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Introduction Increased postprandial factor VII activation is observed after high-fat meals, but is not accompanied by thrombin formation in normal weight individuals. Obesity is associated with a higher circulating concentration of tissue factor (TF) and postprandial uptake of lipopolysaccharide (LPS), and this may increase thrombin formation after high-fat meals. We therefore compared postprandial effects of high-fat meals and low-fat meals on biomarkers of coagulation activation in patients with morbid obesity and investigated whether the response was associated with the gut bacteria composition. Materials and methods A controlled cross-over study was conducted in obese patients (15 women, 5 men, mean BMI = 44.1 kg/m2), where high-fat meals (67 E% fat) and low-fat meals (16 E% fat) were served at 8:15 and 10:00 in a random order on two study days within one week. Blood samples were collected at 08:00 (fasting), 12:00, and 14:00 and analysed for triglycerides, activated FVII (FVIIa), TF, FVIIa-antithrombin (FVIIa-AT), prothrombin fragment 1 + 2 (F1+2), and TF pathway inhibitor (TFPI). The gut bacteria composition, measured as gram-negative bacteria and diversity, was analysed in faecal samples. Results Triglycerides, FVIIa, and FVIIa-AT increased significantly after high-fat meals, whereas F1 + 2 decreased equally and significantly over time after both meals. There were no significant changes in TF and TFPI over time. The postprandial changes in F1 + 2 and TFPI after high-fat meals were negatively correlated with diversity. Conclusions Increased postprandial FVIIa is not accompanied by thrombin formation four hours after high-fat meals in patients with morbid obesity, possibly due to FVIIa-inhibition by AT.

The effect of edoxaban on plasma prothrombin fragment 1+2 (PTF1+2), a sensitive maker of in vivo thrombin generation, has not been fully investigated in nonvalvular atrial fibrillation (NVAF). We compared plasma PTF1+2 levels between 25 NVAF patients receiving warfarin and 100 NVAF patients receiving edoxaban and additionally analyzed the association between plasma PTF1+2 levels and the dose of edoxaban. Plasma PTF1+2 levels were significantly higher in patients receiving edoxaban than in those receiving warfarin (141.5 ± 50.0 pmol/l vs 93.1 ± 55.7 pmol/l, p0.001). The prevalence of plasma PF1+2 levels above the upper limit (229 pmol/l) of the normal range did not differ between the 2 groups (4% vs 4%), whereas the prevalence of plasma PTF1+2 levels below the lower limit (69 pmol/l) of the normal range was significantly lower in patients receiving edoxaban than in those receiving warfarin (1% vs 48%, p0.001). Multiple linear regression analysis identified age and warfarin treatment as independent variables associated with the plasma PTF1+2 level. In a subgroup analysis, plasma PTF1+2 levels were significantly higher in 58 receiving edoxaban of 30 mg/day than in 42 receiving edoxaban of 60 mg/day (157.6 ± 50.8 pmol/l vs 121.6 ± 39.8 pmol/l, p = 0.01); however, after adjusting for confounding factors, the dose of edoxaban was not independently associated with the plasma PTF1+2 level. In conclusion, edoxaban sufficiently inhibits thrombin generation unrelated to its dose in NVAF, although its inhibitory effect is weaker compared with warfarin.

Introduction Coronavirus disease 2019 (COVID‐19) may cause a hypercoagulable state. The D‐dimer is frequently elevated in COVID‐19, but other markers of coagulation activation, including the prothrombin fragment 1.2 (PF1.2) are poorly described. Methods We studied hospitalized adults with COVID‐19 and PF1.2 measurement performed at any time during hospitalization. We evaluated the relationship between PF1.2 and synchronously measured D‐dimer. We utilized receiver operating characteristic (ROC) analysis to evaluate optimal thresholds for diagnosing thrombosis and multivariable logistic regression to evaluate association with thrombosis. Results 115 patients were included [110 (95.7%) critically ill]. PF1.2 and D‐dimer were moderately positively correlated (r=0.542, P523 pmol/L: 69.2% sensitivity, 67.7% specificity; >924 pmol/L: 37.9% sensitivity, 87.8% specificity). In multivariable analysis, a PF1.2 >500 pmol/L was significantly associated with VTE [adjusted odds ratio (OR) 4.26, 95% CI, 1.12‐16.21, P=0.034] and any thrombotic manifestation (adjusted OR 3.85, 95% CI, 1.39‐10.65, P=0.010); conversely, synchronously measured D‐dimer was not significantly associated with thrombosis. 90.6% of patients with a non‐elevated PF1.2 result did not develop VTE. Conclusions PF1.2 may be a useful assay, and potentially more discriminant than D‐dimer, in identifying thrombotic manifestations in hospitalized patients with COVID‐19. This article is protected by copyright. All rights reserved.

Objectives To assess the effects of recombinant human soluble thrombomodulin treatment on 28-day all-cause mortality in subgroups categorized by baseline coagulation biomarker levels (prothrombin fragment 1.2, thrombin-antithrombin complex, D-dimer) in patients with sepsis-associated coagulopathy in the Sepsis Coagulopathy Asahi Recombinant LE Thrombomodulin trial (SCARLET) (NCT01598831). Design Post hoc, subgroup analysis of a randomized, double-blind, placebo-controlled, multinational, multicenter phase 3 study. Setting ICUs at 159 sites in 26 countries. Patients Eight-hundred adults with sepsis-associated coagulopathy defined as international normalized ratio greater than 1.40 and platelet count between 30 × 10/L and 150 × 10/L or greater than 30% decrease within 24 hours with concomitant cardiovascular and/or respiratory failure. Interventions Patients randomized and treated with recombinant human soluble thrombomodulin (0.06 mg/kg/d; n = 395) or equivalent placebo (n = 405) for 6 days. Measurements and main results Recombinant human soluble thrombomodulin did not significantly reduce 28-day all-cause mortality in the Sepsis Coagulopathy Asahi Recombinant LE Thrombomodulin trial: absolute risk reduction was 2.55% (p = 0.32) in patients with sepsis-associated coagulopathy. In this post hoc analysis, mortality steadily increased with increasing baseline prothrombin fragment 1.2 and thrombin-antithrombin complex levels in the placebo group; for those values exceeding the upper limit of normal, the mortality increases in the recombinant human soluble thrombomodulin group were lower or negligible with increasing baseline prothrombin fragment 1.2 and thrombin-antithrombin complex. Consequently, absolute risk reductions were greater in subgroups with higher baseline prothrombin fragment 1.2 or thrombin-antithrombin complex. Absolute risk reductions were also greater in subgroups with baseline coagulation biomarker levels at or above median of the entire study population, ranging from 4.2% (95% CI, -5.0% to 13.4%) to 5.5% (95% CI, -4.0% to 14.9%). Conclusions Compared with patients receiving placebo, patients treated with recombinant human soluble thrombomodulin having higher baseline thrombin generation biomarker levels had lower mortality. Further research regarding the predictive role of coagulation biomarkers for recombinant human soluble thrombomodulin treatment response in sepsis-associated coagulopathy is warranted to evaluate clinical relevance.

