Review: Laboratory markers quantifying prothrombin activation and actions of thrombin in venous and arterial thrombosis do not accurately assess disease severity or the effectiveness of treatment

2006 ◽  
Vol 96 (11) ◽  
pp. 568-577 ◽  
Author(s):  
Frederick Ofosu
Keyword(s):  
Venous Thrombosis ◽  
Arterial Thrombosis ◽  
Cell Activation ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Thrombin Inhibitors ◽  
Treatment Modalities ◽  
Patients At Risk ◽  
Effective Drugs

SummaryThrombin is normally produced for hemostasis and physiological wound healing. Increased thrombin production in vivo, cell activation and inflammation mediated in part by thrombin are hallmarks of both arterial and venous thrombosis. Thrombin generates (pro) coagulant, mitogenic, inflammatory and anticoagulant responses by interacting witha variety of cells in vivo.Both direct and indirect thrombin inhibitors are effective drugs for preventing and treating the consequences of arterial and venous thrombosis. For these reasons, measurements of the production and activities of thrombin in vivo have the potential for gauging the extent of thromboembolism and the responses of patients to anticoagulant, antiplatelet and anti-inflammatory drugs. How-ever, a critical review of published information suggests that measurement of thrombin production and activity in patients at risk for and in patients with significant thrombosis generally does not provide information useful for clinical decision-making. This lack of clinical utility of levels of thrombin production in vivo may arise from two causes: the inability of the measurement to differentiate between physiological (hemostatic) and disease-related (pathological) sources and/or causes of thrombin production in vivo, and the inability of antithrombotic treatment modalities to permanently eliminate the stimuli that cause increased thrombin production evident in venous and arterial thrombosis.

BCH-2763, a Novel Potent Parenteral Thrombin Inhibitor, Is an Effective Antithrombotic Agent in Rodent Models of Arterial and Venous Thrombosis – Comparisons with Heparin, r-Hirudin, Hirulog, Inogatran and Argatroban

1998 ◽  
Vol 79 (02) ◽  
pp. 431-438 ◽  
Author(s):  
Carolyn Finkle ◽  
Annie Pierre ◽  
Lorraine Leblond ◽  
Isabelle Deschenes ◽  
John DiMaio ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Arterial Thrombosis ◽  
Thrombin Inhibitors ◽  
Thrombin Inhibitor ◽  
Direct Thrombin Inhibitors ◽  
Antithrombotic Agent ◽  
Plasma Clot ◽  
Antithrombotic Efficacy

SummaryCurrent clinical use of heparin as an antithrombotic agent is limited by suboptimal efficacy and safety considerations. Thrombin’s central role in thrombosis makes it an attractive target to develop more effective and safer antithrombotic agents. BCH-2763 is a novel, potent (Ki: 0.11 nM), low molecular weight (1.51 kDa), bivalent direct thrombin inhibitor. The antithrombotic efficacy of BCH-2763 in vivo following i.v. bolus plus infusion in rats was compared in arterial and venous thrombosis models with two other bivalent direct thrombin inhibitors, r-hirudin and hirulog, with two catalytic site-directed thrombin inhibitors, inogatran and argatroban, and with heparin. In vivo efficacy was related to inhibition in vitro of fibrin clot formation, thrombin-induced aggregation of rat or human washed platelets and activity of free and plasma clot-bound thrombin. All the direct thrombin inhibitors were effective on both arterial and venous thrombosis at markedly lower fold aPTT increases than heparin. The antithrombotic doses of all inhibitors against venous thrombosis were less than against arterial thrombosis. The rank order of potency based on doses (mg/kg/h) required for full efficacy against arterial thrombosis was BCH-2763 (1.2) inogatran (1.5) r-hirudin (1.8) hirulog (3.3) argatroban ( 3.0); heparin required a markedly higher dose (5.7). In venous thrombosis the doses required for full efficacy were substantially lower for the bivalent (BCH-2763: 0.12; r-hirudin: 0.12; hirulog: 0.18) than for the catalytic site-directed (inogatran: 0.48; argatroban: 0.90) thrombin inhibitors; the dose required for heparin was 0.19. All the direct thrombin inhibitors caused similar shifts in aPTT at doses required to inhibit arterial thrombosis, but BCH-2763 inhibited venous thrombosis at lower aPTT fold increases. In vivo antithrombotic efficacy of direct thrombin inhibitors correlated with their inhibitory activity in vitro against fibrin clot formation and platelet aggregation. In contrast to heparin, all the direct thrombin inhibitors inhibited plasma clot-bound thrombin, but the relative IC50s did not correlate with their antithrombotic efficacy. In summary, direct thrombin inhibitors are more effective than heparin in inhibiting arterial and venous thrombosis in rats with less aPTT increases. BCH-2763 is effective at lower doses than the other direct thrombin inhibitors and for venous thrombosis at a smaller aPTT increase. BCH-2763 may offer an improved therapeutic index in the treatment of thromboembolic complications over heparin and other direct thrombin inhibitors.

