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PubMed1979

Immunologic studies of prothrombin in newborns.

Prothrombin of newborns was investigated by means of the quantitative immunoelectrophoresis and the two-dimensional immunoelectrophoresis. The plasma of 10 of 24 healthy term newborns and of 5 preterm infants taken immediately after birth showed one prothrombin precipitate in the alpha-2-beta-globulin position when a buffer containing 25 mM calcium lactate was used. No differences in the mobility and form of the precipitate could be observed as compared to healthy adults. The plasma of the other 14 term newborns and one small-for-date infant showed two precipitates, one in the alpha-2-beta-globulin position and a second in the alpha-1-globulin position. Twenty-four hr after the injection of vitamin K, the precipitate in alpha-1-globulin position was no longer evident. When a buffer without calcium was used in the two-dimensional immunoelectrophoresis, only one precipitate in the alpha-1-globulin position was found in all newborns. In the quantitative immunologic determination, the prothrombin was found to be decreased as compared to that of adults. The quantitative immunologic determination and the activity assay gave equal results in those infants who had only one precipitate in the two dimensional immunoelectrophoresis. In those newborns, who had two precipitates, the quantitative immunologic determination gave higher results than the measurement of the activity assay. From this study, no evidence of differences between the prothrombin of newborns and that of adults could be derived. Vitamin K deficiency, as judged from the appearance of a second peak in alpha-1-globulin position in the two dimensional immunoelectrophoresis was a frequent findings in term newborns, even on the 1st day of life.

Adult↗
PubMed2004

Improved distinction of factor V wild-type and factor V Leiden using a novel prothrombin-based activated protein C resistance assay.

A new prothrombin-based activated protein C resistance (APC-R) test is described. In this method, the patient sample is prediluted in a plasma depleted of factor V (FV). A reagent containing APC and a specific activator of FV is added. After an incubation period, clotting is initiated by the addition of the FV-dependent prothrombin activator Noscarin. We analyzed 703 samples from patients undergoing thrombophilia screening. By using a predefined cutoff ratio of 2.5, 100% sensitivity and specificity for the detection of a factor V Leiden (FVL) mutation was found. With a cutoff ratio of 1.2, a complete but narrow distinction of FVL heterozygous (n = 192) and FVL homozygous samples (n = 27) was determined. No interference by the international normalized ratio, activated partial thromboplastin time (aPTT), protein S activity, fibrinogen and factor VIII (FVIII) levels, or lupus anticoagulant ratio was detected. The new prothrombin-based APC-R assay provides improved distinction of FV wild-type and FVL carriers compared with the aPTT-based method. By the use of an FV-dependent prothrombin activator, the assay is not influenced by FVIII concentration or lupus anticoagulants.

Blood Coagulation Tests↗
PubMed2004

Prothrombin 20210GA and factor V Leiden mutations in patients less than 55 years old with myocardial infarction.

Several studies claim that prothrombin 20210GA and factor V Leiden mutations are related to arterial thrombosis. We investigated the frequencies of these mutations and their significance in the development of early atherosclerosis in acute myocardial infarction (AMI) patients younger than 55 years of age. We investigated 96 patients with AMI and 77 control subjects. The diagnosis of AMI was established by typical chest pain and ST elevations on the presentation electrocardiogram and characteristic cardiac enzyme elevations. None of the control subjects had evidence of cardiovascular disease. DNA samples were isolated from all subjects and prothrombin 20210GA and factor V Leiden mutations were determined by the RealTime PCR technique with the aid of a Light Cycler device. The prevalence of factor V Leiden mutation was 6.3% and 5.2% in the patient and control groups, respectively (OR 0.6 [95% CI 0.1- 3.9], P = 0.6), whereas the prevalence of prothrombin G20210A mutation was 4.2% and 2.6% in the patient and control groups, respectively (OR 2.8 [95% CI 0.2 - 32.2], P = 0.4). None of the patients had both mutations. Prothrombin 20210GA and factor V Leiden mutations are not significant risk factors for the development of myocardial infarction in patients less than 55 years old in Southern Turkey.