Background Novel oral anticoagulants and warfarin are widely used for stroke prevention in patients with atrial fibrillation. The anticoagulation status of patients receiving warfarin or rivaroxaban has been studied. In this study, we aimed to evaluate the effect of dabigatran and warfarin on preventing thrombin generation (TG). Methods This retrospective study enrolled 237 nonvalvular atrial fibrillation (NVAF) subjects treated with 110 mg dabigatran etexilate twice daily and 224 NVAF patients received adjusted-dose warfarin (international normalized ratio [INR] of 2 to 3)). Coagulation assays, prothrombin fragment 1 + 2 (F1+2), calibrated automated thrombogram, and thrombin–antithrombin complex (TAT) were detected at the steady state. Results Activated partial thromboplastin time (APTT), antithrombin III activity, fibrinogen, and lag time showed no difference between the two groups. Compared to the dabigatran group, prothrombin time and INR values were higher in the warfarin group (all P max), F1+2, and TAT were lower in the warfarin group. The inhibition of TG was still stronger in the warfarin group when the patients were divided into subgroups. Conclusion Conventional coagulation assays are suboptimal for assessing the coagulation status of dabigatran. TG could be used as supplementary assays to evaluate the anticoagulation effect of oral anticoagulants. Our results suggest that warfarin may inhibit TG more aggressively than dabigatran in patients regardless of age and kidney function.

Background: Thrombin generation, thrombin-antithrombin complex (TAT) levels, and prothrombin fragment 1+2 (F1+2) have shown potential as biomarkers of thromboembolic risk. The aims were to establish reference intervals for these three biomarkers and to assess the levels in patients with localized cancer compared with healthy individuals. Methods: We included 124 healthy individuals (57 females and 67 males; aged 21–66 years), 86 patients with low-stage primary lung cancer, and 57 patients with localized head and neck cancer. Thrombin generation was determined by the calibrated automated thrombogram using platelet-poor-plasma reagent containing 1 pM tissue factor and 4 μM phospholipids. TAT and F1+2 were measured using commercial enzyme-linked immunosorbent assays. Reference intervals were calculated as mean ± 1.96 × standard deviation (thrombin generation and F1+2) or 2.5th to 97.5th percentiles (TAT). Results: The reference intervals for thrombin generation parameters were: lag time 4.4–9.4 min, peak thrombin 46–288 nM, time-to-peak thrombin 8–15 min, and endogenous thrombin potential 554–1952 nM x min. The reference interval for TAT was ≤13 μg/l, and for F1+2 it was 47–320 pmol/l. Both low-stage primary lung cancer and head and neck cancer patients had significantly higher TAT (p

Essentials Baseline coagulation activity can be detected in non-bleeding state by in vivo biomarker levels. A detailed mathematical model of coagulation was developed to describe the non-bleeding state. Optimized model described in vivo biomarkers with recombinant activated factor VII treatment. Sensitivity analysis predicted prothrombin fragment 1 + 2 and D-dimer are regulated differently. SummaryBackground Prothrombin fragment 1 + 2 (F1 + 2), thrombin–antithrombin III complex (TAT) and D-dimer can be detected in plasma from non-bleeding hemostatically normal subjects or hemophilic patients. They are often used as safety or pharmacodynamic biomarkers for hemostatis-modulating therapies in the clinic, and provide insights into in vivo coagulation activity. Objectives To develop a quantitative systems pharmacology (QSP) model of the blood coagulation network to describe in vivo biomarkers, including F1 + 2, TAT, and D-dimer, under non-bleeding conditions. Methods The QSP model included intrinsic and extrinsic coagulation pathways, platelet activation state-dependent kinetics, and a two-compartment pharmacokinetics model for recombinant activated factor VII (rFVIIa). Literature data on F1 + 2 and D-dimer at baseline and changes with rFVIIa treatment were used for parameter optimization. Multiparametric sensitivity analysis (MPSA) was used to understand key proteins that regulate F1 + 2, TAT and D-dimer levels. Results The model was able to describe tissue factor (TF)-dependent baseline levels of F1 + 2, TAT and D-dimer in a non-bleeding state, and their increases in hemostatically normal subjects and hemophilic patients treated with different doses of rFVIIa. The amount of TF required is predicted to be very low in a non-bleeding state. The model also predicts that these biomarker levels will be similar in hemostatically normal subjects and hemophilic patients. MPSA revealed that F1 + 2 and TAT levels are highly correlated, and that D-dimer is more sensitive to the perturbation of coagulation protein concentrations. Conclusions A QSP model for non-bleeding baseline coagulation activity was established with data from clinically relevant in vivo biomarkers at baseline and changes in response to rFVIIa treatment. This model will provide future mechanistic insights into this system.

