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PubMed1994

High F1.2 fragment of prothrombin, thrombin-antithrombin III complex (TAT) and soluble fibrin plasma levels demonstrate hypercoagulability induced during loco-regional thrombolytic therapy with rt-PA.

In order to investigate the coagulation and fibrinolysis state in arterial peripheral thrombosis and thrombolysis, we studied 33 consecutive patients (mean age = 65, range: 28-88), 25 males and 8 females diagnosed of acute or subacute lower limb arterial thrombosis, treated with an intrathrombus infusion of rt-PA (0.1 mg/Kg/h) for three hours. Plasma levels of antithrombin III (AT-III), protein C (PC), plasminogen (Pg) and alpha 2-antiplasmin (AP), total and free protein S (PS), thrombin-antithrombin III complex (TAT), F1.2 fragment of prothrombin (F1.2), fibrinogen (Fg), soluble fibrin monomers (FM), tissue-plasminogen activator (t-PA), plasminogen activator inhibitor 1 (PAI-1), total fibrinogen/fibrin degradation products (TDP) and D dimer (DD) were determined prior to the therapeutic regime, at the end of the treatment, and 24 hours later. Levels of AT-III and protein C were somewhat low during the complete study. There was an increase in t-PA, TDP and D Dimer and a decrease of fibrinogen, alpha 2-antiplasmin and plasminogen at 3 hours. An elevation of TAT, fibrin monomers and F1.2 levels was found at three hours. A positive correlation between TAT and F1.2 was observed (r = 0.57, p < 0.05). There was also a positive correlation between soluble fibrin and TAT (r = 0.59, p < 0.05) and with F1.2 (r = 0.56. p < 0.05). These latter facts reflect an hypercoagulable situation induced during loco-regional thrombolytic therapy.

Adult↗
PubMed1995

Comparison of the efficacy of D-dimer, fibrin degradation products and prothrombin fragment 1+2 in clinically suspected deep venous thrombosis.

The diagnostic efficacy of D-dimer, fibrin degradation products (FbDP) and prothrombin fragment 1+2 (F1+2) in patients with clinically suspected deep venous thrombosis (DVT) was investigated. 161 patients suspected of DVT were investigated. The diagnosis DVT was made in 58 patients using isotope leg scanning and ultrasonic duplex scanning. In all patients D-dimer, FbDP and F1+2 levels were determined using a latex method for D-dimer and enzyme-linked immunosorbent assays (EIA) for FbDP and F1+2. For the D-dimer latex assay sensitivity was 69% and specificity 92% (cut-off level 500 ng/ml). For the FbDP assay sensitivity was 100% and specificity 8% (cut-off level 250 ng/ml). For the F1+2 assay sensitivity was 100% and specificity 17% (cut-off level 0.3 nM). Specificity could not be improved by the combination of FbDP and F1+2. We conclude that in our population the use of the latex D-dimer assay, FbDP and F1+2 EIA's have no value as screening tests to rule out the diagnosis DVT in clinically suspected patients.

Adolescent↗
PubMed1996

Monitoring thrombin generation with prothrombin fragment 1.2 assay during cardiopulmonary bypass surgery.

UNLABELLED: Despite high plasma levels of heparin during cardiopulmonary bypass surgery, activation of the coagulation system has been reported. We hypothesize that the coagulation system activity most appropriately could be assessed by molecular markers of thrombin generation. The aim of the present study was to describe the changes in thrombin generation during CPB, using prothrombin fragment F1 + 2 (F1.2) as an indicator and evaluate different blood sampling regimens for interpretation of the F1.2 measurements. Twenty patients, operated under extracorporeal circulation with coronary artery bypass grafting (CABG), comprised the study material. The heparin levels were maintained above 2.5 IU/ml throughout the bypass procedure and the functional AT-III level was kept above 0.5 U/ml. Despite of this anticipated inactivation of the coagulation system, the concentrations of F1.2 and FpA increased throughout CPB, particularly after release of the aortic crossclamp. F1.2 and FpA correlated significantly (R = 0.69). No statistically significant correlation was found between F1.2 formation rate and age, bodyweight, baseline ACT, ACT after 200 IU heparin/kg, average heparin concentration during CPB or average AT-III level during CPB. CONCLUSIONS: Thrombin formation seems to be a continuous process during CPB despite adequate heparinization. The pattern of thrombin generation can be assessed most appropriately in terms of F1.2 generation rate. Extraordinary high levels of F1.2 were seen after release of the aortic crossclamp, indicating that the periods before and after aortic crossclamping should be evaluated separately.