Adult↗
PubMed2004

Snake venom prothrombin activators similar to blood coagulation factor Xa.

Activation of prothrombin to mature thrombin in vivo occurs by the proteolytic action of the prothrombinase complex consisting of serine proteinase factor Xa, and cofactors that include factor Va, Ca(2+) ions and phospholipids. Several exogenous prothrombin activators are found in snake venom. Among these, Group C prothrombin activators resemble the factor Xa-factor Va complex, while Group D activators are structurally and functionally similar to factor Xa. This review provides a detailed description of current knowledge on Group D prothrombin activators and highlights the importance of studying this family of proteins in enhancing our understanding of structure-function relationships in the mammalian prothrombinase complex.

Animals↗
PubMed1989

Home prothrombin time monitoring after the initiation of warfarin therapy. A randomized, prospective study.

STUDY OBJECTIVE: To evaluate the efficacy and accuracy of monitoring prothrombin times at home. DESIGN: Randomized, prospective cohort study. SETTING: Outpatients discharged from a university hospital or a community hospital. PATIENTS: Fifty patients started on warfarin for the first time who demonstrated an ability to use the monitor and who had not achieved a stable response to warfarin in the hospital. INTERVENTION: Oral anticoagulation therapy managed using a portable prothrombin time monitor compared with specialized anticoagulation clinic care. MEASUREMENTS AND MAIN RESULTS: In the 46 patients who completed the 8-week study, the median percentage of time that patients in the home-monitor group (n = 23) were within a range equal to the target prothrombin ratio +/- 0.3, but always above 1.25, was 93%, compared with 75% for patients in the clinic group (n = 23) (P = 0.003). There was no significant difference between groups in the percentage of time above the therapeutic range; however, the percentage of time that patients were subtherapeutic was significantly greater in the clinic group (P less than 0.001). There were no major thromboembolic or hemorrhagic complications in either group. Differences between home monitor measurements and corresponding clinical laboratory measurements using blood samples drawn within 4 hours of the home test were comparable to differences observed between measurements using two different clinical laboratory instruments. CONCLUSIONS: Use of a portable prothrombin time monitor by patients at home is feasible and provides accurate measurements. Patients doing home monitoring achieve superior anticoagulation control compared with those receiving standard anticoagulation clinic care.

Adult↗
PubMed1976

[Prothrombin activation by immobilized thrombin].

The ability of thrombin, immobilized on BrCN-activated Sepharose 4B, to split prothrombin, was studied. Immobilized thrombin retained up to 70% of its esterase activity and about 5% of its coagulating activity; it was also found to induce partial proteolysis of prothrombin. Two products of prothrombin degradation isolated, i.e. P1 (m. w. 50.000-52.000) and P2 (m. w. 22.000-24.000), did not show either the thrombin or the prothrombin activities. P1 was converted into thrombin under the action of tripsin or Factor Xa. The rate of conversion was considerably increased after addition of Factor V, thromboplastin and Ca2+ ions. Intravenous administration of P1 to rats resulted in changes in the coagulating system of blood, which may be probably indicative of the stimulation of the anticoagulating system. P2 possessed no thrombogenic activity.

Animals↗
PubMed1999

Clinical and analytical relevance of the combination of prothrombin 20210A/A and factor V Leiden: results from a large family.

We analysed the clinical and analytical features of 18 subjects from a Spanish family who bear several combinations of two prothrombotic mutations, factor V Leiden (FVL) and prothrombin 20210A. We identified three subjects homozygous for the 20210A prothrombin mutation which additionally were heterozygous for FVL. The combination of both mutations increases the risk of developing venous thrombotic episodes at the earlier age. However, even in association with FVL, the homozygous condition of the prothrombin 20210A mutation requires additional risk factors to induce a thrombotic event. Finally, the plasma level of factor II showed a significant relationship with the prothrombin genotype.

