Role, Laboratory Assessment and Clinical Relevance of Fibrin, Factor XIII and Endogenous Fibrinolysis in Arterial and Venous Thrombosis.

Diseases such as myocardial infarction, ischaemic stroke, peripheral vascular disease and venous thromboembolism are major contributors to morbidity and mortality. Procoagulant, anticoagulant and fibrinolytic pathways are finely regulated in healthy individuals and dysregulated procoagulant, anticoagulant and fibrinolytic pathways lead to arterial and venous thrombosis. In this review article, we discuss the (patho)physiological role and laboratory assessment of fibrin, factor XIII and endogenous fibrinolysis, which are key players in the terminal phase of the coagulation cascade and fibrinolysis. Finally, we present the most up-to-date evidence for their involvement in various disease states and assessment of cardiovascular risk.

Incremental diagnostic role of left atrial strain analysis in thrombotic risk assessment of nonvalvular atrial fibrillation patients planned for electrical cardioversion.

During the COVID-19 pandemic, transesophageal echocardiography (TEE) for left atrial appendage thrombosis (LAAT) detection should be limited to situations of absolute necessity. We sought to identify the main conventional and functional echocardiographic parameters associated with LAAT on TEE in non-valvular atrial fibrillation (NVAF) patients planned for electrical cardioversion (ECV). This retrospective study included 125 consecutive NVAF patients (71.5±7.8 yrs, 75 males), who underwent TEE at our Institution between April 2016 and January 2020, to exclude LAAT before scheduled ECV. All patients underwent a transthoracic echocardiography (TTE) implemented with speckle tracking echocardiography (STE) analysis of left atrial (LA) strain and strain rate (SR) parameters. 28% of patients were diagnosed with LAAT, while 72% without LAAT. Compared to controls, patients with LAAT had significantly higher CHA2DS2-Vasc Score and average E/e' ratio, and significantly lower left ventricular ejection fraction (LVEF). Moreover, LA-peak positive global atrial strain (GSA+) and LA-SR parameters were significantly reduced in patients with LAAT. Multivariate logistic regression revealed that, differently from CHA2DS2-Vasc Score, LVEF (OR 0.88, 95%CI 0.81-0.97, p = 0.01), average E/e' ratio (OR 2.36, 95%CI 1.41-3.98, p = 0.001), and LA-GSA+ (OR 0.57, 95%CI 0.36-0-90, p = 0.01) were independently associated with LAAT. LA-GSA+ (optimal cut-off ≤ 9.1%, AUC 0.95) showed the highest diagnostic performance. Finally, a strong linear correlation of LA peak-to-peak SR with both LA appendage filling (r = 0.86) and emptying (r = 0.83) velocities was demonstrated. TTE implemented with STE analysis of LA mechanics improves thrombotic risk assessment of NVAF patients.

Fast-track thrombolysis protocol for acute limb ischemia.

OBJECTIVE: Catheter-directed thrombolysis in the treatment of acute lower extremity arterial occlusions often requires several interventional sessions to generate successful outcomes. It is typically an expensive procedure, necessitating extended hospital length of stay (LOS) that may be associated with an increase in both local and systemic hemorrhagic complications. Five years ago, we created the fast-track thrombolysis protocol for arteries (FTTP-A) to deal with these concerns. The goal of our protocol is to re-establish patency during the first session of thrombolysis, thus decreasing costs and complications associated with prolonged periods of thrombolytic exposure. METHODS: A retrospective study of 42 patients who were treated for acute limb ischemia at our institution by FTTP-A from January 2014 to February 2019 was performed. FTTP-A includes periadventitial lidocaine injection at the arterial puncture site under ultrasound guidance, contrast arteriography of the entire targeted segment, pharmacomechanical rheolytic thrombectomy of the occluded arterial segment, tissue plasminogen activator infusion along the occluded segment, balloon maceration of the thrombus, and (if deemed necessary) placement of a stent in an area of significant (≥30%) stenosis that is refractory to balloon angioplasty and thrombolysis. After the stenosis or thrombus is cleared, patients are prescribed an oral anticoagulant agent. RESULTS: Primary FTTP-A (50 total interventions) was performed in 42 patients. The median age of patients was 67.2 ± 12.2 years (range, 41-98 years), and 54.8% were male; 59.5% of the procedures were performed on the left lower extremity. Initial arterial access was obtained through the common femoral artery in 39 of 42 cases (92.9%); in the remaining 3 cases, it was obtained in a left bypass access site, a right femoral-popliteal graft, and a right femoral-femoral graft. The mean operative time was 148.9 ± 62.9 minutes (range, 83-313 minutes), and the mean volume of tissue plasminogen activator infused was 9.7 ± 4.0 mg (range, 2-20 mg). The median cost including medications and interventional tools was $4673.19 per procedure. The mean postoperative LOS was 3.1 ± 4.5 days (range, 1-25 days). Median postoperative LOS was 1 day. Mean postoperative follow-up was 27 ± 19.2 months (range, 0-62 months). Single-session FTTP-A was successful in 81% (n = 34/42) of patients; the remaining 8 patients (19%) required a single additional session. Of the 42 patients, 34 (81%) required arterial stenting. Periprocedural complications consisted of one patient with hematuria, which resolved, and one patient with thrombocytopenia, which resolved. No patients experienced rethrombosis within 30 days of FTTP-A. During the 5-year study period, there was no significant local or systemic hemorrhage, limb loss, or mortality related to this protocol. CONCLUSIONS: FTTP-A appears to be a safe, efficacious, and cost-effective procedure in the resolution of acute lower extremity arterial occlusions.

