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PubMed1992

Modifications of bovine prothrombin fragment 1 in the presence and absence of Ca(II) ions. Loss of positive cooperativity in Ca(II) ion binding for the modified proteins.

Chemical modification of bovine prothrombin fragment 1 according to the procedure of D. J. Welsch and G. L. Nelsestuen (1988) [Biochemistry 27, 4946-4952 and ealier papers] provided a series of fragment 1 derivatives in which various nitrogen-containing side chains were N-acetylated and/or N-2,4,6-trinitrophenylated. In addition the des-[Ala-1,Asn-2]- and des-[Ala-1,Asn-2,Lys-3]-fragment 1 derivatives were prepared by limited enzymatic hydrolysis of fragment 1 using cathepsin C and plasmin, respectively. Quantitative studies on the Ca(II) binding of these proteins have been accomplished using 45Ca(II) equilibrium dialysis. Binding of these fragment 1 derivatives to phosphatidylserine/phosphatidylcholine (PS/PC) vesicles (25:75) in the presence of Ca(II) ions has been studied using the light-scattering technique. Acylation of the 5 lysine residues of fragment 1 by the action of acetic anhydride (500-fold molar excess) in the presence of 75 mM Ca(II), pH 8.0, results in loss of positive cooperativity in Ca(II) binding (Scatchard plot) and an increase in the number of Ca(II) ions bound. The Ca(II)-dependent PS/PC binding of the acylated protein is reduced. Removal of 2 and 3 residues from the amino terminus likewise leads to loss of positive cooperativity in Ca(II) binding and reduced binding affinity to PS/PC vesicles. The important role of the amino-terminal 1-10 sequence is discussed. We conclude that positive cooperativity in Ca(II) binding is not a prerequisite for the Ca(II)-dependent binding of bovine prothrombin fragment 1 to PS/PC vesicles.

Animals↗
PubMed2004

Prevalence of factor V Leiden, prothrombin G20210A, and MTHFR C677T mutations in 200 healthy Jordanians.

Thrombophilia is now considered a multi-causal condition, with interplay of acquired genetic risk factors. In order to estimate the frequency of the factor V Leiden, prothrombin G20210A, and MTHFR C677T mutations in the Jordanian population, we screened 200 healthy Jordanian individuals. 40% were females. Mean age was 32.1 years for males and 30.0 years for female participants. A PCR method detected 15.0% factor V Leiden (87% heterozygous, 13% homozygous), 2% prothrombin G20210A (100% heterozygous), and 24% MTHFR C677T (67% heterozygous, 33% homozygous). We conclude that the prevalence of factor V Leiden and MTHFR C677T is elevated in this population of Jordanians. However the incidence of G20210A is relatively low. Quantification of these genetic thrombosis risk factors in various populations will contribute to a better understanding of the interaction of genetic and environmental risk factors.

Adult↗
PubMed2005

Prevalence of factor V Leiden and prothrombin G20210A gene mutation.

OBJECTIVES: To determine the prevalence of factor V Leiden (FVL) and prothrombin gene (PG) 20210A mutations in patients who attended the outpatient clinic and do not have a family history of thrombosis. METHODS: We researched FVL and PG20210A mutations in 151 outpatients (92 males and 59 females) who attended the Pediatrics Polyclinic, Medical Faculty, Dicle University, Turkey between May 2002 and July 2002. Peripheral venous bloods (2 cc) with ethylenediaminetetraacetic acid were used to isolate DNA by high pure polymerase chain reaction (PCR). Later, by using light-cycler FVL (Roche) and prothrombin mutation detection kit (Roche) and light-cycler equipment, FVL and PG20210A gene mutations were determined from the samples in the glass capillary tubes by PCR specific adaptation. For active protein C (APC) resistance, STA-STACLOT APC-R Detection Kit was used. Expected values were evaluated with STA equipment and using STA-STACLOT APC-R procedure. RESULTS: The prevalence of heterozygote mutations of FVL was 4.6% and PG20210A was 0.7%. The FVL mutation frequency obtained in our study is lower than the other studies in Turkey, but in correlation with the results of the other Caucasian populations throughout the world. Active protein C resistance in patients carrying heterozygote mutation of FVL has been found in low rates. Factor V Leiden and PG20210A were confronted in high prevalences in patients who suffer venous thrombosis (VT) CONCLUSION: Scanning of FVL and PG20210A gene mutations may be recommended in high risk groups such as relatives of FVL and PG20210A carriers and relatives of patients with VT, and in during pregnancy, the use of oral contraceptives and before surgery. Routine scanning of FVL and PG20210A gene mutations is not recommended in people who do not have risk factors for VT.