BackgroundRivaroxaban is an oral anticoagulant that effectively prevents thromboembolic complications using fixed doses without requiring laboratory monitoring. In this study, we aimed to examine the coagulation status in patients with non-valvular atrial fibrillation (NVAF) treated with rivaroxaban compared with warfarin.Methods and resultsThe study group consisted of 85 consecutive Japanese patients with NVAF who received rivaroxaban (n=33) or warfarin (n=52) from June 2013 to February 2014. We compared the coagulation status between the rivaroxaban and warfarin treatments. The prothrombin time (PT) values did not significantly differ between the two groups. However, the prothrombin fragment 1+2 (F1+2) level, a marker of thrombin generation, was significantly higher in the rivaroxaban group than the warfarin group (202±88pmol/l vs. 114±79pmol/l, p

Introduction We have recently reported that increased levels of urine prothrombin fragment 1 + 2 reflected radiologically verified deep vein thrombosis. In this study we evaluated whether urine prothrombin fragment 1 + 2 was associated with pulmonary embolism in non-selected patients. Materials and methods Patients with clinical suspected pulmonary embolism were interviewed on comorbidities and medications. Urine was collected from each patient before radiological examination and snap frozen until analysed on urine prothrombin fragment 1 + 2 with an ELISA kit. Imaging of the pulmonary arteries were conducted with contrast enhanced computer tomography. Results Pulmonary embolism was diagnosed in 44/197 patients. Non-significantly higher urine prothrombin fragment 1 + 2 levels were found in non-selected patients with pulmonary embolism vs. those without ( p = 0.324). Significantly higher urine prothrombin fragment 1 + 2 levels were found in the pulmonary embolism positive patients without comorbidities (n = 13) compared to the control group (n = 28) ( p = 0.009). The calculated sensitivity, specificity and negative predictive value using the lowest detectable urine prothrombin fragment 1 + 2 level was 82%, 34% and 87%, respectively. Conclusions There was no significant urine prothrombin fragment 1 + 2 level difference in patients with and without pulmonary embolism. In non-comorbide pulmonary embolism positive patients the urine prothrombin fragment 1 + 2 levels were significantly higher compared to the control group. The negative predictive value found in this study indicates that uF1 + 2 has the potential to identify patients with a low risk of PE.

The appearance of prothrombin fragment 1 + 2 (F1 + 2) in urine has been associated with postoperative hypercoagulability and thromboembolism. We wanted to assess if F1 + 2 was released in urine (uF1 + 2) in patients with procoagulant disorders, and if higher levels were found in patients with radiological verified deep vein thrombosis (DVT).Consecutive patients were interviewed on comorbidities and medications. An unselected total cohort (n = 534) and a control cohort (n = 177) were analysed. A urine sample (10 ml) was collected and snap frozen before levels of uF1 + 2 were measured with an ELISA kit. Visualisation of DVT was done with compression ultrasound, supplied with venography when feasible. All patients were followed up for 3-6 months.DVT was diagnosed in 108/534 patients. Statistical significant higher uF1 + 2 levels were found in patients with DVT (p0.001), in DVT positive patients with ongoing malignancy (p = 0.034) and in pregnant women compared to the control cohort (p0.001). Non-significant increased urine concentrations were found in DVT positive vs. DVT negative patients with infections and traumas.Levels of uF1 + 2 was associated with DVT both in the total cohort and in the control cohort as well as in most patients with coexisting conditions.

Latar belakang: Manifestasi klinis demam berdarah Dengue (DBD) adalah kebocoran plasma dan trombositopenia. Salah satu teori penyebab kedua hal tersebut adalah kadar trombin yang meningkat akibat aktivasi koagulasi. Kadar trombin dapat diwakili oleh kadar F1.2. Tujuan penelitian ini adalah untuk mengetahui hubungan antara kadar F1.2 dengan kebocoran plasma dan trombositopenia pada infeksi Dengue. Metode: Desain penelitian ini adalah potong lintang, mengggunakan plasma EDTA dari pasien terinfeksi virus Dengue. Subyek penelitian adalah 10 subyek dengan kebocoran plasma dan 10 subyek tanpa kebocoran plasma pada infeksi Dengue, 6 sampel berpasangan untuk perbandingan fase kritis dan fase konvalesen, 26 sampel untuk uji korelasi antara kadar F1.2 dengan jumlah trombosit. Hasil: Penelitian menunjukkan kadar F1.2 pada pasien terinfeksi virus Dengue dengan kebocoran plasma (rerata ± 2SD) 147,4 ± 105,82 pg/mL lebih tinggi secara bermakna dibanding tanpa kebocoran plasma 51,3 ±39,92 pg/mL. Kadar F1.2 pada fase kritis dengan median 186,3 (108,6-223,2) pg/mL lebih tinggi secara bermakna dibanding fase konvalesen 46,5 (27,4-51,9) pg/mL. Terdapat korelasi negatif yang bermakna dengan kekuatan sedang antara kadar F1.2 dengan jumlah trombosit, nilai r = - 0,609. Kesimpulan: Terdapat peningkatan aktivasi koagulasi yang ditunjukkan dengan peningkatan kadar F1.2 pada fase kritis, berkaitan dengan kebocoran plasma dan trombositopenia pada pasien terinfeksi virus Dengue. Kata kunci: infeksi Dengue, kebocoran plasma, trombin, fragmen protrombin (F1.2), trombositopenia Background: Clinical manifestations of Dengue hemorrhagic fever are plasma leakage and thrombocytopenia. Both manifestations are thought to be caused by an increased thrombin level due to activation of coagulation. The aim of this study is to look for any association between F1.2 level and plasma leakage and also between F1.2 level and thrombocytopenia in Dengue infected patients. Methods: This study used EDTA plasma from patients infected with Dengue virus. The study design was cross sectional. The thrombin level was represented by the prothrombin fragment 1.2 (F1.2) level. Twenty subjects were enrolled in this study, consisted of 10 subjects with plasma leakage and 10 without plasma leakage, 6 pairs of samples in critical phase and convalescent phase, 26 samples for correlation test between F1.2 level and platelet count. Results: In this study, it was found that the F1.2 level in patients with plasma leakage (mean ± 2 SD) 147.4 ± 105.82 pg/mL is significantly higher compared to patients without plasma leakage 51.3 ±39.92 pg/mL, and the F1.2 level in critical phase has a median of 186.3 (108.6-223.2) pg/mL which is significantly higher compared to convalescent phase 46.5(27.4-51.9) pg/mL. Also it was found that a medium negative correlation between F1.2 level and the thrombocyte count existed, r = - 0.609. Conclusion: The results of the study suggest that there was increased coagulation activation at critical phase in patients infected with Dengue virus associated with plasma leakage and thrombocytopenia. Keywords: Dengue infection, plasma leakage, thrombin, prothrombin fragment (F1.2), thrombocytopenia

Patients with intracerebral hemorrhage during rivaroxaban treatment have small hematoma and favorable outcomes compared with those with warfarin. We investigated its possible mechanism, focusing on prothrombin fragment 1+2 (F1+2), a marker of thrombin generation.In 65 patients with acute cardioembolic stroke (median 77years), rivaroxaban was initiated at 5days after the onset. Plasma F1+2 level (normal range, 69-229pmol/L), prothrombin time (PT), and rivaroxaban concentration evaluated by anti-Xa activity were serially measured.Median plasma F1+2 was 276 (IQR, 195-454) pmol/L before starting rivaroxaban, and significantly decreased to 196 (141-267) and 192 (151-248) on 7 and 28days after rivaroxaban, respectively (both p0.05). Serial measurements of PT and rivaroxaban concentration at trough, 2, 4, and 6h after taking rivaroxaban showed a positive correlation (RRivaroxaban retains a normal thrombin generation even at its peak level with prolonged PT, whereas warfarin at therapeutic levels inhibits thrombin generation. This may partly explain different outcomes in patients complicated with bleeding events.

