scholarly journals Effects of Polymorphisms in Myc-Related Genes on Bleeding Complications in Patients with Stable Warfarin Responses

2019 ◽  
Vol 2019 ◽  
pp. 1-8
Author(s):  
Jeong Yee ◽  
Woorim Kim ◽  
Byung Chul Chang ◽  
Jee Eun Chung ◽  
Kyung Eun Lee ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Degrees Of Freedom ◽  
Heart Valves ◽  
Warfarin Therapy ◽  
Attributable Risk ◽  
Bleeding Complications ◽  
Nucleotide Polymorphisms ◽  
Analysis Model ◽  
Clinical Value ◽  
Increased Risk

Objectives. This study aimed to identify the possible effects of Myc and 8q24 polymorphisms on bleeding complications in patients who maintained international normalized ratio (INR) of 2.0-3.0 with warfarin therapy after cardiac valve replacement. Methods. Twenty-five single nucleotide polymorphisms were analyzed, including VKORC1, CYP2C9, Myc, and 8q24. Univariate and multivariate analyses were conducted to evaluate the associations between genetic polymorphisms and bleeding complications. Attributable risk and the number needed to genotype (NNG) were also calculated to evaluate the potential clinical value of genotyping. Results. We included 142 patients, among whom 21 experienced bleeding complications. Multivariate models showed that patients carrying the CC genotype of rs6983561 and the A allele of rs13281615 at 8q24 had 27.6- and 10.0-fold higher bleeding complications, compared with patients with the A allele and the GG genotype, respectively. For rs6983561, the attributable risk and NNG were 96.4% and 36.8, respectively, whereas, for rs13281615, the attributable risk and NNG were 90.0% and 8.3, respectively. Atrial fibrillation was associated with a 5.5-fold increased risk of bleeding complications. The AUROC value was 0.761 (95% CI 0.659-0.863, p<0.001), and the Hosmer–Lemeshow test showed that the fitness of the multivariate analysis model was satisfactory (χ2=0.846; 3 degrees of freedom; p=0.838). Conclusions. Bleeding complications during warfarin therapy were associated with 8q24 polymorphisms and atrial fibrillation in patients with mechanical heart valves.

Oral anticoagulants in atrial fibrillation with valvular heart disease and bioprosthetic heart valves

Heart ◽  
2019 ◽  
Vol 105 (18) ◽  
pp. 1432-1436 ◽  
Author(s):  
Aaqib H Malik ◽  
Srikanth Yandrapalli ◽  
Wilbert S Aronow ◽  
Julio A Panza ◽  
Howard A Cooper
Keyword(s):  
Atrial Fibrillation ◽  
Heart Disease ◽  
Major Bleeding ◽  
Valvular Heart Disease ◽  
Heart Valves ◽  
Meta Analysis ◽  
Oral Anticoagulants ◽  
Cardiac Events ◽  
Increased Risk ◽  
Randomised Controlled

ObjectiveCurrent guidelines endorse the use of non-vitamin K antagonist oral anticoagulants (NOACs) in patients with atrial fibrillation (AF). However, little is known about their safety and efficacy in valvular heart disease (VHD). Similarly, there is a paucity of data regarding NOACs use in patients with a bioprosthetic heart valve (BPHV). We, therefore, performed a network meta-analysis in the subgroups of VHD and meta-analysis in patients with a BPHV.MethodsPubMed, Cochrane and Embase were searched for randomised controlled trials. Summary effects were estimated by the random-effects model. The outcomes of interest were a stroke or systemic embolisation (SSE), myocardial infarction (MI), all-cause mortality, major adverse cardiac events, major bleeding and intracranial haemorrhage (ICH).ResultsIn patients with VHD, rivaroxaban was associated with more ICH and major bleeding than other NOACs, while edoxaban 30 mg was associated with least major bleeding. Data combining all NOACs showed a significant reduction in SSE, MI and ICH (0.70, [0.57 to 0.85; p<0.001]; 0.70 [0.50 to 0.99; p<0.002]; and 0.46 [0.24 to 0.86; p<0.01], respectively). Analysis of 280 patients with AF and a BPHV showed similar outcomes with NOACs and warfarin.ConclusionsNOACs performed better than warfarin for a reduction in SSE, MI and ICH in patients with VHD. Individually NOACs performed similarly to each other except for an increased risk of ICH and major bleeding with rivaroxaban and a reduced risk of major bleeding with edoxaban 30 mg. In patients with a BPHV, results with NOACs seem similar to those with warfarin and this needs to be further explored in larger studies.

