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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE Table of Contents   
Year : 1994  |  Volume : 5  |  Issue : 1  |  Page : 12-16
Potentiation of the Action of Warfarin by Bezafibrate in Patients with the Nephrotic Syndrome


Division of Hematology, Department of Medicine, College of Medicine and King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia

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   Abstract 

Nephrotic syndrome is associated with thromboembolic disease due to a variety of factors. In addition, therapy with anticoagulants is often met with poor response, to warfarin for example, which occurs due to factors such as reduced serum albumin and binding sites, increased free warfarin with rapid metabolism and clearance, and possible urinary loss. Bezafibrate is known to augment the action of warfarin and improve coagulation profile. In this article, we present three cases with severe nephrotic syndrome associated with hyperfibrinogenemia, hypercholesterolemia and thromboembolic disease who showed poor response to therapy with warfarin. They showed improvement of their coagulation profile upon concomitant administration of bezafibrate.

Keywords: Nephrotic Syndrome, Thrombosis, Anticoagulants, Bezafibrate, Warfarin.

How to cite this article:
Al-Momen AK, Al-Abdul-Kareem H. Potentiation of the Action of Warfarin by Bezafibrate in Patients with the Nephrotic Syndrome. Saudi J Kidney Dis Transpl 1994;5:12-6

How to cite this URL:
Al-Momen AK, Al-Abdul-Kareem H. Potentiation of the Action of Warfarin by Bezafibrate in Patients with the Nephrotic Syndrome. Saudi J Kidney Dis Transpl [serial online] 1994 [cited 2020 Jun 6];5:12-6. Available from: http://www.sjkdt.org/text.asp?1994/5/1/12/41355

   Introduction Top


The association of nephrotic syndrome (NS) with thrombosis is well established for more than 100 years [1] . The overall incidence of renal vein thrombosis is 35%, while that of extra-renal thromboembolic complications is 20% [2],[3],[4] . Several factors may contribute to the increased thrombogenicity in the NS [5],[6] . These include; (a) increased coagulation factors (I,V,VII,VIII,X), (b) reduced coagulation inhibitors {antithrombin III (ATIII), protein C and protein S},(c) impaired fibrinolysis due to reduced Factor XII and plasminogen levels as well as increased oc-2 antiplasmin, (d) enhanced platelet aggregation and, (e) miscellaneous factors such as hypoalbuminemia, hypercholesterolemia, hyperviscosity, contracted intravascular compartment and corticosteroid therapy [2],[3],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25] [Table 1]. The association between NS and thrombosis is commonest in patients with idiopathic membranous nephropathy followed by membrano proliferative glomerulonephritis [5],[26],[27] .

Bezafibrate (BZF), a lipid lowering agent, is a fibric acid derivative with several antithrombotic properties [28],[29],[30],[31] . It can significantly reduce elevated fibrinogen level, enhance fibrinolysis, inhibit platelet aggregation, improve whole blood viscosity and potentiate warfarin action.

In this communication, we present our experience in three cases with the NS associated with thromboembolic disease who showed poor response to warfarin and showed satisfactory changes in the coagulation parameters on concomitant treatment with BZF.


   Patients and Methods Top


Case 1

A 58 year-old man with non-insulin dependent diabetes mellitus and NS was admitted to the hospital with painful swollen right calf. A contrast venogram confirmed the presence of deep vein thrombosis. Ultrasonography showed normal right kidney (11.1 cm) and grossly enlarged, hydronephrotic left kidney measuring 22.5 cm. The remaining investigations were as follows: WBC 6 x 109/l, hematocrit (Hct) 0.45%, platelets 325 x 109/l, ESR 95 mm in the first hour, fasting blood sugar (FBS) 15 mmol/1, blood urea nitrogen (BUN) 13.7 mmol/1, serum creatinine (Se Cr) 202 umol/1, total serum protein 59 gm/1, serum albumin 28 gm/1, 24-hour urinary protein excretion (24hr UP) 6.08 gm, creatinine clearance (Cr Cl) 42 ml/min, fasting serum cholesterol 7.8 mmol/1, and plasma fibrinogen 5.8 gm/1. He was treated with heparin infusion 1000 IU/hr and warfarin 10 mg/day until he was discharged two weeks later on warfarin 7.5 mg/day and glibenclamide 10 mg/day. His international normalization ratio (INR) at discharge was 2.8 (therapeutic range 2 to 3). He remained stable until he was readmitted one year later with sudden, sharp, right sided chest pain with dyspnea and low grade fever (38.2C). A perfusion ventilation (V/Q) lung scan showed a high probability for right basal pulmonary embolism. His INR was 2.1,fibrinogen 7.2 gm/1, albumin 29 gm/1, FBS 17 mmol/1, BUN 11 mmol/1, Se Cr 180 μmol/l, and 24hr UP excretion 6.8 gm. He was restarted on heparin and warfarin was increased to 10 mg/day until he was discharged 12 days later with an INR of 3.

