Fibrin Monomer Levels Research Articles

Establishing Expectancy Values for Fibrin Monomer in Uncomplicated Pregnancy.

Background During pregnancy, a physiological increase of molecular activation markers (MAM) of hemostasis such as prothrombin fragments 1 + 2, thrombin-antithrombin complex, and D-dimers (DD) occurs. Therefore, monitoring MAM levels during pregnancy to evaluate the risk of venous thromboembolism (VTE) may be unreliable; nevertheless, DD analysis in pregnancy is widely performed. In contrast to DD, fibrin monomer (FM) levels have been reported to remain stable during pregnancy. Objectives The main aim of this study was to define the expected range for FM levels in pregnant outpatients. In addition, we examined the impact of the individual VTE risk, as calculated by the pregnancy risk score of the Royal College of Obstetricians and Gynaecologists (RCOG), as well as that of antithrombotic treatment on FM levels. Methods A total of 342 pregnant women seen at our hemostasis unit were included throughout 350 pregnancies in 899 samples. Results Low-risk thrombophilia, but not the RCOG score itself, was found to influence all MAM levels, whereas antithrombotic treatment had only an impact on DD. For FM, a reference range could be calculated irrespective of the pregnancy term, in contrast to other MAMs, which fluctuated throughout pregnancy. Conclusions Our findings suggest a stronger impact of inherited thrombophilia on hemostasis activity during pregnancy as compared with acquired or other predisposing thrombophilic risk factors. FM levels showed a marginal increase during pregnancy in contrast to other MAM and remain a potential candidate to improve the laboratory assessment of VTE risk during pregnancy. Further prospective studies in pregnant patients with suspicion of VTE are needed.

The Role of Fibrin Monomer Compared to D-dimer and CRP in Determining COVID-19 Severity

Fibrin Monomer (FM), as a product of thrombin activity in cleaving fibrinogen, can be used as an early marker of thrombotic events in COVID-19 patients. D-dimer is a commonly used marker of hemostasis as a product of plasmin activity in cleaving polymeric fibrin. D-dimer is often used to help decide whether to initiate anticoagulant administration. This study aims to know whether FM can be used as a marker for thrombotic events such as D-dimer in COVID-19 patients; CRP levels were also examined to determine how inflammation affected the two hemostatic indicators. A total of 93 patients were confirmed with COVID-19 by PCR. The median (min-max) FM in the severe stage was 4.53 (2.26-58.20)ug/mL, whereas, in the mild-moderate stage, it was 4.21 (2.19-32.35 ug/mL. There are significant differences in median D-dimer levels in severe stages to mild-moderate, respectively 0.46 (0.14–7.58) and 0.7890, and ages. The level of FM that can be used to differentiate the severe stage is > 4.46 ug/mL (sensitivity 56.3%, specificity 58.0%) as in the D-dimer level is > 0.58 ug/mL ((sensitivity 75.0%, specificity 65.2%). There is a moderate positive correlation between fibrin monomer and D-dimer, a weak positive correlation between D-dimer and CRP, and no correlation between FM and CRP. This study concludes that the FM median level is higher in severe COVID-19 than in D-dimer. Fibrin monomer levels have a positive correlation with D-dimer. Fibrin Monomer levels are not affected by CRP.

Fibrin monomers evaluation during hospitalization for COVID-19 is a predictive marker of in-hospital mortality.

Coagulopathy is one of the main triggers of severity and worsening of Coronavirus disease 2019 (COVID-19) particularly in critically ill patients. D-dimer has been widely used to detect COVID-19 coagulation disorders and has been correlated with outcomes such as disease severity and in-hospital mortality. Involvement of other fibrin degradation products, particularly fibrin monomers (FM), remains an ongoing question. We performed a monocentric study of adult patients with COVID-19, who were admitted either in the medical ward (MW) or in the intensive care unit (ICU) and who had FM measurements performed on them during the first wave of COVID-19 outbreak. We analyzed the positivity of FM levels (FM > 7 µg/mL) to assess the ability of FM monitoring during the first days of hospitalization to predict COVID-19 outcomes. In our cohort, 935 FM measurements were performed in 246 patients during their first 9 days of hospitalization. During patient follow-up, the FM levels were higher in patients admitted directly to the ICU than in those admitted to the MW. Moreover, we observed significantly increased levels of FM in patients when the data were stratified for in-hospital mortality. At hospital admission, only 27 (11%) patients displayed a positive value for FM; this subgroup did not differ from other patients in terms of severity (indicated by ICU referral at admission) or in-hospital mortality. When analyzing FM positivity in the first 9 days of hospitalization, we found that 37% of patients had positive FM at least once during hospitalization and these patients had increased in-hospital mortality (p = 0.001). Thus, we used non-adjusted Kaplan-Meier curves for in-hospital mortality according to FM positivity during hospitalization and we observed a statistically significant difference for in-hospital mortality (hazard ratio = 1.48, 95% CI: 1.25-1.76, p < 0.001). However, we compared the AUC of FM positivity associated with a ratio of D-dimer >70% and found that this combined receiver operating characteristic (ROC) curve was superior to the FM positivity ROC curve alone. Monitoring of FM positivity in hospitalized patients with COVID-19 could be a reliable and helpful tool to predict the worsening condition and mortality of COVID-19.