Prognostic Relevance of Left Ventricular Thrombus Motility: Assessment by Pulsed Wave Tissue Doppler Imaging.

Pulsed wave tissue Doppler imaging (PW-TDI) easily detects motion of cardiac structures. Hence, PW-TDI could be of value for assessing potentially cardioembolic masses. We sought to evaluate the prognostic value of left ventricular (LV) thrombus mobility assessed by PW-TDI. In 83 consecutive patients with echocardiographically detected LV thrombi, PW-TDI echocardiographic study was performed. At 1-year follow-up, the composite of major adverse cardiovascular events (MACE) defined as all-cause mortality plus hospitalizations for stroke/systemic embolism was evaluated. Seventy-two patients (77.1 ± 13.1 year/old, 32 males) were studied. All thrombi were located at the LV apex. At 1-year follow-up, 17 cardioembolic events occurred. By univariable Cox analysis, variables associated with MACE were heart rate (hazard ratio: 1.02, 95% CI: 1.00-1.05; P = .03), thrombi with mobile free edge (hazard ratio: 3.25, 95% CI: 1.25-8.44; P = .01), hypoechoic thrombi (hazard ratio: 2.86, 95% CI: 1.10-7.42; P = .03), and mass peak antegrade velocity (Va) ≥10 cm/s (hazard ratio: 8.79, 95% CI: 2.00-38.5; P = .004). By multivariable analysis, thrombi with mobile free edge (hazard ratio: 3.54, 95% CI: 1.23-10.2; P = .02), and mass peak Va ≥10 cm/s (hazard ratio: 7.97, 95% CI: 1.60-39.6; P = .01) retained statistical significance. Mass peak Va ≥10 cm/s predicted the composite end point with 94% sensitivity and 85% specificity (area under the curve = 0.86). In conclusion, PW-TDI allows objective prognostication of LV thrombi embolic risk.

Questions and Answers on Practical Thrombotic Issues in SARS-CoV-2 Infection: A Guidance Document from the Italian Working Group on Atherosclerosis, Thrombosis and Vascular Biology.

In patients with coronavirus disease 2019 (COVID-19), the prevalence of pre-existing cardiovascular diseases is elevated. Moreover, various features, also including pro-thrombotic status, further predispose these patients to increased risk of ischemic cardiovascular events. Thus, the identification of optimal antithrombotic strategies in terms of the risk-benefit ratio and outcome improvement in this setting is crucial. However, debated issues on antithrombotic therapies in patients with COVID-19 are multiple and relevant. In this article, we provide ten questions and answers on risk stratification and antiplatelet/anticoagulant treatments in patients at risk of/with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection based on the scientific evidence gathered during the pandemic.

The hypercoagulable state in COVID-19: Incidence, pathophysiology, and management.

The 2019 coronavirus disease (COVID-19) presents with a large variety of clinical manifestations ranging from asymptomatic carrier state to severe respiratory distress, multiple organ dysfunction and death. While it was initially considered primarily a respiratory illness, rapidly accumulating data suggests that COVID-19 results in a unique, profoundly prothrombotic milieu leading to both arterial and venous thrombosis. Consistently, elevated D-dimer level has emerged as an independent risk factor for poor outcomes, including death. Several other laboratory markers and blood counts have also been associated with poor prognosis, possibly due to their connection to thrombosis. At present, the pathophysiology underlying the hypercoagulable state is poorly understood. However, a growing body of data suggests that the initial events occur in the lung. A severe inflammatory response, originating in the alveoli, triggers a dysfunctional cascade of inflammatory thrombosis in the pulmonary vasculature, leading to a state of local coagulopathy. This is followed, in patients with more severe disease, by a generalized hypercoagulable state that results in macro- and microvascular thrombosis. Of concern, is the observation that anticoagulation may be inadequate in many circumstances, highlighting the need for alternative or additional therapies. Numerous ongoing studies investigating the pathophysiology of the COVID-19 associated coagulopathy may provide mechanistic insights that can direct appropriate interventional strategies.