Adult↗
PubMed1999

Prevalence of prothrombin G20210A, factor V G1691A (Leiden), and methylenetetrahydrofolate reductase (MTHFR) C677T in seven different populations determined by multiplex allele-specific PCR.

Individuals belonging to six racial groups (African American, Asian Indian, Caucasian, Hispanic, Korean, Native American), and a seventh group comprised of referred patients with thrombosis were genotyped for the prothrombin G20210A mutation, the factor V G1691A (Leiden) mutation, and the methylenetetrahydrofolate reductase (MTHFR) C677T mutation by multiplexed allele-specific PCR. The prothrombin 20210A and factor V 1691A allele frequencies in the thrombosis patients, 3.2% and 9.5%, were significantly higher than those in the random Caucasians, 1.3% and 1.8%, (p = 0.043 and p <0.001, respectively). The relative risk of venous thrombosis was determined to be 2.4-fold for carriers of the prothrombin 20210A allele (odds ratio = 2.54; 95% confidence interval = 0.94, 6.82) and 4.5-fold for carriers of the factor V 1691A allele (odds ratio = 5.06; 95% confidence interval = 2.25, 11.36). Among the seven populations, significant differences were observed in the MTHFR 677T allele distribution, however this mutation was not determined to be a risk factor for venous thrombosis in the patient group studied, either alone or in combination with the prothrombin 20210A and/or the factor V 1691A allele(s).

Alleles↗
PubMed1999

Analysis of urinary concentrations of calcium phosphate crystal-associated proteins: alpha2-HS-glycoprotein, prothrombin F1, and osteopontin.

It has been reported that prothrombin F1 and osteopontin (OPN) have strong inhibitory effects on calcium oxalate crystallization and are produced in stone-forming kidneys in animal models. It is important to evaluate urinary concentrations of these proteins for patients with renal stones and healthy control subjects. Urinary macromolecules were collected from nine healthy individuals, nine stone-formers, and five patients with primary hyperparathyroidism (HPT). Each 50-mg aliquot of urinary macromolecules was mixed with calcium phosphate solution, and calcium phosphate crystal-precipitated proteins (alpha2-HS-glycoprotein, prothrombin F1, and OPN) were obtained. The proteins were analyzed by anion-exchange chromatography. Furthermore, OPN levels in whole urine from 18 healthy individuals, 31 stone-formers, and two patients with HPT were measured using a new enzyme immunoassay system. The elution peaks for prothrombin and OPN were significantly smaller for the stone-formers and patients with HPT, compared with the healthy control subjects. Urinary concentrations of OPN assessed using the enzyme-linked immunosorbant assay were significantly lower for stone-formers. Lower urinary excretion of prothrombin F1 and OPN by stone-formers might be one of the reasons for stone formation.

Adult↗
PubMed2000

Factor V Leiden mutation, prothrombin gene mutation, and deficiencies in coagulation inhibitors associated with Budd-Chiari syndrome and portal vein thrombosis: results of a case-control study.

In a collaborative multicenter case-control study, we investigated the effect of factor V Leiden mutation, prothrombin gene mutation, and inherited deficiencies of protein C, protein S, and antithrombin on the risk of Budd-Chiari syndrome (BCS) and portal vein thrombosis (PVT). We compared 43 BCS patients and 92 PVT patients with 474 population-based controls. The relative risk of BCS was 11.3 (95% CI 4.8-26.5) for individuals with factor V Leiden mutation, 2.1(95% CI 0.4-9.6) for those with prothrombin gene mutation, and 6.8 (95% CI 1.9-24.4) for those with protein C deficiency. The relative risk of PVT was 2.7 (95% CI 1.1-6.9) for individuals with factor V Leiden mutation, 1.4 (95% CI 0.4-5.2) for those with prothrombin gene mutation, and 4.6 (95% CI 1.5-14.1) for those with protein C deficiency. The relative risk of BCS or PVT was not increased in the presence of inherited protein S or antithrombin deficiency. Concurrence of either acquired or inherited thrombotic risk factors was observed in 26% of the BCS patients and 37% of the PVT patients. We conclude that factor V Leiden mutation and hereditary protein C deficiency appear to be important risk factors for BCS and PVT. Although the prevalence of the prothrombin gene mutation was increased, it was not found to be a significant risk factor for BCS and PVT. The coexistence of thrombogenic risk factors in many patients indicates that BCS and PVT can be the result of a combined effect of different pathogenetic mechanisms.

