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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2020  |  Volume : 31  |  Issue : 2  |  Page : 545-548
Coagulopathy in the nephrotic syndrome

Department of Nephrology, Rajagiri Hospital, Aluva, Cochin, Kerala, India

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Date of Submission22-Apr-2019
Date of Acceptance01-Jun-2019
Date of Web Publication09-May-2020


Coagulopathy in the nephrotic syndrome (NS) is very rare. Simultaneous prolongation of both prothrombin time and activated partial thromboplastin time suggests common coagulation pathway abnormality such as liver dysfunction, Vitamin K deficiency, disseminated intravascular coagulation, or primary fibrinolysis. This results in difficulty in proceeding with renal biopsy and tissue diagnosis. We report one such case of NS with coagulopathy and refractoriness to correction with blood products, which led us to make a diagnosis of AL amyloidosis, which was confirmed with abdominal fat pad biopsy and other work-up.

How to cite this article:
Simon SP, Thomas J. Coagulopathy in the nephrotic syndrome. Saudi J Kidney Dis Transpl 2020;31:545-8

How to cite this URL:
Simon SP, Thomas J. Coagulopathy in the nephrotic syndrome. Saudi J Kidney Dis Transpl [serial online] 2020 [cited 2022 Jan 28];31:545-8. Available from: https://www.sjkdt.org/text.asp?2020/31/2/545/284035

   Introduction Top

Venous and arterial thrombosis in nephrotic syndrome (NS) is well known, but coagulo- pathy is rare. In NS, simultaneous prolongation of prothrombin time (PT) and activated partial thromboplastin time (aPTT) indicate the involvement of intrinsic and extrinsic pathways or common pathways, and rarely, this can be due to AL amyloidosis. Coagulopathy in AL amyloidosis is most commonly due to factor X deficiency, and it is due to the adsorption of clotting factors into amyloid fibrils. Even though acquired coagulation factor deficiency is very well reported in AL amyloidosis, it is rarely reported as one of the presenting features in association with NS.

   Case Report Top

Informed consent was obtained from the patient before publishing the case.

Our patient, a 72-year-old lady with no comorbidities was admitted for evaluation of slowly progressive swelling of both legs over few months associated with dyspeptic symptoms. She had anasarca, normal blood pressure, and no other significant systemic findings. Her preliminary investigations were suggestive of NS with urine protein creatinine ratio of 12, with benign sediments. Her serum protein was 55 g/L with albumin 11 g/L with mild renal dysfunction (blood urea 16.42 mmol/L and creatinine 145 pmol/L), total cholesterol was 6.6 mmol/L and corrected calcium was 2.45 mmol/L. Her hemoglobin was 135 g/L with a normal platelet count.

We planned her for renal biopsy. However, she had persistently elevated coagulation parameters (PT/INR was 1.9 and aPTT 42s), despite correction with fresh frozen plasma and Vitamin K. Even though her D dimer was mildly elevated, fibrinogen was not decreased (759 ng/mL and 344 mg/dL, respectively), hence we ruled out disseminated intravascular coagulation. She also had high alkaline phos- phatase and gamma-glutamyl transpeptidase (530 U/L and 281 U/L) with normal alanine aminotransferase and aspartate aminotrans- ferase. As a part of the evaluation for NS in the elderly, we did tumor markers. Her CA19-9 and CA125 were mildly elevated with normal carcino embryonic antigen. Computed tomography of the abdomen did not reveal any evidence of intra-abdominal malignancy. We were not able to proceed with renal biopsy due to persistent coagulopathy.

In view of persistent coagulopathy refractory to correction, we thought of the possibility of amyloidosis, and work-up showed suspicious M band in serum electrophoresis and high free light chain ratio of 8.68 (kappa 308 and lambda 35.5) with very high BNP values (>25,000 pg/mL). Hence, we planned for abdominal fat pad biopsy, which showed Congo red positive eosinophilic fibrils with apple-green birefringence on polarising microscopy and no plasma cell infiltrates [Figure 1] and [Figure 2]. IHC kappa Lambda staining was inconclusive. Bone marrow study showed only 6% plasma cells with cellular marrow with erythroid hyperplasia with focal kappa restricted amyloid deposits [Figure 3] and [Figure 4]. Echo-cardiogram showed concentric left ventricular hypertrophy with LVOT obstruction and grade 3 diastolic dysfunction.
Figure 1: Abdominal fat pad biopsy showing stratified squamous epithelium with underlying fibrocollagenous tissue, no atypical cells and no plasma cell infiltrate.

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Figure 2: Abdominal fat pad biopsy showing Congo red positive eosinophilic fibrils which showed apple-green birefringence on polarising microscopy.

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Figure 3: Congo red staining of bone marrow showing focal amyloid deposit.

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Figure 4: Bone marrow study showing hypercellular marrow with polyclonal plasmacytosis.

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She was referred for hematology opinion for further management and was started on chemotherapy (cybordex). Subsequently she was doing good on medications, NS and coagulopathy were under control; in addition, her alkaline pho- sphatase level showed a declining trend.