HEMATURIA AND OTHER KINDS OF BLEEDINGS ON NON-VITAMIN K ANTAGONIST ORAL ANTICOAGULANTS IN PATIENTS WITH ATRIAL FIBRILLATION: AN UPDATED OVERVIEW ON OCCURRENCE, PATHOMECHANISMS AND MANAGEMENT

2020 ◽  
Vol 73 (11) ◽  
pp. 2528-2534
Author(s):  
Dagmara Wojtowicz ◽  
Anna Tomaszuk-Kazberuk ◽  
Jolanta Małyszko ◽  
Marek Koziński
Keyword(s):  
Atrial Fibrillation ◽  
Vitamin K ◽  
Anticoagulant Activity ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Vitamin K Antagonist ◽  
Bleeding Complications ◽  
Reversal Agents ◽  
Limited Availability ◽  
Increased Risk

Non-vitamin K antagonist oral anticoagulants (NOACs) are currently recommended for oral anticoagulation in patients with non-valvular atrial fibrillation. In the setting, NOACs effectively prevent from stroke and systemic embolic events. In spite of the favorable safety profile of NOACs when compared with vitamin K antagonists, the use of any kind of anticoagulation is associated with an increased risk of bleeding. However, there is still a lack of direct comparisons of effectiveness and safety among NOACs. The results of indirect comparisons and meta-analyses suggest that the risk of various types of hemorrhagic complications differ among the particular NOACs. Management of bleeding in patients under NOAC therapy can be challenging because of limited availability of antidotes and the lack of routine laboratory test monitoring the NOAC anticoagulant effect. In case of life-threatening or critical site bleeding, reversal of NOAC anticoagulant activity is essential together with immediate implementation of causative treatment. Moreover, some patients on chronic NOAC therapy may require urgent surgery or invasive procedures. Specific reversal agents for NOACs have been developed, i.e. more widely available idarucizumab for the factor IIa inhibitor (dabigatran) and andexanet alfa for the factor Xa inhibitors (rivaroxaban, apixaban, edoxaban) with limited availability. This review summarizes the occurrence and management of NOAC-related bleeding complications with a particular emphasis on hematuria.

CHECKING THE ASSOCIATION OF FIVE SNP WITH UNVALVED ATRIAL FIBRILLATION IN PATIENTS WITH ACUTE CORONARY SYNDROME

2021 ◽  
pp. 42-52
Author(s):  
Lozhkina N.G. ◽  
Gurazheva A.A. ◽  
Maksimov V.N.
Keyword(s):  
Atrial Fibrillation ◽  
Acute Coronary Syndrome ◽  
Acute Coronary Syndrome Patient ◽  
Study Groups ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Coronary Syndrome ◽  
Increased Risk ◽  
Male Patients ◽  
European Society Of Cardiology

