Role of Hemostatic Factors on the Risk of Venous Thrombosis in People With Impaired Kidney Function

Ocak, Gürbey; Vossen, C. Y.; Lijfering, Willem M.; Verduijn, Marion; Dekker, Friedo W.; Rosendaal, Frits R.; Cannegieter, Suzanne C.

doi:10.1161/circulationaha.113.002385

Cited by 51 publications

(47 citation statements)

References 34 publications

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“…Our findings suggest that CKD‐induced activation of inflammation and procoagulation are in the causal pathway between eGFR and VTE. We confirmed prior findings that the studied biomarkers D‐dimer FVIII and CRP are more adverse with worsening kidney function (confirming our rationale for choosing them for this study). We also confirmed that D‐dimer , FVIII and CRP were strongly associated with VTE.…”

Section: Discussionsupporting

confidence: 89%

“…We are aware of only one prior study of mediators of the relationship between eGFR and VTE. The Multiple Environmental and Genetic Association (MEGA) casecontrol study included 2473 patients with recent VTE and 2936 matched controls in the Netherlands between 1999 and 2004, and accounted for genetic mutations and confounders such as recent surgery or immobilization [4]. Similar to the findings here, adjustment for FVIII or von Willebrand factor (VWF) measured after the VTE fully explained the association of eGFR with VTE, supporting the conclusion of both studies that FVIII and/or VWF may mediate the association of kidney function with VTE.…”

Section: Discussionmentioning

confidence: 99%

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Mechanisms and mitigating factors for venous thromboembolism in chronic kidney disease: the REGARDS study

Cheung

Zakai

Callas

et al. 2018

Journal of Thrombosis and Haemostasis

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Background Chronic kidney disease (CKD) is associated with venous thromboembolism (VTE) risk via unknown mechanisms. Whether factors associated with reduced VTE risk in the general population might also be associated with reduced VTE risk in CKD patients is unknown. Objectives To determine whether thrombosis biomarkers attenuate VTE risk, and whether factors associated with reduced VTE risk are similarly effective in CKD patients. Methods Baseline biomarkers were measured in a cohort (294 VTE cases; 939 non-cases) from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a nationwide prospective cohort study of 30 239 persons aged ≥45 years with 4.3 years of follow-up. The hazard ratio (HR) of VTE per 10 mL min 1.73 m decrease in estimated glomerular filtration rate (eGFR), and the percentage attenuation of this HR by each biomarker, were calculated. Associations of protective factors (physical activity, lower body mass index [BMI], and aspirin, warfarin and statin use) with VTE were estimated in those with and without CKD. Results The HR for VTE with lower eGFR was 1.13 (95% confidence interval [CI] 1.02-1.25), and VTE risk was attenuated by 23% (95% CI 5-100) by D-dimer, by 100% (95% CI 50-100) by factor VIII, and by 15% (95% CI 2-84) by C-reactive protein. Normal BMI was associated with lower VTE risk in those without CKD (HR 0.47, 95% CI 0.32-0.70), but not in those with CKD (HR 1.07, 95% CI 0.51-2.22). Statin use, physical activity and warfarin use were associated with lower VTE risk in both groups. Conclusions Procoagulant and inflammatory biomarkers mediated the association of eGFR with VTE. Higher physical activity, statin use and warfarin use mitigated VTE risk in those with CKD and those without CKD, but normal BMI did not mitigate VTE risk in CKD patients.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Mechanisms and mitigating factors for venous thromboembolism in chronic kidney disease: the REGARDS study

Cheung

Zakai

Callas

et al. 2018

Journal of Thrombosis and Haemostasis

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“…7, 9, 11, 21, 22 A meta-analysis of five studies, the largest work thus far, demonstrated an association between eGFR and VTE risk 11 and our findings extend this finding to a large, contemporary US cohort. We hypothesized that different eGFR equations used in previous research, including individual studies from the meta-analysis, may have led to conflicting results on the association of kidney disease measures and VTE.…”

Section: Discussionsupporting

confidence: 80%

Measures of Kidney Disease and the Risk of Venous Thromboembolism in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) Study

