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PubMed2003

Cloning of a prothrombin activator-like metalloproteinase from the West African saw-scaled viper, Echis ocellatus.

Systemic envenoming by the saw-scaled viper, Echis ocellatus, is responsible for more deaths than any other snake in West Africa. Despite its medical importance, there have been few investigations into the toxin composition of the venom of this viper. Here we describe the isolation of E. ocellatus venom gland cDNAs encoding a protein of 514 amino acids that showed 91% sequence similarity to Ecarin, a prothrombin-activating metalloproteinase from the venom of the East African viper, E. pyramidum leakeyi, that induces severe consumption coagulopathy. Structural similarities between the E. ocellatus metalloproteinase and analogues in venoms of related vipers suggest that antibodies raised to phylogenetically conserved E. ocellatus metalloproteinase domains may have potential for cross-specific and cross-generic neutralisation of analogous venom toxins.

Amino Acid Sequence↗
PubMed2005

Living donor liver transplantation for hepatocellular carcinoma: a special reference to a preoperative des-gamma-carboxy prothrombin value.

BACKGROUND: Des-gamma-carboxy prothrombin (DCP) is a sensitive marker related to vascular invasion of hepatocellular carcinoma (HCC). The aim of this study was to clarify the risk factors of HCC recurrence in living donor liver transplantation (LDLT) with special reference to preoperative DCP values. METHODS: Forty consecutive adult HCC patients who underwent LDLT were examined for a correlation between the DCP value and vascular invasion. Risk factors for recurrence were also investigated using clinicopathological variables including preoperative DCP levels. RESULTS: The incidence of positive histological vascular invasion in patients with DCP values above 300 mAU/mL was higher than that with those with DCP value below 300 mAU/mL. Other significant risk factors for recurrence were over 5 cm tumor diameter, not meeting the Milan criteria, AFP value >400 ng/mL, histological vascular invasion, poorly differentiated histology, and male gender. Among the patients who did not meet the Milan criteria, those with both no more than 5 cm of tumor diameter and no more than 300 mAU/mL DCP exhibited a good prognosis. CONCLUSIONS: A high DCP value, namely >300 mAU/mL correlated with histological vascular invasion and was one of the strongest prognostic variables. Therefore, special attention should be paid to HCC patients with high DCP values. No correlation between the number of tumor nodules and recurrence was found; therefore, the Milan criteria may require revision regarding the number of tumor nodules.

Adult↗
PubMed2005

Factor V Leiden, prothrombin 20210A, methylenetetrahydrofolate reductase 677T, and population genetics.

Thrombosis results from the interaction between predisposing genetic polymorphisms and acquired risk factors. Two of the main prothrombotic alleles, Factor V (FV) Leiden and prothrombin 20210A, are only encountered among European populations. They are estimated to have arisen about 21,000-34,000 years ago as founding mutations after the evolutionary divergence of Caucasians from Asians, and have been subsequently dispersed by the Neolithic migrations. These polymorphisms may have developed by means of genetic drift or natural selection by possibly conferring a reduced risk of bleeding. Of note, FV Leiden is nearly absent in the Basques, a European population of pre-Neolithic individualization. The C677T mutation of the methylenetetrahydrofolate reductase gene may induce hyperhomocysteinemia and could slightly increase the risk of arterial or venous thrombosis and pregnancy loss in individuals with folic acid deficiency. Through a selective phenomenon, the frequency of the mutation may parallel the intake of this vitamin within populations. Hence, this allele is underrepresented in Sub-Saharan Africa, Indonesia, and in the Inuits and a positive North to South gradient has been described in Europe. Thus, these three inherited prothrombotic polymorphisms represent interesting tools for population genetics studies.

Evolution, Molecular↗
PubMed1994

Translational diffusion of bovine prothrombin fragment 1 weakly bound to supported planar membranes: measurement by total internal reflection with fluorescence pattern photobleaching recovery.