Adult↗
PubMed1984

Prothrombin fragment 1-membrane interactions: a calcium-43 NMR study.

The 43Ca NMR spectra are reported for solutions of prothrombin fragment 1 in the presence and absence of phospholipid. The calcium NMR spectrum permits distinction between three thermodynamic classes of calcium-binding interactions. The calcium ion in the lipid-free solutions was labile, with maximum residence times estimated for the average protein site in the range of 0.5-1 ms. The calcium spectrum was sensitive to the protein association and the addition of phospholipid, which appears to sharpen the calcium specificity for the protein sites. The calcium NMR spectra in the presence of phospholipid are similar to those in lipid-free solutions, which suggests that the calcium ion remains labile in the lipid-protein complex.

Animals↗
PubMed1991

The diagnostic value of the assay of des-gamma-carboxy prothrombin in the detection of small hepatocellular carcinoma.

Des-gamma-carboxy prothrombin (DCP) assay was performed by a staphylocoagulase method in 35 consecutive patients with small (less than 5 cm), resectable hepatocellular carcinoma (HCC). They also simultaneously received serum alpha-fetoprotein (AFP) assay. According to diagnostic strategy, patients were divided into two groups. Group I consisted of eight patients who were candidates for a mass screening project for HCC with elevated AFP levels (greater than 20 ng/ml). Five of these patients had an increased DCP level (greater than 6 U/l). Group II included 27 victims of chronic hepatitis B or cirrhosis whose tumors were detected by ultrasonography during regular follow-up. In this group, increased DCP and AFP levels were observed in 11 and 16 cases, respectively. Of 14 patients with smaller HCC (less than 3 cm), only three had elevated DCP levels, while eight patients had an abnormal AFP level. When these two assays were combined, 18 of 27 patients in group II and nine of 14 patients with smaller HCC (less than 3 cm) revealed elevation of one or both of the two markers. A total of 16 out of 35 patients with small HCC had abnormal DCP levels. In conclusion, DCP assay is less sensitive than AFP assay in the detection of small HCC, and the combination of both markers has little complementary effect.

Biomarkers↗
PubMed1990

Characterization of the Alu-rich 5'-flanking region of the human prothrombin-encoding gene: identification of a positive cis-acting element that regulates liver-specific expression.

The nt sequence of 6127 bp of sequence upstream of the human prothrombin-encoding gene (F2) has been determined. Since we previously characterized 417 bp of DNA immediately upstream from the transcription start point (tsp), 6544 bp of continuous flanking sequence are known. Eleven Alu repeat sequences present in this region comprise 45% of the sequence; other repetitive sequences were identified by searching GenBank. The tsp was found to be heterogeneous by exon mapping and primer extension analysis. To localize the cis-acting sequences responsible for the liver-specific expression of F2, hybrid cat genes were constructed with various lengths of F2 5'-flanking region cloned upstream from a promoterless cat gene. After transfection into HepG2 and HeLa cells, it was inferred that the region between nt -1101 and -798 was required for synthesis in HepG2 cells; no synthesis was observed using these constructs in HeLa cells. Two sequences for known liver-specific or regulatory cis-acting sequences were identified in this region.

Amino Acid Sequence↗
PubMed1993

Intraoperative measurement of activated partial thromboplastin time and prothrombin time by a portable laser photometer in patients following cardiopulmonary bypass.