Persisting Endothelial Cell Activation and Hypercoagulability after Recovering from COVID-19: The Roadmap-Post COVID-19 Study

Background: In patients with severe COVID-19, activation of blood coagulation and endothelial cells orchestrated with complement activation and cytokine storm leads to disease worsening and death. Hypercoagulable state and endothelial cell activation and fibrinolytic unbalance are common alterations in patients with COVID-19 hospitalized either at the conventional medical ward or at the intensive care unit (ICU). Two systematic reviews highlight that D-dimer values are higher in non survivors as well as in patients with severe COVID-19 than in those with mild disease, showing the association between D-dimer levels and disease severity or death. Nevertheless, there are limited data in small series of patient, on the persistence of hypercoagulability and endothelial cell activation following recovery from COVID-19. Aims: To investigate the persistence of endothelial cell activation and hypercoagulability after recovery from COVID-19. Patients/Methods. COVID-19 survivors (n = 208) and 30 healthy individuals were enrolled in this study. Methods: In ,total, 208 COVID-19 survivors were included in the study; 125 males (60%) and 83 females (40%) with a median age of 50 years (IQR = 20, range 18 to 78 years). Biomarkers of hypercoagulability and endothelial cell activation: The procoagulant phospholipid-dependent clotting time (PPL-ct) was measured using a factor Xa-based clotting assay STA®-Procoag-PPL. Free-TFPI levels were measured with the ELISA Free TFPI, Asserachrom®; D-dimer and fibrin monomers (FM) were measured by STA Liatest D-Di and STA Liatest FM; soluble thrombomodulin (sTM) was measured by Asserachrom® TM. All assays were from Diagnostica Stago, Asnières, France. Heparanase-levels were measured with ELISA kits R&D. Systems (Lille France). Detection of anti-SARS-CoV2 antibodies: IgG and IgA anti-SARS-CoV-2 antibodies were detected in the sera of the survivors using a semi-quantitative commercial ELISA methodology (Euroimmun Medizinische Labordiagnostika AG, Lubeck, Germany) Results: The median interval between symptom onset and screening for SARS-CoV-2 antibodies was 62 days (IQR = 22 days). Antibodies against SARS-CoV-2 were detected in all survivors enrolled in the study. The median level of IgG and IgA antibodies was 5.68 U (IQR = 6.19) and 3.62 U (IQR = 5.36), respectively. In 112 survivors with known blood group, 48 (43%) were group O, 44 (39%) were group A, 14 (13%) were group B, and 6 (5.4%) were group AB. Survivors showed significantly higher levels of D-Dimers, FM, TFPI, and heparanase as compared to that of the control group. Survivors had significantly shorter PPL-ct . One out of four of COVID-19 survivors showed increase at least one biomarker of endothelial cell activation or hypercoagulability (Table1). Elevated D-dimer was associated with older age. Elevated FM was associated with female gender. Elevated heparanase was independently associated with male gender. Decreased Procoag-PPL clotting time was associated with female gender. Univariate and multivariate logistic regression analysis examining predictors of hypercoagulability in study cohort of COVID-19 survivors are reported in table 2 . The interval between COVID-19 diagnosis and assessment was not associated with the changes of the studied biomarkers. Conclusion: The ROADMAP-postCOVID-19 study offers an analysis of a large panel of biomarkers of endothelial cell activation and hypercoagulability in survivors of COVID-19. The study documents that two months after symptoms' onset, activation of endothelial cells, in vivo thrombin generation, and fibrin lysis are frequent phenomena up to two months from COVID-19 symptom onset. The data presented herein allow to propose that evaluation of blood hypercoagulability (using D-dimer for instance) and endothelial cell activation could offer the possibility of prompt identification of COVID-19 survivors at risk of post-COVID-19 vascular complications. The findings of the present study underline the need for a thorough evaluation of a potential correlation between the sustained hypercoagulability and endothelial cell activation with the symptomatology of long-COVID-19 to apply anticipated diagnostic and therapeutic strategies. The clinical relevance of the identified biomarkers of endothelial activation and hypercoagulability in the assessment of the risk of long COVID-19 must be investigated in a prospective study. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Features of hemostasis in patients with non-ST-elevation myocardial infarction