Previous work has shown that bovine prothrombin fragment 1 binds to substrate-supported planar membranes composed of phosphatidylcholine (PC) and phosphatidylserine (PS) in a Ca(2+)-specific manner. The apparent equilibrium dissociation constant is 1-15 microM, and the average membrane residency time is approximately 0.25 s-1. In the present work, fluorescence pattern photobleaching recovery with evanescent interference patterns (TIR-FPPR) has been used to measure the translational diffusion coefficients of the weakly bound fragment 1. The results show that the translational diffusion coefficients on fluid-like PS/PC planar membranes are on the order of 10(-9) cm2/s and are reduced when the fragment 1 surface density is increased. Control measurements were carried out for fragment 1 on solid-like PS/PC planar membranes. The dissociation kinetics were similar to those on fluid-like membranes, but protein translational mobility was not detected. TIR-FPPR was also used to measure the diffusion coefficient of the fluorescent lipid NBD-PC in fluid-like PS/PC planar membranes. In these measurements, the diffusion coefficient was approximately 10(-8) cm2/s, which is consistent with that measured by conventional fluorescence pattern photobleaching recovery. This work represents the first measurement of a translational diffusion coefficient for a protein weakly bound to a membrane surface.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed2000

Stability of prothrombin time and activated partial thromboplastin time tests under different storage conditions.

Prothrombin time (PT) and activated partial thromboplastin time (aPTT) are common laboratory tests that are useful in the diagnosis of coagulation disorders and monitoring anticoagulant therapy. Recent expansions in the outreach laboratory services at our institution prompted us to investigate the shipping limitations for some tests, including PT and aPTT. Although we followed NCCLS guidelines for the collection of blood specimens, we observed falsely elevated PT and aPTT values due to the different storage conditions. The objective of this study is to determine the effect of conditions and duration of storage on PT and aPTT tests using plasma and whole blood samples, respectively. For this study, 36 plasma samples with normal and prolonged PT and aPTT were exposed to different storage conditions. Blood was centrifuged immediately and plasma was stored at room temperature (RT), refrigerated at 4 degrees C, or frozen at -20 degrees C. The samples were analyzed at 0 h and repeated at 6, 12 and 24 h under various conditions. Although statistically significant differences were observed for plasma samples for normal PT tests after 12 h at refrigerated and frozen storage conditions, the differences would not change the clinical interpretation of the results. On the other hand, samples stored refrigerated or at RT showed significant differences for aPTT at 24 h. These differences would change clinical interpretation, especially for samples with normal or near normal aPTT times. Interestingly, aPTT was significantly higher for samples stored frozen when compared to refrigerated and RT conditions at 6 h. Similar patterns were also observed on ten whole blood samples with normal PT and aPTT values. In conclusion, either plasma or whole blood samples can be accepted for PT testing up to 24 h and for aPTT testing up to 12 h only, when transported either at RT or at 4 degrees C.

Humans↗
PubMed1999

Genetic determinants of heritable venous thrombosis: genotyping methods for factor V(Leiden)A1691G, methylenetetrahydrofolate reductase C677T, prothrombin G20210A mutation, and algorithms for venous thrombosis investigations.

OBJECTIVES: To implement cost effective and clinically relevant thrombophilic genotyping and homocysteine analysis in our coagulation laboratory. METHODS: We describe genotyping assays for three of the genetic defects associated with hereditary thrombosis: factor V(Leiden) A1691G, methylenetetrahydrofolate reductase C677T, and prothrombin gene G20210A. A second confirmatory assay for factor V(Leiden) using allele specific oligonucleotide polymerase chain reaction is also presented. We suggest an algorithm for the rational integration of the traditional assays routinely used to investigate venous thrombosis with genotyping and plasma homocysteine measurements. RESULTS: These polymerase chain reaction based assays were designed to be performed under identical reaction conditions, permitting simultaneous setup, amplification, digestion, and analysis. CONCLUSIONS: The three genotyping assays presented are robust and relatively easy to perform. Use of an algorithm will ensure efficient resource utilization and minimize unnecessary testing.

5,10-Methylenetetrahydrofolate Reductase (FADH2)↗
PubMed1997

Recombinant factor VIIa corrects prothrombin time in cirrhotic patients: a preliminary study.

