-GPI or with anti OX-LDL were reasonably sensitive (38%, 48%, and 58%, respectively) and specific (87%, 80% and 72%, respectively) for a history of thrombosis. A high risk of arterial thrombosis (TIA or stroke) was associated with positivity of IgG-aCL, anti beta 2-GPI, and anti-prothrombin. Venous thrombosis was significantly associated with all other assays except IgM-aCL and anti-prothrombin. No test correlated with CHD, but the number of affected patients was small. There were three multiplex SLE families with two patients having a history of thrombosis: no consistent pattern of aPL or anti OX-LDL was found in these patients. CONCLUSION: IgG-aCL alone or in combination with anti beta 2-GPI or anti OX-LDL are sensitive and specific tests for detecting SLE patients at increased risk of thrombosis. The aetiopathogenesis of thrombosis in familial SLE appears to be multifactorial.

Adult↗
PubMedDate not supplied

Postinfection purpura fulminans in a patient heterozygous for prothrombin G20210A and acquired protein S resistance.

Purpura fulminans usually consists of large, often symmetrical, spreading ecchymosis, which may later develop into extensive areas of skin necrosis and peripheral gangrene. Postinfectious purpura fulminans associated with an autoantibody directed against protein S has been described. The interaction and the contribution of recently described mutations such as factor V Leiden and prothrombin G20210A to the development and progression of postinfectious purpura fulminans and venous thrombosis is not known. The authors describe a patient heterozygous for prothrombin G20210A who developed purpura fulminans and extensive venous thrombosis secondary to acquired protein S deficiency.

Autoantibodies↗
PubMed1994

A simple method for evaluating prothrombin time in severe liver disease.

A measurement of prothrombin time by a new, whole blood capillary system was evaluated for use in severe liver disease, such as fulminant and chronic hepatic failure. The measurement required a single drop of fresh, whole blood and was easily performed at bedside. Results were available within 5 minutes after collection of the blood samples. Good correlation was observed between prothrombin time values determined by the rapid method and those determined with the laboratory method (r = .89). The laboratory method was used as a reference. The whole blood system may be especially helpful in emergency situations, when central laboratory services are not available.

Acute Disease↗
PubMed1997

Prothrombin time determination. The lack of need for a discard tube and 24-hour stability.

The National Committee for Clinical Laboratory Standards (NCCLS) recommends that all coagulation studies be done on a specimen from the tube drawn second or later. For patients receiving long-term anticoagulant therapy, this may require that the first tube of blood drawn be discarded for each prothrombin evaluation. In a prospective study we compared the prothrombin times (PTs) as international normalized ratios (INRs) from a series of three tubes obtained from 241 patients receiving consistent dosages of oral anticoagulant therapy to determine the need for discarding the first tube drawn, as well as the stability of PT determinations over a 24-hour period. Tube one was treated as the discard tube. Tubes one and two were analyzed within the laboratory's standard 4-hour time frame, while tube three was kept stoppered at room temperature, centrifuged a half hour before PT determination, and analyzed after a 24-hour delay. Comparisons of the INRs were made in four ranges comprising 1.2 to 2.0, 2.1 to 3.5, 3.6 to 5.9, and 6.0 or more. Most INR comparisons were less than the 10% maximum variance listed as acceptable by the NCCLS. A comparison of INR results between tube two and tube one showed a statistically significant difference only for the INR range of 6.0 or more. The comparison of the 24-hour specimen with tube one showed statistically significant differences in paired t testing for the first three INR cohorts. However, the 95% confidence intervals demonstrated that these mean differences were probably too small to be clinically significant. For the fourth cohort (INR > or = 6.0) the mean difference was not significantly different on paired t testing, but the 95% confidence interval was larger at -0.07 to 0.839. In this sample of outpatients receiving consistent dosages of oral anticoagulant therapy the use of a discard tube seemed unnecessary, and the 24-hour stability of PT determinations was documented.

Adult↗
PubMed1977

Normotest--thrombotest discrepancy in congenital coagulation disorders of the prothrombin complex and in coumarin-treated patients: a nonspecific phenomenon.

A Normotest (NT)-Thrombotest (TT) discrepancy is claimed to reflect the presence of coumarin-induced inhibitors or intravascular coagulation, or both. The results of this study indicate, however, that a significant NT-TT discrepancy is also present in all plasmas from patients who have congenital coagulation disorders of the prothrombin complex. None of these patients had received an anticoagulant or showed any sign of intravascular clotting; nevertheless the discrepancy observed was similar to that found in plasmas of coumarin-treated patients: average values were 0.437 and 0.450, respectively. As no inhibitor was present in the congenital coagulation disorders, except in hemophilia BM, the phenomenon does not appear to be specific for coumarin plasma. This indicates that the NT/TT discrepancy is a non-specific phenomenon that does not seem to provide any additional information about coumarin-treated patients compared with that obtainable by means of a simple prothrombin time test.

Acenocoumarol↗
PubMed1991

An analysis of duplicate testing of prothrombin time and activated partial thromboplastin time assays.