Management of thoracic aortic lesions - the future is endovascular

VASA ◽  
2012 ◽  
Vol 41 (3) ◽  
pp. 163-176 ◽  
Author(s):  
Weidenhagen ◽  
Bombien ◽  
Meimarakis ◽  
Geisler ◽  
A. Koeppel
Keyword(s):  
Thoracic Aorta ◽  
Clinical Decision Making ◽  
Treatment Options ◽  
Clinical Decision ◽  
Clinical Results ◽  
Treatment Modalities ◽  
Traumatic Rupture ◽  
Descending Thoracic Aorta ◽  
New Treatment ◽  
Aneurysm Dissection

Open surgical repair of lesions of the descending thoracic aorta, such as aneurysm, dissection and traumatic rupture, has been the “state-of-the-art” treatment for many decades. However, in specialized cardiovascular centers, thoracic endovascular aortic repair and hybrid aortic procedures have been implemented as novel treatment options. The current clinical results show that these procedures can be performed with low morbidity and mortality rates. However, due to a lack of randomized trials, the level of reliability of these new treatment modalities remains a matter of discussion. Clinical decision-making is generally based on the experience of the vascular center as well as on individual factors, such as life expectancy, comorbidity, aneurysm aetiology, aortic diameter and morphology. This article will review and discuss recent publications of open surgical, hybrid thoracic aortic (in case of aortic arch involvement) and endovascular repair in complex pathologies of the descending thoracic aorta.

scholarly journals Application of standards and models in body composition analysis

2015 ◽  
Vol 75 (2) ◽  
pp. 181-187 ◽  
Author(s):  
Manfred J. Müller ◽  
Wiebke Braun ◽  
Maryam Pourhassan ◽  
Corinna Geisler ◽  
Anja Bosy-Westphal
Keyword(s):  
Body Composition ◽  
Clinical Decision Making ◽  
Compartment Model ◽  
Clinical Decision ◽  
Whole Body ◽  
Composition Analysis ◽  
Body Composition Analysis ◽  
Physical Functions ◽  
Body Components

The aim of this review is to extend present concepts of body composition and to integrate it into physiology. In vivo body composition analysis (BCA) has a sound theoretical and methodological basis. Present methods used for BCA are reliable and valid. Individual data on body components, organs and tissues are included into different models, e.g. a 2-, 3-, 4- or multi-component model. Today the so-called 4-compartment model as well as whole body MRI (or computed tomography) scans are considered as gold standards of BCA. In practice the use of the appropriate method depends on the question of interest and the accuracy needed to address it. Body composition data are descriptive and used for normative analyses (e.g. generating normal values, centiles and cut offs). Advanced models of BCA go beyond description and normative approaches. The concept of functional body composition (FBC) takes into account the relationships between individual body components, organs and tissues and related metabolic and physical functions. FBC can be further extended to the model of healthy body composition (HBC) based on horizontal (i.e. structural) and vertical (e.g. metabolism and its neuroendocrine control) relationships between individual components as well as between component and body functions using mathematical modelling with a hierarchical multi-level multi-scale approach at the software level. HBC integrates into whole body systems of cardiovascular, respiratory, hepatic and renal functions. To conclude BCA is a prerequisite for detailed phenotyping of individuals providing a sound basis for in depth biomedical research and clinical decision making.

Abstract W P266: A Simple Score for Prediction of Outcome after Cerebral Venous Thrombosis

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Miguel A Barboza ◽  
Erwin Chiquete ◽  
Antonio Arauz ◽  
Jonathan Colín ◽  
Alejandro Quiroz-Compean ◽  
...  
Keyword(s):  
Decision Making ◽  
Venous Thrombosis ◽  
Predictive Value ◽  
Cerebral Venous Thrombosis ◽  
Goodness Of Fit ◽  
Clinical Decision Making ◽  
Case Fatality ◽  
Clinical Decision ◽  
Classification Systems ◽  
Cox Proportional Hazards Model

