The hypercoagulability paradox of chronic kidney disease: The role of fibrinogen

doi:10.1016/j.amjsurg.2017.08.039

The American Journal of Surgery

Volume 214, Issue 6, December 2017, Pages 1215-1218

https://doi.org/10.1016/j.amjsurg.2017.08.039 Get rights and content

Abstract

Background

Chronic kidney disease (CKD) patients have increased rates of bleeding as well as thrombosis. Fibrinogen and platelets combine to generate a mature clot, but in CKD platelets are dysfunctional. Therefore, we hypothesize that CKD patients have increased clot strength due to elevated fibrinogen levels.

Methods

Retrospective review of CKD patients (n = 84) who had rTEG and fibrinogen levels measured. They were compared to healthy controls (n = 134).

Results

CKD patients had statistically significant increases in ACT, angle, MA and decreases in LY30 compared to controls. Fibrinogen levels were increased in CKD patients compared to reference range. Fibrinogen levels had a positive correlation with MA (rho = 0.709, p < 0.0001) in CKD patients.

Conclusions

Patients with CKD manifest a coagulopathy consisting of delayed clot formation, but increased final clot strength and decreased clot breakdown. Furthermore, the elevated clot strength is mediated by increased fibrinogen levels in CKD patients.

Introduction

Chronic Kidney Disease (CKD) patients have a paradoxical hemostatic potential, with increased rates of bleeding, but are prone to thrombosis.2, 3 Increased bleeding is thought to be driven principally by platelet dysfunction, with additional contributions from alterations in the coagulation cascade with deranged vWF and platelet interactions, increased nitric oxide and impaired fibrinolysis, as well as the sequelae of anemia.2, 4, 5 Clinically relevant bleeding has been reported in 24–50% of patients on HD, with a >2-fold increased prevalence compared to patients without ESRD.2, 6

Increased rates of thrombosis, on the other hand, manifest as deep venous thrombosis (DVT), pulmonary embolus (PE), thrombosis of arteriovenous fistula or hemodialysis access catheter, or acute coronary syndromes.2, 6 VTE event rates are doubled in the presence of CKD.⁶ The mechanisms driving this pro-thrombotic state are unclear.³

Thrombelastography (TEG) is a viscoelastic hemostatic assay that has been widely used in clinical settings as it more closely approximates the in vivo clotting characteristics compared to standard coagulation assays.¹ Standard coagulation assays use platelet poor plasma (PPP), while TEG used whole blood and therefore represents contributions from red blood cells, platelets, white blood cells in addition to clotting factors found in PPP.¹ TEG measures different hemostatic variables: the rate of clot formation (activated clotting time (ACT)), rate of clot propagation (angle), clot strength (maximal amplitude (MA)) and clot breakdown 30 min after achieving maximum clot strength (LY30). TEG has been shown to predict thrombotic complications in a wide variety of patient populations, with an elevated MA as the best predictor.7, 8, 9 As TEG provides detailed descriptions of the different phases of clot formation and predicts clinical outcomes, it provides a good tool to characterize the hemostatic potential in CKD.

MA is composed of contributions from platelets as well as fibrinogen that combine to generate a mature clot.10, 11 CKD has been associated with both platelet dysfunction as well as hyperfibrinogenemia.2, 5, 12 Thrombocytopenia has been successfully compensated for by the addition of fibrinogen concentrate.¹³ Additionally, fibrinogen concentrates have been used clinically used in European centers for the treatment of traumatic coagulopathy.13, 14, 15 Therefore, it seems reasonable that despite the presence of platelet dysfunction in renal failure, the elevated fibrinogen levels could compensate for this to drive increased clot strength. We hypothesize that increased fibrinogen levels in patients with CKD will correlate with increased clot strength and an increased MA on TEG.

Section snippets

Study design

This was a single center, retrospective review of patients undergoing dialysis access surgery by a single surgeon at Denver Health Medical Center from 4/2013–10/2016. This group of CKD patients was compared to healthy controls.

Blood samples from healthy volunteers

Nursing staff collected samples from volunteers at an outpatient clinic after approval by the Colorado Multi-institutional Review Board. The study was open to patients and hospital staff not taking antiplatelet or anticoagulant medication. Volunteers with any medical

Patient population

134 healthy volunteers and 84 CKD patients were included in the study. Healthy volunteers had a median age of 31 (27–38) and were 47% male. CKD patients had a median age of 57 years (52.5–62), were 60.7% male, and 66% of patients were on dialysis (65% on HD, 1.1% on PD). Healthy patients and controls differed in age (p < 0.0001) but not in proportion of patients that were male or female. Of patients not on dialysis (n = 28), 25 had a GFR available preoperatively. These patients were stratified

Discussion

Chronic kidney disease generates a distinct hemostatic potential as compared to normal controls. CKD patients manifest a coagulopathy consisting of delayed clot formation with increased final clot strength and decreased clot breakdown when compared to healthy patients. The increased clot strength (MA) that is seen in this population is mediated by supra-normal fibrinogen levels. The increased clot strength and decreased clot breakdown is attenuated in patients receiving HD.

Our data aligns with

Funding

This study was supported in part by US Army Medical Research Acquisition Act of the Department of Defense under Contract Award Number W81XWH1220028, National Institute of General Medical Sciences grants: T32-GM008315 and P50-GM49222. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Department of Defense or the National Institutes of Health. We receive research support from Haemonetics LLC and TEM GmbH, but have no financial

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The hypercoagulability paradox of chronic kidney disease: The role of fibrinogen

Abstract

Background

Methods

Results

Conclusions

Introduction

Section snippets

Study design

Blood samples from healthy volunteers

Patient population

Discussion

Funding

Am J Med

Am J Kidney Dis

J Thromb Haemost

J Clin Anesth

J Surg Res

Am J Kidney Dis

The place of viscoelastic testing in clinical practice

Br J Haematol

Haemostasis in chronic kidney disease

Nephrol Dial Transpl

Fibrin breakdown products and fibrinolysis in renal disease

J Clin Pathol

Platelet dysfunction and end-stage renal disease

Semin Dial