Background: Coronary thrombosis is the key pathogenic mechanism of acute heart attack, including non-ST segment elevation (NSTEMI). Given that, the detection of reliable markers of hemostasis disorders is important in the process of optimizing the diagnosis of NSTEMI. Material and methods: The study was conducted on 54 patients with NSTEMI (average age 69.7±1.5 years). In 60% of cases, 3-vessel disease was noted; 56% of patients had ejection fraction &gt;50%, and Killip class I of heart failure was revealed in 78% of patients. With the help of the STA-Liatest (France) equipment, the blood tests determined the following hemostasis markers: fibrin monomers (FM), thrombotic complex activity of factors II, VII and X. Additional markers like Procoag, the coagulation indicator dependent on circulating phospholipids or SPA, D-dimers, as well as factors C, S and antithrombin III were appreciated. The values of these markers determined by the same method in 20 healthy persons (control group) were used as normal values. Results: Circulating level of FM on admission was increased twice, while the values of Procoag and SPA were significantly decreased by 35.3% compared to the control. Factors C, S and antithrombin III were 54-80% of the control value range, and D-dimers were within the permissible values. In the acute phase of the heart attack, a deterioration of hemostasis indicators was noted, excepting the D-dimers. The levels of FM determined 24 and 72 hours after revascularization were consistently increased (up to 3.8 times) compared to the control, while Procoag and SPA decreased by 54-57%. Further reduction of factors C, S and antithrombin III accounted for 42-54% of normal indicators. After 5 days, an improvement in hemostasis markers was observed, but a significant difference still remained comparing to the control group. Conclusions: The hemostasis particularities discovered in patients with NSTEMI indicate the features of an activated prothrombotic status, and FM could be an important diagnostic marker of NSTEMI, due to its most significant deviation from the normal value (&gt;100%). It can reliably reflect the thrombin level, which triggers the last enzymatic phase of thrombus formation.

Persisting Endothelial Cell Activation and Hypercoagulability after COVID-19 Recovery—The Prospective Observational ROADMAP-Post COVID-19 Study

Background. Hypercoagulable state and endothelial cell activation are common alterations in patients with COVID-19. Nevertheless, the hypothesis of persistent hypercoagulability and endothelial cell activation following recovery from COVID-19 remains an unresolved issue. Objectives. To investigate the persistence of endothelial cell activation and hypercoagulability after recovery from COVID-19. Patients/Methods. COVID-19 survivors (n = 208) and 30 healthy individuals were enrolled in this study. The following biomarkers were measured: procoagulant phospholipid-dependent clotting time (PPL-ct), D-Dimer, fibrin monomers (FM), free Tissue factor pathway inhibitor (free-TFP)I, heparinase, and soluble thrombomodulin (sTM). Antibodies against SARS-CoV-2 (IgG and IgA) were also measured. Results. The median interval between symptom onset and screening for SARS-CoV-2 antibodies was 62 days (IQR = 22 days). Survivors showed significantly higher levels of D-Dimers, FM, TFPI, and heparanase as compared to that of the control group. Survivors had significantly shorter PPL-ct. Elevated D-dimer was associated with older age. Elevated FM was associated with female gender. Elevated heparanase was independently associated with male gender. Decreased Procoag-PPL clotting time was associated with female gender. One out of four of COVID-19 survivors showed increase at least one biomarker of endothelial cell activation or hypercoagulability. Conclusions. Two months after onset of COVID-19, a significant activation of endothelial cells and in vivo thrombin generation persists in at least one out of four survivors of COVID-19. The clinical relevance of these biomarkers in the diagnosis and follow-up of patients with long COVID-19 merits to be evaluated in a prospective clinical study.

Therapeutic Plasma Exchange is Safe and Efficacious in Normalizing Increased Plasma Viscosity Associated with COVID-19

BackgroundCOVID-19 associated hyperviscosity is a potential driver for the increased rates of thrombotic complications and multi-organ failure associated with severe COVID-19. Limited experience suggests a promising role for Therapeutic Plasma Exchange (TPE) in COVID-19 management based on the hypothesis that clinical benefit is derived from reduction in plasma viscosity. However, systematic study evaluating the safety and efficacy of TPE in these patients has not been done.ObjectiveTo evaluate the safety and efficacy of TPE in a subset of critically ill patients with COVID-19 and elevated blood viscosity in a randomized controlled trial (RCT).Study Design and MethodsThis study was conducted in the intensive care units (ICUs) of 3 hospitals in our health system, with a limited initial enrollment target of 20 patients. Participants included adult COVID-19 patients with moderate elevation in plasma viscosity (2.3-3.5 centipoise) or significant hyperfibrinogenemia (>800 mg/dL) that were not improving despite standard supportive care. Patients with bacterial or fungal coinfection or moribund patients were specifically excluded. Upon enrollment, patients were randomized 1:1 to the treatment group (1 plasma volume TPE with frozen plasma (FP) replacement on 2 consecutive days) or control group (continued standard of care (SOC)). Primary measures included the safety/tolerability of TPE and change in plasma viscosity levels after TPE versus SOC. Secondary measures included evaluation of various clinical and laboratory parameters, including fibrinogen and other coagulation-related markers, mortality, bleeding and thromboembolic complications, ICU length of stay and time to discharge after enrollment.ResultsPreliminary analysis of collected data demonstrates that TPE is safe and well-tolerated in these patients, with adverse events limited to one mild occurrence of tachycardia that improved upon decreasing the flow rate. There was significant decrease in plasma viscosity in the TPE treatment group, compared to the SOC control group. Secondary measures of select laboratory parameters also show a significant decrease in fibrinogen, von Willebrand factor (vWF), Factor VIII, and erythrocyte sedimentation rate in the TPE treatment group. No significant differences were seen in levels of fibrin monomer, total IgG, total IgM, total protein, or total albumin between the two groups. Data collection and analysis for clinical parameters are ongoing. Conclusions and RelevanceHere we report preliminary results suggesting that TPE is safe and effective for normalizing plasma viscosity in critically ill COVID-19 patients. Concomitant removal of large plasma proteins (fibrinogen, vWF) hints at their role in driving the increased viscosity associated with severe disease, which may contribute to clotting and end-organ damage in COVID-19. Based on lack of change in total IgG/IgM levels, TPE is not anticipated to hinder the patient’s humoral immunity by removing existing anti-SARS-CoV-2 specific antibodies. These results warrant further studies on the utility of TPE to mitigate critical illness in COVID-19 patients.