Background and purpose: Cerebral venous thrombosis (CVT) not always implies a good prognosis. There is a need for robust and simple classification systems of severity after CVT that help in clinical decision-making. Methods: We studied 467 patients (81.6% women, median age: 29 years, interquartile range: 22-38 years) with CVT who were hospitalized from 1980 to 2014 in two third-level referral hospitals. Bivariate analyses were performed to select variables associated with 30-day mortality to integrate a further multivariate analysis. The resultant model was evaluated with the Hosmer-Lemeshow test for goodness of fit, and on Cox proportional hazards model for reliability of the effect size. After the scale was configured, security and validity were tested for 30-day mortality and modified Rankin scale (mRS) >2. The prognostic performance was compared with that of the CVT risk score (CVT-RS, 0-6 points) as the reference system. Results: The 30-day case fatality rate was 8.7%. The CVT grading scale (CVT-GS, 0-9 points) was integrated by stupor/coma (4 points), parenchymal lesion >6 cm (2 points), mixed (superficial and deep systems) CVT (1 point), meningeal syndrome (1 point) and seizures (1 point). CVT-GS was categorized into mild (0-3 points, 1.1% mortality), moderate (4-6 points, 19.6% mortality) and severe (7-9 points, 61.4% mortality). For 30-day mortality prediction, as compared with CVT-RS (cut-off 4 points), CVT-GS (cut-off 5 points) was globally better in sensitivity (85% vs 37%), specificity (90% vs 95%), positive predictive value (44% vs 40%), negative predictive value (98% vs 94%), and accuracy (94% vs 80%). For 30-day mRS >2 the performance of CVT-GS over CVT-RS was comparably improved. Conclusion: The CVT-GS is a simple and reliable score for predicting outcome that may help in clinical decision-making and that could be used to stratify patients recruited into clinical trials.

scholarly journals Real-time utilisation of administrative data in the ED to identify older patients at risk: development and validation of the Dynamic Silver Code

BMJ Open ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. e033374 ◽  
Author(s):  
Daniela Balzi ◽  
Giulia Carreras ◽  
Francesco Tonarelli ◽  
Luca Degli Esposti ◽  
Paola Michelozzi ◽  
...  
Keyword(s):  
At Risk ◽  
Cohort Study ◽  
Real Time ◽  
Administrative Data ◽  
Older Patients ◽  
Clinical Decision Making ◽  
External Validation ◽  
Clinical Decision ◽  
Patients At Risk ◽  
Ed Visits

ObjectiveIdentification of older patients at risk, among those accessing the emergency department (ED), may support clinical decision-making. To this purpose, we developed and validated the Dynamic Silver Code (DSC), a score based on real-time linkage of administrative data.Design and settingThe ‘Silver Code National Project (SCNP)’, a non-concurrent cohort study, was used for retrospective development and internal validation of the DSC. External validation was obtained in the ‘Anziani in DEA (AIDEA)’ concurrent cohort study, where the DSC was generated by the software routinely used in the ED.ParticipantsThe SCNP contained 281 321 records of 180 079 residents aged 75+ years from Tuscany and Lazio, Italy, admitted via the ED to Internal Medicine or Geriatrics units. The AIDEA study enrolled 4425 subjects aged 75+ years (5217 records) accessing two EDs in the area of Florence, Italy.InterventionsNone.Outcome measuresPrimary outcome: 1-year mortality. Secondary outcomes: 7 and 30-day mortality and 1-year recurrent ED visits.ResultsAdvancing age, male gender, previous hospital admission, discharge diagnosis, time from discharge and polypharmacy predicted 1-year mortality and contributed to the DSC in the development subsample of the SCNP cohort. Based on score quartiles, participants were classified into low, medium, high and very high-risk classes. In the SCNP validation sample, mortality increased progressively from 144 to 367 per 1000 person-years, across DSC classes, with HR (95% CI) of 1.92 (1.85 to 1.99), 2.71 (2.61 to 2.81) and 5.40 (5.21 to 5.59) in class II, III and IV, respectively versus class I (p<0.001). Findings were similar in AIDEA, where the DSC predicted also recurrent ED visits in 1 year. In both databases, the DSC predicted 7 and 30-day mortality.ConclusionsThe DSC, based on administrative data available in real time, predicts prognosis of older patients and might improve their management in the ED.

