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BACKGROUND: The coagulation response during vascular injury with uninterrupted administration of direct oral anticoagulants has not been elucidated. OBJECTIVE: Our aim was to evaluate differences in coagulation responses after vascular injury between uninterrupted direct thrombin inhibitor and direct factor Xa inhibitor recipients. METHODS: Patients scheduled for catheter ablation for atrial fibrillation were randomly assigned to receive dabigatran or apixaban in this prospective, randomized, comparative, parallel-group study. Venous blood was collected 3 times: 180 minutes after taking the anticoagulant on the day before the procedure, before vascular punctures of the ablation procedure, and 10-15 minutes after the start of vascular punctures. RESULTS: Forty-two patients were enrolled. The prothrombin fragment 1+2 level, the primary end point, was much larger after vascular puncture in the uninterrupted dabigatran recipients (median, 83 pmol/L; interquartile range, 56-133 pmol/L) than in the uninterrupted apixaban recipients (median, 1 pmol/L; interquartile range, -3 to 19 pmol/L; P < .001). Antithrombin levels decreased after vascular puncture in dabigatran recipients, and both protein C and antithrombin levels decreased after vascular puncture in apixaban recipients. CONCLUSION: Unlike uninterrupted apixaban, uninterrupted dabigatran does not inhibit thrombin generation in response to vascular injury.

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Background and aims: A prothrombotic state was demonstrated in patients with Cushing's syndrome and is involved in the development and progression of cardiovascular and renal damage in hypertensive patients. This study was designed to examine the relationships between cortisol secretion and the hemostatic and fibrinolytic systems in hypertension. Methods: In 149 middle-aged, nondiabetic, essential hypertensive patients free of cardiovascular and renal complications, we measured hemostatic markers that express the spontaneous activation of the coagulation and fibrinolytic systems and assessed daily cortisol levels (8 AM, 3 PM, 12 AM; area under the curve, AUC-cortisol) together with the cortisol response to dexamethasone overnight suppression (DST-cortisol). Results: Plasma levels of D-dimer (D-dim), prothrombin fragment 1 + 2 (F1 + 2), and von Willebrand factor (vWF) were progressively and significantly higher across tertiles of AUC-cortisol and DST-cortisol, whereas no differences were observed in fibrinogen, tissue plasminogen activator, plasminogen activator inhibitor-1, antithrombin III, protein C, and protein S. D-dim, F1 + 2, and vWF were significantly and directly correlated with age and both AUC-cortisol and DST-cortisol. Multivariate regression analysis showed that both AUC-cortisol and DST-cortisol were related to plasma D-dim, F1 + 2, and vWF independently of age, body mass index, blood pressure, and renal function. Conclusion: Greater daily cortisol profile and cortisol response to overnight suppression are independently associated with a prothrombotic state in hypertensive patients and might contribute to the development of organ damage and higher risk of cardiovascular complications.

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BACKGROUND: The interaction of central nervous system inflammation and coagulation system activation in multiple sclerosis (MS) receives increasing attention for its diagnostic and therapeutic potential. During blood-brain barrier (BBB) disruption, fibrinogen migrates into the CNS and contributes to inflammation. In the coagulation cascade, fibrinogen is converted into fibrin by thrombin, which itself is cleaved from prothrombin by activated factor XII. We hypothesized that the conversion of prothrombin to thrombin can be quantified by prothrombin fragment 1+2 (PF1.2) in cerebrospinal fluid (CSF). Primary endpoint was the correlation between PF1.2, D-dimer and fibrinogen in CSF of patients with neuroinflammatory diseases. Secondary endpoints were PF1.2 levels depending on presence of contrast enhancement (CE) on MRI, and correlation between PF1.2 with serum-CSF albumin quotient (Qalb). Additionally, an exploratory analysis of CSF PF1.2 levels to distinguish between MS-patients and controls without neurological disease was performed. METHODS: Patients admitted for a suspected inflammatory CNS disease were prospectively recruited from October 2017 to December 2020. Citrated CSF samples were obtained and analyzed for PF1.2, fibrinogen and D-dimer using a highly sensitive luminescent oxygen channeling immunoassay. Patient clinical data and final diagnoses were retrospectively collected and analyzed. RESULTS: 187 patients were included, of whom 116 received diagnoses of relapsing-remitting (RRMS), primary-progressive MS, clinically or radiologically isolated syndrome, or anti-aquaporin-4-/anti-myelin-oligodendrocyte-glycoprotein-antibody-related diseases. CSF analysis of those 116 patients revealed a correlation between PF1.2 and CSF fibrinogen (ρ=.315; p<.001) as well as between PF1.2 and CSF D-dimer (ρ=.531; p<.001). Among all 187 patients, CSF PF1.2 was increased in patients with CE on MRI (n=71; 147.38 pmol/l; IQR 83.68-215.36) compared to patients without CE (n=86; 100.03 pmol/l; IQR 33.87-162.80; p=.008). CSF PF1.2 correlated significantly with Qalb (ρ=.445; p<.001). No differences of CSF PF1.2 levels were observed between RRMS (131.48 pmol/l, IQR 42.75-204.10) and disease controls (102.28 pmol/l; IQR 55.60-159.94; p=.606). CONCLUSION: In patients with autoimmune inflammatory CNS diseases PF1.2 correlated strongly with fibrinogen and D-dimer in CSF, indicating coagulation system activation. The findings suggest that thrombin generation might require acute BBB dysfunction to exert autoimmune effects in the CNS.