Endothelial dysfunction and hypercoagulability in severe sickle-cell acute chest syndrome

RationaleAcute pulmonary hypertension (PH) may develop during sickle-cell acute chest syndrome (ACS), and is associated with an increased mortality. Its mechanisms remain poorly known. We questioned whether there is endothelial dysfunction and hypercoagulability in severe ACS, with and without acute PH.MethodsIn a prospective monocentre cohort follow-up study, all sickle-cell adult patients with ACS admitted to the intensive care unit underwent transthoracic echocardiography and measurement of biomarkers of coagulation, endothelial activation and platelet and erythrocyte activation. Acute PH was defined as a high echocardiographic probability of PH. The biological profiles of sickle-cell patients were analysed at the time of ACS, contrasting with the existence of acute PH, and compared with steady-state and with non-sickle-cell controls (healthy subjects and community-acquired pneumonia).ResultsMost patients (36 patients with 39 ACS episodes; 23 males; median age 27 years) had thoracic pain, dyspnoea and computed tomography scan lung consolidation. Acute PH was diagnosed in seven (19%) patients. Erythrocyte- and platelet-derived microparticles and the pro-coagulant activity of microparticles were higher in ACS patients with acute PH, compared with their counterparts. Compared with healthy controls, ACS patients had higher levels of tissue factor, fibrin monomers, D-dimer, release of pro-coagulant microparticles and erythrocyte- and platelet-derived microparticles. Compared with community-acquired pneumonia patients, ACS patients had increased levels of fibrin monomers and erythrocyte- and platelet-derived microparticles.ConclusionsSevere ACS is characterised by endothelial dysfunction and hypercoagulability, with a marked pro-coagulant profile in cases of associated PH.

Procoagulant Phospholipid Dependent Clotting Time: A New Tool for the Identification of Multiple Myeloma Patients at Risk Poor Treatment Response

Background: Research has long focused on the implications of platelet, endothelial cell and blood coagulation activation in the risk of venous thromboembolism in patients with multiple myeloma (MM). Given the pivotal role of the malignant cell in coagulation activation we studied the association between biomarkers of hypercoagulability and cancer cell activity.Aim: Using data from the prospective, longitudinal observational study ROADMAP-MM CAT (PROspective Risk Assessment anD bioMArkers of hyPercoagulability for the identification of patients with Multiple Myeloma at risk for Cancer Associated Thrombosis) we aimed to identify biomarkers of cellular and plasma hypercoagulability that play a role in determining response to the anti-myeloma treatment.Methods: Newly diagnosed patients with MM were enrolled. Patients on anticoagulant treatment were excluded. A standardized clinical research form (CRF) was completed at enrollment (T0) and at 3 months post treatment initiation (T1). Blood samples were collected at the same time points. Procoagulant phospholipid-dependent clotting time (Procoag-PPL®), tissue factor activity (TFa), thrombomodulin activity (TMa), factor VIIa, factor V (FV), antithrombin (AT), fibrin monomers (FM) and D-Dimers were measured with respective assays from Diagnostica Stago (Asnieres, France) on a STA-R® analyzer (Diagnostica Stago). Plasma levels of P-Selectin and heparanase were measured with ELISA Kits from Cusabio Biotech (from CliniSciencies, France) and R&D Systems (Lille France), respectively. Samples of platelet-poor plasma (PPP) were assessed for thrombin generation (TG) with the TF 5pMPPP-Reagent® on Calibrated Automated Thrombogram (Stago, France). The control group (CG) consisted of 30 healthy age and sex-matched individuals.Results. A total of 100 treatment naïve MM patients were enrolled. Median age was 66.5±12.0 (37-88) years and 54% of the population was male. Disease stage was distributed as follows: 24.3% ISS-I, 20.4% ISS II and 55.3% ISS-III. Bortezomib-based therapy was given to 64.1% of the patients, thalidomide based in 6.8% and lenalidomide-based in 24.3%. Median time to follow up was 11.5 months. There were 16 deaths overall and mortality rate was 162/1000 person-years (median time of death since diagnosis 4.5 months, range 1-9 months). At T1, patients with stable disease (n=8) and progressive disease (n=14) were classified as non-responders. A total of 78 patients achieved at least a partial response and were classified as responders. Compared to controls at T0, MM patients showed significantly increased levels of TFa, D-Dimers and FM and significantly shorter Procoag-PPL clotting time. P-selectin levels were significantly decreased and heparanase levels significantly increased. FVIIa, FV and AT were not significantly different between patients and controls. MM patients showed significantly increased lag-time and ttPeak and significantly lower Peak, ETP and MRI as compared to the control group. TFa and D-dimer levels decreased significantly 3 months post treatment initiation (T1) whereas TMa and AT significantly decreased. At T1 thrombin generation was further attenuated (lower ETP and Peak, prolongation of ttPeak and lower MRI). Univariate analysis demonstrated that among the studied biomarkers only short PPL-ct was associated with a significantly increased risk of no response to treatment. The area under the curve (AUC) in a plot of PPL-ct against no response to treatment (receiver operator curve analysis) was 0.7 (p=0.01).Conclusion. The prospective ROADMAP-CAT multiple myeloma study demonstrates for the first time that among a large number of hypercoagulability biomarkers assessed in newly diagnosed treatment-naïve MM patients, PPL-ct, that reflects the amount of procoagulant microparticles present in plasma, is a significant predictor of poor treatment response. A prospective trial is required to evaluate the potential role of this biomarker in anti-myeloma treatment optimization. [Display omitted] DisclosuresTerpos:Amgen: Honoraria, Other: SC member, Research Funding; Takeda: Honoraria, Other: SC member, Research Funding; Genesis/Celgene: Honoraria, Other: DMC member, Research Funding; Janssen: Honoraria, Research Funding; BMS: Honoraria; Abbvie: Honoraria; GSK: Honoraria. Garderet:Takeda: Honoraria; Amgen: Honoraria.

