Diagnostic Accuracy in Acute Venous Thromboembolism: Comparing D-Dimer, Thrombin Generation, Overall Hemostatic Potential, and Fibrin Monomers.
ABSTRACT: Introduction ?For acute venous thromboembolism (VTE), a biomarker with higher specificity than D-dimer would be of great clinical use. Thrombin generation and overall hemostatic potential (OHP) reflect the hemostatic balance by globally assessing multiple coagulation factors and inhibitors. These tests discriminate between healthy controls and patients with a prothrombotic tendency but have yet to be established as clinical biomarkers of VTE. Objective ?This study compares endogenous thrombin potential (ETP) and OHP to D-dimer and fibrin monomers (FM) in outpatients with suspected VTE. Methods ?A cross-sectional diagnostic study where 954 patients with suspected pulmonary embolism or deep venous thrombosis were recruited consecutively from the medical emergency department at Karolinska University Hospital. D-dimer, FM, OHP, and ETP were analyzed in a subpopulation of 60 patients with VTE and 98 matched controls without VTE. VTE was verified either by ultrasonography or computed tomography and clinical data were collected from medical records. Results ?Compared with healthy controls, both VTE and non-VTE patients displayed prothrombotic profiles in OHP and ETP. D-dimer, FM, ETP area under the curve (AUC), and ETP T lag were significantly different between patients with VTE and non-VTE. The largest receiver-operating characteristic AUCs for discrimination between VTE and non-VTE, were found in D-dimer with 0.94, FM 0.77, and ETP AUC 0.65. No useful cutoff could be identified for the ETP or the OHP assay. Conclusion ?Compared with D-dimer, neither ETP nor OHP were clinically viable biomarkers of acute venous thrombosis. The data indicated that a large portion of the emergency patients with suspected VTE were in a prothrombotic state.
Project description:It is common knowledge that cancer patients are more prone to develop venous thromboembolic complications (VTE). It is therefore not surprising that patients with hepatocellular carcinoma (HCC) present with a significant risk of VTE, with the portal vein being the most frequent site (PVT). However, patients with HCC are peculiar as both cancer and liver cirrhosis are conditions that can perturb the hemostatic balance towards a prothrombotic state. Because HCC-related hypercoagulability is not clarified at all, the aim of the present review is to summarize the currently available knowledge on epidemiology and pathogenesis of non-malignant thrombotic complications in patients with liver cirrhosis and HCC. They are at increased risk to develop both PVT and non-splanchnic VTE, indicating that both local and systemic factors can foster the development of site-specific thrombosis. Recent studies have suggested multiple and often interrelated mechanisms through which HCC can tip the hemostatic balance of liver cirrhosis towards hypercoagulability. Described mechanisms include increased fibrinogen concentration/polymerization, thrombocytosis, and release of tissue factor-expressing extracellular vesicles. Currently, there are no specific guidelines on the use of thromboprophylaxis in this unique population. There is the urgent need of prospective studies assessing which patients have the highest prothrombotic profile and would therefore benefit from early thromboprophylaxis.
Project description:UNLABELLED: BACKGROUND:Cardiovascular disease with disturbances in the haemostatic system, might lead to thrombotic complications with clinical manifestations like acute myocardial infarction (AMI) and stroke. Activation of the coagulation cascade with subsequent increased thrombin generation, characterizes a prothrombotic phenotype. In the present study we investigated whether prothrombotic markers were associated with risk factors and clinical subgroups in a cohort of patients with angiographically verified coronary artery disease (CAD). The patients were randomized to long-term treatment with the antiplatelet drugs aspirin or clopidogrel, and we further investigated the effect on hypercoagulability of such treatment for 1 year, of which limited data exists. METHODS:Venous blood samples were collected in fasting condition between 08:00 and 10:30 am, at baseline when all patients were on aspirin therapy (n?=?1001) and in 276 patients after 1 year follow-up on aspirin or clopidogrel. In vivo thrombin generation was assessed by prothrombin fragment 1?+?2 (F1+2) and D-dimer, and the endogenous thrombin potentiale (ETP) in the calibrated automated thrombogram (CAT) assay, representing ex vivo thrombin generation. In addition soluble tissue factor (sTF) and free- and total tissue factor pathway inhibitor (TFPI) were measured. RESULTS:We found age to be significantly associated with F1+2 and D-dimer (??=?0.229 and ? =0.417 respectively, p <0.001, both). Otherwise, only weak associations were found. F1+2 and D-dimer were higher in women compared to men (p <0.001 and p?=?0.033, respectively). Smokers had elevated levels of ETP compared to non-smokers (p?=?0.014). Additionally, patients on renin-angiotensin system (RAS) inhibition showed significantly higher levels of F1+2, compared to non-users (p?=?0.013). Both aspirin and clopidogrel reduced levels of ETP after 12 months intervention (p?=?0.003 and p <0.001, respectively) and the levels of F1+2 were significantly more reduced on aspirin compared to clopidogrel (p?=?0.023). CONCLUSIONS:In the present population of stable CAD, we could demonstrate a more hypercoagulable profile among women, smokers and patients on RAS medication, assessed by the prothrombotic markers F1+2, D-dimer and ETP. Long-term antiplatelet treatment with aspirin alone seems to attenuate thrombin generation to a greater extent than with clopidogrel alone. The study is registered at http://www.clinicaltrials.gov: NCT00222261.