Introduction Diabetes is a prothrombotic state involving a more thrombogenic fibrin network. In the present study we investigated the effects of lipid-lowering therapy with atorvastatin on fibrin network structure and platelet-derived microparticles in patients with type 1 diabetes and dyslipidemia. Materials and Methods Twenty patients were treated with atorvastatin (80 mg daily) or placebo during 2 months in a randomized, double-blind, cross-over study. Fibrin network permeability, expression of glycoprotein IIIa, P-selectin and tissue factor on platelet-derived microparticles, plasma endogenous thrombin potential, plasminogen activator inhibitor-1 and tissue plasminogen activator antigen levels were assessed. Additionally, levels of plasma fibrinogen, high-sensitivity C-reactive protein and glycated haemoglobin were measured. Results During treatment with atorvastatin, fibrin network permeability increased (p = 0.01), while endogenous thrombin potential and expression of glycoprotein IIIa, P-selectin and tissue factor decreased (p In vitro experiments indicated that platelet-derived microparticles influence the fibrin network formation as fibrin network permeability decreased significantly when platelet-derived microparticles were added to normal plasma. Baseline levels of plasminogen activator inhibitor-1 and tissue plasminogen activator antigen as well as plasma fibrinogen and high-sensitivity C-reactive protein were within reference values and not significantly changed during atorvastatin treatment, while glycated haemoglobin increased 0.3% (p Conclusions Novel treatment effects were found in patients with type 1 diabetes and dyslipidemia during atorvastatin therapy, i.e. a more porous fibrin network, to which reduced expression of glycoprotein IIIa, P-selectin and tissue factor on platelet-derived microparticles may contribute. The observed impairment of glycemic control during long-term statin treatment deserves attention.

Aims: To investigate the association between intima-media thickness of brachial and common carotid arteries and factors of the coagulation- and fibrinolysis-system with left ventricular diastolic dysfunction in patients with a previous myocardial infarction. Patients and methods: One hundred and twenty three patients, men (76%) and women (24%) aged between 32and 81 years with a history of previous acute myocardial infarction were included. B-mode ultrasound of common carotid and brachial arteries and echocardiography with tissue Doppler imaging (TDI) were evaluated. Factors of the coagulation- and fibrinolysis-system were also measured. Results: In patients with previous myocardial infarction, late diastolic filling time was significantly and positively associated with log Prothrombin fragment 1 + 2 (P < 0.001) and with calculated intima-media area (cIMa) of the both common carotid and brachial arteries (P < 0.05). Mitral early-to-late flow velocity ratio (E/A) was significantly and negatively associated with log Prothrombin fragment 1 + 2 (P < 0.001), total cholesterol and cIMa of the both common carotid and brachial arteries (P < 0.05). Moreover both late diastolic filling time and mitral E/A correlated significantly with age and systolic blood pressure. In stepwise multiple regression analysis, log Prothrombin fragment 1 + 2 remained the only variable with independent significant correlation to late diastolic filling time and mitral E/A. Conclusions: In a population sample of patients with myocardial infarction, late diastolic filling time and mitral E/A were associated with cIMa of common carotid and brachial arteries, systolic blood pressure, and prothrombin fragment 1 + 2, suggesting a relationship between diastolic dysfunction, thrombin generation and atherosclerosis. (Echocardiography 2010;27:651-658).

Prothrombin fragment 1 + 2 (F1 + 2) is considered to be useful for diagnosis of thrombosis. However, the evidence for a diagnosis of thrombosis by F1 + 2 is still not well established. The plasma concentrations of F1 + 2, soluble fibrin, D-dimer, and thrombin-antithrombin complex were measured in 694 patients suspected of having thrombosis and then were correlated with thrombosis. Plasma concentrations of F1 + 2, soluble fibrin, D-dimer, and thrombin-antithrombin complex were significantly higher in patients with thrombosis, compared with patients without thrombosis. When cutoff values of more than 300 pmol/L for F1 + 2 were used for the diagnosis, more than 50% of the patients were thus found to have thrombosis. The findings showed that F1 + 2, soluble fibrin, D-dimer, and thrombin-antithrombin complex have similar diagnostic ability. The plasma concentration of F1 + 2 closely was well correlated with thrombin-antithrombin complex, soluble fibrin, and D-dimer. Finally, F1 + 2 is one of the most useful parameters for the diagnosis of thrombosis.

Prothrombin fragment 1+2 measured in spot urine (uF1+2) is an indicator of thrombin generation. We examined whether measured levels of uF1+2 can be used to differentiate between patients who do and do not acquire sustained coagulation activation after total hip arthroplasty (THA).We performed two separate studies in patients undergoing THA. Study 1 was a prospective pilot study aiming to roughly estimate the extent of pre- and postoperative fluctuations in the uF1+2 concentration. Study 2 was a larger prospective cohort study aiming to verify the findings of Study 1 and to examine the association between the uF1+2 concentrations and risk of vascular thrombotic complications (VTC) or death. Finally, we sought to define a cut-off concentration value that could be used to identify patients with a sustained uF1+2 elevation after the first postoperative week. The urine samples were analysed by ELISA. In both studies thromboprophylaxis was used for at least 7 days after the operation.The operative trauma resulted in elevation of the uF1+2 level in all patients compared with the preoperative level and levels in the healthy volunteers. Ten out of 113 patients (8.8%) in the second study suffered VTC or death, assumed to be caused by a coagulation problem. Analysis of variance revealed the following statistically significant associations: pre- vs. postoperative log uF1+2 levels (P0.0001), log uF1+2 levels comparing patients with and without events (P=0.004); and the individual log uF1+2 levels (P0.0001). A cut-off value of uF1+2 concentration between 0.3 and 0.5 nmol/l had a sensitivity and a negative predictive value between100% and 90%, and specificity between 45% and 63% and overall accuracy between 50% and 65%. This value was obtained by the analysis of a receiver operating characteristic curve with the purpose of identifying patients with sustained coagulation activation on day 5 after operation.Our studies suggest that measured levels of uF1+2 can be potentially used to assess the individual risk of VTC after THA and to test for non-invasive detection of sustained coagulation activation.