FM Combined With NIHSS Score Contributes to Early AIS Diagnosis and Differential Diagnosis of Cardiogenic and Non-Cardiogenic AIS.

A growing researchers have suggested that fibrin monomer (FM) plays an important role in early diagnosis of thrombotic diseases. We explored the application of FM in the diagnosis and classification of acute ischemic stroke (AIS). The differences in FM, D-dimer, and NIHSS scores between different TOAST (Trial of ORG 10172 in Acute Stroke Treatment) types were analyzed with one-way ANOVA; the correlation between FM, D-dimer and NIHSS score in patients with different TOAST classification was analyzed by Pearson linear correlation. The ROC curve was utilized to analyze the diagnostic performance. 1. FM was more effective in diagnosing patients with AIS than D-dimer. 2. The FM level in cardiogenic AIS was significantly different from that in non-cardiogenic patients (P < 0.05); the NIHSS score in cardiogenic stroke was significantly higher than in atherosclerotic and unexplained stroke group. Whereas, no statistical difference was observed in the D-dimer level between these groups (P > 0.05). 3. The correlation between FM and NIHSS scores in the cardiogenic (r = 0.3832) and atherosclerotic (r = 0.3144) groups was statistically significant. 4. FM exhibited the highest diagnostic efficacy for cardiogenic AIS; furthermore, FM combined with the NIHSS score was more conducive to the differential diagnosis of cardiogenic and non-cardiogenic AIS. FM detection contributes to the early diagnosis of AIS, and is important for the differential diagnosis of different TOAST types of AIS. Moreover, FM combined with the NIHSS score is valuable in the differential diagnosis of cardiogenic and non-cardiogenic AIS.

Особенности гемостаза у пациенток с бесплодием в программах вспомогательных репродуктивных технологий

Study Objective: To evaluate the impact of multifollicular ovarian stimulation in in vitro fertilisation (IVF) programmes on hemostasis. Study Design: perspective comparative study. Materials and Methods. The study included 68 patients divided into two groups: study group (n = 36) — infertile patients; control group (n = 32) — healthy non-pregnant women of reproductive age. The protocol with gonadotrophin releasing hormone antagonists was used for ovulation stimulation. Hemostasis system in study patients was evaluated in 2 weeks after embryos were transferred to uterus; in control group — on day 20–22 of menstrual period. For the study group, we evaluated clotting test parameters of hemostasis system, D-dimers (D-d) and fibrin monomer (FM). Study Results. We have not found statistically significant differences between hemostasis screening results of study groups. We have identified increase in pro-coagulatory properties of blood in the study group patients: increase in FM and D-d (р &lt; 0.0001 in both cases). There is an association between study parameters and pregnancy (p &lt; 0.001) and no association with obesity, age and infertility. Conclusion. In IVF programme, FM and D-d levels rise, evidencing hypercoagulation development. An increase in FM levels was even more significant and can be used as an early and specific fibrogenesis marker. Keywords: assisted reproductive technologies, fibrin monomer, D-dimer, hypercoagulation, venous thromboembolic events.