Adult↗
PubMed2000

Risk for subsequent venous thromboembolic complications in carriers of the prothrombin or the factor V gene mutation with a first episode of deep-vein thrombosis.

Carriers of a mutation in the prothrombin (clotting factor II) or factor V gene have a 2- to 4-fold greater risk for venous thromboembolism than subjects without the mutations. Whether both mutations also predispose to recurrent venous thromboembolism is unclear. Outpatients who had a first episode of proven symptomatic deep-vein thrombosis and a long-term follow-up were studied. The outcome measure was the cumulative incidence of confirmed venous thromboembolic complications. Two hundred fifty-one patients were enrolled in the study. Mean duration of follow-up was 8.3 years. The prothrombin gene mutation was demonstrated in 27 patients (prevalence, 10.8%; 95% CI, 6.9 to 14.6), and the factor V gene mutation was demonstrated in 41 patients (prevalence, 16.3%; 95% CI, 11.8 to 20.9). The cumulative incidence of venous thromboembolic complications after 10 years was 61.3% (95% CI, 35.7 to 87.9), and the hazard ratio was 2.4 (95% CI, 1.3 to 4.7; P =.004) in patients with the prothrombin gene mutation); the cumulative incidence of venous thromboembolic complications after 10 years was 55.2% (95% CI, 36.4 to 74.0), and the hazard ratio was 2.4 (95% CI, 1.4 to 4.1; P =.001) in patients with the factor V gene mutation. In comparison, the cumulative incidence of venous thromboembolic complications after 10 years was 23.1% (95% CI, 16.2 to 30.1) in patients without the mutations. Prothrombin and factor V gene mutations occur frequently in patients with venous thrombosis and are associated with an increased risk for recurrent venous thromboembolic complications.

Adult↗
PubMed2000

Identification and three-dimensional structural analysis of nine novel mutations in patients with prothrombin deficiency.

Prothrombin deficiency is an autosomal recessive disorder associated with a moderately severe bleeding tendency. In this study, 13 patients with prothrombin deficiency were screened for the presence of alterations in the prothrombin gene, and nine novel candidate mutations were identified. Of 11 patients with hypoprothrombinemia, ten are homozygous for five mutations and one patient is a compound heterozygote. The two patients with dysprothrombinemia are homozygous for two mutations. Eight of nine mutations are missense ones associated with single amino acid substitutions in the propeptide (Arg-1Gln, Arg-2Trp), the kringle-1 (Asp118Try) and kringle-2 (Arg220Cys) domains and the catalytic serine protease domain (Gly330Ser, Ser354Arg. Arg382His and Arg538Cys). The ninth mutation is an in-frame deletion of 3 bp that results in the omission of one amino acid (del Lys 301/302). The combination of these missense mutations with crystal structures for alpha-thrombin and the prothrombin fragments 1 and 2 resulted in new insight into the function of alpha-thrombin. The hypoprothrombinemia mutations were inferred to affect either the cleavage of the propeptide from the Gla domain, the stability of the kringle-1 and -2 domains, or the close association of the A and B chains of the serine protease domain. The dysprothrombinemia mutations were inferred to directly affect catalytic function through their location at the active site crevice or exosite 1 within the serine protease domain.