Factor V↗
PubMed2005

[Frequency of prothrombin gene G20210A variant in the 3'-untranslated region in Zhuang ethnic Chinese].

OBJECTIVE: To ascertain the frequency of prothrombin (FII) gene 3'-untranslated region (3'-UT) G20210A variant and to explore whether this mutation is related to arterial thrombosis in Chinese Zhuang population. METHODS: Seventy-six patients with cerebral thrombosis, 23 patients with myocardial infarction and 106 healthy Chinese Zhuang persons were studied. The G20210A mutant allele of the prothrombin gene in all blood specimens was investigated by DNA extraction, polymerase chain reaction amplification, Hind III digestion and polyacrylamide gel electrophoresis. RESULTS: The patients and normal control subjects were all homozygous for the normal G20210G allele, and there was no FII G20210A variant. CONCLUSION: Factor II gene 3'-UT G20210A mutant allele is absent in the 99 Chinese Zhuang ethnic patients with ischemic stroke and myocardial infarction and is absent in 106 normal healthy Zhuang people. FII G20210A mutation may not be a major risk factor for thrombogenesis in ethnic Chinese.

3' Untranslated Regions↗
PubMedDate not supplied

Are factor V and prothrombin mutations associated with increased risk of oral cancer?

BACKGROUND: Methylenetetrahydrofolate reductase is associated with pathogenesis of both thrombosis and oral cancer. Therefore, a search for a similar association of other thrombosis-related factors with oral cancer is justified. PATIENTS AND METHODS: In order to investigate whether the coagulation factor V Leiden and prothrombin G20210A mutations increase the risk of oral cancer, we searched for these mutant alleles by RFLP analysis in DNA samples of 102 patients with oral cancer and 120 healthy controls. RESULTS: Neither the Leiden nor the G20210A alleles were found in statistically different frequencies in the two groups. In addition, no statistical difference was observed in parameters such as sex, age and positive family history for cancer. Nevertheless, a significant difference was observed for Leiden in patients with a positive history for thrombophilia (p < 0.001). CONCLUSION: There seems to be no association of prothrombin, and possibly a minor contribution of factor V, in oncogenesis in the oral region.

Adult↗
PubMed2005

[Recurrent vascular access trombosis associated with the prothrombin mutation G20210A in a adult patient in haemodialysis].

Vascular access-related complications are a frequent cause of morbidity in haemodialysis patients and generate high costs. We present the case of an adult patient with end-stage renal disease and recurrent vascular access thrombosis associated with the prothrombin mutation G20210A and renal graft intolerance. The clinical expression of this heterozygous gene mutation may have been favoured by inflammatory state, frequent in dialysis patients. In this patient, the inflammatory response associated with the renal graft intolerance would have favored the development of recurrent vascular access thrombosis in a adult heterozygous for prothrombin mutation G20210A. In the case of early dysfunction of haemodialysis vascular access and after ruling out technical problems, it is convenient to carry out a screening for thrombophilia.

Anticoagulants↗
PubMed1991

[Control of the treatment with oral anticoagulants and prothrombin time].

There are many patients on oral anticoagulant therapy monitored with prothrombin time (Quick Test). Differences in sensitivity of the various types of tissue thromboplastins are the cause of the different results and common therapeutic ranges, calibrated reference thromboplastins with a defined International Sensibility Index (ISI) have become available. The ISI is used to estimate the International Normalized Rate (INR) which is used as a universal scale for the expression of the prothrombin time results in the control of oral anticoagulant therapy.

Administration, Oral↗
PubMed1977

[Effect of alclofenac on the prothrombin level in patients under treatment with anticoagulants].

Simultaneous administration of the anticoagulants acenocoumarol, phenprocoumon or chlorindion and the antirheumatic substance alclofenac in long term trials has no observable influence on the prothrombin time of stabilized patients. When the anticoagulant (acenocoumarol or phenprocoumon) and the alclofenac therapy are begun simultaneously, a variation of the dose is necessary. Either a one-third lower initial dosage can be given, or, after attaining the maximal anticoagulation effect on the prothrombin time (48 h after beginning acenocoumarol therapy, 72 h with phenprocoumarol), a lower daily dosage must be administered once, in comparison to the other group without alclofenac therapy. The maintenace dosage is not influenced by alclofenac.