Soleal vein dilatation in the early phase of hospitalization is associated with subsequent development of deep vein thrombosis in patients with acute stroke.

To evaluate the usefulness of soleal vein (SOV) diameter as a predictor of new onset of deep vein thrombosis (DVT) in acute stroke patients. A total of 121 acute stroke patients who were admitted within 48h of onset underwent a calf vein ultrasonography (CVUS) examination within 7days after hospitalization. They were evaluated for the presence of DVT and risk factors including maximum SOV diameter. Next, the patients in whom DVT was not detected at the first CVUS examination underwent a second CVUS examination on the 21st hospital day, and were evaluated for the presence of new DVT. DVT was detected in 27 of 121 patients at the first CVUS examination. A significant association was noted between the presence of DVT and higher levels of soluble fibrin monomer, D-dimer, and C-reactive protein, and a higher rate of having cancer concomitantly. Furthermore, 50 of 94 patients without DVT at the first CVUS examination underwent a second CVUS examination. Of the 94 patients, 44 were excluded, because they were discharged by the 21st day. Note that DVT was newly developed in 12 of the 50 patients who underwent the second CVUS. A significant association was found between the presence of new DVT and the rate of history of stroke, hematocrit level, and maximum SOV diameter at the first examination. In our acute stroke patients, SOV dilation, history of stroke, and elevated hematocrit level were found to be associated with risk of developing a new DVT.

Uninterrupted Dabigatran Administration Provides Greater Inhibition against Intracardiac Activation of Hemostasis as Compared to Vitamin K Antagonists during Cryoballoon Catheter Ablation of Atrial Fibrillation.

Background. Cerebral thromboembolism is a rare but feared complication of transcatheter ablation in patients with atrial fibrillation (AF). Here, we aimed to test which pre-procedural anticoagulation strategy results in less intracardiac activation of hemostasis during ablation. Patients and methods. In this observational study, 54 paroxysmal/persistent AF patients undergoing cryoballoon ablation were grouped according to their periprocedural anticoagulation strategy: no anticoagulation (oral anticoagulation (OAC) free; n = 24), uninterrupted vitamin K antagonists (VKA) (n = 11), uninterrupted dabigatran (n = 17). Blood was drawn from the left atrium before and immediately after the ablation procedure. Cryoablations were performed according to standard protocols, during which heparin was administered. Heparin-insensitive markers of hemostasis and endothelial damage were tested from intracardiac samples: D-dimer, quantitative fibrin monomer (FM), plasmin-antiplasmin complex (PAP), von Willebrand factor (VWF) antigen, chromogenic factor VIII (FVIII) activity. Results. D-dimer increased significantly in all groups post-ablation, with lowest levels in the dabigatran group (median [interquartile range]: 0.27 [0.36] vs. 1.09 [1.30] and 0.74 [0.26] mg/L in OAC free and uninterrupted VKA groups, respectively, p < 0.001). PAP levels were parallel to this observation. Post-ablation FM levels were elevated in OAC free (26.34 [30.04] mg/L) and VKA groups (10.12 [16.01] mg/L), but remained below cut-off in all patients on dabigatran (3.98 [2.0] mg/L; p < 0.001). VWF antigen and FVIII activity increased similarly post-ablation in all groups, suggesting comparable procedure-related endothelial damage. Conclusion. Dabigatran provides greater inhibition against intracardiac activation of hemostasis as compared to VKAs during cryoballoon catheter ablation.

Abnormal Biomarkers at Rest in Individuals with Sickle Cell Trait

Abstract Individuals with sickle cell trait (SCT) participate in competitive athletics and/or military training. Some have vigorously trained or competed without incident, while others have encountered serious medical complications. Universal precautions are recommended to reduce the risk of exercise collapse associated with sickle cell trait (ECAST) and exertion related death (ERD). However, there remain deaths in sport and military training attributed to SCT. ECAST and/or ERD are relatively unpredictable and are accompanied by rhabdomyolysis, thrombosis, hemolysis, renal dysfunction, and inflammation. Abnormal thrombotic markers have been reported in subjects with SCT at rest. This pilot study measured total protein (myolysis/hemolysis), creatine kinase (myolysis), haptoglobin (hemolysis), D-dimer and fibrin monomers (thrombosis) at rest in four subjects with SCT and four healthy controls at four time intervals at least two weeks apart. AS subjects demonstrated lower haptoglobin, higher total protein, and higher creatine kinase levels compared to AA subjects, suggesting subclinical hemolysis and myocyte destruction at rest. D-dimer and fibrin monomer were positive in 56.3% and 12.5% respectively of SCT subjects and negative for all AA subjects. The SCT subjects demonstrated day-to-day variability of D-dimer and fibrin monomer levels with positive tests on some, but not all of the four testing occasions. These data support previous findings that SCT subjects exhibit thrombotic activity at rest and suggest the potential for hemolysis and myolysis. These abnormal biomarkers may prove useful to predict risk (baseline values), identify responders to exercise, or identify early stage onset of ECAST (during exercise) to reduce exertion-related adverse events.