Increased levels of urine prothrombin fragment 1 + 2 was recently reported to be associated with imaging-verified venous thromboembolism. In this study we evaluated the relationship between plasma D-dimer and plasma and urine prothrombin fragment 1 + 2 in patients with suspected venous thromboembolism. Urine and blood samples were collected from patients with suspected pulmonary embolism or deep vein thrombosis. The samples were analysed with commercially available ELISA kits. The diagnosis of venous thromboembolism was verified with contrast-enhanced computer tomography of the pulmonary arteries or lower extremity deep vein compression ultrasound and venography as appropriate. Venous thromboembolism was diagnosed in 150 of 720 patients. Significantly higher levels of plasma D-dimer and prothrombin fragment 1 + 2 in plasma and urine were found in those with imaging-confirmed venous thromboembolism versus those without (P

Veno-occlusive disease (VOD) of the liver remains a major complication after hematopoietic stem cell transplantation (SCT). VOD is thought to develop after hepatic endothelial cells are damaged by high-dose chemotherapy or radiation, causing microthrombosis in hepatic venules. However, the precise mechanisms leading to VOD are not well defined, and a diagnosis is often difficult to establish. It is also difficult to predict which patients are most likely to develop VOD. Elevated levels of homocysteine (HC) have been associated with thrombosis, and prothrombin fragment 1 + 2 (F1 + 2) is a measurable marker for coagulation. Therefore, we performed a prospective cohort study to determine if HC or F1 + 2 levels could be used to predict the development of VOD prior to SCT, or to help establish a diagnosis of VOD in association with other clinical parameters. Plasma levels of these factors were measured before conditioning and serially for 21 days after SCT in 42 consecutive patients undergoing SCT. Eleven of 26 allogeneic SCT recipients developed VOD, whereas no autologous SCT recipient (n = 16) developed VOD (p = 0.008). In patients who developed VOD, HC levels were consistently higher than those seen in non-VOD patients after day 7 of SCT. Patients with VOD also had higher levels of F1 + 2 after SCT, although this marker was less consistently elevated over time. A logistic regression model that evaluated all serial measures of HC and F1 + 2 showed a moderate sensitivity and specificity in diagnosing VOD in allogeneic SCT patients, but neither marker was useful to predict development of VOD when tested prior to SCT.

Impaired haemostasis is common in patients with end-stage renal disease, and may cause either thrombotic or bleeding complications. The purpose of this study was to assess whether plasma markers of coagulation activation in patients undergoing chronic haemodialysis (HD) can identify high-risk individuals, and to test the relevancy of type of vascular access or dialysis filter. We measured plasma levels of prothrombin fragment 1+2, fibrin D-dimers and tissue factor in 82 HD patients before and after dialysis. Clinical endpoints during the year following blood sampling were thrombosis in blood access, changes in blood access, other thromboembolic events, bleeding complications, ischaemic vascular disease, or death. We found elevated baseline levels of all three parameters in HD patients, compared to normal reference ranges. Plasma levels of all parameters (particularly fibrin D-dimers) were significantly higher in patients with prosthetic grafts and central venous dialysis catheters than in patients with native vessels. Patients with AV-fistulas or grafts who had bleeding complications (n=7) had significantly higher plasma levels of fibrin D-dimer and prothrombin fragment 1+2. Bleeding complications also occurred more frequently among the patients with prosthetic grafts (3/18) or central venous dialysis catheters (3/11) compared with those with grafts from native vessels (1/53). Other than a bleeding tendency, our data do no show any correlation between coagulation parameters and other clinical complications during haemodialysis. In conclusion, we found elevated plasma levels of markers of coagulation activation among HD patients. High levels of D-dimers and prothrombin fragment 1+2 correlated to bleeding diathesis instead of thromboembolism, and this tendency was most pronounced in patients with prosthetic grafts.

A 50-year-old man with dilated cardiomyopathy was admitted to our hospital due to heart failure symptoms. Although prothrombin fragment 1+2 (F1+2) was significantly elevated, there was no thrombus in the left ventricle by echocardiography. However, anticoagulation therapy was started because of a possibility of thrombus formation. On the 4th day, F1+2 was persistently elevated and echocardiography detected intraventricular thrombi. After surgical removal of thrombi, F1+2 level decreased rapidly. F1+2 elevation preceded echocardiographic detection of intraventricular thrombi. Therefore, when F1+2 is significantly elevated, echocardiography should be performed meticulously and repeatedly to detect a thrombus.

A total of 260 consecutive patients, referred for hypercoagulable assessment, was included in this study. Four coagulation activation markers were utilized to assess these patients [enzyme-linked immunosorbent assays for soluble fibrin polymer (TpP), prothrombin fragment 1.2, thrombin-antithrombin complex, and D-dimer]. The mean levels of the activation markers directly correlated with the number of hypercoagulable abnormalities. The percentage of patients with increased TpP levels for each group was lower than the other activation markers. The findings indicate that activation markers reflect the number of underlying thrombophilic abnormalities. Our data suggest that there is a utility in performing a panel of coagulation activation markers to assess the thrombotic risk. The measurement of soluble fibrin polymer may be more reflective of an impending vascular event.