Aged↗
PubMed1991

The gamma-carboxyglutamic acid and epidermal growth factor-like domains of factor X. Effect of isolated domains on prothrombin activation and endothelial cell binding of factor X.

Factor Xa is the enzymatically active constituent of the prothrombinase complex, which catalyzes the conversion of prothrombin to thrombin. We have isolated fragments, from tryptic digests of factor X, that consists of the gamma-carboxyglutamic acid (Gla) region linked to one or two epidermal growth factor (EGF)-like domains. Calcium ion binding measurements indicated that these fragments have a native conformation. The factor X-GlaEGF fragments inhibit factor Xa-induced blood clotting in a manner suggesting that they compete with factor Xa for phospholipid binding sites. The same conclusion was reached when thrombin generation was studied in a system of purified components (factor Xa, factor Va, prothrombin, phospholipid, and Ca2+). There was no evidence for a strong interaction between the EGF-like domains of factor Xa and factor Va in either system. However, experiments in the purified system without phospholipid indicated a direct, albeit weak, interaction between the Gla region of factor Xa and factor Va and between the COOH-terminal EGF-like domain of factor Xa and factor Va. Using domain-specific Fab fragments, we have confirmed that the conformation of the serine protease region alters dramatically upon activation of factor X. Furthermore, we have demonstrated that the conformation of the Gla region is affected by the activation, whereas the EGF-like domains appear to be unaltered. The association constant for factor X binding to endothelial cells was two orders of magnitude lower than that for binding of factor IX to these cells. Binding of the Gla and GlaEGF fragments suggested Gla-mediated binding to phospholipid rather than binding to a specific receptor.

1-Carboxyglutamic Acid↗
PubMed1991

[Standardized prothrombin time determinations and optimal anticoagulant therapy].

WHO and other international organizations have recommended the introduction of a standardized prothrombin time determination. This would allow a universal scale for the intensity of oral anticoagulation therapy to be used. A prerequisite is the use of thromboplastin, calibrated against the international reference thromboplastin, standardized methodology etc. This permits every prothrombin time determination to be expressed as International Normalized Ratio (INR). The introduction of INR facilitates the implementation of optimal oral anticoagulation as defined by larged international studies.

Anticoagulants↗
PubMed1989

[Interaction of human prothrombin with tissue thromboplastin].

The binding of 125I-labeled human prothrombin to native and papain-treated tissue thromboplastin in the presence of CaCl2 or EDTA was studied. The Scatchard plots for the protein binding suggest the presence at thromboplastin surface of two types of binding sites, high affinity [Kd(app) = 7.4.10(-8) M] and moderate affinity [Kd(app) = 7.9.10(-5) M]. The removal of Ca2+ did not influence the Kd (values for these) sites but markedly reduced their number. Proteolysis by papain caused a decrease in the affinity of high affinity sites without affecting the Kd values of the moderate affinity sites yet caused a proportional increase in the number of both high and moderate affinity sites in the presence of Ca2+. At low prothrombin concentrations a positive cooperativity of protein binding at high affinity sites in the presence of Ca2+ was observed.

Calcium↗
PubMed1988

An approach to assigning in vitro potency to unfractionated and low molecular weight heparins based on the inhibition of prothrombin activation and catalysis of thrombin inhibition.

Unfractionated and low molecular weight (LMW) heparins with good antithrombotic activity invariably catalyze thrombin inhibition and inhibit the appearance of thrombin activity in contact-activated plasma. Conversely, the antithrombotic efficacy of LMW heparins decreases as their ability to catalyze thrombin inhibition and to inhibit the appearance of thrombin activity in plasma decrease. The activated partial thromboplastin time (APTT) has proven a reliable test for assaying unfractionated heparin. We therefore compared 2 unfractionated and 3 LMW heparins on the basis of the minimum concentrations required to double the APTT of normal plasma and by then determined how this anticoagulant effect was achieved. The amount of unfractionated and LMW heparin which doubled the APTT was found to be equivalent to approximately 0.25 antithrombin units. This concentration of each glycosaminoglycan completely inhibited prothrombin activation for 45 s after CaCl2 was added to contact-activated plasma; accelerated thrombin inhibition by purified antithrombin III by approximately 50-fold; and accelerated thrombin inhibition equally by antithrombin III in undiluted plasma. This concentration of the three LMW heparins increased, by approximately 70-fold, the rate of factor Xa inhibition by purified antithrombin III compared to the 50-fold increase seen with the two unfractionated heparins. These results thus suggest that tests based on the inhibition of prothrombin activation and/or on the catalysis of thrombin inhibition provide a useful basis for assigning in vitro potency to both unfractionated and LMW heparins.