Вackground. It is known that 5–21% of patients with acute coronary syndrome (ACS) develop atrial fibrillation (AF), which entails an increased risk of recurrence of myocardial infarction, heart failure, and increased mortality. The genetic predisposition to AF has been actively studied in recent years, but the data on the association of certain single nucleotide polymorphisms (SNPs) in the development of AF are contradictory, which determines the relevance of this study. Purpose of the study. To study five SNPs for associations with the development of non-valvular atrial fibrillation in patients with acute coronary syndrome Patient Characterization and Research Methods. The study included female and male patients not younger than 18 years old with ACS and AF (n = 133) and ACS without AF (n = 133) ACS was diagnosed according to the criteria of the European Society of Cardiology (2015; 2017). The study was approved by the Ethics Committee (Minutes No. 102 dated November 24, 2017). The observation period was 12 months. In addition to the standard examination, all patients underwent a SNP study: rs6795970 (Scn10a), rs2200733 (4th stage), rs11556924 (ZC3HC1), rs599839 (PSRC1), rs10824026 (10th stage). Statistical analysis was performed using Statistica 12.1 StatSoft. Results. The results of the rs599839 study showed that the GG genotype was significantly less common in the ACS + AF group compared to the ACS group without AF (OR 0.11 CI 95% 0.01; 0.86 p = 0.0163). A reliable connection was lost when divided by sex and by age (older and younger than 55). Allele G rs599839 significantly correlates with AF (p = 0.0043; OR 1.56). The T allele rs11556924 is highly reliably associated with a predisposition to atrial fibrillation (p = 0.0043; OR 1.93). Genotype GG rs10824026 is conditionally protective in terms of the risk of AF in patients with ACS. For rs6795970 (p = 0.290) and rs2200733 (p = 0.30), there were no statistically significant differences between the study groups. Conclusion. The study verified the association of rs6795970 (Scn10a), rs2200733, rs11556924, rs599839, rs10824026 with AF associated with ACS. The genotypes GG rs599839 and GG rs10824026 were found to be conditionally protective in relation to the risk of AF in patients with ACS.

scholarly journals Antithrombotic therapy according to baseline bleeding risk in patients with atrial fibrillation undergoing percutaneous coronary intervention: applying the PRECISE-DAPT score in RE-DUAL PCI

2020 ◽  
Author(s):  
Francesco Costa ◽  
Marco Valgimigli ◽  
Philippe Gabriel Steg ◽  
Deepak L Bhatt ◽  
Stefan H Hohnloser ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Antithrombotic Therapy ◽  
Bleeding Risk ◽  
Coronary Intervention ◽  
Bleeding Complications ◽  
Event Analysis ◽  
Increased Risk ◽  
Safety Endpoint ◽  
High Bleeding Risk ◽  
The Impact

Abstract Aims Patients with atrial fibrillation undergoing coronary intervention are at higher bleeding risk due to the concomitant need for oral anticoagulation and antiplatelet therapy. The RE-DUAL PCI trial demonstrated better safety with dual antithrombotic therapy (DAT: dabigatran 110 or 150 mg b.i.d., clopidogrel or ticagrelor) compared to triple antithrombotic therapy (TAT: warfarin, clopidogrel or ticagrelor, and aspirin). We explored the impact of baseline bleeding risk based on the PRECISE-DAPT score for decision-making regarding DAT vs. TAT. Methods and results A score ≥25 points qualified high bleeding risk (HBR). Comparisons were made for the primary safety endpoint International Society of Thrombosis and Haemostasis major or clinically relevant non-major bleeding, and the composite efficacy endpoint of death, thrombo-embolic events, or unplanned revascularization, analysed by time-to-event analysis. PRECISE-DAPT was available in 2336/2725 patients, and 37.9% were HBR. Compared to TAT, DAT with dabigatran 110 mg reduced bleeding risk both in non-HBR [hazard ratio (HR) 0.42, 95% confidence interval (CI) 0.31–0.57] and HBR (HR 0.70, 95% CI 0.52–0.94), with a greater magnitude of benefit among non-HBR (Pint = 0.02). Dual antithrombotic therapy with dabigatran 150 mg vs. TAT reduced bleeding in non-HBR (HR 0.60, 95% CI 0.45–0.80), with a trend toward less benefit in HBR patients (HR 0.92, 95% CI 0.63–1.34; Pint = 0.08). The risk of ischaemic events was similar on DAT with dabigatran (both 110 and 150 mg) vs. TAT in non-HBR and HBR patients (Pint = 0.45 and Pint = 0.56, respectively). Conclusions PRECISE-DAPT score appeared useful to identify AF patients undergoing PCI at further increased risk of bleeding complications and may help clinicians identifying the antithrombotic regimen intensity with the best benefit–risk ratio in an individual patient.

scholarly journals Time in Therapeutic Range Using a Nomogram for Dose Adjustment of Warfarin in Patients on Hemodialysis With Atrial Fibrillation