Adolescent↗
PubMedDate not supplied

[Cerebral venous thrombosis and familial prothrombin gene G20210a mutation].

INTRODUCTION: The prothrombin gene variant G20210A was first described as a risk factor for deep vein thrombosis, and recently for cerebral venous thrombosis, although reported cases had other concomitant risk factors. CLINICAL CASES: A 33 years old woman, with no previous vascular nor thrombotic risk factors, was admitted with thrombosis of superior longitudinal, lateral and sigmoid right sinus. The father had deep venous thrombosis 3 years before. One year later, the 29 year old sister of the proband, developed massive deep venous thrombosis, when she was 8 months pregnant. Laboratory investigations showed elevated anticardiolipin antibodies titer in the proband. Prothrombin activity was in the normal range in the 3 patients. Prothrombin gene mutation G 20210A was detected in the 3 patients. CONCLUSION: As the presence of more than one thrombophilic factor (in the reported case, prothrombin G20210A mutation and anticardiolipin antibodies) increases the likehood of a thrombotic event, it is useful to screen for thrombotic genetic conditions, even when other vascular risks are present, and vice versa.

Adult↗
PubMed1975

Activation of human prothrombin by a procoagulant fraction from the venom of Echis carinatus. Identification of a high molecular weight intermediate with thrombin activity.

In the presence of a procoagulant fraction (Echis carinatus procoagulant) isolated from the venom of the saw-scaled viper Echis carinatus sochureki, purified human prothrombin (P1) is completely converted to thrombin. The first step is the removal of an NH2-terminal peptide (F1) representing approximately one-third of the prothrombin molecule. The remaining peptide (P2) is then cleaved by the action of E.c. procoagulant to yield a two-chain, disulfide-bridged protein (P'2) which has the same molecular weight as P2. P'2 has enzymic (thrombin) activity, as evidence by incorporation of radiolabeled diisopropylphosphate into its heavy chain (TB), hydrolysis of p-toluenesulfonylarginine methyl ester, and clotting of fibrinogen. Relative to thrombin, its esterolytic activity greatly exceeds its clot-promoting activity. Examination of the polypeptide chains obtained by reducing P'2 has shown that its larger chain (TB) is indistinguishable from the heavy chain of thrombin. Its other chain (F2TA) consists of the light chain (TA) of thrombin bound by peptide linkage to the protion of the prothrombin molecule which had been adjacent to F1. Removal of this portion (F2) is catalyzed by thrombin (and, evidently, by P'2), but not by the E.c. procoagulant. When F2 is removed from P'2, the remaining two-chian protein is indistinguishable from thrombin by any of the criteria applied--molecular weight, subunit chain composition, or enzymic activity. Polyacrylamide gel electrophoresis was carried out in sodium dodecyl sulfate before and after disulfide reduction of samples generated in the presence and in the absence of diisopropylphosphorofluoridate, which inhibits thrombin but not the E.c. procoagulant. Such experiments showed that thrombin (and probably P'2), as well as E.c. procoagulant, catalyzes the release of F1. Furthermore, thrombin brings about the cleavage of F1 to yield a two-chain, disulfidebridged protein (F'1). These observations, particularly those made in the course of characterizine P'2, have led to the conclusion that cleavage of the peptide bond connecting the TA and TB portions of the prothrombin molecule (or its derivatives) produces a serine active center and, hence, a molecule possessing thrombin activity. This cleavage is catalyzed by the E.c. procoagulant but not by thrombon itself.

Animals↗
PubMed2002

Substitution of Gly-548 to Ala in the substrate binding pocket of prothrombin Perijá leads to the loss of thrombin proteolytic activity.