Project description:Observational data suggest an acquired prothrombotic state may contribute to the pathophysiology of COVID-19. These data include elevated D-dimers observed among many COVID-19 patients. We present a retrospective analysis of admission D-dimer, and D-dimer trends, among 1065 adult hospitalized COVID-19 patients, across 6 New York Hospitals. The primary outcome was all-cause mortality. Secondary outcomes were intubation and venous thromboembolism (VTE). Three-hundred-thirteen patients (29.4%) died, 319 (30.0%) required intubation, and 30 (2.8%) had diagnosed VTE. Using Cox proportional-hazard modeling, each 1 ?g/ml increase in admission D-dimer level was associated with a hazard ratio (HR) of 1.06 (95%CI 1.04-1.08, p < 0.0001) for death, 1.08 (95%CI 1.06-1.10, p < 0.0001) for intubation, and 1.08 (95%CI 1.03-1.13, p = 0.0087) for VTE. Time-dependent receiver-operator-curves for admission D-dimer as a predictor of death, intubation, and VTE yielded areas-under-the-curve of 0.694, 0.621, and 0.565 respectively. Joint-latent-class-modeling identified distinct groups of patients with respect to D-dimer trend. Patients with stable D-dimer trajectories had HRs of 0.29 (95%CI 0.17-0.49, p < 0.0001) and 0.22 (95%CI 0.10-0.45, p = 0.0001) relative to those with increasing D-dimer trajectories, for the outcomes death and intubation respectively. Patients with low-increasing D-dimer trajectories had a multivariable HR for VTE of 0.18 (95%CI 0.05-0.68, p = 0.0117) relative to those with high-decreasing D-dimer trajectories. Time-dependent receiver-operator-curves for D-dimer trend as a predictor of death, intubation, and VTE yielded areas-under-the-curve of 0.678, 0.699, and 0.722 respectively. Although admission D-dimer levels, and D-dimer trends, are associated with outcomes in COVID-19, they have limited performance characteristics as prognostic tests.
Project description:OBJECTIVES:To investigate how many general practitioner (GP)-referred venous thromboembolic events (VTEs) are diagnosed during 1 year in one geographical region and to investigate the (urgent) referral pathway of VTE diagnoses, including the role of laboratory D-dimer testing. DESIGN:Historical cohort study. SETTING:GP patients of 47 general practices in a demarcated geographical region of 161 503 inhabitants in the Netherlands. PARTICIPANTS:We analysed all 895 primary care patients in whom either the GP determined a D-dimer value or who had a diagnostic work-up for suspected VTE in a non-academic hospital during 2015. PRIMARY AND SECONDARY OUTCOME MEASURES:The primary outcomes of this study were the total number of VTEs per year and the diagnostic pathways-including the role of GP determined D-dimer testing-of patients urgently referred to secondary care for suspected VTE. Additionally, we explored the use of an age-adjusted D-dimer cut-off. RESULTS:The annual VTE incidence was 0.9 per 1000 inhabitants. GPs annually ordered 5.1 D-dimer tests per 1000 inhabitants. Of 470 urgently GP-referred patients, 31.3% had a VTE. Of those urgently referred based on clinical assessment only (without D-dimer testing), 73.8% (96/130) had a VTE; based on clinical assessment and laboratory D-dimer testing yielded 15.0% (51/340) VTE. Applying age-adjusted D-dimer cut-offs to all patients aged 50 years or older resulted in a reduction of positive D-dimer results from 97.9% to 79.4%, without missing any VTE. CONCLUSIONS:Although D-dimer testing contributes to the diagnostic work-up of VTE, GPs have a high detection rate for VTE in patients who they urgently refer to secondary care based on clinical assessment only.