BACKGROUND & AIMS: Cirrhotic patients with a prolonged prothrombin time (PT) are known to have low levels of factor VII. Because the current modalities to correct this problem are not ideal, recombinant factor VIIa (rFVIIa) may be useful in correcting the prolonged PT observed in the coagulopathy of cirrhosis. The aim of this study was to evaluate the effectiveness of rFVIIa in nonbleeding volunteer patients with the coagulopathy of cirrhosis. METHODS: A preliminary, single-center, dose-escalation trial was performed. Cirrhotic patients with a PT of > 2 seconds above the upper limit of the reference value received an intramuscular injection of vitamin K. Ten patients whose PT did not correct to within 2 seconds above the control of the upper limit of the reference value were given three successive dosages of rFVIIa (5, 20, and 80 micrograms/kg) during a 3-week period. RESULTS: The mean PT transiently corrected to normal in all three dosage groups. No adverse effects were noted. There was no evidence of the induction of disseminated intravascular coagulation. CONCLUSIONS: This preliminary trial shows rFVIIa to be effective in transiently reversing the prolonged PT in a select group of nonbleeding cirrhotic patients. These preliminary observations support conducting a large-scale efficacy trial.

Adult↗
PubMed1999

Occurrence of anti-prothrombin and anti-beta2-glycoprotein I antibodies in patients with history of thrombosis.

New evidence indicates that antibodies to beta2-glycoprotein I (anti-beta2GPI) or to human prothrombin (anti-II)(or to both of these) are specific markers of the antiphospholipid syndrome (APS). They have been mainly associated with thrombotic complications in patients with APS. However, some studies have reported that elevated levels of anti-II, but not of anfi-beta2GPI, imply a risk of venous thrombosis (VT) or arterial thrombosis (AT) in subjects with no previous thrombosis and no antiphospholipid antibodies (aPL) by ELISA. The present study Included 180 patients with a history of thrombosis, 83 of them without aPL (group I) and the remaining 97 diagnosed as having APS (group II). Anti-beta2GPI was found in only 1 of the 83 patients from group I but was found in approximately 50% of those from group II (P < .0001). In contrast, positive anti-II was detected with a high prevalence in patients from group I (VT, 22.6%; AT, 26.7%) and in those from group II (VT, 37.5%; AT, 14.6%). No statistical differences were found in the prevalence of anti-II between the two groups of patients. On the other hand, such a difference was significant when compared with results in a normal group (1/67, 1.4%, P < .0001). These data Indicate that anti-II occurs frequently in patients with previous thrombosis either with or without lupus anticoagulant activity. Accordingly, testing of anti-II might be clinically useful in the evaluation for thrombophilla.

Adult↗
PubMed1993

Standardization of prothrombin times in newborn infants.

The prothrombin time (PT) for patients receiving warfarin varies widely, reflecting the heterogeneity of thromboplastin reagents. The International Committee on Thrombosis and Haemostasis recommends that PT values for these patients be expressed as international normalized ratios. This study showed that thromboplastin reagents also significantly influence PT values in neonatal plasma and that expressing PT values as international normalized ratios decreases this variability.

Adult↗
PubMed1995

Home monitoring of warfarin therapy in children with a whole blood prothrombin time monitor.

We prospectively evaluated a capillary whole blood prothrombin time (PT) monitor (Biotrack, Ciba Corning) in an outpatient pediatric anticoagulation clinic (40 clinic patients) and in age-matched healthy subjects (30 control subjects). Subsequently, 23 children requiring warfarin therapy were placed on a home program (home patients) using the PT monitor; their parents were trained and the results followed by clinic staff. The PT results were reported as internationalized normalized ratios (INRs). The laboratory and PT-monitor INR values were similar for the clinic patients and the control subjects (y = 0.76x + 0.38; r = 0.93; p < 0.001). The accuracy of the PT monitor (the difference between INR values and the laboratory INR) was best at an INR of 2.5 to 3.5; 90% of paired INR values were within 0.8 INR units. The average duration of monitoring for home patients was 13 months (range, 2 to 60 months). They had an average of 3 dose measurements (range, 1 to 11 measurements) and 1.8 dose changes (range, 0.6 to 4.5 changes) per month. Of the 599 measurements, 63% were within the therapeutic range, similar to those for clinic patients; the dose requirements were also similar. There was 1 significant bleeding event, a subdural hematoma in a patient with an INR of 4.1, and 1 catheter-related thrombotic event with an INR of 1.2; both children recovered. Of the 23 families, one discontinued home monitoring because of parental discomfort, 2 children died of their primary disease, 6 completed warfarin therapy, and 14 remain on the home program. We conclude that the whole blood PT/INR monitor is safe and offers practical advantages to children requiring anticoagulation.

Adolescent↗
PubMed1995

Des-gamma-carboxy prothrombin and proliferative activity of hepatocellular carcinoma.