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BACKGROUND: Increased activation of the coagulation cascade and diminished fibrinolysis combine to promote fibrin deposition and polyp formation in chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP). More information is needed concerning mechanisms of coagulation in CRSwNP. OBJECTIVE: We investigated the mechanisms as well as the initiation and regulation of coagulation cascade activation in CRS. METHODS: Samples were collected from 135 subjects with CRSwNP, 80 subjects with chronic CRS without nasal polyps (NP), and 65 control subjects. The levels of activated factor X (FXa), prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complex, tissue factor (TF), and TF pathway inhibitor (TFPI) were monitored in CRS by real-time PCR, ELISA, immunohistochemistry, or immunofluorescence. Heteromeric complexes of TF with activated factor VII (FVII) and TF with activated FVII and FXa were assessed by coimmunoprecipitation and Western blotting. RESULTS: Increased levels of FXa, F1+2, and thrombin-antithrombin complex were detected in NP tissue compared to uncinate tissue from CRS and control subjects. Although free TF protein levels were not increased in NP, immunoprecipitation of TF in NP tissue revealed increased complexes of TF with FVII. Local expression of FVII was detected in sinonasal mucosa, and the ratio of TFPI to FXa was lower in NP tissue. CONCLUSION: The coagulation cascade is associated with NP compared to control and uncinate tissue from CRS patients, and TF and FVII are produced locally in sinonasal mucosa in patients. TF and FVII can activate the extrinsic coagulation pathway, suggesting that this pathway may activate fibrin deposition in CRSwNP. Reduced formation of the complex of FXa and TFPI in NP may reduce natural suppression of the extrinsic coagulation pathway in CRSwNP.

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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 <0.0001) and F1+2 (p < 0.0001) concentrations than healthy individuals. However, this was not reflected in the thrombin generation assay. CONCLUSION: Reference intervals for thrombin generation, TAT as well as F1+2 were established. Patients with localized cancer had significantly elevated TAT and F1+2. TAT and F1+2 may hold potential for identifying hypercoagulation in cancer patients.

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OBJECTIVE: It remains unclear whether atrial fibrillation (AF) alone determines systemic changes in hemocoagulation. Our aim was to examine the prothrombin fragment F1+2 and fibrinopeptide A (FPA) as early markers of coagulation activity still in the first twenty-four hours of paroxysmal AF (PAF) and to correlate them with the arrhythmia onset. METHODS: 51 non-anticoagulated patients (26 men, 25 women, aged 59.84±1.6 years) and 52 controls (26 men, 26 women, aged 59.50±1.46 years) were sequentially selected. F1+2 and FPA plasma levels were measured by enzyme-linked immunoassays. RESULTS: F1+2 was significantly higher in patients (292.61pmol/L±14.03pmol/L vs 183.40pmol/L±8.38pmol/L; p<0.001). FPA was also substantially higher (4.47ng/mL±0.25 ng/mL vs 3.09ng/mL±0.15ng/mL, p<0.001). Among the potential predictors for these deviations: age, gender, BMI, PAF duration and CHA2DS2-VASc score, it was established that higher F1+2 and FPA plasma levels were independently associated only with PAF duration (p<0.05). Moreover, longer episodes were associated with higher values of F1+2 (Adjusted R2 = 0.68) and FPA (Adjusted R2 = 0.70). CONCLUSIONS: Increased coagulation activity was present still in the first twenty-four hours of PAF clinical presentation. The disease itself was associated with increasing hypercoagulability over time, suggesting its importance as an independent risk factor for thromboembolic events.