Protein S (PS) is a vitamin K-dependent plasma protein and serves as a cofactor for the anticoagulant activities of activated protein C (APC). We investigated the effects of different PS concentrations on prothrombin activation and thrombin generation in cord and adult plasma containing APC and different amounts of alpha 2-macroglobulin (a2-M). Prothrombin activation was assessed by monitoring the time-course of prothrombin fragment 1+2 (F1+2) generation. Thrombin generation curves were determined by means of a subsampling technique using the chromogenic substrate S-2238. We demonstrate a dose-dependent inhibition of the anticoagulant action of PS by a2-M: suppression of F1+2 and thrombin generation due to addition of PS was stronger in plasma containing low amounts of a2-M than in plasma with elevated a2-M levels. Since no complex formation between a2-M and PS was observed by means of SDS-PAGE, we attribute decreased anticoagulant action of PS at high a2-M levels to enhanced complex formation between APC and a2-M. Thereby, APC is subtracted from its cofactor PS, resulting in suppressed formation of the anticoagulant APC/PS complex. Thus, our data suggest that a2-M, besides its well-known anticoagulant effects, also acts as a procoagulant by suppressing the formation of the anticoagulant APC/PS complex. Our findings have implications particularly on thrombin generation and inhibition in cord plasma, since a2-M levels in newborns are elevated over adult values and the antithrombotic APC/PS pathway is up-regulated at birth. Therefore, elevated levels of a2-M might restrict the up-regulation of the APC/PS pathway.

Rivaroxaban is non-inferior to warfarin for the treatment of venous thromboembolism, with regard to clinical efficacy and safety. The ex-vivo effects of warfarin versus therapeutic dose rivaroxaban on in-vivo markers of coagulation activation and thrombin generation remain undefined. The aim of this study was to compare the effects of warfarin and therapeutic dose rivaroxaban on ex-vivo thrombin generation (TG), and the in-vivo markers of coagulation activation, prothrombin fragment 1.2 (F1.2), thrombin-antithrombin complex (TAT), and D-dimer.Eighty-five patients with venous thromboembolism were studied, 45 on warfarin, target INR 2.5 and 40 on rivaroxaban 20mg once daily.Anticoagulation was in therapeutic range in 71% (32/45) warfarin and 65% (26/40) rivaroxaban treated patients. 8 patients on warfarin and 9 patients on rivaroxaban had subtherapeutic INR and rivaroxaban levels respectively. Both rivaroxaban and warfarin reduced endogenous thrombin potential (ETP) and peak thrombin, and prolonged lag time and time to peak, compared to normal controls (p0.0001). The lag time and time to peak TG were longer, and peak thrombin was lower in patients receiving rivaroxaban (p0.0001) compared with warfarin, although warfarin-treated patients had lower ETP (p=0.0008). In-vivo coagulation activation markers were within the normal ranges in all rivaroxaban-treated patients (including those with levels considered to be subtherapeutic) and in 37/45 warfarin-treated patients who had an INR≥2.0. The warfarin-treated patients with subtherapeutic INRs exhibited slightly raised F1.2 and/or TAT.In conclusion, both rivaroxaban and warfarin provided effective anticoagulation, as assessed by inhibition of TG and makers of in-vivo coagulation activation.

A common mutation in the prothrombin gene (G20210A) is associated with elevated prothrombin levels and thrombosis. The pathomechanism related to the G20210A mutation is currently not understood and the interdependence of prothrombin activity and prothrombin concentration in plasma is still poorly defined. Six of 191 blood donors examined in the present study carried the prothrombin allele G20210A. Despite the small number of cases, plasma samples from these individuals had significantly higher prothrombin activities than wild type carriers, whereas their prothrombin concentrations-although elevated-did not differ significantly from wild type. In subjects with the G20210A mutation there was also no significant correlation between prothrombin activity and concentration. Analyzing data from healthy blood donors without the prothrombin G20210A mutation, we found only weak correlations between prothrombin activity and concentration of immunoreactive prothrombin. Samples with a relatively high prothrombin concentration but low activity were observed as well as samples with a relatively high activity for a given concentration (hyperactive prothrombin). F1+2 concentrations as indicators of activated coagulation were only elevated in 13 of 125 investigated samples and could not explain any of these findings. Dysfunctional variants of prothrombin, a well known phenomenon, may be responsible for the former, and we speculate that posttranscriptionally modified prothrombin species may explain the observed functional diversity of this factor including hyperactivity. The genotype-phenotype association of the non-coding G20210A mutation is not clear cut. Therefore, further studies are needed to determine which factors apart from the known G20210A polymorphism regulate prothrombin concentration and/or activity and may trigger the manifestation of thrombosis.

A proportion of mitral stenosis patients with left atrial spontaneous echo contrast but without thrombus exhibit a regional hypercoagulable state, characterized by increased left atrial levels, but normal venous levels, of prothrombin fragment 1+2 (F1+2), a marker of thrombin generation. Valve dilatation by balloon mitral valvuloplasty has beneficial effects on left atrial spontaneous echo contrast, but its effect on left atrial thrombin generation is unknown. We examined the effects of balloon mitral valvuloplasty on venous and left atrial levels of F1+2 in 37 patients with mitral stenosis, divided into those with normal (group 1; n = 22) and those with increased (group 2; n = 15) regional left atrial thrombin generation, as described previously. The mitral valve area increased by a similar degree after the valvuloplasty procedure in the two groups. In group 1, the venous (P < 0.005) and left atrial (P < 0.0005) levels of F1+2 increased similarly after valvuloplasty, and as a result the left-atrial–venous F1+2 difference was unchanged. The venous F1+2 level also increased after valvuloplasty in group 2 (P < 0.005); however, in contrast with group 1, the left atrial level decreased (P < 0.03) and as a result the left-atrial–venous difference fell (P < 0.05). These results show that balloon mitral valvuloplasty results in an immediate increase in thrombin generation, but a decrease in the left-atrial–venous F1+2 difference, in patients with increased left atrial thrombin generation. The divergent changes in venous and left atrial levels of F1+2 further highlight the limitations of assessing regional changes in coagulation activity by measuring venous levels of coagulation markers.

We examined various nonSTAT commercially available coagulation activation markers in an attempt to help diagnose or exclude the often subtle clinical presentations of proximal deep vein thrombosis (PDVT) and pulmonary embolism (PE). Fifty-five patients presenting to the Emergency Department were completely assessed. Eleven patients were diagnosed with PDVT, six patients were diagnosed with PE, and three patients were diagnosed with both PDVT and PE. Thrombus precursor protein (TpP) excluded the diagnosis in 19 of the 35 patients negative for PDVT and/or PE, D-Dimer in 15 patients, prothrombin fragment 1.2 in 17 patients, and thrombin-antithrombin (TAT) in 14 patients. Both the TpP and TAT enzyme-linked immunosorbent assay (ELISA) tests had 100% sensitivity and negative predictive value for evaluating PDVT and/or PE. The TpP ELISA had the highest specificity (54%) of all four markers studied.