Assessment of Platelet Thrombus Formation under Flow Conditions in Patients with Acute Kawasaki Disease.

OBJECTIVE: To assess platelet thrombus formation (PTF) under flow conditions in patients with Kawasaki disease. Previously available platelet activation data were limited for nonphysiological shear stress condition. The total thrombus-formation analysis system (T-TAS) was developed for quantitative PTF analysis. STUDY DESIGN: In total, 33 patients with acute Kawasaki disease were assessed. Whole blood samples, obtained immediately before treatment and 1 week and 1 month after treatment, were assessed using the T-TAS with a collagen-coated platelet chip under high shear values (1000 s-1 [PL12] and 2000 s-1 [PL24]). Measures, such as time to reach 5 kPa above the base pressure (T5+α) and area under the curve for flow pressure curve for 10 minutes (AUC10) were analyzed to quantify PTF. RESULTS: Immediately before treatment, the median PL12-T5+α and PL24-T5+α were 3.3 minutes (IQR 2.0-4.5) and 1.3 minutes (0.9-1.9), respectively, and both values were significantly lower in adult controls (3.5 minutes [2.9-6.4] and 2.8 minutes [1.8-4.8]; P = .015 and P < .001, respectively). In addition, the PL12-AUC10 (151.7 U [94.5-279.9]) significantly decreased in adult controls (234.1 U [110.5-306.5], P = .007). By contrast, at 1 week and 1 month after the start of treatment, the T5+α was longer, and the PL12-AUC10 and PL24-AUC10 decreased. CONCLUSIONS: In patients with acute Kawasaki disease, the PTF had an early onset and weak stability.

The key events of thrombus formation: platelet adhesion and aggregation.

Thrombus formation is a complex, dynamic and multistep process, involving biochemical reactions, mechanical stimulation, hemodynamics, and so on. In this study, we concentrate on its two crucial steps: (i) platelets adhered to a vessel wall, or simply platelet adhesion, and (ii) platelets clumping and arrested to the adherent platelets, named platelet aggregation. We report the first direct simulation of three modes of platelet adhesion, detachment, rolling adhesion and firm adhesion, as well as the formation, disintegration, arrestment and consolidation of platelet plugs. The results show that the bond dissociation in the detachment mode is mainly attributed to a high probability of rupturing bonds, such that any existing bond can be quickly ruptured and all bonds would be completely broken. In the rolling adhesion, however, it is mainly attributed to the strong traction from the shear flow or erythrocytes, causing that the bonds are ruptured at the trailing edge of the platelet. The erythrocytes play an important role in platelet activities, such as the formation, disintegration, arrestment and consolidation of platelet plugs. They exert an aggregate force on platelets, a repulsion at a near distance but an attraction at a far distance to the platelets. This aggregate force can promote platelets to form a plug and/or bring along a part of a platelet plug causing its disintegration. It also greatly influences the arrestment and consolidation of platelet plugs, together with the adhesive force from the thrombus.

Feasibility of a circulation model for the assessment of endovascular recanalization procedures and periprocedural thromboembolism in-vitro.

Aim of this study was to establish a simple and highly reproducible physiological circulation model to investigate endovascular device performance. The developed circulation model included a pneumatically driven pulsatile pump to generate a flow rate of 2.7 L/min at 70 beats per minute. Sections from the superficial femoral arteries were used in order to simulate device/tissue interaction and a filter was integrated to analyze periinterventional thromboembolism of white, red and mixed thrombi. The working fluid (3 L) was a crystalloid solution constantly tempered at 36.5 °C. To evaluate the model, aspiration thrombectomy, stent-implantation and thrombectomy with the Fogarty catheter were performed. Usability of the model was measured by the System Usability Scale (SUS) - Score. Histological specimens were prepared and analyzed postinterventional to quantify tissue/device interaction. Moreover, micro- and macroembolism were evaluated for each thrombus entity and each device. Results were tested for normality using the D'Agostino-Pearson test. Statistical comparisons of two groups were performed using the Student's t-test. All devices were able to remove the occlusions after a maximum of 2 attempts. First-pass-recanalization was not fully achieved for aspiration thrombectomy of mixed thrombi (90.6%), aspiration thrombectomy of red thrombi (84.4%) and stent-implantation in occlusions of red thrombi (92.2%). Most micro- and macroembolism were observed using the Fogarty catheter and after stent-implantation in occlusions of white thrombi. Histological examinations revealed a significant reduction of the vascular layers suggesting vascular damage after use of the Fogarty catheter (327.3 ± 3.5 µm vs. 440.6 ± 3.9 µm; p = 0.026). Analysis of SUS rendered a mean SUS-Score of 80.4 which corresponds to an excellent user acceptability of the model. In conclusion, we describe a stable, easy to handle and reproducible physiological circulation model for the simulation of endovascular thrombectomy including device performance and thromboembolism.