Co-administration of iloprost and eptifibatide in septic shock (CO-ILEPSS)\u2014a randomised, controlled, double-blind investigator-initiated trial investigating safety and efficacy

BackgroundPart of the pathophysiology in septic shock is a progressive activation of the endothelium and platelets leading to widespread microvascular injury with capillary leakage, microthrombi and consumption coagulopathy. Modulating the inflammatory response of endothelium and thrombocytes might attenuate this vicious cycle and improve outcome.MethodThe CO-ILEPSS trial was a randomised, placebo-controlled, double-blind, pilot trial. Patients admitted to the intensive care unit with septic shock were randomised and allocated in a 2:1 ratio to active treatment with dual therapy of iloprost 1 ng/kg/min and eptifibatide 0.5 μg/kg/min for 48 h or placebo. The primary outcomes were changes in biomarkers reflecting endothelial activation and disruption, platelet consumption and fibrinolysis. We compared groups with mixed models, post hoc Wilcoxon signed-rank test and Mann-Whitney U test.ResultsWe included 24 patients of which 18 (12 active, 6 placebo) completed the full 7-day trial period and were included in the per-protocol analyses of the primary outcomes. Direct comparison between groups showed no differences in the primary outcomes. Analyses of within-group delta values revealed that biomarkers of endothelial activation and disruption changed differently between groups with increasing levels of thrombomodulin (p = 0.03) and nucleosomes (p = 0.02) in the placebo group and decreasing levels of sE-Selectin (p = 0.007) and sVEGFR1 (p = 0.005) in the active treatment group. Platelet count decreased the first 48 h in the placebo group (p = 0.049) and increased from baseline to day 7 in the active treatment group (p = 0.023). Levels of fibrin monomers declined in the active treatment group within the first 48 h (p = 0.048) and onwards (p = 0.03). Furthermore, there was a significant reduction in SOFA score from 48 h (p = 0.024) and onwards in the active treatment group.Intention-to-treat analyses of all included patients showed no differences in serious adverse events including bleeding, use of blood products or mortality.ConclusionOur results could indicate benefit from the experimental treatment with reduced endothelial injury, reduced platelet consumption and ensuing reduction in fibrinolytic biomarkers along with improved SOFA score. The results of the CO-ILEPSS trial are exploratory and hypothesis generating and warrant further investigation in a large-scale trial.Trial registrationClinicaltrials.com, NCT02204852 (July 30, 2014); EudraCT no. 2014-002440-41

Abnormal Biomarkers at Rest in Individuals with Sickle Cell Trait

<h3>ABSTRACT</h3> Individuals with sickle cell trait (SCT) participate in competitive athletics and/or military training. Some have vigorously trained or competed without incident; whereas, others have encountered serious medical complications. Universal precautions are recommended to reduce the risk of exercise collapse associated with sickle cell trait (ECAST) and exercise-related death (ERD). However, there remain deaths in sport and military training attributed to SCT. ECAST and/or ERD are relatively unpredictable and are accompanied by rhabdomyolysis, thrombosis, hemolysis, renal dysfunction, and inflammation. Abnormal thrombotic markers have been reported in patients with SCT at rest. This pilot study measured total protein (TP; myolysis/hemolysis), creatine kinase (CK; myolysis), haptoglobin (hemolysis), dimerized plasmin fragment D (D-dimer), and fibrin monomers (thrombosis) at rest in 4 patients with SCT and 4 healthy patients at 4-time intervals at least 2 weeks apart. <i>AS</i> patients demonstrated lower haptoglobin, higher TP, and higher CK levels compared with <i>AA</i> patients, suggesting subclinical hemolysis and myocyte destruction at rest. Findings for the D-dimer and fibrin monomer tests were positive in 56.3% and 12.5%, respectively, of SCT patients and negative for all <i>AA</i> patients. The SCT patients demonstrated day-to-day variability of D-dimer and fibrin monomer levels with positive test results on some, but not all, of the 4 testing occasions. These data support previous findings that SCT patients exhibit thrombotic activity at rest and suggest the potential for hemolysis and myolysis. These abnormal biomarkers may prove useful to predict risk (baseline values), identify responders to exercise, or identify early-onset ECAST (during exercise) to reduce exertion-related adverse events.

