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Nephrol Dial Transplant (1996) 11: 1627-1630

Case Report

NephrologyDialysis

Transplantation

Intraeardiae thrombus in an adult patient with nephrotic syndrome

S. K. Mak, P. N. Wong, K. F. Lee, L. H. Fung and A. K. M. Wong

Renal Unit, Department of Medicine, Kwong Wah Hospital, Hong Kong

Key words: left atrial thrombus; membranous glom-erulonephritis; nephrotic syndrome

Introduction

Thromboembolic phenomena including renal veinthrombosis remain one of the most serious complica-tions of patients with nephrotic syndrome. Althoughthe literature on the changes of the various bloodcoagulation and fibrinolysis factors seems to be confus-ing, the well-documented increased incidence of throm-botic events in nephrotic patients would suggest acausal relationship. In all adult series of nephrotics,venous thrombosis and pulmonary embolism are muchmore common than arterial thrombosis, which hasbeen mainly reported in children. Intraeardiae throm-bus is among the rarest arterial thromboses reportedin the literature. Six paediatric patients with intraeard-iae thrombi have been reported including two fromEgli's series [1]. We report an adult with membranousglomerulonephritis with nephrotic syndrome complic-ated by left atrial appendage thrombus leading toperipheral arterial embolism and limb loss. Resolutionof the atrial thrombus was documented after remissionof the nephrotic syndrome and anticoagulation.

Case Report

A 65-year-old woman was admitted to our unit becauseof bilateral ankle swelling for 10 days. She had nohistory of intermittent claudication, heart or renaldiseases, nor any history of venereal exposure. Thefamily history was also unremarkable and she hadstopped smoking 4 years ago. On admission, apartfrom bilateral ankle oedema, physical examination wasnormal. Her blood pressure was 120/80 mmHg andexamination of the peripheral pulses and cardiovas-cular system was unremarkable. Her haemoglobin was12 g/dl and haematocrit 36%. She had heavy pro-teinuria (11.86 g/24 h), hyaline casts in urine, and a

Correspondence and offprint requests to: Dr Siu Ka Mak, Renal Unit,Department of Medicine, Kwong Wah Hospital, Waterloo Road,Kowloon, Hong Kong.

creatinine clearance of 87 ml/min/1.73 m2. Serum ureawas 6.1 mmol/1 (17.1mg/dl), serum creatinine75 umol/1 (0.85 mg/dl), albumin 13 g/1 (1.3 g/dl), andblood glucose 4.4 mmol/1 (79.3 mg/dl). Fasting serumcholesterol was 10.3 mmol/1 (398 mg/dl) and triglycer-ide 2.6 mmol/1 (231 mg/dl). The serum antinuclearantibody titre was less than 1:40. The C3 and C4complement levels and immunoglobulin levels (IgG,IgA, IgM) were within normal ranges. HBsAg andanti-HCV antibody were negative. She had a reactiveVenereal Disease Research Laboratory test at 1 in 4,and her fluorescent treponemal antibody-absorptiontest was subsequently found to be positive. A percutan-eous renal biopsy was performed.

The biopsy specimen contained 18 glomeruli, ofwhich one was sclerosed. The remaining showed diffusethickening of the capillary basement membrane andmoderately increased mesangial matrix. Argyrophilicspikes on the peripheral capillary walls were present.The tubular epithelium had abundant foamy cytoplasmin places and interlobular arteries showed moderateintimal thickening. Immunofluorescence examinationrevealed granular IgG, C3 and Clq deposition in themesangium and capillary basement membrane.Electron-microscopy study confirmed the presence ofnumerous subepithelial electron-dense deposits in theglomerulus characteristic of stage I membranous glom-erulonephritis.

Screening for malignancies including IgA antibodyagainst EB virus viral capsid antigen, alpha fetalprotein, carcinoembryonic antigen, stool for occultblood, chest X-ray and abdominal ultrasonographywere all negative. Her nephrotic syndrome respondedto diuretic treatment with an averaged daily urineoutput of 1.2 1 and weight loss of 0.5 kg/day. She wasstarted on prednisolone at 1 mg/kg/day. She was wellwhen followed-up at 1 week, but 2 weeks after dis-charge she was readmitted because of sudden onset ofleft leg pain. She still had mild ankle oedema despitelosing 10 kg in weight since onset. Her daily urineoutput was 1 1. The left leg was cold, cyanotic withblunted tactile sensation and absent dorsalis pedis andposterior tibial pulses. All other peripheral pulses werenormal and examination of the cardiovascular systemwas otherwise unremarkable. Her haematocrit was29% and platelet count 323 000/mm3. Serum urea was

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6.7mmol/l (18.8 mg/dl), serum creatinine 79 umol/1(0.89mg/dl) and albumin 15 g/1 (1.5g/dl). She stillhad 4.2 g/24 h proteinuria. Activated partial throm-boplastin time and prothrombin time were normal.Anticardiolipin antibody and lupus anticoagulantwere negative. Emergency arterial embolectomy wasperformed.

