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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2008  |  Volume : 19  |  Issue : 1  |  Page : 137-141
Amyloidosis and Vascular Thrombosis

Department of Medicine, King Fahad Medical City, Riyadh, Saudi Arabia

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Amyloidosis is a rare systemic disorder of protein metabolism with progressive extra­cellular deposition of insoluble fibrillary protein, disorganization of tissue architecture, and subsequent organ dysfunction. Primary amyloidosis is the most common form of this disorder, however, it can develop secondary to plasma cell dyscrasias such as multiple myeloma (MM); 10-15% of MM patients may develop amyloidosis of vital organs. Amyloidosis is usually associated with bleeding, but less commonly with thrombosis. We present a 52-year-old Saudi female with amyloidosis secondary to multiple myeloma. She presented with both venous and extensive arterial thrombosis. Although relatively rare, plasma cell dyscrasias such as amyloidosis and multiple myeloma could present with thrombotic rather than hemorrhagic complications.

Keywords: Amyloidosis, multiple myeloma, plasma cell dyscrasias, thrombosis

How to cite this article:
Adamu B. Amyloidosis and Vascular Thrombosis. Saudi J Kidney Dis Transpl 2008;19:137-41

How to cite this URL:
Adamu B. Amyloidosis and Vascular Thrombosis. Saudi J Kidney Dis Transpl [serial online] 2008 [cited 2021 Jun 24];19:137-41. Available from: https://www.sjkdt.org/text.asp?2008/19/1/137/37454

   Introduction Top

Amyloidosis (AL) is a rare systemic disorder of protein metabolism with progressive extra­cellular deposition of insoluble fibrillary pro­tein, disorganization of tissue architecture, and subsequent organ dysfunction. [1] Primary AL is the most common form of this dis­order, however, it can develop secondary to plasma cell dyscrasias such as multiple mye­loma (MM); 10-15% of MM patients may develop amyloidosis of vital organs. AL is usually associated with bleeding, but less commonly with thrombosis.

   Case Presentation Top

A 52-year-old Saudi female was admitted on May 21 st , 2007 with chief complaint of pain in both legs for five months prior to presentation. The pain was dull aching maximally at the calves. It was induced initially only while walking, but progressed to pain at rest one week prior to admission. In addition, the patient had history of painless swelling of both feet 2 months prior to presentation, however, she observed no swelling in other parts of her body. She noted frothiness of the urine for about the same duration, but without other urinary symptoms. Review of the systems was unremarkable but for history of dyspepsia and menopause. There was no other personal or family history of any recurrent or chronic medical illnesses.

General and systemic physical examina­tions of the patient at presentation were unremarkable, except for the lower limbs, where she had absent pulsations at the femoral, popliteal, and posterior tibial arteries bilaterally, as well as absent left dorsalis pedis artery pulsation. The lower limb circum­ference at tibial tuberosity was 32 cm on the right and 30 cm on left. The initial working diagnosis was peripheral vascular disease and deep venous thrombosis. We assessed the patient for hypercoagulable causes particularly occult malignancy and anti­phospholipid antibody syndrome.

Baseline laboratory investigations revealed essentially normal blood count, coagulation profile, renal and liver functions, and lipid profile. Albumin blood level was 24 g/L. Urine dipstick revealed proteinuia 3+ and blood 2+. Urine microscopy revealed 8 red cells per high power field, but no significant pyuria or casts. 24-hour urine protein was 6.12 g/day. C-reactive protein was very high at presentation, 9027 mg/L (reference range 0- 5.99).

Doppler ultrasound revealed a totally occluded abdominal aorta (below the renal arteries), bilateral common iliac arteries, as well as proximal parts of the femoral arteries. There was evidence of right femoral vein thrombosis. Runoff aortogram [Figure - 1] revealed complete occlusion of the abdominal aorta below renal arteries, as well as bilateral iliac and femoral arteries with reconstitution of the femoral arterial blood flow distally through collaterals.

Tumor markers such as CA-125, carcino­embryonic antigen (CEA), alphafetoprotein were negative. Screening for inherited thrombophilia such as activated protein C resistance (Factor V Leiden), and prothrombin 20210 gene mutation were all negative. Anti­phospholipid antibodies were negative. Protein S and protein C levels were normal. Plasma homocystein level was marginally elevated, 17.9 µmol/L (reference range 5­13). Hepatitis B and C screenings were negative. Antinuclear antibody and antineutrophil cytoplasmic antibodies were negative.