Project description:Essentials The role of statins in hemostasis and venous thromboembolism (VTE) prophylaxis is not clear. This trial assessed whether rosuvastatin use affects thrombin generation in patients with VTE. Endogenous thrombin potential and peak were decreased by 10% and 5% with rosuvastatin therapy. These results provide basis for trials on the efficacy of statins in reducing recurrent VTE risk. SUMMARY: Background Statin therapy could form an alternative prophylactic treatment for venous thromboembolism (VTE) if statins are proven to downregulate hemostasis and prevent recurrent VTE, without increasing bleeding risk. Objectives The STAtins Reduce Thrombophilia (START) trial investigated whether statin affects coagulation in patients with prior VTE. Patients/methods After anticoagulation withdrawal, patients were randomized to rosuvastatin 20 mg day-1 for 4 weeks or no intervention. Plasma samples taken at baseline and at the end of the study were analyzed employing thrombin generation assay. Results and conclusions The study comprised 126 rosuvastatin users and 119 non-users. Mean age was 58 years, 61% were men, 49% had unprovoked VTE and 75% had cardiovascular (CV) risk factors. Endogenous thrombin potential (ETP) increased from baseline to end of study in non-statin users (mean 97.22 nm*min; 95% CI, 40.92-153.53) and decreased in rosuvastatin users (mean -24.94 nm*min; 95% CI, -71.81 to 21.93). The mean difference in ETP change between treatments was -120.24 nm*min (95% CI, -192.97 to -47.51), yielding a 10.4% ETP reduction by rosuvastatin. The thrombin peak increased in both non-statin (mean 20.69 nm; 95% CI, 9.80-31.58) and rosuvastatin users (mean 8.41 nm; 95% CI -0.86 to 17.69). The mean difference in peak change between treatments was -11.88 nm (95% CI, -26.11 to 2.35), yielding a 5% peak reduction by rosuvastatin. Other thrombin generation parameters did not change substantially. The reduction in ETP and peak by rosuvastatin was more pronounced in the subgroups of participants with CV risk factors and with unprovoked VTE. We conclude that rosuvastatin reduces thrombin generation potential in patients who had VTE.
Project description:Background:The risk of venous thromboembolism (VTE) is increased after a myocardial infarction (MI). Some prothrombotic genotypes associated with VTE have also been associated with risk of MI. Whether prothrombotic single-nucleotide polymorphisms (SNPs) further increase the risk of VTE in MI patients is scarcely investigated. Aim:To study the combined effect of MI and prothrombotic SNPs on the risk of VTE. Methods:Cases with incident VTE (n = 641) and a randomly sampled subcohort weighted for age (n = 1761) were identified from the 4 to 6 surveys of the Tromsø Study (1994-2012). DNA was genotyped for rs8176719 (ABO), rs6025 (F5), rs1799963 (F2), rs2066865 (FGG), and rs2036914 (F11). Hazard ratios (HRs) for VTE with 95% confidence intervals (CIs) were estimated by categories of risk alleles and MI status. Results:Patients with MI had a 1.4-fold increased risk of VTE, and adjustments for the 5 SNPs, either alone or in combination, did not affect this relationship (adjusted HR, 1.52; 95% CI, 1.12-2.07). In subjects without MI, an increased risk of VTE was observed for each of the individual SNPs (?1 vs. 0 risk alleles), and the risk increased linearly with increasing number of risk alleles in the 5-SNP score. The combination of MI and prothrombotic genotypes, either as individual SNPs or in the 5-SNP score, did not result in an excess risk of VTE. Conclusion:The relationship between MI and VTE was not explained by these 5 prothrombotic genotypes. Prothrombotic genotypes did not yield an excess risk of VTE in patients with MI.
Project description:Klippel-Trenaunay syndrome (KTS) is a congenital condition redefined by Oduber et al (2008) by the coexistence of vascular malformations and disturbed soft tissue or bony growth, including hypertrophy or hypotrophy in the same or opposite sides of the body. The anomalies may involve part of a limb, a whole limb, a limb girdle, or a hemibody. Vascular malformations may involve veins, capillaries, or lymphatics although venous or capillary malformations are essential for the diagnosis. Associated venous anomalies include dysplasia, valvular malformations, and varicosities. Congenital venous anomalies are often associated with disturbances of blood flow and should be considered as prothrombotic states. However, such anomalies are not considered in Wells scores and used to determine the risk for venous thromboembolism (VTE). We present the case of a male with unrecognized crossed dissociated form of KTS and unsuspected VTE. The pathophysiology and the treatment of VTE in KTS are discussed. We suggest physicians to be aware of KTS and that its recognition in a critically ill patient should prompt consideration for appropriate prophylaxis for high-risk category for VTE. Dedicated duplex sonography should be obtained if VTE is suspected. We also suggest a modification of the Wells scores to reflect the association of KTS and VTE.