The left leg perfusion improved immediately post-operation but it deteriorated again 24 h later.Arteriogram was performed showing a blocked poplit-eal artery with absence of collaterals, suggestive ofembolization. 2D echocardiogram (Fig. 1) revealed ahyperechoeic mass at the left atrial appendage suggest-ive of an intracardiac thrombus. This was confirmedby transoesophageal echocardiography showing thethrombus with no stalk seen. The left atrium was notenlarged and no valvular lesion nor regional dyskinesiawas found. She was in sinus rhythm and no arrhythmiawas detected in the 24-h Holter ECG monitoring.She was started on heparin infusion and embolectomyrepeated 2 days after her first operation. An organizedclot at the popliteal artery was found and evacuatedwith a longitudinal arteriotomy at just below the kneelevel. However, poor back flow was obtained despitemultiple attempts of embolectomy down to the anklelevel. Histology of the clot section confirmed thediagnosis of fibrin thrombus. Postoperatively, her leftleg circulation improved but the forefoot remainedunder-perfused and she required a Syme's above-ankleamputation 16 days later.

Her recovery was complicated by wound infectionwith Pseudomonas aeruginosa which required stumprevision on day 21. Her prednisolone dosage wastherefore tapered down prematurely at 4 weeks ofhigh-dose treatment when she still had 3.2 g/24 h pro-teinuria. She was warfarinized to keep the Internationalnormalized ratio 1.5-2. She was also treated with acourse of penicillin for her positive syphilis serologyand the VDRL test became negative after treatment.

At 4 months after presentation, she was free fromoedema, her left lower limb stump was healthy and

S. K. Mak el al.

she could walk independently with her prosthesis. Herproteinuria had dropped to 2.7 g/24 h, her serum creat-inine was 68 umol/1 (0.77 mg/dl) and creatinine clear-ance 79ml/min/1.73 m2. She was on prednisolone15 mg alternate day and 1 mg warfarin daily. 2Dechocardiogram was repeated showing no intracardiacthrombus (Fig. 2). This resolution was confirmed bymagnetic resonance imaging, and all her drugs werestopped at 6 months. Her proteinuria was then0.14 g/24 h, serum creatinine 86 umol/1 (0.97 mg/dl)and creatinine clearance 106ml/min/1.73 m2. Hercoagulation inhibitor levels were checked only afteranticoagulation was stopped, they were all withinnormal limits (protein C 1.39I.U./ml (normal, 0.7-1.4), total protein S 0.77 I.U./ml (normal, 0.64-1.1),free protein S 0.3 I.U./ml (normal, 0.18-0.35) andantithrombin III 1.05 I.U./ml (normal, 0.8-1.2)).Factor VIII activity was 235% and factor IX activity154% (normal, 40-150%).

Discussion

Nephrotic syndrome has been associated with hyper-coagulability and an increased incidence of both venousand arterial thrombosis in adults and children. Whileapproximately half of the nephrotic children withthrombotic complications had arterial thrombosis, themajority of adult patients had venous thrombosis [1,2].The sites of arterial thrombosis reported in nephroticpatients include coronary, femoral, pulmonary, cereb-ral, mesenteric, renal, aortic, subclavian, and commoniliac arteries [3,4]. Intracardiac thrombosis has onlybeen reported in six paediatric patients including twofrom Egli's survey [1,2], but details of them were notavailable. Our patient, who developed left atrialappendage thrombus soon after the onset of nephroticsyndrome, is the first adult case of intracardiac throm-bosis described in the literature.

Apart from the nephrotic syndrome, our patient hadno other identifiable predisposing factors for the arter-ial thrombosis (e.g. use of oral contraceptives, pro-

Fig. 1. Regional expansion image of the parasternal short axis two-dimensional echocardiograin showing the thrombus at the left atrialappendage. LA, left atrium; LAA, left atrial appendage; RV, rightventricle.

Fig. 2. Repeat parasternal short axis two-dimensional echocardiog-ram showing disappearance of thrombus at the left atrial appendage.LA, left atrium; LAA, left atrial appendage; RV, right ventricle.


Intracardiac thrombus in nephrotic syndrome

longed immobility, malignancy). Screening for lupusanticoagulant, anticardiolipin antibody, and primaryhypercoagulable states related to deficiencies of coagu-lation inhibitors (antithrombin III, protein C and freeprotein S) were all negative. Moreover, intracardiacthrombus occurs almost exclusively in patients withvalvular heart disease, prosthetic heart valves, enlargedleft atrium, atrial fibrillation, or low cardiac outputstate [5]. None of these factors was present in ourpatient.