A bone marrow aspiration revealed a hyper­cellular marrow (90%) with increased plasmacells. The percentage of plasma cells was not determined because of inadequate amount of bone marrow necessary for accurate assessment. Serum protein electrophoresis revealed no monoclonal band. Urine protein electrophoresis and immunofixation was positive for Bence Jones protein type kappa.

A kidney biopsy revealed normal glome­rular cellularity with rare amorphous material [Figure - 2]. The tubules were normal, but with rare tubular casts. Immunofluorence study was negative for IgG, IgA, fibrinogen and C3, but IgM staining revealed periarteriolar pattern. Congo red stain was positive for amyloid deposits [Figure - 3], and immuno­fluorescence confirmed their presence by the apple green birefringence [Figure - 4].

Echocardiography revealed features sugges­tive of infiltrative cardiomyopathy with a restrictive pattern and severe biventricular dysfunction with ejection fraction about 30%. Nerve conduction studies revealed generalized sensorimotor polyneuropathy predominantly axonal with possible myopathy. An upper gastrointestinal endoscopy revealed a 2 x 3 cm submucosal antral mass.

The patient was diagnosed as AL secondary to multiple myeloma, and was started on heparin because of arterial and venous throm­bosis. In addition, she was treated with melphalan 8 mg daily and prednisoline 100 mg daily administered for 5 days every 4 to 6 weeks for 6-8 cycles. She was prescribed lisinopril 5 mg daily and gabapentin 400 mg thrice a day. At her most recent clinic visit, she revealed clinical improvement with less pain and better ambulation.

   Discussion Top

Although primary AL could explain most of the clinical findings in the patient presented above, the finding of fractured intratubular casts is a characteristic of myeloma kidney and not a feature of amyloidosis. The finding of kappa type Bence Jones protein is also more common in MM, as the detectable M­protein in primary AL patients consists of lambda light chains in 70% of cases. [1]

Coagulation problems in AL are clinically associated with bleeding, mostly factor X abnormalities, while thrombosis is a less common feature of the disease. [2] Our patient represents this rarity by developing arterial and venous thrombosis. Many putative factors have been implicated in the patho­genesis of thrombosis in paraproteinemias. [3] A malignancy associated thrombophilic state, particularly the cytokine induced elevated levels of factor VIII and von Willebrand factor, has been implicated in the patho­genesis of the coagulopathy. Although the levels of factor VIII and von Willebrand factor have not been assayed in this patient, this could play a role, since this patient revealed very high levels of C-reactive protein at presentation. C-reactive protein is a down­stream target of interleukin 6, therefore, it could be an indirect evidence of elevated levels of this cytokine.

Another factor implicated in the patho­genesis of thrombosis in the paraproteinemias, though excluded in this patient, is an abnor­mally high plasma level of immunoglobulin and associated hyperviscosity. [4] Deficiency of natural anticoagulants (protein S and C) may also be thrombogenic. Although protein S and C levels were normal in this patient, this does not exclude functional deficiency, as this has been reported in patients with MM. [3] A potential prothrombotic factor in this patient is nephrotic syndrome, which is a well recognized risk factor for thrombosis. [5] Among the various causes of nephrotic syndrome, some types are particularly asso­ciated with a definite increase in risk of throm­bosis; membranous nephropathy, membrano­proliferative glomerulonephritis, minimal change disease, and possibly renal amyloidosis as in this patient. [5],[6] very low levels of serum albumin seems to be a surrogate measure of increased risk, however, thrombo­embolism may develop even with a modest decrease of this parameter.

Surgical intervention was not contemplated for the arterial thrombosis because the patient revealed adequate collateral circulation and improved on medical therapy.

This patient posed management challenges. Hematopoietic cell transplantation (HCT), which would have allowed use of high dose melphalan, was contraindicated in her be­cause of low cardiac ejection fraction around 30%. [7] Alternative newer agents such as thalidomide are also unsuitable for this patient because of neuropathy, which was reported to occur in up to 80% of patients on prolonged therapy. [8] Lenalidomide, an immuno­modulatory derivative of thalidomide, may be a better choice. The proteasome inhibitor, bortezomib, is a newer agent that demons­trates significant activity in a number of refractory hematological and solid malign­nancies, including multiple myeloma. [9]

There is paucity of data on AL and its prevalence in Saudi Arabia. In a clinico­pathologic study of the patterns of glome­rular diseases in Saudi Arabia (1989 - 1994), Mitwalli et al reported no AL cases. [10] The index case in this presentation represents AL secondary to MM in a Saudi patient.