THE ROLE OF ENDOTHELIAL DYSFUNCTION AS A PART OF SYSTEMIC INFLAMMATORY RESPONSE IN PATHOGENESIS OF AGGRESSIVE AND INDOLENT NON-HODGKIN’S LYMPHOMAS

Objective. To study of manifestation of angiogenic and hemostatic forms of endothelial dysfunction and systemic inflammatory response in patients with non-Hodgkin’s lymphomas at the onset of disease. Material and methods. A total of 99 patients were enrolled in this study, including 55 patients with aggressive variants and 44 patients with indolent variants. The average age was 60.71±10.63 years. The serum level of vascular endothelial growth factor (VEGF) was measured as a marker of angiogenic form of endothelial dysfunction, the serum levels of thrombomodulin, D-dimers, soluble fibrin-monomer complex (SFMC) and level of Willebrand factor activity were used for evaluation of hemostatic form of endothelial dysfunction. To assess the degree of systemic inflammation response the serum levels of proinflammatory cytokines – TNF-α, IL-1β, IL-6 were measured, as well as serum level of acute phase proteins – C-reactive protein (CRP), fibrinogen. The serum level of IL-4 was used to evaluate antinflammation resistance. Results and discussion. Proinflammatory cytokine (TNF-α, IL-1β and IL-6) content was higher in both studied groups compare to the control group. Serum concentration of anti-inflammatory cytokine IL-4 in studied groups did not differ from the level in the controls group. CRP and fibrinogen serum content was increased only in group of patients with aggressive variants. There was a significant correlation between the level of CRP and proinflammatory cytokines in aggressive lymphoma group. Serum content of VEGF, thrombomodulin, D-dimers, SFMC and Willebrand factor activity were increased in both studied group in comparison with the control group. Concentration of thrombomodulin, D-dimers, SFMC and Willebrand factor activity was higher in patients with aggressive than in patients with indolent lymphomas. Conclusion. The signs of angiogenic and hemostatic forms of endothelial dysfunction in patients with aggressive and indolent variants of non-Hodgkin’s lymphoma were detected, as well as manifestation of systemic inflammatory response and attenuation of anti-inflammatory resistance with development of cytokines imbalance with proinflammatory cytokines predominance. The manifestations of systemic inflammatory response and hemostatic type of endothelial dysfunction with activation of coagulation were displayed more prominently in the aggressive lymphoma group.

Hepatic microcirculatory thrombosis in acute-on-chronic hepatic failure

BackgroundAcute-on-chronic hepatic failure is an increasing number of identified distinct disorders encompassing an acute deterioration of hepatic functions in patients with chronic liver diseaseAimThe aim was to evaluate the possibility of hepatic microcirculatory thrombosis in acute-on-chronic hepatic failure and the value of plasma fibrin monomer (FM) and D-dimer in the diagnosis.Patients and methodsA total of 50 patients with chronic hepatitis C infection developing new-onset ascites, encephalopathy, and/or jaundice with raised international normalisation ratio (INR) (group 1); group 2 included 30 patients with compensated chronic hepatitis C virus infection who served as the control group. Ascetic fluid examination and culture were done for group 1, in addition to complete blood count, liver enzymes, INR, serum bilirubin and albumin, blood culture, α-fetoprotein, D-dimer, plasma FM, abdominal ultrasound, and Doppler for portal vein were done for all patients groups.ResultsGroup 1was subdivided according to the level of FM into subgroups A and B. FM showed a significant difference between group 1A and other groups; group IB showed nonsignificant elevation of the level of FM and a significant increase in D-dimer compared with the control group. A marked reduction in portal flow mean velocity in group 1A was recorded with further deterioration of portal flow direction after 2 weeks from the admission time. Three months follow-up showed significant reduction of FM, improvement of portal flow mean velocity and direction in group 1A; FM was significantly positively correlated with portal flow mean velocity.ConclusionHepatic microcirculatory thrombosis may occur in acute-on-chronic hepatic disease; determination of the FM and D-dimer level may be useful biomarkers predicting hepatic microcirculatory thrombosis.

P-064: Measures of thrombodynamics test and fibrin monomer level in pregnant women with complicated obstetric history

P-064: Measures of thrombodynamics test and fibrin monomer level in pregnant women with complicated obstetric history

Intracardiac Hemostasis and Fibrinolysis Parameters in Patients with Atrial Fibrillation.

Aims To identify intracardiac hemostasis or fibrinolysis abnormalities, which are associated with atrial fibrillation (AF) and increase the risk of thromboembolism. Patients and Methods Patient group consisted of 24 patients with AF and control group included 14 individuals with other supraventricular tachycardia undergoing transcatheter radiofrequency ablation. Blood samples were drawn from the femoral vein (FV), left atrium (LA), and left atrial appendage (LAA) before the ablation procedure. Fibrinogen, factor VIII (FVIII) and factor XIII activity, von Willebrand factor (VWF) antigen, thrombin-antithrombin (TAT) complex, quantitative fibrin monomer (FM), plasminogen, α2-plasmin inhibitor, plasmin-α2-antiplasmin (PAP) complex, PAI-1 activity, and D-dimer were measured from all samples. Results Levels of FVIII and VWF were significantly elevated in the FV and LA of AF patients as compared to controls. TAT complex, FM, PAP complex, and D-dimer levels were significantly elevated in the LA as compared to FV samples in case of both groups, indicating a temporary thrombotic risk associated with the catheterization procedure. Conclusions None of the investigated hemostasis or fibrinolysis parameters showed significant intracardiac alterations in AF patients as compared to non-AF controls. AF patients have elevated FVIII and VWF levels, most likely due to endothelial damage, presenting at both intracardiac and systemic level.