BACKGROUND: Des-gamma-carboxy prothrombin (DCP) is a useful marker for the prognosis of hepatocellular carcinoma (HCC). In this report we investigated the relationship between the positivity of DCP and proliferative activity of HCC and discuss the cause of poor prognosis of DCP-positive HCC. METHODS: Immunohistochemical and clinicopathologic study was done in 114 patients with resected HCC measuring less than 6 cm in diameter by using monoclonal antibody for proliferating cell nuclear antigen (PCNA). RESULTS: PCNA labeling index (PCNA-LI) was significantly higher in the patients with DCP-positive HCC than in those with DCP-negative HCC; also a positive correlation was noted between the PCNA-LI and the DCP level. We divided patients into two groups according to the PCNA-LI. In the high PCNA-LI group the patients with DCP-positive HCC exhibited a higher PCNA-LI than did the patients with DCP-negative HCC. As for pathologic prognostic factors, the DCP-positive high PCNA-LI group showed the highest incidence of tumor thrombus of the portal vein and intrahepatic metastasis while also exhibiting the lowest recurrence-freedom rate. From multivariate analysis we find that DCP, as well as PCNA-LI, is one of the risk factors for recurrence of HCC after hepatectomy. CONCLUSIONS: Our results thus suggest that DCP-positive HCC showed high PCNA-LI, and this might be the main cause for early intrahepatic spread and poor prognosis of DCP-positive HCC.

Adult↗
PubMed2000

Prothrombin G20210A, factor V Leiden, and factor XIII Val34Leu: common mutations of blood coagulation factors and deep vein thrombosis in Austria.

Mutations in the gene for prothrombin (F2 20210A) and factor V (F5 1691A, factor V Leiden) are established risk factors for deep venous thrombosis (DVT). Recently, a mutation in the gene for factor XIII (F13 100T) leading to a Valine-Leucine exchange at amino acid position 34 has been reported to be protective against DVT. To analyze the role of these mutations for DVT in Austria, we analyzed their prevalence in 154 patients with documented DVT and 308 sex- and age-matched control subjects. Allele frequencies of F2 20210A, F5 1691A, and F13 100T were 0.018, 0.039, and 0.274 among controls, and 0.045, 0.120, and 0.211 among patients, respectively. Odds ratios for DVT associated with F2 20210A, F5 1691A, and F13 100T alleles were 2.5 (95% CI: 1.1-5.7), 3.4 (95% CI: 1.9-5.8), and 0.7 (95% CI: 0.5-1.0). We conclude that F2 20210A, F5 1691A, and F13 100T are common mutations in the Austrian population. F2 20210A and F5 1691 increase the risk for DVT, whereas F13 100T is associated with a decreased risk for DVT. Routinely, analysis of these mutations may help to analyze the individual risk for DVT.

Adolescent↗
PubMed2000

Accuracy of a portable prothrombin time monitor (Coagucheck) in patients on chronic oral anticoagulant therapy: a prospective multicenter study.

A portable prothrombin time (PT) monitor allows patients on oral anticoagulant therapy (OAT) to measure their PT at home. The purpose of the study was to evaluate the accuracy and precision of a portable PT monitor (Coagucheck, Roche Diagnostics, Mannheim, Germany) as compared with laboratory methods. The prospective study was conducted in four centers of the Italian Federation of Anticoagulation Clinics. A one-month instruction phase was followed by a six-month surveillance phase. Seventy-eight subjects on stable OAT (48 men, 30 women, age range: 18-75) were selected on a volunteer basis. Dual measurements of INR values were performed in each subject both from finger capillary blood by the monitor and from venous blood by the Anticoagulation Clinic laboratory in three instruction sessions. The mean difference (bias) of the monitor INR results when compared with the average of laboratory INR and monitor INR results was -0.025 (limits of agreement-LA: -0.84/+0.81 INR units). The mean bias was -0.0675 (LA: -0.37/+0.23), +0.018 (LA: -0.39/+0.35), and +0.039 (LA: -0.49/+0.55), respectively, for INR values lower than 2.0, between 2.0 and 3.0, and greater than 3.0. The overall precision coefficient of monitor INR was 0.370, while it was 0.23, 0.46, 0.29, and 0.21, respectively, in Centers 1, 2, 3, and 4. The overall variation coefficient was 6.5% while it was 3.7%, 8.5%, 4.7%, and 4.9%, respectively, in Centers 1, 2, 3, and 4. Coagucheck has an acceptable level of accuracy for INR values in the range between 2.0 and 3.0. A wide variation in monitor performance was found among centers.