Intraoperative capabilities to rapidly assess coagulation status following cardiopulmonary bypass (CPB) may be of benefit in providing optimal hemostasis and transfusion management, because CPB causes abnormalities in coagulation that may increase morbidity and mortality. The Ciba Corning 512 coagulation monitor (Ciba Corning, Medfield, MA) is a compact and portable device that rapidly determines the prothrombin time (PT) and activated partial thromboplastin time (APTT) in whole blood samples. One hundred patients requiring CPB had APTT and PT determined in whole blood specimens by the 512 coagulation monitor and in plasma specimens by the hospital laboratory from the same arterial blood sample obtained after protamine administration. Correlation coefficients of 0.95 and 0.77 were obtained for the paired APTT and PT tests, respectively (P < 0.01). A bias of 12.6 seconds and 0.77 seconds was determined for the APTT and PT, respectively. The 95% confidence intervals of the bias of the APTT and PT were 9.7 seconds to 15.5 seconds and 0.3 seconds to 1.16 seconds, respectively. The 512 coagulation monitor provided APTT and PT results in less than 3 minutes compared to approximately 45 minutes for the hospital laboratory. A reduction in accuracy was associated with the 512 coagulation monitor PT and APTT when different sampling sites were used. The 512 coagulation monitor accuracy was not affected by a variation of hemoglobin concentration or platelet count between 6 and 12 gm/dL and 15 to 300 x 10(9)/L, respectively. In conclusion, the 512 coagulation monitor provided a rapid APTT and PT result, but the APTT was less accurate. Speeding access to hospital laboratory results would be even more efficacious and accurate.

Adult↗
PubMed2005

EPCR Ser219Gly: elevated sEPCR, prothrombin F1+2, risk for coronary heart disease, and increased sEPCR shedding in vitro.

We have progressively analysed three studies of coronary heart disease (CHD) for a variant in EPCR (Ser219Gly). Initially, in a prospective study, NPHSII, while no overall CHD-risk was identified in heterozygotes, homozygotes for 219Gly exhibited a three-fold elevated risk (HR 3.3, CI 1.22-8.96). In diabetics within NPHSII, there was a suggestion that 219Gly+ was associated with elevated CHD-risk (HR 1.89, CI 0.39-9.06) although numbers were small. To further assess the effect of the variant in diabetes, a case-control study of MI, HIFMECH, was used, in which previous analysis had defined a group with metabolic syndrome, by factor analysis. A significant CHD-risk interaction was identified between genotype and the 'metabolic syndrome' factor (interaction p=0.009). To further assess CHD-risk for this variant in type-2 diabetes and to assess the effect of the variant upon thrombin generation and plasma levels of soluble EPCR, a cross-sectional study of type-2 diabetes was used. A significant CHD-risk was identified for European Whites (OR 2.84, CI 1.38-5.85) and Indian Asians in this study (OR 1.6, CI 1.00-2.57) and the frequency of 219Gly was two-fold higher in Indian Asians. Soluble EPCR levels were strongly associated with genotype, with homozygotes for 219Gly having four-fold higher levels (p<0.0001). In vitro studies of EPCR-transfected cells suggested increased basal release of sEPCR from cells expressing the 219Gly EPCR phenotype. Furthermore, in base-line samples from NPHSII and in the diabetic study, a significant increase in prothrombin F1+2 level was observed for 219Gly. The increased CHD-risk and thrombin generation appears to be acting through increased shedding of the Gly allele from the cell surface.

Animals↗
PubMed2006

Combined therapy with ramipril and simvastatin has beneficial additive effects on tissue factor activity and prothrombin fragment 1+2 in patients with type 2 diabetes.