DECISION MAKING IN PEDIATRIC SPINAL DEFORMITY

Neurosurgery ◽  
2008 ◽  
Vol 63 (suppl_3) ◽  
pp. A54-A68 ◽  
Author(s):  
Justin S. Smith ◽  
Christopher I. Shaffrey ◽  
Mark F. Abel ◽  
Christopher P. Ames
Keyword(s):  
Decision Making ◽  
Spinal Deformity ◽  
Pediatric Patients ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Nonoperative Treatment ◽  
Treatment Modalities ◽  
Decision Making Process ◽  
History Of ◽  
Diagnosis And Classification

ABSTRACT OBJECTIVE To review the concepts involved in the decision-making process for management of pediatric patients with spinal deformity. METHODS The literature was reviewed in reference to pediatric deformity evaluation and management. RESULTS Pediatric spinal deformity includes a broad range of disorders with differing causes, natural histories, and treatments. Appropriate categorization of pediatric deformities is an important first step in the clinical decision-making process. An understanding of both nonoperative and operative treatment modalities and their indications is requisite to providing treatment for pediatric patients with spinal deformity. The primary nonoperative treatment modalities include bracing and casting, and the primary operative treatments include nonfusion instrumentation and fusion with or without instrumentation. In this article, we provide a review of pediatric spinal deformity classification and an overview of general treatment principles. CONCLUSION The decision-making process in pediatric deformity begins with appropriate diagnosis and classification of the deformity. Treatment decisions, both nonoperative and operative, are often predicated on the basis of the age of the patient and the natural history of the disorder.

In-Vivo Evaluation of Severity of Microvascular Impairments and Epicardial Coronary Stenoses Using Fundamental Fluid Dynamics Endpoints

2008 ◽  
Author(s):  
Koustubh D. Ashtekar ◽  
Edward Kim ◽  
Abhijit S. Roy ◽  
Tarek A. Helmy ◽  
Mohamed A. Effat ◽  
...  
Keyword(s):  
Clinical Decision Making ◽  
Clinical Decision ◽  
Fractional Flow ◽  
In Vivo Evaluation ◽  
Flow Reserve ◽  
Coronary Stenoses ◽  
Decision Making Processes ◽  
Epicardial Stenosis ◽  
Treatment Procedures

Coronary circulation is mainly regulated by two serial resistances, namely, epicardial stenosis and microvascular impairments, both causing abnormal coronary blood circulation [1]. Delineation of the true severities of these diseases is important to guide clinical decision-making processes for the selection of appropriate treatment procedures [2]. The presently used diagnostic parameters: FFR (fractional flow reserve defined as the ratio of distal to proximal hyperemic pressure) and CFR (coronary flow reserve defined as ratio of basal to hyperemic flow) [1], for the evaluation of severity of epicardial coronary stenosis are well established in clinical practice. On the other hand, current methods to evaluate the microcirculatory status are limited [3].

Compression hosiery for venous disorders and oedema: a question of balance

2020 ◽  
Vol 25 (Sup9) ◽  
pp. S26-S32
Author(s):  
Jeanette Muldoon ◽  
Sylvie Hampton ◽  
Sarah Gray ◽  
Trish Cosham
Keyword(s):  
Clinical Decision Making ◽  
Compression Therapy ◽  
Clinical Decision ◽  
Self Management ◽  
Treatment Modalities ◽  
Treatment Pathway ◽  
Compression Bandages ◽  
New Type ◽  
Venous Disorders

Compression therapy for venous and lymphatic conditions may be delivered via a range of treatment modalities using many different technologies, depending on the patient's condition and needs. Clinical decision-making relies on accurate assessment of the patient, their presenting and underlying clinical condition, skill and training of the applier and the available resources. However, changes in the patient's condition or lifestyle may necessitate re-evaluation of the treatment pathway. Generally, compression bandages and Velcro wraps are used in the intensive acute phase of treatment, with self-management using compression hosiery or wraps being used for long-term maintenance to prevent recurrence. Although guidelines recommend the highest class of compression hosiery for maximum effectiveness, clinical evidence shows practical challenges associated with application and tolerance of higher pressures and stiffness. An audit of a new type of compression garment was conducted, and it showed that incorporating stiffness into circular knitted hosiery helped overcome some of these challenges with improvements in limb size, skin softening and wound size. Additionally, self-management was facilitated by the ease of donning and doffing.