Project description:The incidence of venous thromboembolism (VTE), including lower extremity deep vein thrombosis (DVT) and pulmonary embolism (PE) is increasing. The increase in suspicion for VTE has lowered the threshold for performing imaging studies to confirm diagnosis of VTE. However, only 20% of suspected cases have a confirmed diagnosis of VTE. Development of pulmonary embolism rule-out criteria (PERC) and update in pre-test probability have changed the paradigm of ruling-out patient with low index of suspicion. The D-dimer test in conjunction to the pre-test probability has been utilized in VTE diagnosis. The age appropriate D-dimer cutoff and inclusion of YEARS algorithm (signs of the DVT, hemoptysis and whether PE is the likely diagnosis) for the D-dimer cutoff have been recent updates in the evaluation of suspected PE. Multi-detector computed tomography pulmonary angiography (CTPA) and compression ultrasound (CUS) are the preferred imaging modality to diagnose PE and DVT respectively. The VTE diagnostic algorithm do differ in pregnant individuals. The prerequisite of avoiding excessive radiation has recruited planar ventilation-perfusion (V/Q) scan as preferred in pregnant patients to evaluate for PE. The modification of CUS protocol with addition of the Valsalva maneuver should be performed while evaluating DVT in pregnant individual.
Project description:Denser fibrin networks which are relatively resistant to lysis can predispose to post-thrombotic syndrome (PTS). Histidine-rich glycoprotein (HRG), a blood protein displaying antifibrinolytic properties, is present in fibrin clots. We investigated whether HRG may affect the risk of PTS in relation to alterations to fibrin characteristics. In venous thromboembolism (VTE) patients, we evaluated plasma HRG levels, plasma clot permeability, maximum absorbance, clot lysis time and maximum rate of increase in D-dimer levels released from clots after 3 months of the index event. We excluded patients with cancer and severe comorbidities. After 2 years of follow-up, 48 patients who developed PTS had 18.6% higher HRG at baseline. Baseline HRG positively correlated with clot lysis time, maximum absorbance, and thrombin-activatable fibrinolysis inhibitor (TAFI) activity but was inversely correlated with plasma clot permeability and maximum rate of increase in D-dimer levels released from clots. On multivariate regression model adjusted for age, fibrinogen and glucose, independent predictors of PTS were recurrent VTE, baseline HRG level, and TAFI activity. VTE recurred in 45 patients, including 30 patients with PTS, and this event showed no association with elevated HRG. Our findings suggest that increased HRG levels might contribute to the development of PTS, in part through prothrombotic fibrin clot properties.
Project description:Associations of Raynaud's phenomenon (RP) with venous thromboembolism (VTE) are unclear. We investigated the occurrence of RP together with prothrombotic state markers and fibrin clot properties in VTE patients. In this prospective cohort study we enrolled 360 patients free of known autoimmune disease. D-dimer, von Willebrand factor (vWF), plasma clot permeability (Ks), clot lysis time (CLT) along with fibrinolysis activators and inhibitors were determined at least 3 months since the VTE event. The presence/absence of RP was diagnosed at least 6 months before VTE. Primary RP occurred in 57 subjects (17%) with a 3.6-fold higher prevalence among women. Patients with RP had 11% higher fibrinogen, 16% higher vWF, 5% lower Ks, and 10% longer CLT (all p?<?0.05). Females with RP (21%) had 6.6% lower Ks, 11.2% longer CLT, and 18.5% higher vWF (all p?<?0.05) compared with men. CLT was predicted by PAI-1 and vWF levels. Regression analysis showed that RP was a predictor of prolonged CLT in the whole patient group (OR 3.46, 95% CI 1.92-6.24) and in women following VTE (OR 2.75, 95% CI 1.31-5.78). Primary RP patients tend to form denser plasma fibrin clots displaying impaired lysability and increased endothelial damage. RP might be a novel risk factor for VTE, especially in women.