2021 ◽  
Vol 8 ◽  
pp. 205435812110460
Author(s):  
Kimberly Defoe ◽  
Jenny Wichart ◽  
Kelvin Leung
Keyword(s):  
Atrial Fibrillation ◽  
Therapeutic Range ◽  
Chart Review ◽  
Warfarin Therapy ◽  
Small Sample Size ◽  
Retrospective Chart Review ◽  
Small Sample ◽  
Time In Therapeutic Range ◽  
Increased Risk ◽  
Chi Square Analysis

Background: Patients treated with hemodialysis and prescribed warfarin typically have lower time in therapeutic range (TTR) compared to the general population. This may result in less benefit or increased risk of over anticoagulation in these patients. Objective: To assess effectiveness of use of an electronic nomogram for the management of warfarin therapy in patients treated with hemodialysis. Design: Retrospective chart review. Setting: Adult patients treated with hemodialysis. Patients: Patients on hemodialysis receiving warfarin for the management of atrial fibrillation (AF) with therapy managed by nursing led electronic nomogram. Measurements: Time in therapeutic range (as fraction and Rosendaal). Methods: Retrospective chart review over 1 year of international normalized ratio (INR) results was completed, and TTR was calculated. Comparison of patients with TTR greater than 60% to those less than 60% was completed using chi-square analysis. Results: Of 43 patients with warfarin therapy managed by the nomogram, the mean TTR was 55.2% (calculated by fraction method) or 61.2% (calculated by Rosendaal method). More than half of the patients (63.5%) had moderate to good control, defined as TTR greater than 60%. Female sex, liver disease, or history of substance use and more medication holds were associated with lower TTR. Limitations: Small sample size and retrospective nature of review. Conclusions: The results of this review supports the use of an electronic, nursing-led nomogram for the maintenance management of warfarin therapy in stable patients treated with hemodialysis, as use results in TTR greater than 60% for more than half of patients.

scholarly journals Anticoagulation after Spontaneous Intraparenchymal Hemorrhage in Patients with Mechanical Heart Valves and Concomitant Atrial Fibrillation

2021 ◽  
Author(s):  
Jennifer H. Kang ◽  
Michael L. James ◽  
Allison Gibson ◽  
Ovais Inamullah ◽  
Gary Clay Sherrill ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Heart Valves ◽  
Brain Parenchyma ◽  
Mechanical Heart Valves ◽  
Bleeding Complications ◽  
Intraparenchymal Hemorrhage ◽  
Single Institution ◽  
Discharge Disposition ◽  
Timing Of Initiation ◽  
The Brain

Abstract Aim Patients with mechanical heart valves and coexisting atrial fibrillation (AFib-MHV) who suffer an intraparenchymal hemorrhage (IPH, defined as bleeding solely within the brain parenchyma and/or ventricle) are at a high risk of thromboembolism without anticoagulation. Data are lacking regarding the safety of early re-initiation of anticoagulation in these patients. Patients and Methods We performed a descriptive, single-institution retrospective analysis of patients with AFib-MHV who suffered a non-traumatic, supratentorial IPH between July 2013 and June 2017. We analyzed the patients and IPH characteristics, anticoagulation and antiplatelet use, the occurrence of thrombotic and hemorrhage complications, and discharge disposition. We described the timing of initiation of anticoagulation and outcomes after IPH while in-patient. Results Six patients with AFib-MHV suffered a spontaneous IPH. Four were initiated on anticoagulation prior to discharge, of whom two were initiated within 3 days post-hemorrhage. These patients suffered no bleeding complications and were discharged home with a modified Rankin Scale of 1. Conclusion Patients with AFib-MHV who suffer a spontaneous IPH are a rare population to study. Further studies to guide the management of restarting anticoagulation in this select population are warranted.