Immunohistochemistry was applied to AMeX-fixed tissue sections of 12 adenocarcinomas of the stomach (seven intestinal adenocarcinomas and five diffuse carcinomas), 12 adenocarcinomas of the pancreas (nine ductal adenocarcinomas and three signet ring carcinomas), and 12 squamous cell carcinomas of the larynx obtained at surgical resection to examine the possibility of extravascular activation of blood coagulation in cancer tissues by exploring the in loco patterns of distribution of fibrinogen, a final product of blood coagulation, fibrin, and a by-product of coagulation reactions (prothrombin fragment 1+2). Gastric, pancreatic, and laryngeal cancers exhibited fibrinogen antigen in abundance throughout the tumor stroma. Fibrin was detected along the edges of nests of carcinoma cells and at the host-tumor interface. Prothrombin fragment 1+2 was present in the blood vessels in areas of neoangiogenesis at the host-tumor interface (gastric and pancreatic cancer tissues) and on the tumor cell bodies (pancreatic and laryngeal cancer tissues). The presence of prothrombin fragment 1+2 in cancer tissues appears to be a good indicator of coagulation activation and thrombin generation at the tumor burden.

Objectives:does open surgery for abdominal aortic aneurysm (AAA) influence coagulation?Methods:in 23 patients operated on for AAA, cubital blood was sampled pre-, intra- and postoperatively. Femoral blood was also sampled intraoperatively.Results:preoperatively, prothrombin fragment 1+2 (F1+2), thrombin–antithrombin complex (TAT) and soluble fibrin (SF) were elevated in AAA patients. During aortic clamping all parameters increased significantly in cubital blood (p

Objectives To determine the effect of two low-dose monophasic oral contraceptives containing either 2 mg chlormadinone acetate or 150 μg desogestrel on blood clotting and fibrinolysis.Methods In vivo markers of intravascular coagulatory and fibrinolytic activity were measured in 45 volunteers randomly assigned to a 6-month treatment with one of the two study preparations.Results During oral contraceptive use, the procoagulatory activity increased (increased prothrombin fragment 1+2), the anticoagulatory capacity changed (increased protein C activity, decreased activated protein C sensitivity, decreased protein S activity and decreased antithrombin III activity) and the fibrinolytic system was activated (increased concentrations of plasmin-antiplasmin complexes and d-dimer as well as total fibrin degradation products). There were no relevant differences between the two medication groups.Conclusion Our results demonstrate that both oral contraceptive preparations have comparable effects on the hemostatic sy...

Thrombin cleaves single-chain urokinase-type plasminogen activator (scu-PA) into a virtually inactive two-chain form (tcu-PA/T), a process that may protect a blood clot from early fibrinolysis. It is not known under what circumstances tcu-PA/T can be generated in vivo. We have studied the occurrence of tcu-PA/T in human subjects with a varying degree of hypercoagulability. tcu-PA/T was assessed in the plasma of patients with disseminated intravascular coagulation (DIC), endotoxin-treated volunteers, patients with unstable angina pectoris, and patients selected for hip replacement. Relationships between tcu-PA/T and several markers reflecting thrombin generation were examined. tcu-PA/T was observed only in the plasma of patients with DIC and was associated with all thrombin markers and with scu-PA and urokinase antigen. Prothrombin fragment 1 + 2 and urokinase antigen were independent predictors of tcu-PA/T. The fact that tcu-PA/T could not be detected in the other three groups was explained by a lower extent of thrombin generation, a greater inhibition of thrombin by antithrombin, or less available urokinase antigen in these groups. The contribution of scu-PA to total urokinase antigen was decreased in the patients with DIC because of inactivation by thrombin, which may be an additional explanation for the inadequate fibrinolysis observed in these patients. These findings show that scu-PA can be inactivated in the circulation under severe pathophysiologic circumstances and that the process of inactivation depends not only on the generation of thrombin but also on the control of thrombin activity by its inhibitor antithrombin. (J Lab Clin Med 1999;134:161-67)

Haemostatic factors may play a part in the development of acute coronary heart disease.To evaluate as predictors of major coronary events (fatal and non-fatal myocardial infarctions and sudden death) levels of fibrinogen, von Willebrand factor, prothrombin fragment 1+2, thrombin-antithrombin complex, plasminogen activator inhibitor activity and C-reactive protein.We studied 131 men, aged 56-77 years, with treated hypertension and at least one additional cardiovascular risk factor (hypercholesterolaemia, diabetes mellitus or smoking). These patients were recruited from a continuing risk factor intervention study. The mean observation time was 3.0 years.Fourteen patients died and 16 had a major coronary event during the follow-up period. After adjustments for other risk factors, levels of prothrombin fragment 1+2 and C-reactive protein were independent predictors of major coronary events. The other measured haemostatic variables were not significantly associated with major coronary events during follow-up. Fibrinogen and prothrombin fragment 1+2 levels were independent predictors for mortality.Among treated hypertensive men, levels of prothrombin fragment 1+2 and C-reactive protein were independent predictors of major coronary events.

We studied 172 Greek patients (72 men aged 44.0 +/- 16.7 years and 100 women aged 46.5 +/- 14.1 years) with an unexplained thrombophilic tendency. One hundred and four apparently healthy persons (63 men aged 34.2 +/- 10.0 years and 41 women aged 37.1 +/- 13.3 years) were included as a control group. We performed the activated protein C resistance (APC-r) test using a clotting test (Chromogenix kit), detection of factor V Leiden using polymerase chain reaction (PCR)-restriction fragment length polymorphisms and measurement of thrombin-antithrombin complexes (TAT) and prothrombin fragment 1 + 2 (F1 + 2) levels with an immunoenzymatic assay. The normal range for the APC-r test (> 2.12) was determined from the controls. The factor V Leiden mutation was found in 31.9% of all the patients tested, in 28.1% of the unrelated patients with documented thrombophilic tendency of unknown origin and in 4.8% of the healthy controls. The APC-r test had a sensitivity of 0.42 and a specificity of 0.91 for the detection of factor V Leiden. Furthermore, we found no significant difference in levels of TAT and F1 + 2 between patients with and without the mutation and there was no correlation between aPC-r values and levels of TAT and F1 + 2.