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Hypercoagulability in ST-segment elevation myocardial infarction (STEMI) as related to long-term clinical outcome is not clarified. We aimed to investigate whether prothrombin fragment 1+2 (F1+2), d-dimer, and endogenous thrombin potential (ETP) measured in the acute phase of STEMI were associated with outcome. Blood samples were drawn median 24 hours after symptom onset in 987 patients with STEMI. Median follow-up time was 4.6 years. Primary outcome was a composite of all-cause mortality, reinfarction, stroke, unscheduled revascularization, or rehospitalization for heart failure; secondary outcome was total mortality. The number of combined end points/total mortality was 195/79. Higher levels of d-dimer and F1+2 were observed with both end points (all P < .005), whereas ETP was significantly lower ( P < .01). Dichotomized at medians, increased risk was observed for levels above median for F1+2 and d-dimer (combined end point P = .020 and P = .010 and total mortality P < .001, both), while an inverse pattern was observed for ETP ( P < .02, both). Adjusting for covariates, d-dimer was still associated with reduced risk of total mortality ( P = .034) and receiver operating characteristic curve analyses showed area under the curve of 0.700 (95% confidence interval, 0.640-0.758). The hypercoagulable state in acute STEMI seems to be of importance for clinical outcome.

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Whether trough-phase rivaroxaban concentrations provide sufficient anticoagulation needs more study. We evaluated levels of coagulation activation markers in the trough concentration phase in nonvalvular atrial fibrillation (NVAF) patients, and the correlation between these markers and rivaroxaban concentration. Fifty-five Japanese NVAF patients received 24-week rivaroxaban treatment of either 15 or 10 mg once-daily in the morning. Of these, 26 patients had no history of anticoagulant therapy (naive group) and 29 had switched from warfarin (warfarin group). D-dimer and prothrombin fragment 1 + 2 (F1 + 2) levels, and protein C activities were measured at 0 (baseline), 12 and 24 weeks of rivaroxaban treatment just before the patient's regular dosing time (trough phase). For 49 patients, D-dimer, F1 + 2, and rivaroxaban concentrations were also measured twice between 28 and 32 weeks of rivaroxaban treatment at non-trough times to achieve a range of drug concentrations for correlation analysis. For the naive group, D-dimer and F1 + 2 levels were significantly reduced (p < 0.01) from baseline at 12 and 24 weeks. For the warfarin group, these values were unchanged for D-dimer but significantly increased (p < 0.01) for F1 + 2. Protein C activity was unchanged in the naive group and was increased (p < 0.01) in the warfarin group. Prothrombin time (r = 0.92, p < 0.0001) and activated partial thromboplastin time (r = 0.54, p < 0.0001) correlated with rivaroxaban concentration, but not D-dimer and F1 + 2 levels. In conclusion, rivaroxaban in the trough phase is comparable to warfarin in reducing D-dimer levels. Although trough level rivaroxaban suppresses F1 + 2 less than warfarin, the higher activities of protein C with rivaroxaban treatment compared to warfarin treatment may counterbalance this. Lack of correlation between rivaroxaban concentration and D-dimer and F1 + 2 levels suggests that trough concentrations of rivaroxaban reduce their concentrations as effectively as higher levels do.

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Objective To investigate the relationship between prothrombin fragment 1+2 (F1+2) and peripherally inserted central catheter (PICC) associated thrombosis in cervical cancer patients, and provide certain clinical basis of early prevention in peripherally inserted central catheter associated thrombosis in cervical cancer patients. Methods One hundred and forty cervical patients with PICC were enrolled in this study, and they were divided into thrombosis group (35 patients) and non-thrombosis group (105 patients). The level of F1+2 was examined using enzyme-linked immunoassay, and was analyzed according to the clinic features. Results The level of F1+2 was correlated with clinical stage (r = 0.640, P = 0.004);but was not correlated with age, type of tumor and concurrent radiochemotherapy (P>0.05). The level of F1+2 in thrombosis group was (520.343 ± 121.759) pmol/L, in non- thrombosis group was (388.361 ± 104.873) pmol/L, and there was significant difference (P =0.001). The multi-factors Logistic analysis showed that the level of F1+2 (OR=1.011, P=0.001) and age (OR = 21.025, P = 0.031) were independent risk factors for the PICC associated with thrombosis in cervical cancer. Conclusions The level of F1+2 is closely related with clinical stage and PICC associated thrombosis, and it is an independent risk factor for the PICC associated with thrombosis in cervical cancer.