Tissue factor (TF) plays a pivotal role in thrombus formation. Statins and angiotensin converting enzyme inhibitors attenuate expression of TF by distinct mechanism. Therefore, we hypothesized that combined therapy with simvastatin and ramipril may have additive beneficial anti-atherogenic effects to lower TF activity when compared with either drug alone. This was a randomized, double-blind, placebo-controlled cross-over trial with three treatment arms (each 2 months) and two washout periods (each 2 months). Fifty patients with type 2 diabetes were given simvastatin 20 mg and placebo, simvastatin 20 mg and ramipril 10 mg, or ramipril 10 mg and placebo daily during each treatment period. Simvastatin and ramipril monotherapy tended to reduce TF activity (0.53 to 0.46 nM, P=0.056; 0.54 to 0.50 nM, P=0.167, respectively) while combined therapy had a significant effect (0.64 to 0.43 nM, P<0.001). All three therapies significantly reduced prothrombin fragment 1+2 (F1+2) levels from their respective baselines (P=0.037, P<0.001, and P=0.057, respectively). Combined therapy significantly reduced TF activity and F1+2 levels to a greater extent than either simvastatin or ramipril alone (P=0.029 and P=0.040 by ANOVA, respectively). Percent changes in TF activity and percent changes in F1+2 levels were significantly correlated. All three therapies reduced CD40 ligand levels from their respective baselines (P=0.098, P<0.001, and P=0.002, respectively) with no significant differences among these three therapies (P=0.204 by ANOVA). Ramipril combined with simvastatin significantly reduces plasma TF activity and F1+2 levels to a greater extent than monotherapy with either drug in patients with type 2 diabetes.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2005

The human prothrombin kringle-2 derived peptide, NSA9, is internalized into bovine capillary endothelial cells through endocytosis and energy-dependent pathways.

Human prothrombin kringle-2 and its partial peptide, NSA9 (NSAVQLVEN), have been reported to have potent anti-angiogenic activities. Here, the internalization mechanism of NSA9 into bovine capillary endothelial (BCE) cells was examined using lactate dehydrogenase (LDH) release assay, fluorescence microscopy, and flow cytometry. LDH release assay results suggested that the integrity of the BCE cell membrane was unaffected by NSA9. Fluorescence microscopy indicated that internalized NSA9 was localized in the cytoplasm around the nucleus, and showed a punctuated fluorescence pattern, which is indicative of endocytic vesicles. Also, the cellular internalization of NSA9 is significantly inhibited by depletion of the cellular ATP pool, endocytosis inhibitors such as chloroquine and nocodazole, and incubation at low temperature (4 degrees C). In addition, the anti-proliferative activity of NSA9 against BCE cells was diminished in the presence of endocytosis or metabolic inhibitors. In conclusion, these results strongly suggest that NSA9 might exert its anti-proliferative activity through internalization into BCE cells by endocytosis and energy-dependent pathways.

Adenosine Triphosphate↗
PubMedDate not supplied

Overuse of prothrombin and partial thromboplastin coagulation tests in medical inpatients.

INTRODUCTION: In the monitoring of anticoagulant therapy, prothrombin time (PT) is used to measure the effect of warfarin, whereas the partial thromboplastin time (PTT) measures the therapeutic effect of unfractionated heparin. Low molecular weight heparin (LMWH) does not require routine monitoring. OBJECTIVE: We collected data on the frequency of simultaneous PT and PTT requests, where only one or neither is indicated, and estimated the potential cost savings if ordering was appropriate. METHODS: The study was performed at Nassau University Medical Center, a major teaching institution in East Meadow, New York. Inpatient charts were reviewed consecutively until 50 patients prescribed warfarin alone, intravenous heparin alone, or LMWH alone were selected. We then determined which coagulation tests were performed each day for these patients by review of their computerized laboratory results. The costs of laboratory tests were obtained from the hospital laboratory and were used to calculate potential savings. RESULTS: PT and PTT coagulation tests were requested together in all 50 patients. Seventeen patients on LMWH alone had 30 sets of PT/PTT performed (60 tests). Seventeen patients on intravenous heparin had 87 PTs performed. Twelve patients on warfarin had 60 PTTs performed. In total, 232 unneeded PT or PTTs were ordered in these 50 patients, or 4.6 per patient during hospitalization. CONCLUSION: The review of the records of 50 medical inpatients found that PT and PTT were invariably requested together, despite a lack of indication. The 50 patients incurred a total of $2434 in unneeded costs. If representative of common clinical practice, significant cost savings may be possible. Education, computerization, and information on costs of individual tests may reduce unneeded investigations.