Cheung

Zakai

Folsom

et al. 2017

American Journal of Kidney Diseases

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Background Kidney disease has been associated with venous thromboembolism (VTE) risk, but results conflict and there is little information regarding blacks. Study Design Prospective cohort study Setting & Participants 30,239 black and white adults aged 45 years or older enrolled in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study 2003–2007. Predictors Estimated glomerular filtration rate (eGFR) using the combined creatinine-cystatin C (eGFRcr-cysC) equation and urinary albumin-creatinine ratio (ACR). Outcomes The primary outcome was adjudicated VTE, and secondary outcomes were provoked and unprovoked VTE separately. Mortality was a competing risk event. Results Over 4.6 years’ follow-up, 239 incident VTE events occurred over 124,624 person-years. Cause-specific HRs of VTE were calculated using proportional hazards regression adjusted for age, sex, race, region of residence and body mass index. The adjusted VTE HRs for eGFRcr-cysC 60–<90, 45–<60 and <45 versus ≥90 ml/min/1.73m2 were 1.28 (95% CI, 0.94–1.76), 1.30 (95% CI, 0.77–2.18) and 2.13 (95% CI, 1.21–3.76). The adjusted VTE HRs for ACR 10–<30, 30–<300, ≥300 versus <10 mg/g were 1.14 (95% CI, 0.84–1.56), 1.15 (95% CI, 0.79–1.69) and 0.64 (95% CI, 0.25–1.62). Associations were similar for provoked and unprovoked VTE. Limitations Single measurement of eGFR and ACR may have led to misclassification. Smaller numbers of events may have limited power. Conclusions There was an independent association of low eGFR (<45 vs ≥90 mL/min/1.73 m2) with VTE risk, but no association of ACR and VTE.

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“…Factor VIII and von Willebrand factor have been reported to contribute to venous thromboembolism in patients with CKD, but both of these coagulation regulators are acute phase reactant proteins, hence this observation might simply reflect an association of endothelial dysfunction (and secondary hypercoagulability) with inflammation 84 . In patients with advanced CKD, plasma levels of soluble thrombomodulin are elevated, reflecting endothelial dysfunction, whereas levels of aPC are reduced, providing a potential link between CKD, endothelial dysfunction and hypercoagulability 87,89–91 .…”

Section: Modulation Of Haemostasis In Renal Diseasementioning

confidence: 99%

The emerging role of coagulation proteases in kidney disease

2015

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A role of coagulation proteases in kidney disease beyond their function in normal haemostasis and thrombosis has long been suspected, and studies performed in the past 15 years have provided novel insights into the mechanisms involved. The expression of protease-activated receptors (PARs) in renal cells provides a molecular link between coagulation proteases and renal cell function and revitalizes research evaluating the role of haemostasis regulators in renal disease. Renal cell-specific expression and activity of coagulation proteases, their regulators and their receptors are dynamically altered during disease processes. Furthermore, renal inflammation and tissue remodelling are not only associated, but are causally linked with altered coagulation activation and protease-dependent signalling. Intriguingly, coagulation proteases signal through more than one receptor or induce formation of receptor complexes in a cell-specific manner, emphasizing context specificity. Understanding these cell-specific signalosomes and their regulation in kidney disease is crucial to unravelling the pathophysiological relevance of coagulation regulators in renal disease. In addition, the clinical availability of small molecule targeted anticoagulants as well as the development of PAR antagonists increases the need for in-depth knowledge of the mechanisms through which coagulation proteases might regulate renal physiology.

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Role of Hemostatic Factors on the Risk of Venous Thrombosis in People With Impaired Kidney Function

Cited by 51 publications

References 34 publications

Mechanisms and mitigating factors for venous thromboembolism in chronic kidney disease: the REGARDS study

Mechanisms and mitigating factors for venous thromboembolism in chronic kidney disease: the REGARDS study

Measures of Kidney Disease and the Risk of Venous Thromboembolism in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) Study

The emerging role of coagulation proteases in kidney disease

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