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INTRODUCTION: 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. MATERIALS AND METHODS: 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. RESULTS: 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 p<0.05). Serial measurements of PT and rivaroxaban concentration at trough, 2, 4, and 6h after taking rivaroxaban showed a positive correlation (R2=0.69, p<0.01). PT at 4h after rivaroxaban was significantly prolonged compared with trough (16.6 versus 11.5s, p<0.0001). F1+2 at 4h was also decreased compared with trough (160 (123-245.5) versus 196 (141-266.5), p=0.04), but no patients showed F1+2 below the normal range at 4h. In other 34 patients with warfarin treatment (77years), median PT-INR and F1+2 were 2.06 (1.75-2.50) and 75 (48-111) (p<0.0001 versus 4h after rivaroxaban). Notably, of those with PT-INR≥2.0 (18/34), 12 (12/18, 67%) showed F1+2 below the normal range. CONCLUSIONS: Rivaroxaban 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.

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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. SUMMARY: Background 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.

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INTRODUCTION: Increased thromboembolic disorders and chemotherapy-induced thromboembolic events are well known phenomena in patients with breast cancer. Antithrombin III (AT III) inactivates thrombin, resulting in increased thrombin-antithrombin (TAT) levels. Activated factor X cleaves prothrombin and thrombin, resulting in increased levels of prothrombin fragment 1+2 (F 1+2). Increased TAT and F 1+2 levels show coagulation activation. The aim of this study was to examine plasma levels of TAT and F 1+2 and the effect of anthracycline-based chemotherapy on plasma TAT and F 1+2 in patients with operable breast cancer. MATERIALS AND METHODS: Seventy patients and 30 age-matched healthy controls were enrolled. Levels of TAT and F 1+2 were investigated before and after adjuvant chemotherapy. Basal levels (pre-chemotherapy) of TAT and F 1+2 in patients were compared with those in healthy controls and patient levels after 3 cycles of chemotherapy. Levels of TAT and F 1+2 were determined using the ELISA method. RESULTS: TAT and d-dimer levels were significantly higher in patients, (P: 0.02 and P<0.001, respectively). Post-chemotherapy F 1+2 levels were higher than basal levels (P: 0.02). F 1+2 levels were higher in patients, although the difference was not statistically significant (P: 0.52). There was no difference between basal and post-chemotherapy TAT levels. DISCUSSION: In conclusion, while higher post-chemotherapy F 1+2 levels suggest that the cumulative effect of chemotherapy increases the risk of thrombosis, TAT and d-dimer levels indicate that the effect of the cancer further increases the risk of thrombosis in patients with operable breast cancer.

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INTRODUCTION: 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. METHODS: Eighty-five patients with venous thromboembolism were studied, 45 on warfarin, target INR 2.5 and 40 on rivaroxaban 20mg once daily. RESULTS: 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 (p<0.0001). The lag time and time to peak TG were longer, and peak thrombin was lower in patients receiving rivaroxaban (p<0.0001) 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. CONCLUSION: In conclusion, both rivaroxaban and warfarin provided effective anticoagulation, as assessed by inhibition of TG and makers of in-vivo coagulation activation.

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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.

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INTRODUCTION: Hypercoagulation was suggested to be involved in preterm birth etiology; however, the coagulation state of preterm parturients remains unelucidated. The study aim was to evaluate the haemostatic system of pregnant women with premature uterine contractions (PUC). MATERIALS AND METHODS: The cohort study population consisted of 76 healthy pregnant women admitted with regular PUC. The study group included 38 women who experienced preterm birth; 14 of them had preterm premature rupture of membranes (PPROM). The control group included 38 women who eventually had term delivery. Groups were matched for maternal age, number of births and gestational age at admission. Blood samples were tested for haemostatic parameters and coagulation activation markers. RESULTS: Significantly shorter PT and aPTT were documented in the study compared to control group (25.7±2 vs. 27.4±2.7seconds, P=0.003, and 9.96±0.5 vs. 10.1±0.4seconds, P=0.05, respectively), although differences in absolute values were small. There was no significant difference between the two groups in levels of: fibrinogen, D-dimer, protein C-global, free protein S antigen, factor VIII activity, Von Willebrand factor, plasminogen activator inhibitor-1, prothrombin fragments F1+2 (PT F1+2), tissue factor and tissue factor pathway inhibitor. Women with PPROM had significantly lower PT F1+2 levels compared to those who had preterm delivery with intact membranes (351±99 vs. 561±242pmol/L, P=0.003). CONCLUSIONS: Shortened PT and aPTT, reflecting increased thrombotic activity in maternal plasma, could serve as a marker of real preterm labor in women with premature uterine contractions. Further prospective studies in a larger cohort are warranted to validate these findings.