Anticoagulants↗
PubMed2026

Prothrombin complex concentrate (PCC) vs. non-PCC strategies for warfarin reversal in left ventricular assist device recipients: A systematic review and meta-analysis.

BACKGROUND: Left ventricular assist devices (LVADs) prolong survival in end-stage heart failure, and warfarin thromboprophylaxis is recommended to prevent device thrombosis and thromboembolic complications. When bleeding occurs or emergency surgery is required, rapid anticoagulation reversal is critical. Prothrombin complex concentrate (PCC) provides rapid reversal; however, its risk-benefit profile in LVAD recipients remains unclear. We conducted a systematic review and meta-analysis comparing PCC with non-PCC strategies for warfarin reversal in LVAD recipients. METHODS: MEDLINE, Embase, and Scopus were searched through June 2025 for studies of PCC versus non-PCC strategies for warfarin reversal in LVAD recipients. Two reviewers independently extracted data. Random-effects models were used to pool arm-level estimates and to pool head-to-head comparisons using mean differences or risk ratios (RRs). RESULTS: Eighteen studies involving 779 patients were included. Arm-level pooled estimates for PCC versus non-PCC comparators were 24.0% versus 15.8% for mortality, 16.5% versus 12.1% for thrombotic events, and 3.1 versus 5.7 for FFP units. Arm-level time to INR correction was longer with PCC overall (16.5 versus 13.6&#xa0;h), driven by one elective cohort, but faster within the ICH subgroup (6.0 versus 13.7&#xa0;h). In head-to-head comparisons, PCC achieved faster INR correction than non-PCC comparators (mean difference&#xa0;-&#xa0;7.6&#xa0;h; p&#xa0;=&#xa0;0.001) and required fewer FFP units (-2.6&#xa0;units; p&#xa0;=&#xa0;0.019), with no significant difference in all-cause mortality (RR 1.14; p&#xa0;=&#xa0;0.490) or thrombotic events (RR 1.43; p&#xa0;=&#xa0;0.176). CONCLUSIONS: In head-to-head studies, PCC was associated with faster INR correction and lower FFP requirements than non-PCC strategies, whereas mortality and thrombotic events did not differ significantly. Given the observational evidence, wide confidence intervals, and heterogeneity, equivalent safety cannot be established, and prospective studies are needed to define the relative safety and effectiveness of the two approaches. IMPLICATIONS FOR CLINICAL PRACTICE: PCC-based strategies may be considered for urgent warfarin reversal in LVAD recipients, particularly when rapid INR reduction or avoidance of large-volume plasma transfusion is clinically important. Treatment decisions should account for the indication, bleeding severity, and underlying thrombotic risk. TRIAL REGISTRATION: CRD42024573925.

Humans↗
PubMed2005

Characterization of monoclonal anti-beta2-glycoprotein-I and anti-prothrombin antibody fragments generated by phage display from a patient with primary antiphospholipid syndrome.

The molecular structure of antibodies associated with autoimmune thrombosis is beginning to be understood. We describe the binding specificities and sequence analysis of anti-beta2-glycoprotein-I (anti-beta2GP-I) or anti-prothrombin (anti-PT) antibody fragments generated by phage display from a patient with primary antiphospholipid syndrome (APS). We obtained 39 positive clones, two that had the correct size reacted with beta2GP-I (Beta 1 and Beta 2). Ten clones with the same restrictive pattern recognized PT (Prot 1) and cross-reacted with beta2GP-I. All three clones recognized anionic and zwitterionic phospholipids. The V(H) regions of both anti-beta2GP-I clones are members of the VH4 family. Prot 1 has a V(H) segment of the VH3 family. The Beta 1 J(H) segments are J(H)5b and J(H)4b for Beta 2 and Prot 1. V(L) genes are V(lambda)1, 3 and 1, respectively. No J(L) was identified for Beta 1, while Beta 2 and Prot 1 carry J(lambda)3b genes. Beta 1 and Beta 2 carry highly conserved germ-line V(H) and V(L) genes. Mutations of the Prot 1 gene appear to be antigen-dependent, most are hotspot mutations located in the CDR 1 and 2 regions. Our work suggests that some anti-beta2GP-I from patients with primary APS are natural autoantibodies. Our work may also help to explain the frequent coexistence of anti-beta2GP-I and anti-PT in the same patient.