Two groups of 15 patients each with disseminated intravascular coagulation in association with septic disease were treated with low-molecular-weight heparin (lmw-heparin) in different dosages (group I: 1.5-5 IE/kg body weight (BW) per hour; group II: 8-15 IE/kg BW). We studied the levels of D-dimer, thrombin-antithrombin III complex (TAT), prothrombin fragments 1 and 2 (PTF), and global tests of coagulation like prothrombin time (PT), activated partial thromboplastin time (PTT), thrombin time (TT) and platelet count, plasminogen activation (PA) and fibrinogen concentration to estimate the success of heparin therapy in the two groups. TT and fibrinogen concentration were not suitable to follow the course of the coagulation disorder, PT, PTT, platelet count progressively PA, D-dimer, TAT, and PTF normalised progressively after heparinisation. However, only the last three parameters were sensitive enough to show different effects of variable dosages of lmw-heparin. D-dimer, TAT, and PTF levels declined in proportion with heparin concentrations, and thus appear to be the most useful parameters for monitoring the therapeutic effect of heparin in septic coagulopathies.

The physiology of the hemostatic system in infancy and childhood is different from that in adulthood. Despite differences in several components of the coagulation and fibrinolytic systems, there is no evidence that children are at greater risk for hemorrhagic or thrombotic problems compared with adults 1 , 2 . Advances in understanding of the biochemistry of the hemostatic mechanism have led to the development of sensitive immunochemical methods for measuring peptides or enzyme-inhibitor complexes that are liberated with the activation of the coagulation and fibrinolytic systems in vivo [3] . Activation markers of coagulation and fibrinolysis have been measured in newborns, infants and children with a variety of underlying disorders 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 . However, reference ranges for children of different age have hitherto not been established. The aim of the present study was to document thrombin-antithrombin III-complex (TAT), prothrombin fragment 1+2 (F1+2), plasmin-α2-antiplasmin-complex (PAP) and D-dimer in healthy children and to determine whether age-related differences can be demonstrated.

The principal aim of this study was to evaluate, on biochemical grounds, whether injection of a low-osmolar nonionic contrast medium (iohexol) can induce a prothrombotic state and/ or a change in fibrinolysis. Fifteen patients were submitted to urographic examination and the assays listed below were performed: before the injection (To), 1 h after (Ti), and 24 h after (T24) the injection of the contrast medium. The following assays were performed: fibrinopeptide A (FPA), prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complex (TAT), and D dimer (D-D). The assays were carried out on 6 of the patients to whom a saline infusion was administered. Only a mild statistically significant increase was found in FPA levels at 1 h after injection of the contrast medium (mean and CI 95%: T0 4.4, 3.7-5.5; T, 6.0, 4.9-9.1; p = 0.003). F1+2, TAT and D-D did not show any significant change after the injection. These findings show that after injection of iohexol, only a mild, though statistically significant, increase in FPA levels was observed as an expression of increased thrombin activity. In the absence of any significant increases in TAT, F1+2 and D-D, we have no evidence of a prethrombotic state.

Udgivelsesdato: null-null The techniques adopted for venipuncture and the mixing of aspirated blood with anticoagulant were evaluated for their possible contribution in pre-analytical variation in estimating plasma prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complex (TAT), soluble fibrin and total fibrin(ogen) degradation products. Antecubital vein blood samples were simultaneously collected in 20 subjects from either arm by technologists with high and less blood sampling experience employing a crossover design. F1+2 and TAT were significantly higher in plasma obtained by a less experienced technologist. Three different mixing procedures of blood with anticoagulants did not influence the levels of the markers. The results emphasize that experienced technologists should preferably be selected for collecting blood for analysis of coagulation markers.

症候性および無症候性ラクナ梗塞例の血漿プロトロンビン・フラグメント1+2 (F1+2) 値を測定し, ラクナ梗塞に凝固亢進状態があるか否か, また症候の有無により凝固能に相違があるか否かを検討した.対象は有症候のラクナ梗塞61例 (急性期26例, 慢性期35例), 無症候性ラクナ梗塞34例および非梗塞67例である。ラクナ梗塞急性期群の収縮期血圧は対照群より有意に高値であった (p

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.

OBJECTIVES AND METHODS The aims of the present work were to assess the presence of thrombin generation in Crohn's disease and in ulcerative colitis by using the prothrombin fragment 1 + 2 and the thrombin-antithrombin III complex assays and to study the possible relationships between these markers and disease activity. RESULTS Prothrombin fragment 1 + 2 and thrombin-antithrombin III complex were significantly raised in patients with Crohn's disease (n = 69) and with ulcerative colitis (n = 25) as compared with healthy controls (n = 50). In Crohn's disease these two markers of thrombin generation were correlated with the Van Hees index (P < 0.05 and P < 0.001, respectively); values were significantly different from controls even in the patient group displaying the lowest disease activity (P < 0.001). No correlation was found with tumour necrosis factor alpha and C-reactive protein; nevertheless patients with C-reactive protein less than or equal to 10 mg/l had significant lower values of prothrombin fragment 1 + 2 (P < 0.03). In ulcerative colitis prothrombin fragment 1 + 2 and thrombin-antithrombin III complex were significantly increased by comparison with controls, were higher in patients with pancolitis and correlated with C-reactive protein (P < 0.002 and P < 0.009, respectively). CONCLUSION These data show that prothrombin fragment 1 + 2 and thrombin-antithrombin III complex are increased in inflammatory bowel diseases and suggest that thrombin generation might be an early event in their pathogenesis.

Abstract Plaque rupture with the exposure of a tissue factor–rich procoagulant surface is considered the common pathogenetic mechanism of unstable angina and myocardial infarction. Activated factor VII, the key enzyme for initiating blood coagulation under resting conditions, is increased in pathological situations associated with tissue factor exposure. We measured the plasma levels of activated factor VII and studied their relation with signs of coagulation enzyme activity in patients with acute coronary syndromes. The plasma levels of activated factor VII, prothrombin fragment 1+2, and fibrinopeptide A were measured on admission in consecutive patients presenting with acute myocardial infarction (n=28), unstable angina (n=32), and stable angina (n=17) and in age- and sex-matched healthy individuals (n=33). Plasma determinations of the same markers were also repeated at 15 days and 3 and 6 months. On admission, the patients with unstable angina or myocardial infarction had significantly higher plasma levels of prothrombin fragment 1+2 ( P P P P