Four months later he was readmitted with sudden onset of slurred speech and right sided hemiparesis. A computerized tomogram of the brain excluded a hemorrhagic lesion. His INR at the time of admission was 1.6, and fibrinogen 7.8 gm/1, albumin 27 gm/1, 24 hr UP 6.6 gm, BUN 12 mmol/1, Se Cr 200 u.mol/1. He was given heparin and warfarin was gradually increased up to 15 mg/day but the INR remained between 1.4 and 1.8. The patient was discharged on warfarin 15 mg/ day, glibenclamide 15 mg/day and since he had a hypercoagulable state with recurrent thromboembolic disease and hyperlipidemia, he was started on BZF 200 mg orally twice daily with close monitoring of coagulation profile. Warfarin effect was augmented and INR remained satisfactory. The dose of warfarin was adjusted downwards and was stopped after two months. Subsequently the patient was only continued on BZF along with glibenclamide. His laboratory results after three months of BZF therapy showed FBS 11 mmol/1, albumin 32 gm/1, fibrinogen 3.2 gm/1, BUN 9 mmol/1 and Se Cr 160 u.mol/1. He has been on this treatment for 18 months with follow-up every one to three months without any complications.

Case 2

A 45 year-old man presented with NS~ of unknown etiology, secondary polycythemia and bilateral renal vein thrombosis documented by angiography. Laboratory results were as follows: WBC 6.8 x 109 /I with normal differential count, RBC 7.2 x 1012/l, Hb 20 gm/dl, Hct 0.62%, MCV 84 fl, platelet count 215 x 109/l, ESR 0 mm/hr, BUN 7 mmol/1, Se Cr 105 jimol/1, 24hr UP 12.8 gm, albumin 25 gm/1, fibrinogen 8.92 gm/1, cholesterol 8.1 mmol/1, and FBS 5.3 mmol/1. He was treated initially with venesection, heparin and warfarin upto 15 mg/day. No change in prothrombin time (PT) and INR was observed after two weeks of anticoagulant therapy. Eventually, he was given bezafibrate in a dose of 200 mg orally three times daily. Warfarin dosage was gradually reduced and it was stopped three months later at which point of time, cholesterol and fibrinogen levels were reduced to 4.6 mmol/1 and 3.6 gm/1 respectively. He has been under follow-up every two to three months for the last eight months and no complications have been noted.

Case 3

A 37 year-old man with idiopathic membranous GN, was admitted to the hospital with left loin pain and worsening of peripheral edema and proteinuria. A renal venogram indicated a left renal vein thrombosis. Other laboratory findings were as follows: WBC 8 x 109/l, Hb 16.3 gm/dl, Hct 0.50%, platelets 380 x 109/l, ESR 54 mm/hr, FBS 8 mmol/1, BUN 7 mmol/1, Se Cr 115 umol/1, serum albumin 24 gm/1, 24hr UP 11.5 gm, fibrinogen 7.8 gm/1, cholesterol 9.3 mmol/1. The patient was treated with heparin infusion and warfarin 10 mg/day. Warfarin was increased gradually by 2.5 mg every 2-3 days up to 20 mg/day without obtaining a therapeutic INR for 3 weeks. At this point, he was started on BZF 200 mg orally thrice daily with close monitoring of coagulation profile and warfarin dose. In one month his warfarin requirement was reduced to 5 mg/ day with INR of 2.7 and his albumin became 32 gm/L, fibrinogen 4.1 gm/1, cholesterol 4.7 mmol/L, and 24hr UP 6.3 gm. At the end of three months, fibrinogen level became 2.9 gm/L. Warfarin was stopped and he was kept on a maintenance dose of BZF 200 mg twice daily. He has bee on follow-up every three months and has had no complications.


   Discussion Top


Poor response to anticoagulant therapy in patients with severe NS can be explained in part by:

(a) Acquired ATIII deficiency which leads to poor response to heparin [11],[12] . This is augmented by elevated or hyperactive platelets [32],[33] .

(b) Increased levels of the vitamin K dependent factors II, VII and X which results in poor response to warfarin [9] .

This is aggravated by a reduced activity of the vitamin K dependent coagulation inhibitors, protein C and protein S [13],[14] .

(c) Reduced warfarin binding sites due to low albumin level and affinity to many drugs including warfarin. This leads to excess free drug with rapid metabolism and clearance and hence, reduced effectiveness [34],[35],[36],[37] .

(d) Possible urinary loss of warfarin.

The exact mechanism of action of bezafibrate which leads to augmentation of warfarin effect is not clear [38] . It seems that bezafibrate augments warfarin effect by its own antithrombotic mechanisms which include lowering of fibrinogen level, reduction in blood viscosity, inhibition of platelet functions and enhancement of fibrinolysis [29],[30],[39],[40],[41],[42] . It is possible that bezafibrate reduces fibrinogen level by enhancing fibrinolysis through activation of fibrinolytic enzymes (plasminogen activators) similar to its ability to activate lipoprotein lipase and hepatic triglyceride hydrolase with subsequent enhancement of lipid catabolism [43] .

Our experience with these three cases showed that concommitant use of BZF potentiates the action of warfarin and improves the coagulation profile of these patients. The commonly noted side effects of BZF were not observed in 'any of our patients in spite of the prolonged use.

It seems that bezafibrate could be of potential benefit in selected cases of NS complicated by thromboembolic disease and showing poor response to warfarin. However, one should always remember that the dose of BZF has to be adjusted according to the serum creatinine level [44],[45] .


   Acknowledgement Top


The authors would like to thank Ms. Vergie Vicente for the excellent secretarial assistance.

 
   References Top

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Correspondence Address:
Abdul-Kareem Al-Momen
Department of Medicine, College of Medicine, P.O. Box 2925, Riyadh 11461
Saudi Arabia
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