Prothrombin Perijá is a dysprothrombin derived from a homozygous patient that manifests low thrombin activity upon activation in a one-stage assay. Purified prothrombin Perijá showed normal appearance on SDS-PAGE. and was cleaved normally to form alpha-thrombin by the prothrombinase complex. The activated form, thrombin Perijá, however, did not show any proteolytic activity towards native substrates, fibrinogen, protein C or various synthetic substrates for alpha-thrombin, but it was able to bind to antithrombin III, although the binding capacity was markedly reduced even in the presence of heparin. Thrombin Perijá showed full reactivity toward a small inhibitor, DFP, indicating that the molecular defect is in the substrate binding site in the thrombin molecule but not in the active site itself. By DNA sequence analysis of the patient prothrombin gene, we identified a G to C mutation at nucleotide 20016 in exon 14, which predicts a Gly-548 to Ala substitution in the prothrombin Perijá molecule. The structural modeling of thrombin Perijá suggests that Ala-548 is located close to the limb of the cavity wall of the substrate binding pocket, and that the methyl group blocks protrusion of the guanidino group of Arg into the cavity. This steric hindrance may well inhibit the access of Arg-containing substrates to the catalytic Ser-525 leading to the loss of proteolytic activity.

Alanine↗
PubMed1975

Potato inhibitors of intrinsic prothrombin activators.

The potato protease inhibitors inhibit intrinsic prothrombin activators and trypsin activation of prothrombin. The inhibitors 5a and 5b are responsible for the intrinsic prothrombin activator inhibition. This inhibition is progressive. No inhibition by these inhibitors of tissue thromboplastin activation of prothrombin or thrombin activity was observed.

Animals↗
PubMed2002

Pseutarin C, a prothrombin activator from Pseudonaja textilis venom: its structural and functional similarity to mammalian coagulation factor Xa-Va complex.

Several snake venoms contain procoagulant proteins that can activate prothrombin. We have purified pseutarin C, a prothrombin activator from the venom of the Australian brown snake (Pseudonaja textilis). It converts prothrombin to thrombin by cleaving both the peptide bonds Arg(274)-Thr(275) and Arg(323)-Ile(324), similar to mammalian factor Xa. It is a protein complex (approximately 250 Kd) consisting of an enzymatic and a non- enzymatic subunit. These subunits were separated by reverse phase HPLC and their interactions with bovine factor Xa and factor Va were studied. The enzymatic subunit of pseutarin C has an approximately 13 fold higher affinity for bovine factor Va (K(d) of 11.4 nM for pseutarin C enzymatic subunit--bovine factor Va interaction as compared to a K(d) of 147.4 nM for the bovine factor Xa-Va interaction). The non-enzymatic component, however, was unable to activate bovine factor Xa. N-terminal sequence analysis of the catalytic subunit of pseutarin C showed approximately 60% homology to mammalian factor Xa and approximately 78% homology to trocarin, a group D prothrombin activator from Tropidechis carinatus venom. Structural information for the non-enzymatic subunit of pseutarin C was obtained by amino terminal sequencing of several internal peptides. The sequence data obtained indicates that the non-enzymatic subunit of pseutarin C has similar domain architecture like the mammalian factor Va and the overall homology is approximately 55%. Thus pseutarin C is the first venom procoagulant protein that is structurally and functionally similar to mammalian factor Xa-Va complex.

Animals↗
PubMedDate not supplied

[Activation of prothrombin, modified by maleic anhydride, some properties of N-maleyl-thrombin with free alpha-amino groups].

Conditions for the acylation of bovine prothrombin by maleic anhydride are worked out. The reaction is shown to modify not more than 95% of amino groups. The changes in hydrodynamic and electrophoretic properties testify about structural changes of prothrombin as a result of the modification of free amino groups. The activation of maleyl-prothrombin to maleyl-thrombin took place in 25% sodium citrate only in the presence of thrombin and the Xa factor. The increase of modified amino groups in prothrombin resulted in the decrease of the activity of generated maleyi-thrombin. The main fraction of maleyl-thrombin with free alpha-amino groups had a sedimentation coefficient of 2.1 S and possessed a residual esterase activity.

Amines↗