Catalysis↗
PubMed1989

Interference of coumarin therapy with the "Heptest" owing to declining prothrombin concentrations.

The Heptest kit (Haemachem, Inc., St. Louis, MO) for quantifying heparin in plasma is based on heparin-mediated inhibition of factor Xa, resulting in prolongation of clotting time. In 19 of 55 plasma samples obtained from 32 patients concurrently receiving coumarin and heparin, Heptest results exceeded true heparin values by more than 0.2 int. unit/mL; four samples showed a deviation exceeding 0.4 int. unit/mL. We show here that these deviations are caused by coumarin-induced decreases of plasma prothrombin. This problem can be circumvented by adding purified prothrombin or normal plasma to the assay mixture.

Coumarins↗
PubMed1988

[Measurement of Gla proteins by dot method and clinical study (protein S, protein C, and prothrombin)].

In this study, as a new assay method for Gla protein antigens, the "dot immunobinding assay" which is used on screening for a large number of antibodies (Dot method) was applied. Plasma protein S(PS), protein C(PC) and prothrombin were measured in normal and toxemic pregnant women by the "dot method". The results obtained are as follows. 1. The PS concentration in the third trimester was significantly decreased, with a count of 90.0 +/- 18.6%. 2. PC in the first trimester was significantly decreased, with a count of 81.2 +/- 15.0%. 3. In the other periods, PS and PC were slightly decreased but not significantly. There was no remarkable change in PS or PC in normal third trimester pregnancy or in toxemia of pregnancy. 4. Prothrombin was increased during pregnancy, but not significantly. 5. There was a good correlation between PS and PC concentrations (r = 0.52, p less than 0.01).

Female↗
PubMed1987

Four methods compared for measuring des-carboxy-prothrombin (PIVKA-II).

PIVKA-II (Protein Induced by Vitamin K Absence) is abnormal des-carboxylated prothrombin, which is present in vitamin K deficiency or in patients using warfarin. With a sensitive method for PIVKA-II, biochemical vitamin K deficiency can be established before clinical symptoms occur. We give an overview of methods used to detect PIVKA-II, and four selected methods are inter-compared: (a) measuring total factor II including PIVKA-II by using Echis carinatus snake venom as an activator of prothrombin; (b) measuring PIVKA-II by using snake venom as an activator of factor II after adsorption of functional factor II onto barium sulfate; (c) electrophoresis-immunofixation method; and (d) enzyme immunoassay. We found d to be the most sensitive and reliable method for PIVKA-II.

Adsorption↗
PubMed1987

Multicenter evaluation of a chromogenic substrate method for photometric determination of prothrombin time.

A multicenter study of a chromogenic substrate method for photometric determination of prothrombin time was conducted in order to evaluate its clinical application. Seven laboratories participated in the study using a total of 742 plasma samples from 417 patients on oral anticoagulant therapy, 261 healthy subjects and 64 patients with different diseases especially of the liver as well as 30 patients with hereditary deficiency of coagulation factors II, V, VII, X. The chromogenic PT method was compared to a standardized coagulometric PT assay which uses the same sensitive human placenta thromboplastin calibrated against international reference preparations. A high correlation of the prothrombin ratio values of the chromogenic and the coagulometric assay was obtained in 402 plasma samples (r = 0.940; y = 1.02x - 0.1). The study showed that the chromogenic PT reagent is sensitive to deficiency of the coagulation factors of the extrinsic pathway but not affected by heparin up to 1 IU/ml because of the heparin antagonist added. The precision (coefficient of variation) of the photometric method ranged between 0.6 and 3% (intraassay CV) and between 1.4 and 5.8 (interassay CV). The International Sensitivity Index (ISI) obtained for the used lot was 1.09. The therapeutical range in percentage activity for patients in a stable phase of an anticoagulant therapy was found to be from 15 to 27 percent of normal. The results of the clinical evaluation proved the good comparability of the new chromogenic PT test with coagulometric methods, its high factor sensitivity, good reproducibility and easy performance.

Anticoagulants↗