Gas6 Regulates Thrombin-Induced of VCAM-1 Expression by a FoxO1 Dependent Mechanism

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 5192-5192
Author(s):  
Richard Robins ◽  
Catherine A. Lemarie ◽  
Mark D. Blostein
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Venous Thrombosis ◽  
Cell Biology ◽  
Cell Activation ◽  
Conflicts Of Interest ◽  
Vascular Dysfunction ◽  
Soluble Form ◽  
Endothelial Cell Activation

Abstract Abstract 5192 Forkhead proteins play a broad role in endothelial cell biology. These factors mediate cell adhesion to extracellular matrix, regulate the expression of pro-inflammatory and pro-thrombotic genes, and participate in cell repair, proliferation and apoptosis. FoxOs are known downstream targets of the PI3K/Akt signaling pathway. Phosphorylation of FoxO transcription factors results in their translocation from the nucleus to the cytoplasm, thereby inhibiting their transcriptional activity. It has recently been shown that the deletion of the three FoxO isoforms in endothelial cells protects mice from vascular dysfunction. Gas6, a member of the vitamin K-dependent family of proteins, has been shown to protect endothelial cells from apoptosis and promote endothelial cell activation in vivo. It has been shown that the expression of ICAM-1 and VCAM-1 were blunted in the absence of gas6. Interestingly, a role for VCAM-1 in the pathogenesis of venous thrombosis has been proposed. Elevated levels of the soluble form of VCAM-1 have been detected in the serum of patients with venous thrombosis. We previously demonstrated that the anti-apoptotic effect of gas6 was mediated partially through FoxO1, but overall, the signalling mechanisms occurring downstream of gas6 remain largely unknown. We hypothesize that gas6 promotes thrombin-induced VCAM-1 expression through the regulation of FoxO1 in endothelial cells. Western blot analysis demonstrated that thrombin induced time dependent phosphorylation of FoxO1 with a maximum at 30 minutes in WT (p<0. 05) but not in gas6 deficient (−/−) cells. In addition, thrombin reduced the nuclear content of FoxO in WT (p<0. 05) but not in gas6−/− endothelial cells. Using qPCR, we found that mRNA expression of VCAM-1 was increased after 30 minutes of stimulation with thrombin in WT cells (p<0. 05). More importantly, thrombin-mediated induction of VCAM-1 was blunted in gas6−/− endothelial cells. We found that FoxO1 siRNA increased basal VCAM-1 expression in WT endothelial cells. Taken together, our data demonstrate that gas6 is a crucial mediator of FoxO1 that regulates thrombin-induced VCAM-1 expression. This pathway may explain the pro-thrombotic and pro-inflammatory role of gas6. Disclosures: No relevant conflicts of interest to declare.

Venous and Arterial Thromboses: Two Sides of the Same Coin?

2017 ◽  
Vol 44 (03) ◽  
pp. 239-248 ◽  
Author(s):  
Giuseppe Lippi ◽  
Emmanuel Favaloro
Keyword(s):  
Venous Thrombosis ◽  
Arterial Thrombosis ◽  
Thrombus Formation ◽  
Coronary Intervention ◽  
Convincing Evidence ◽  
Adjunctive Treatment ◽  
Composition And Structure ◽  
Platelet Aggregates ◽  
Von Willebrand

AbstractArterial and venous thromboses are sustained by development of intraluminal thrombi, respectively, within the venous and arterial systems. The composition and structure of arterial and venous thrombi have been historically considered as being very different. Arterial thrombi (conventionally defined as “white”) have been traditionally proposed to be composed mainly of fibrin and platelet aggregates, whilst venous thrombi (conventionally defined as “red”) have been proposed as mostly being enriched in fibrin and erythrocytes. This archaic dichotomy seems ever more questionable, since it barely reflects the pathophysiology of thrombus formation in vivo. Both types of thrombi are actually composed of a complex fibrin network but, importantly, also contain essentially the same blood-borne cells (i.e., red blood cells, leukocytes, and platelets), and it is only the relative content of these individual elements that differ between venous and arterial clots or, otherwise, between thrombi generated under different conditions of blood flow and shear stress. Convincing evidence now suggests that either white or red intracoronary thrombi may be present in patients with myocardial infarction and, even more importantly, red thrombi may be more prone to distal embolization during percutaneous coronary intervention than those with lower content of erythrocytes. Conversely, it is now accepted that components traditionally considered to be involved “only” in arterial thrombosis are also represented in venous thrombosis. Thus, platelets comprise important components of venous clots, although they may be present in lower amounts here than in arterial thrombi, and von Willebrand factor is also represented in both arterial and venous thrombi. Of importance, such evidence thus supports the concept that adjunctive treatment normally associated to prevention of arterial thrombosis (e.g., aspirin) may have a role also in prevention and treatment of venous thrombosis.

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