Nephrotic syndrome is associated with profoundchanges in the turnover and levels of many plasmaproteins, including the coagulation factors. The dysreg-ulated zymogens (especially Factors II, VII and X)[6], co-factors (Factors V and VIII) [6,7], and fibrino-gen levels [8], fibrinolytic system [1 ], coagulation inhib-itors [9,10], and platelet aggregation [11,12] have beenlinked to the hypercoagulable state in nephrotic syn-drome. It has been shown that all these disturbanceshave a general tendency to correlate with the degreeof hypoalbuminaemia [4,11,13]. Our patient belongedto the group with a serum albumin level below 15 g/1(1.5 g/dl) and therefore was more likely to be asso-ciated with profound changes in these regulatorysystems, and subsequently an increased risk of throm-boembolic complications.

Although there is no evidence that different mechan-isms are involved in venous and arterial thrombosis,the preponderance of coronary artery thrombosis inthose patients with hypercholesterolaemia [14] andfemoral artery thrombosis following local trauma [13]suggest the importance of local factors in arterialthrombotic events in nephrotic syndrome. However,these are not evident in our case.

In the context of an altered state of coagulation andfibrinolysis in nephrotic syndrome, immobilization andcontracted blood volume as a result of diuresis are themain precipitating factors for thromboembolic com-plications. Our patient had lost 10 kg in weight over 3weeks when she developed peripheral arterial embol-ism. Although she was then still having mild ankleoedema, intravascular contraction is probable in thepresence of hypoalbuminaemia. This is one of thepossible precipitating factors in her case, though thehaematocrit then was only 29%.

Whether she had recurrent embolization from theatrial thrombus or indeed had local propagation fromthe initial embolism, the fact that she was put onheparin and yet developed further peripheral arterialblockade reinforces the doubt on the usefulness ofheparin in nephrotic patients [1]. This stems from thefact that heparin also binds to a2-macroglobulin andinterferes with its action on thrombin. The net effectof heparin in the presence of a low concentration ofantithrombin III in nephrotic state may therefore beadverse in terms of thrombin antagonism.

Corticosteroids have been shown to raise the concen-tration of several clotting factors, especially factor III,and accelerate the prothrombin times and whole bloodclotting times [15]. However, corticosteroids alsodepress platelet function in vitro [16] and decrease

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fibrinolytic activity with incomplete breakdown of thethrombus [17], making its overall contribution tothromboembolic complications uncertain [18].

Although membranous nephropathy accounts formore than half of the adult patients with renal venousthrombosis [1], and is also the most common associ-ated glomerulopathy in reported cases of arterialthromboses in adult nephrotic patients [4], the exist-ence of a genuine independent association with throm-boembolic complications is still uncertain andunexplained.

Glomerular involvement is a relatively rare but well-described complication of congenital or secondaryacquired syphilis. Syphilitic nephropathy has also beenreported in latent syphilis [19]. Membranous glom-erulonephritis is the most common histological findingand the usual presentation is nephrotic syndrome,which tends to be transient, either undergoing spontan-eous remission or responding promptly to antisyphilitictherapy [20]. Antibody elution studies performed onrenal biopsy specimens had demonstrated the presenceof antitreponemal antibody within the glomerularimmune-complex deposits, suggesting the glomerulardeposition of treponemal antigen-antitreponemal anti-body complexes [20]. Our patient achieved partialremission of nephrotic syndrome 5 weeks after thepenicillin treatment despite the premature tailing downof the high-dose corticosteroids. Complete remissionwas documented 7 months after her VDRL becamenegative. The histology and clinical course are thereforecompatible with syphilitic nephropathy. However, thetypical findings of glomerular hypercellularity (due toendothelial and mesangial cell proliferation and thenumerous leukocytes) and 'humps' appearance ofsubepithelial electron-dense deposits associated withdiffusely fused epithelial cells foot processes [21] wereabsent in our patient. She might therefore be sufferingfrom a histologically milder form of the nephropathy,presenting with stage I membranous glom-erulonephritis.

In conclusion, our patient represents the first adultpatient to be described with the complication of leftatrial thrombus due to the hypercoagulable state asso-ciated with nephrotic syndrome. It resulted in peri-pheral arterial embolism with subsequent limb loss.Apart from the histology being membranous nephro-pathy, a quite severe nephrotic state, and a markeddiuresis, no other known predisposing factors waspresent. Upon achieving remission of the nephroticsyndrome, together with adequate anticoagulation, thepatient had complete resolution of the atrial thrombus.Although it has been consistently found that Chinesehave a low incidence of venous thrombosis after strokeor postoperation [22,23], the presence of 'risk factors'of a low serum albumin level and a histology ofmembranous glomerulonephritis would lead one toconsider anticoagulation. The question of whether togive all nephrotic patients prophylactic warfarinremains unanswered and awaits a prospective trial orthe development of a reliable haemostatic marker topredict the risk.


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Received for publication: 10.3.96Accepted: 22.3.96