   Discussion Top

The association between NS with intravas- cular coagulation and thromboembolic disease is a well-known entity. However, coagulopathy in NS is less well recognized.[1]

The NS is associated with amyloidosis and rarely can have coagulopathy. Up to 85% of patients with amyloidosis have one or more abnormal coagulation tests.[2] Prolonged thrombin time and reptilase time are the most common coagulation abnormalities in AL-amyloidosis.[2],[3] Increased primary fibrinolysis has been reported in patients with systemic AL-amyloidosis. Endothelium damaged by amyloid protein may release plasminogen activator. Also, amyloid fibrils selectively adsorb fibrinolysis inhibitory factors, thus increasing fibrinolysis. Vascular infiltration by amyloid fibrils also prolong bleeding time and increase capillary fragility.[4]

Acquired factor deficiencies have been reported in patients with AL-amyloidosis and rarely with other types of amyloidosis. In patients with amyloidosis, factor X deficiency is the most commonly reported, with a frequency between 7% and 14%. Rarely factor IX and 11 deficiency also occur in AL amyloidosis.

Combined deficiency of blood clotting factors IX and X is also reported in systemic amyloi- dosis. This unique deficiency state is marked by refractoriness to Vitamin K as well as to transfusion therapy. Majority of the bleeding manifestations in patients with systemic AL- amyloidosis are mild to modest. Bleeding manifestations include easy bruising, spontaneous ecchymosis, purpura, or bleeding from mucosal membranes.

Factor X is a coagulation factor involved in both the intrinsic and extrinsic pathways, explaining the prolongation of PT and aPTT. However, factor X levels do not correlate with the magnitude of prolongation of these coagulation parameters. Furthermore, in factor X deficiency due to AL amyloidosis, the factor levels may not be the major determinant of bleeding complications or their severity, since these patients may have other hemostatic defects.

The mechanisms for coagulation factor deficiency in systemic AL-amyloidosis are multi- factorial. It is hypothesized that the Vitamin K dependent factors have a special affinity for amyloid deposits due to an unusual amino acid (gamma-carboxyglutamic acid) present in these factors and gets adsorbed into it. Mumford et al found that hepatic amyloid deposit was associated with prolongation of thrombin time, although whole-body amyloid load was not associated with the prolongation of INR or aPTT.[5] Hepatic synthetic defect or urinary protein losses due to NS are not causes of the factor X deficiency. Furthermore, increased anti-thrombin activity corresponded in time to the emergence of monoclonal IgG kappa light chain paraprotein.[6]

Treatment of factor X deficiency associated with AL amyloidosis is difficult. Replacement with prothrombin complexes and plasma may not be yielding as the factor X in these products would get adsorbed onto the amyloid and thus, be removed from the circulation quickly. Recombinant factor VIIa and plasma exchange have been reported to be successful. By removing a considerable burden of amyloid, splenectomy has been shown to improve the coagulopathy. Finally, treating the underlying disease with chemotherapy and stem cell transplantation can lead to an improvement in factor X levels.[7]

Our case is interesting due to the rarity of its presentation as coagulopathy with NS and the difficulty in making a tissue diagnosis for NS due to persistent and refractory coagulopathy, which made us to think of the possibility of amyloidosis.

Additionally, our case highlights key diagnostic and therapeutic challenges and strategies: (1) work up to establish a unifying etiology for both NS and the bleeding disorder; (2) decision making to obtain a tissue biopsy, select the site of biopsy and understand the relative yields for each site; (3) recognizing the risk and managing peri-procedural bleeding; and (4) developing a treatment strategy with the lowest risk of possible complications.

   Conclusion Top

NS secondary to amyloidosis is common, but coagulopathy in NS is rarely seen. We report one such case with NS with no obvious features to suspect amyloidosis other than coagulopathy. We encountered difficulty to proceed with renal biopsy and hence made a diagnosis with abdominal fat pad biopsy.

Conflict of interest: None declared.

   References Top

Greipp PR, Kyle RA, Bowie EJ. Factor-X deficiency in amyloidosis: A critical review. Am J Hematol 1981;11:443-50  Back to cited text no. 1
Gamba G, Montani N, Anesi E, et al. Clotting alterations in primary systemic amyloidosis. Haematologica 2000;85:289-92  Back to cited text no. 2
Gastineau DA, Gertz MA, Daniels TM, Kyle RA, Bowie EJ. Inhibitor of the thrombin time in systemic amyloidosis: A common coagulation abnormality. ' Blood 1991;77:2637-40  Back to cited text no. 3
Liebman H, Chinowsky M, Valdin J, Kenoyer G, Feinstein D. Increased fibrinolysis and amyloidosis. Arch Intern Med 1983;143:678- 82  Back to cited text no. 4
Mumford AD, O’Donnell J, Gillmore JD, Manning RA, Hawkins PN, Laffan M. Bleeding symptoms and coagulation abnormalities in 337 patients with AL-amyloidosis. Br J Haematol 2000;110:454-60  Back to cited text no. 5
McPherson RA, Onstad JW, Ugoretz RJ, Wolf PL. Coagulopathy in amyloidosis: Combined deficiency of factors IX and X. Am J Hematol 1977;3:225-35  Back to cited text no. 6
Manikkan AT. Factor X deficiency: An uncommon presentation of AL amyloidosis. Ups J Med Sci 2012;117:457-9.  Back to cited text no. 7

Correspondence Address:
Sneha P Simon
Department of Nephrology, Rajagiri Hospital, Aluva, Cochin, Kerala
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DOI: 10.4103/1319-2442.284035

PMID: 32394933

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


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