Clinical and Economic Benefits of Stent Grafts in Dysfunctional and Thrombosed Hemodialysis Access Graft Circuits in the REVISE Randomized Trial.

PURPOSE: To compare reinterventions and associated costs to maintain arteriovenous graft hemodialysis access circuits after rescue with percutaneous transluminal angioplasty (PTA), with or without concurrent Viabahn stent grafts, over 24 months. MATERIALS AND METHODS: This multicenter (n = 30 sites) study evaluated reintervention number, type, and cost in 269 patients randomized to undergo placement of stent grafts or PTA alone. Outcomes were 24-month average cumulative number of reinterventions, associated costs, and total costs for all patients and in 4 groups based on index treatment and clinical presentation (thrombosed or dysfunctional). RESULTS: Over 24 months, the patients in the stent graft arm had a 27% significant reduction in the average number of reinterventions within the circuit compared to the PTA arm (3.7 stent graft vs 5.1 PTA; P = .005) and similar total costs ($27,483 vs $28,664; P = .49). In thrombosed grafts, stent grafts significantly reduced the number of reinterventions (3.7 stent graft vs 6.2 PTA; P = .022) and had significantly lower total costs compared to the PTA arm ($30,329 vs $37,206; P = .027). In dysfunctional grafts, no statistical difference was observed in the number of reinterventions or total costs (3.7 stent graft vs 4.4 PTA; P = .12, and $25,421 stent graft and $22,610 PTA; P = .14). CONCLUSIONS: Over 24 months, the use of stent grafts significantly reduced the number of reinterventions for all patients, driven by patients presenting with thrombosed grafts. Compared to PTA, stent grafts reduced overall treatment costs for patients presenting with thrombosed grafts and had similar costs for stenotic grafts.

Subjective Global Assessment-Dialysis Malnutrition Score and arteriovenous fistula outcome: A comparison with Charlson Comorbidity Index.

INTRODUCTION:: Malnutrition is a well-recognized risk factor for all-cause mortality in hemodialysis patients. However, its role for arteriovenous fistulas outcome has not been exhaustively investigated. Our aim was to point out the impact of Subjective Global Assessment-Dialysis Malnutrition Score as independent predictor of arteriovenous fistulas thrombosis (vascular access thrombosis) and/or significant stenosis (vascular access stenosis). In addition, we compared it with the widespread Charlson Comorbidity Index. METHODS:: We assessed 57 hemodialysis patients for a 2-year interval and evaluated the incidence of vascular access thrombosis and/or stenosis. Linear regression analysis was used to test the relation of variables with Subjective Global Assessment-Dialysis Malnutrition Score at baseline. Logistic and Cox regression analysis evaluated markers as predictors of both vascular access thrombosis and stenosis. Receiver operating characteristic curve analysis was used to compare area under the curve values of Subjective Global Assessment-Dialysis Malnutrition Score, Charlson Comorbidity Index, and modified Charlson Comorbidity Index. RESULTS:: Age and Charlson Comorbidity Index were positively related to Subjective Global Assessment-Dialysis Malnutrition Score: B = 0.06 (95% CI = 0.01; 0.11) and B = 0.31 (95% CI = 0.01; 0.63). Higher albumin and normalized protein catabolic rate levels had a protective role against vascular access failure: OR = 0.67 (95% CI = 0.56; 0.81) and OR = 0.46 (95% CI = 0.32; 0.67), respectively. Higher Subjective Global Assessment-Dialysis Malnutrition Score and Charlson Comorbidity Index values were significant risk factors: HR = 1.42 (95% CI = 1.04; 1.92) and HR = 1.48 (95% CI = 1.01; 2.17), respectively. Area under the curve of Subjective Global Assessment-Dialysis Malnutrition Score was significantly higher than those of both Charlson Comorbidity Index and modified Charlson Comorbidity Index: 0.70 (95% CI = 0.50; 0.88) versus 0.61 (95% CI = 0.41; 0.80) and 0.55 (95CI% = 0.41; 0.70). CONCLUSION:: Subjective Global Assessment-Dialysis Malnutrition Score, as well as Charlson Comorbidity Index, are useful tools to predict vascular access failure and should be carefully and periodically evaluated in order to check significant variations that may compromise vascular access survival.