Amino Acid Sequence↗
PubMed2003

Duplex PCR-RFLP for simultaneous detection of factor V Leiden and prothrombin G20210A.

The authors have used a primer-engineered duplex polymerase chain reaction (PCR) -restriction fragment length polymorphism (RFLP) for the simultaneous detection of factor V Leiden and prothrombin G20210A mutations. The method involves the generation of HindIII RFLPs, and the restricted amplification products are analyzed by agarose gel electrophoresis in a single gel lane. This method is simple an inexpensive, and readily adaptable to the routine in a clinical molecular diagnostic laboratory other that our own.

Electrophoresis, Agar Gel↗
PubMed2004

Four-color multiplex 5' nuclease assay for the simultaneous detection of the factor V Leiden and the prothrombin G20210A mutations.

We developed a real-time multiplex four-color assay for the simultaneous detection of the factor V Leiden (FVL) and prothrombin (PT) G20210A mutations in one closed tube using a single thermocycling protocol. The assay combines the power of multiplex PCR with the specificity provided by allele-specific oligonucleotide (ASO) hybridization using the 5' nuclease assay format. Human genomic DNA is prepared from whole blood with standard procedures. A 97-bp DNA sequence of the coagulation factor V gene is co-amplified with a 111-bp DNA sequence of the coagulation factor II (PT) gene using four PCR primers. In addition, the reactions included four differentially labeled ASO probes for the specific detection of the different FVL/PT G20210A genotypes. To evaluate the assay's performance characteristics, we performed a comparison of two methods. We analyzed DNA samples from 52 individuals with known FVL/PT G20210A genotypes that were previously genotyped with an assay that combined PCR with the use of restriction fragment length polymorphisms. We found a 100% concordance between the results generated by both methodologies. We conclude that the four-color multiplex assay is specific and reproducible for the detection of the FVL/PT G20210A mutations, and it can be easily adapted for the detection of other SNPs.

Alleles↗
PubMed2004

Quality assurance program for whole blood prothrombin time-international normalized ratio point-of-care monitors used for patient self-testing to control oral anticoagulation.

Whole blood coagulation monitors are increasingly used for patient self-testing to control oral anticoagulation, but there are no comprehensive quality assurance (QA) programs to check their performance. We report on the experience with one of such programs applied in a field study where patients on prothrombin time (PT)-international normalized ratio (INR) self-testing were asked to bring their monitors to the anticoagulation clinic for checking. PT-INR testing was performed three times over 3 months with 14 patient's monitors and test strips on three recalcified QA plasmas by an experienced laboratory operator. Each patient was also asked to perform PT-INR self-testing (his/her own capillary blood) which was then compared to the laboratory PT-INR (plasma). Overall, the comparison between the observed and the consensus PT-INR on QA plasmas was acceptable with the majority of measurements lying within +/-15% or 20% of the consensus values. The comparison between the PT-INR self-testing and the laboratory method was also acceptable: overall, there was no statistical significant difference between the mean PT-INR values and the majority of paired measurements were less than 15% or 20% apart. In conclusion, our results show that the proposed QA scheme is feasible and may be implemented on a larger scale. Monitors should be recalled periodically to the clinic where they have been prescribed to the patient. During each visit, the clinic may check the monitors and patient self-testing performance as described. Such comprehensive QA system would make monitoring of oral anticoagulant treatment by self-testing safer and more effective.

Administration, Oral↗