Oral Warfarin and the Thrombin Inhibitor Dabigatran Increase Blood Pressure in Rats: Hidden Danger of Anticoagulants?

Ware, Kyle; Vance, Jay; Muni, Navin; Hebert, Lee A.; Satoskar, Anjali A.; Nadasdy, Gyongyi; Ivanov, Iouri; Nádasdy, Tibor; Rovin, Brad H.; Brodsky, Sergey V.

doi:10.1093/ajh/hpu129

Cited by 21 publications

(14 citation statements)

References 26 publications

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“…Treatment with enalapril or albuterol did not change the anticoagulation effects of dabigatran (Figure 1a). Dabigatran alone increased systolic but not diastolic blood pressure; these effects were similar to those that we described earlier (Ware, Vance, et al, 2015). Treatment with enalapril/dabigatran resulted in the reduction of both systolic and diastolic blood pressures not only compared to dabigatran alone, but to the baseline as well (Figure 1b,c).…”

Section: Resultssupporting

confidence: 91%

“…Increased systemic blood pressure accelerates the progression of glomerulosclerosis in 5/6 nephrectomy rats and mice (Bidani et al, 1994). Our data indicate that anticoagulants, including warfarin and dabigatran, increase systolic blood pressure in both control and 5/6 nephrectomy rats (Ware, Vance, et al, 2015), which may participate in the ARN development. Treatments with ACE inhibitors or angiotensin receptor blockers provide renoprotection in 5/6 nephrectomy rats (Goncalves et al, 2004;Meyer et al, 1987;Vavrinec et al, 2012).…”

Section: Introductionmentioning

confidence: 59%

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Role of glomerular filtration rate‐modifying drugs in the development of anticoagulant‐related nephropathy

et al. 2021

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Section: Resultssupporting

confidence: 91%

Section: Introductionmentioning

confidence: 59%

Role of glomerular filtration rate‐modifying drugs in the development of anticoagulant‐related nephropathy

et al. 2021

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“…Based on our data, the hypertensive effect of warfarin does not change with CKD progression. Indeed, the BP increase from baseline was similar in sham-operated rats and in 5/6 nephrectomy rats at different stages of CKD progression [41] . These data suggest that CKD patients may not be at a higher risk for hypertension associated with warfarin.…”

Section: Experimental Models Of Wrnmentioning

confidence: 69%

“…Our latest data indicate that anticoagulants increase blood pressure (BP) in rats [41] . Warfarin and dabigatran both increased systolic BP in control and 5/6 nephrectomy rats in a dose-dependent manner.…”

Section: Experimental Models Of Wrnmentioning

confidence: 99%

Anticoagulants and acute kidney injury: clinical and pathology considerations

Brodsky

2014

Kidney Research and Clinical Practice

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We have recently identified a new clinical syndrome in patients receiving warfarin for anticoagulation therapy. This syndrome has been named warfarin-related nephropathy (WRN), and patients with chronic kidney disease (CKD) appear to be particularly susceptible. WRN is defined as an acute increase in international normalized ratio (INR) to >3.0, followed by evidence of acute kidney injury (AKI) within 1 week of the INR increase. AKI was defined as a sustained increase in serum creatinine of greater than or equal to 0.3 mg/dL. The AKI cannot be explained by any other factors, and the kidney biopsy demonstrates extensive glomerular hemorrhage with tubular obstruction by red blood cells (RBCs). Beyond AKI, WRN is a significant risk factor for mortality within the first 2 months of diagnosis and it accelerates the progression of CKD. We demonstrated that 5/6 nephrectomy in rats is a suitable experimental model to study WRN. Animals treated with warfarin showed an increase in serum creatinine and morphologic findings in the kidney similar to those in humans with WRN. Our recent evidence suggests that novel oral anticoagulants may induce AKI. Diagnosis of WRN may be challenging for a renal pathologist. A few cases with suspected WRN and pathologic considerations are described.

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“…Supporting this hypothesis, administration of PAR antagonists to animal models of CKD recapitulates some of the features of ARN, and administration of vitamin K attenuates these findings . Hypertension has been recently reported as a complication of treatment with both warfarin and dabigatran in animal models, implying that endothelial damage resulting from decreased thrombin levels (the common pathway between these agents) is operational in terms of both glomerular injury and, possibly, new‐onset hypertension exacerbating the renal injury .…”

Section: Mechanismmentioning

confidence: 79%

Anticoagulation‐related nephropathy

Wheeler

Giugliano

Rangaswami

2016

Journal of Thrombosis and Haemostasis

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Summary. Anticoagulation-related nephropathy (ARN) is a significant but underdiagnosed complication of anticoagulation that is associated with increased renal morbidity and all-cause mortality. Originally described in patients receiving supratherapeutic doses of warfarin who had a distinct pattern of glomerular hemorrhage on kidney biopsy, ARN is currently defined as acute kidney injury (AKI) without obvious etiology in the setting of an International Normalized Ratio (INR) of > 3.0. The underlying molecular mechanism is thought to be warfarin-induced thrombin depletion; however, newer studies have hinted at an alternative mechanism involving reductions in activated protein C and endothelial protein C receptor signaling. Prompt recognition of ARN is critical, as it is associated with accelerated progression of chronic kidney disease, and significant increases in short-term and long-term all-cause mortality. Prior investigations into ARN have almost universally focused on anticoagulation with warfarin; however, recent case reports and animal studies suggest that it can also occur in patients taking novel oral anticoagulants. Differences in the incidence and severity of ARN between patients taking warfarin and those taking novel oral anticoagulants are unknown; a post hoc analysis of routinely reported adverse renal outcomes in clinical trials comparing warfarin and novel oral anticoagulants found no significant difference in the rates of AKI, a prerequisite for ARN. Given the significant impact of ARN on renal function and all-cause mortality, a thorough understanding of the pathophysiology, molecular mechanisms, clinical spectrum and therapeutic interventions for ARN is crucial to balance the risks and benefits of anticoagulation and optimize treatment.

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Oral Warfarin and the Thrombin Inhibitor Dabigatran Increase Blood Pressure in Rats: Hidden Danger of Anticoagulants?

Cited by 21 publications

References 26 publications

Role of glomerular filtration rate‐modifying drugs in the development of anticoagulant‐related nephropathy

Role of glomerular filtration rate‐modifying drugs in the development of anticoagulant‐related nephropathy

Anticoagulants and acute kidney injury: clinical and pathology considerations

Anticoagulation‐related nephropathy

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