Computational Fluid Dynamics Assessment Associated with Transcatheter Heart Valve Prostheses: A Position Paper of the ISO Working Group.

The governing international standard for the development of prosthetic heart valves is International Organization for Standardization (ISO) 5840. This standard requires the assessment of the thrombus potential of transcatheter heart valve substitutes using an integrated thrombus evaluation. Besides experimental flow field assessment and ex vivo flow testing, computational fluid dynamics is a critical component of this integrated approach. This position paper is intended to provide and discuss best practices for the setup of a computational model, numerical solving, post-processing, data evaluation and reporting, as it relates to transcatheter heart valve substitutes. This paper is not intended to be a review of current computational technology; instead, it represents the position of the ISO working group consisting of experts from academia and industry with regards to considerations for computational fluid dynamic assessment of transcatheter heart valve substitutes.

Experimental Assessment of Flow Fields Associated with Heart Valve Prostheses Using Particle Image Velocimetry (PIV): Recommendations for Best Practices.

Experimental flow field characterization is a critical component of the assessment of the hemolytic and thrombogenic potential of heart valve substitutes, thus it is important to identify best practices for these experimental techniques. This paper presents a brief review of commonly used flow assessment techniques such as Particle image velocimetry (PIV), Laser doppler velocimetry, and Phase contrast magnetic resonance imaging and a comparison of these methodologies. In particular, recommendations for setting up planar PIV experiments such as recommended imaging instrumentation, acquisition and data processing are discussed in the context of heart valve flows. Multiple metrics such as residence time, local velocity and shear stress that have been identified in the literature as being relevant to hemolysis and thrombosis in heart valves are discussed. Additionally, a framework for uncertainty analysis and data reporting for PIV studies of heart valves is presented in this paper. It is anticipated that this paper will provide useful information for heart valve device manufacturers and researchers to assess heart valve flow fields for the potential for hemolysis and thrombosis.

Introducing the pro-coagulant contact system in the numerical assessment of device-related thrombosis.

Thrombosis is a major concern in blood-coated medical devices. Contact activation, which is the initial part of the coagulation cascade in device-related thrombosis, is not considered in current thrombus formation models. In the present study, pro-coagulant reactions including the contact activation system are coupled with a fluid solver in order to evaluate the potential of the contact system to initiate thrombin production. The biochemical/fluid model is applied to a backward-facing step configuration, a flow configuration that frequently appears in medical devices. In contrast to the in vivo thrombosis models in which a specific thrombotic zone (injury region) is set a priori by the user to initiate the coagulation reaction, a reactive surface boundary condition is applied to the whole device wall. Simulation results show large thrombin concentration in regions related to recirculation zones without the need of an a priori knowledge of the thrombus location. The numerical results align well with the regions prone to thrombosis observed in experimental results reported in the literature. This approach could complement thrombus formation models that take into account platelet activity and thrombus growth to optimize a wide range of medical devices.

Thromboelastography and Thromboelastometry in Assessment of Fibrinogen Deficiency and Prediction for Transfusion Requirement: A Descriptive Review.

Fibrinogen is crucial for the formation of blood clot and clinical outcomes in major bleeding. Both Thromboelastography (TEG) and Rotational Thromboelastometry (ROTEM) have been increasingly used to diagnose fibrinogen deficiency and guide fibrinogen transfusion in trauma and surgical bleeding patients. We conducted a comprehensive and comparative review on the technologies and clinical applications of two typical functional fibrinogen assays using TEG (FF TEG) and ROTEM (FIBTEM) for assessment of fibrinogen level and deficiency, and prediction of transfusion requirement. Clot strength and firmness of FF TEG and ROTEM FIBTEM were the most used parameters, and their associations with fibrinogen levels as measured by Clauss method ranged from 0 to 0.9 for FF TEG and 0.27 to 0.94 for FIBTEM. A comparison of the interchangeability and clinical performance of the functional fibrinogen assays using the two systems showed that the results were correlated, but are not interchangeable between the two systems. It appears that ROTEM FIBTEM showed better associations with the Clauss method and more clinical use for monitoring fibrinogen deficiency and predicting transfusion requirements including fibrinogen replacement than FF TEG. TEG and ROTEM functional fibrinogen tests play important roles in the diagnosis of fibrinogen-related coagulopathy and guidance of transfusion requirements. Despite the fact that high-quality evidence is still needed, the two systems are likely to remain popular for the hemostatic management of bleeding patients.