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INTRODUCTION: Renal transplant recipients are at increased risk of venous thromboembolic events, which is in part caused by their treatment with maintenance immunosuppressive drugs. Because we observed an increased incidence of venous thromboembolic events in renal transplant recipients treated with the mTOR inhibitor (mTORi) everolimus, we aimed to identify prothrombotic mechanisms of this immunosuppressive drug. MATERIALS AND METHODS: In a single center study, nested in a multi-center randomized controlled trial, we measured parameters of coagulation, anti-coagulation and fibrinolysis in renal transplant recipients, receiving the mTORi everolimus (n=16, mTOR group) and compared them to a similar patient group, receiving a calcineurin inhibitor and/or mycophenolate sodium (n=20, non-mTOR group). All patients were at least 6 months following transplantation with a stable transplant function. RESULTS: The use of an mTORi was associated with significantly higher levels of von Willebrand factor, prothrombin fragment 1+2, thrombin-activatable fibrinolysis inhibitor and plasminogen activator inhibitor-1 as compared to a non-mTORi based immunosuppressive regimen. CONCLUSIONS: Treatment with an mTORi leads to increased endothelial activation, thrombin formation and impaired fibrinolysis in renal transplant recipients. This suggests an increased risk of thrombotic events in renal transplant recipients treated with mTOR inhibitors. A prospective study to establish the precise risk of thrombotic events in these patients is urgently needed.

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INTRODUCTION: The contribution of the contact system to arterial thrombosis is unclear, results of clinical studies are conflicting. Particularly, little is known about the involvement of the contact system in the progression of arterial thrombosis. Therefore, we investigated the activation of the contact system during an acute myocardial infarction (AMI) and 3 and 6 months following the acute event. METHODS: Plasma of patients with a first AMI was collected on admission and 3 and 6 months after the AMI. The levels of complexes of activated factor XI (FXIa), FXIIa and kallikrein with C1 esterase inhibitor (C1INH) and the levels of complexes of FXIa with α1-antitrypsin (AT) were measured in these plasmas. Recurrent cardiovascular events were recorded during a one year period after the AMI. RESULTS: We observed that the levels of FXIa-C1INH were elevated during the acute phase compared to the steady-phase 3 and 6 months after the AMI. The levels of FXIa-AT, FXIIa-C1INH and kallikrein-C1INH did not change over time. The levels of FXIa-C1INH, FXIa-AT, FXIIa-C1INH and kallikrein-C1INH were not predictive for a recurrent event. CONCLUSION: We observed that during an AMI, the activation of FXI was increased. The levels of FXIIa-C1INH were not elevated, suggesting that activation of FXI during the acute phase did not result from contact activation. The levels of the enzyme inhibitor complexes were not predictive for a recurrent event one year after the first AMI.

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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.

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BACKGROUND: The purpose of this study is to evaluate the diagnostic usefulness of the quantitation of D-dimer, thrombin-antithrombin III complex (TAT) and prothrombin fragment 1 2 (F1 2) in patients with DIC or venous thrombosis. METHODS: The quantitation of D-dimer, TAT and F1 2 by ELISA (Behring, Germany) were done with the specimens from eighty eight patient plasma. The patients were classified as DIC, probable DIC and non-DIC based on the DIC criteria by reserach committee in Japan, and the patients with deep vein thrombosis (DVT) or pulmonary embolism (PE) were included. RESULTS: All eighteen DIC patients showed the increased D-dimer ELISA and fourteen patients showed the increased TAT and F1 2. According to the results of quantitative D-dimer, TAT and F1 2 tests, probable DIC and the group with increased results of above three tests among non-DIC were considered as DIC. Two patients with PE showed increased results of above three tests. Among nine DVT patients, eight patients showed increased results of D-dimer ELISA and F1 2, but TAT was increased in only six patients. Among forty six patients with negative results of D-dimer semiquantitation (latex agglutination), twenty seven patients (59%) revealed increased results of D-dimer quantitation (ELISA). CONCLUSIONS: D-dimer quantitation by ELISA is the most sensitive test in the diagnosis of DIC and venous thrombosis. The quantitation of D-dimer, TAT and F1 2 can increase the diagnostic rate of DIC and venous thrombosis, and the developement of the new quatitating reagents with more rapid and individual procedures will contribute to the accurate and rapid diagnoses of them.

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