In conclusion, although rare, amyloidosis can be secondary to multiple myeloma and patients can present with thrombotic rather than hemorrhagic complications. The diag­nosis of plasma cell dyscrasias should be in the differential diagnosis in any patient who presents with a thrombotic state.

   Questions Top

Dr. Akram Askar (chairman of the club, King Khaled University Hospital): the presentation is open to discussion.

Audience: Can stem cell transplantation change the prognosis if the patient has renal function impairment or failure?

Speaker: we prefer not to subject the patients with MM and acute renal failure to trans­plantation and usually we start with steroids.

Audience: What about the role of plasma­pheresis in MM associated with renal failure?

Speaker: There is no role for plasma­pheresis if MM is associated with AL. Even for multiple myeloma alone we found borderline benefit of plasmapheresis.

Dr. Askar: What the exact role of thalido­mide in the management of MM?

Speaker: Thalidomide has become the first choice for therapy for MM. It does not adversely affect stem cell transplantation as melphalan. So, beside its anti-inflammatory effects, it has less untoward side effects.

Speaker: Lastly, I would like to comment on the heparin use in this case. We avoided the use of warfarin because the GI problems in the patient and the multiple drugs she was on for her original disease. We preferred the injectable anticoagulation with heparin because of better control due to its short­acting property.

   References Top

1.Muller AM, Geibel A, Neumann HP, et al. Primary (AL) amyloidosis in plasma cell disorders. Oncologist.2006;11(7):824-30.  Back to cited text no. 1    
2.Srkalovic G, Cameron MG, Deitcher SR, Kattke-Marchant K, Hussein MA. Incidence and risk factors of venous thrombo­embolism (VTD) in patients with amyloidosis. Int Semin Surg Oncol 2005;2:17.  Back to cited text no. 2  [PUBMED]  [FULLTEXT]
3.Zangari M, Elice F, Tricot G. Hemostatic dysfunction in paraproteinemias and amyloidosis. Semin Thromb Hemost 2007; 33(4):339-49.  Back to cited text no. 3    
4.O'kane MJ, Wisdom GB, Desai ZR, Archbold GP. Inhibition of fibrin monomer polymerization by myeloma immunoglobulin. J Clin Pathol 1994;47(3):266-8.  Back to cited text no. 4    
5.Richard JG. Prophylactic anticoagulation in nephrotic syndrome: A clinical conundrum. J Am Soc Nephrol 2007;18(8):2221-5.  Back to cited text no. 5    
6.Singhal R, Brimble KS. Thrombo-embolic complications in the nephrotic syndrome: Pathophysiology and clinical management. Thromb Res 2006;118(3):397-407.  Back to cited text no. 6    
7.Dispenzieri A, Lacy MQ, Kyle RA, et al. Eligibility for hematopoietic stem-cell transplantation for primary systemic amyloidosis is a favorable prognostic factor for survival. J Clin Oncol 2001;19(14): 3350-6.  Back to cited text no. 7    
8.Kyle RA, Rajkumar SV. Treatment of relapsed or resistant multiple myeloma. Up Todate 15.3. 2007.  Back to cited text no. 8    
9.Armand JP, Burnett AK, Drach J, Harousseau JL, Lowenberg B, San Miguel J. The emerging role of targeted therapy for hematologic malignancies: Update on bortezomib and tipifarnib. Oncologist 2007;12(3):281-90.  Back to cited text no. 9    
10.Mitwalli AH, Al Wakeel JS, Al Mohaya SS, et al. Pattern of glomerular disease in Saudi Arabia. Am J Kidney Dis 1996; 27 (6):797-802.  Back to cited text no. 10    

Correspondence Address:
Bappa Adamu
Nephrology Division, Department of Medicine, King Fahad Medical City, P.O. Box 59046, Riyadh 11525
Saudi Arabia
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PMID: 18087144

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  [Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4]

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