Monitoring Warfarin Therapy with the International Normalized Ratio

1994 ◽  
Vol 28 (2) ◽  
pp. 242-244 ◽  
Author(s):  
Patricia A. Howard
Keyword(s):  
Ct Scan ◽  
Heart Valves ◽  
Warfarin Therapy ◽  
Medical Center ◽  
Current System ◽  
International Normalized Ratio ◽  
Bleeding Complications ◽  
Warfarin Dosage ◽  
Local Hospital ◽  
Traditional System

OBJECTIVE: To report a case of suboptimal warfarin monitoring. CASE SUMMARY: A patient with a history of rheumatic heart disease and a mechanical mitral valve was admitted to the local hospital complaining of left-sided weakness. At the time, she was receiving warfarin 5 mg/d. Upon admission her prothrombin time (PT) was 15 s. An initial computed tomography (CT) scan of the head was negative. On the basis of the initial findings, it was unclear whether the symptoms were caused by a cerebrovascular accident (CVA). The patient was transferred to the University Medical Center for a more thorough evaluation. The diagnosis of CVA was confirmed by a repeat CT scan seven days after the event. On the basis of the information obtained from the local hospital, it was determined that the initial PT of 15 s converted to an International Normalized Ratio (INR) of 1.5, which is below the recommended range for patients with mechanical heart valves. Prior to discharge, the warfarin dosage was increased to obtain an INR in the recommended range of 2.5–3.5. DISCUSSION: This case illustrates the problems that exist with the current system of PT reporting and the potential advantages of using the INR. Variations in the sensitivity of the thromboplastin reagents used to perform the PT may result in misinterpretation of the level of anticoagulation and errors in warfarin dosage adjustments. The potential for suboptimal anticoagulation is greatly increased in patients, such as the one reported here, who are having PTs performed by multiple laboratories. CONCLUSIONS: To maximize efficacy and minimize the risk of bleeding complications, warfarin therapy must be individualized and closely monitored. Standardization of PT monitoring through the use of the INR would significantly reduce the potential for suboptimal anticoagulation associated with the traditional system of reporting.

Abstract 16393: In Hospital Outcomes and Prevalence of Comorbidities in Patients With Amyloidosis With and Without Atrial Fibrillation - Insight From National Inpatient Sample (nis) Database (2013-14)

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Asim Kichloo ◽  
Shakeel Jamal ◽  
Beth Bailey ◽  
muhammad shah zaib ◽  
HUH Virk ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Cardiogenic Shock ◽  
Restrictive Cardiomyopathy ◽  
Multiple Organ ◽  
Bleeding Complications ◽  
National Inpatient Sample ◽  
Risk Of Mortality ◽  
Organ Systems ◽  
Increased Risk

Introduction: Amyloidosis is a systemic illness that affects multiple organ systems including cardiovascular, renal, gastrointestinal and pulmonary systems manifesting as restrictive cardiomyopathy, atrial and ventricular arrhythmias, nephrotic syndrome and gastrointestinal hemorrhage. Unknown is whether co-occurrence atrial fibrillation (AF), further worsens the outcomes in systemic amyloidosis. Hypothesis: Atrial Fibrillation worsen clinical outcomes in Amyloidosis. Methods: Patients with diagnosis of amyloidosis with and without concurrent AF were identified by querying the Healthcare Cost and Utilization (HCUP), specifically, National Inpatient Sample for year 2016 based on ICD10 codes. Results: During 2016, a total of 2997 patients were admitted with diagnosis of Amyloidosis, out of which 918 had concurrent AF. There was an increased risk of mortality (7.4% vs 5.6%), heart block (6.8% vs 2.8%), cardiogenic shock (5% vs 1.6%), placement of an ICD/CRT/PPM (14.5% vs 4.5%), renal failure (29% vs 21%), heart failure (66% vs 30%) and bleeding complications (5.7% vs 2.8%) in patients with diagnosis of Amyloidosis and concurrent AF when compared to patients with only diagnosis of Amyloidosis. It’s interesting to note that patients with amyloidosis without comorbid AF had increased risk of stroke when compared to concurrent AF (7.9% vs 3.4%). Conclusions: Concurrent AF increases the risk of heart failure, cardiogenic shock, supraventricular tachycardia, bleeding complications and an overall increase in mortality in patients with amyloidosis.