Administration, Oral↗
PubMed2000

Manufacturing of a prothrombin complex concentrate aiming at low thrombogenicity.

The paper describes the production of a prothrombin complex concentrate (PCC) with high virus safety and a well-balanced content of vitamin K-dependent clotting factors and inhibitors. Solid-phase extraction is followed in a second step by optimized anion exchange chromatography using a radial column. A step for virus removal by nanofiltration is introduced in addition to the solvent/detergent step. By speeding up the chromatographic step, the period of time required for production is reduced considerably. The activities of the four vitamin K-dependent clotting factors II, VII, IX and X are in ratios of about 1:1:1:1. Protein C, Protein S, and Protein Z are also present in therapeutically effective concentrations. The product shows no thrombogenicity, in either in vivo nor in vitro models. Clinical investigations show that the PCC is a safe and efficient preparation for the substitutive treatment of FIX or FVII in patients suffering from the respective deficiencies. All bleeding episodes have been efficiently controlled with relatively low doses of the concentrate. The surgical procedures have been conducted without any problems in severely FIX and FVIII deficient patients.

Animals↗
PubMed2001

Long-term use of oral contraceptive therapy in women with the prothrombin 20210 G-A polymorphism without thrombotic complications: a study of 13 women (12 heterozygotes and 1 homozygote).

Thirteen female patients with the prothrombin 20210 G-A abnormality (twelve heterozygotes and one homozygote) were selected out of 551 patients admitted to our Department of Medicine or to our Outpatient Hemostasis Units between January 1999 and October 2000. The selection was based on the fact that all patients had taken or were still taking oral contraceptives (OC) for a period of 3 years or longer than 3 years. None of these patents as gathered from history, physical examination, private physician records and our records has shown any DVT during or immediately after OC intake. Physical and compression ultrasonography examinations at the time of study were all negative. The average length of oral contraceptives therapy (OCT) was 10 years (range 3-23). The average age of patients at the time of oral contraception was 30 years. The 13 women had also 17 pregnancies without any venous thrombosis. The observations casts several doubt about the prothrombotic effect of this polymorphism. Since DVT has been shown to occur occasionally even in normal women, it is likely that the same may occur in women with this polymorphism regardless of the existence or not of any pathogenetic relationship between the two phenomena. Occasional reports suggesting a link between this polymorphism and oral contraception-related venous thrombosis should be carefully evaluated in order to avoid premature and incorrect conclusions.

Adult↗
PubMed2002

Dilute prothrombin time-based lupus ratio test. Integrated LA testing with recombinant tissue thromboplastin.

The lupus ratio (LR) test is a normalized ratio of the clotting times obtained with low and high phospholipid (PL) concentrations, where the test plasma is mixed 1:1 with normal pooled plasma (NP). As an integrated, automated, and computer-assisted assay, this principle has been applied to the dilute activated partial thromboplastin time (dAPTT) and dilute Russell viper venom time (dRVVT) test systems. In this study, we used recombinant thromboplastin to develop an automated LR test based on the dilute prothrombin time (dPT). Using plasma samples from a selected group of patients (N=92) with a well-defined lupus anticoagulant (LA) status, the dPT-based LR test showed fair agreement with the dAPTT-based LR test (kappa=.60, P<.001) and good agreement with the dRVVT-based LR test (kappa=.78, P<.001) regarding the classification of plasmas as LA-negative or -positive. Most discordant plasmas were low positive. Correlation between dPT- and dRVVT-positive LRs was only moderate (r(s)=.51, P=.002), and correlation between dPT- and dAPTT-positive LRs was nonsignificant (r(s)=.23, P=.18). Using dilutions of pooled LA-positive plasma, the dAPTT-based LR test appeared to be the most sensitive of the three tests. This study confirms the general validity of the LR principle and shows that the dPT-based LR test yields reproducible results. The low coefficients of variation (CV) of the LR assays, combined with a fairly low correlation among the three tests, support the assumption of antibody heterogeneity of LA-positive plasmas and the desirability of performing more than one test.

Adult↗