An evaluation of duplicate prothrombin time (PT) and activated partial thromboplastin time (aPTT) assays determined by the MCA 110 coagulation analyzer was undertaken to develop analytical duplicate performance criteria to quantitate the risks associated with single versus duplicate procedures. Included in the study were 1,277 patient samples. On the basis of the currently recommended therapeutic range for prothrombin ratios, a variation of approximately 10% or more between duplicates was considered to be unacceptable. For aPTT assays, the recommended therapeutic range for heparin therapy was usually 1.5 to 2.5 times the baseline value, and variations of up to 25% might be considered acceptable. With these relatively lenient criteria, approximately 2% of PT and 1.3% of aPTT assays had differences between duplicate values that were unacceptable. From this data the authors concluded that the frequency of errors produced by single estimations was too great for satisfactory clinical practice.

Humans↗
PubMed1981

Studies on the structures of the carbohydrate moiety of human prothrombin.

Human prothrombin contains three asparagine-linked sugar chains in one molecule. The sugar chains were quantitatively liberated as radioactive oligosaccharides from the polypeptide moiety by hydrazinolysis followed by N-acetylation and Nab3H4 reduction. All of the oligosaccharides contain N-acetylneuraminic acid. The neutral oligosaccharides obtained from all acidic oligosaccharides by sialidase digestion are identical. By the combination of sequential exoglycosidase digestion and methylation analysis, the structures of the asparagine-linked sugar chains of human prothrombin were confirmed to be as follows: (sequence in text).

Carbohydrate Sequence↗
PubMed2001

Cost-effectiveness of screening and extended anticoagulation for carriers of both factor V Leiden and prothrombin G20210A.

Carriers of a double thrombophilic mutation (factor V Leiden and prothrombin G20210A) are at high risk of a recurrent venous thromboembolism (VTE), and may benefit from a longer course of secondary prophylaxis. We examined the costs and health benefits of screening for both the mutations, provided that double heterozygotes undergo 2 years of anticoagulation as compared to the standard 6 months. We thus pooled the available evidence and calculated that the OR for recurrence in double heterozygotes was 5.9 (95% CI 2.65-13.20). A Markov model tracked patients' health lifelong, and calculated that prolonged prophylaxis saved 26 quality-adjusted days of life and $410 per double heterozygote treated. Screening all the patients with venous thromboembolism thus provided one additional day of life at the cost of 13624 $/QALY (95% CI 12 965-22 889). Screening was not cost-effective in those cohorts with a low prevalence of the mutations, a high bleeding risk or in those where prophylaxis prevented <65% of recurrences. Screening for factor V Leiden and prothrombin G20210A, with prolonged prophylaxis of double carriers, is cost-effective in most patients with VTE.

Aged↗
PubMed1994

Cellular localization of tissue factor and prothrombin in the estrogen-treated immature rat uterus.

The immediate early responses of the immature rat uterus to estradiol include increases in tissue factor and prothrombin, two proteins of the coagulation cascade. Both attain maximum activity within 3 h after the administration of estradiol and return to control levels after 12-18 h. The presence of the two proteins allows the generation of thrombin (a known growth factor for fibroblasts) in the uterus at the time when uterine growth begins. To further our hypothesis that thrombin is an estrogen-regulated uterine growth factor, we used immunohistochemistry, Western blotting, and coagulation assays to localize the cell types in which these proteins are increased by estradiol. Tissue factor is increased in both the stromal and the epithelial cells. Increased prothrombin is localized primarily along the basement membrane that separates the epithelial and stromal layers and also at the luminal surface of the epithelium.

Amino Acid Sequence↗
PubMed1995

Is Ca(II) ion binding to prothrombin fragment 1 intrinsically cooperative, or is the cooperative binding accounted for by self-association?

The recent suggestion that the apparent cooperativity seen in the binding of Ca(II) ions to prothrombin fragment 1 is due to protein aggregation is evaluated. Since (1) we find that the Ca(II) ion binding is not dependent upon protein concentration, (2) the analytical expression for the equilibrium constant of the aggregation model is unrealistically large when evaluated at realistic Ca(II) ion concentrations, and (3) a very simple allosteric cooperative binding model (Monod) can be shown to fit the experimental data, we conclude that the aggregation explanation for the apparent cooperativity in the Ca(II) ion binding by prothrombin fragment 1 is not correct.

Animals↗
PubMed1998

Simple and rapid combined genetic diagnosis of mutation (1691 G-->A) of the factor V gene and (20210 G-->A) of the prothrombin gene.

We have developed a rapid method which allows us simultaneously to determine two genetic variations that are associated with an increased risk of venous thrombosis: the 20210 G-->A mutation present in the 3'-UT region of the prothrombin gene and the 1691 G-->A mutation giving rise to factor V Leiden. Our strategy involves the coamplification of exon 10 of the factor V gene and of the region 3' from the prothrombin gene using modified oligonucleotides, permitting the introduction of a single HindIII cleavage site in fragments bearing one of the mutations. As a result of its time- and cost-saving features, this combined method should be considered for screening large numbers of patients.

DNA Mutational Analysis↗