P4796Risk prediction of atrial fibrillation in the community combining biomarkers and genetics

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
C Boerschel ◽  
A Ohlrogge ◽  
B Geelhoed ◽  
T Niiranen ◽  
A S Havulinna ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Predictive Value ◽  
Polygenic Risk Score ◽  
Nucleotide Polymorphisms ◽  
Clinical Model ◽  
C Statistic ◽  
Increased Risk ◽  
Cox Proportional Hazard Models ◽  
Research And Education ◽  
Clinical Potential

Abstract Background Classical cardiovascular risk factors (CVRF), biomarkers and genetic variation have been suggested for risk assessment of atrial fibrillation (AF). Purpose To evaluate their clinical potential, we analysed their individual and combined effectiveness in AF prediction. Methods In N=6945 individuals of the FINRISK 1997 cohort, we assessed the predictive value of CVRF, N-terminal pro B-type natriuretic peptide (NT-proBNP) and 145 recently identified single nucleotide polymorphisms (SNPs) for incident AF. Results Over a median follow-up of 17.8 years, N=551 participants (7.9%) developed AF. In multivariable-adjusted Cox proportional hazard models, NT-proBNP (hazard ratio (HR) per standard deviation (SD) 1.90, 95% confidence interval (CI): 1.71–2.11, P<0.001) and the polygenic risk score (PRS) (HR per SD 1.66, 95% CI: 1.51–1.84, P<0.001) were significantly related to incident AF. The discriminatory ability improved asymptotically with increasing numbers of SNPs. Compared to a clinical model, AF risk prediction was significantly improved by addition of NT-proBNP and the PRS. The C-statistic for the combination of all CVRF, NT-proBNP and the PRS reached 0.82 compared to 0.77 for CVRF only (P<0.001). Comparing the highest versus lowest quartile, age remained the strongest risk factor with a 15-fold increased risk of AF. The highest quartiles of NT-proBNP and the PRS both showed an approximately 3-fold increased AF risk compared to the lowest quartiles. C-Index for AF prediction Conclusions The PRS and the established biomarker NT-proBNP predicted incident AF comparably. Both provided incremental predictive value over standard clinical variables. Further improvements for the PRS are likely with the discovery of additional SNPs. Acknowledgement/Funding European Research Council, German Ministry of Research and Education, DZHK, European Union Seventh Framework Programme, CHANCES, THL

Prospective evaluation of a pharmacogenetics-guided warfarin loading and maintenance dose regimen for initiation of therapy

Blood ◽  
2011 ◽  
Vol 118 (11) ◽  
pp. 3163-3171 ◽  
Author(s):  
Inna Y. Gong ◽  
Rommel G. Tirona ◽  
Ute I. Schwarz ◽  
Natalie Crown ◽  
George K. Dresser ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Venous Thromboembolism ◽  
Time Course ◽  
Warfarin Therapy ◽  
Anticoagulation Therapy ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Cyp2c9 Genotype ◽  
Epoxide Reductase ◽  
Initiation Of Therapy

Abstract Single-nucleotide polymorphisms in genes that affect warfarin metabolism (cytochrome P450 2C9 gene, CYP2C9) and response (vitamin K epoxide reductase complex 1 gene, VKORC1) have an important influence on warfarin therapy, particularly during initiation; however, there is a lack of consensus regarding the optimal pharmacogenetics-based initiation strategy. We conducted a prospective cohort study in which patients requiring warfarin therapy for atrial fibrillation or venous thromboembolism were initiated with a novel pharmacogenetics-initiation protocol (WRAPID, Warfarin Regimen using A Pharmacogenetics-guided Initiation Dosing) that incorporated loading and maintenance doses based on genetics, clinical variables, and response (n = 167, followed up for 90 days), to assess the influence of genetic variations on anticoagulation responses. Application of the WRAPID algorithm resulted in a negligible influence of genetic variation in VKORC1 or CYP2C9 on time to achievement of first therapeutic response (P = .52, P = .28) and risk of overanticoagulation (P = .64, P = .96). After adjustment for covariates, time to stable anticoagulation was not influenced by VKORC1 or CYP2C9 genotype. Importantly, time spent within or above the therapeutic range did not differ among VKORC1 and CYP2C9 genotype groups. Moreover, the overall time course of the anticoagulation response among the genotype groups was similar and predictable. We demonstrate the clinical utility of genetics-guided warfarin initiation with the WRAPID protocol to provide safe and optimal anticoagulation therapy for patients with atrial fibrillation or venous thromboembolism.

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