Coagulopathy in a patient with nephrotic syndrome

A 55-year-old Caucasian woman presented with a 5-week history of increasing lower limb edema associated with a two-pound daily weight gain. She was feeling well otherwise; she denied shortness of breath, chest discomfort, recurrent headaches, myalgia, arthlagia, or constitutional symptoms. She had respiratory infection 4 months before, but the infection has resolved. The patient presented with peripheral edema. The differential diagnosis includes right-sided heart failure, liver cirrhosis, nephrotic syndrome, drug-induced edema, and lymphoedema. Her preceding upper respiratory tract infection suggests postinfectious cardiac or renal pathology. The patient did not have any prior bleeding episode. The medical history was significant for Graves' disease treated with radioactive iodine ablation. The only medication was daily thyroid supplementation. She was married and had two uncomplicated pregnancies. She was a lifelong nonsmoker. She denied any alcohol intake or illicit drug use. She was a pharmacist without any known exposure to toxic chemicals. On examination her vital signs were normal. She was not in any distress. Examination of her legs revealed bilateral pitting peripheral edema up to the knee level. There was no jaundice, lymphadenopathy, or bleeding sign. Her cardiac examination was normal and her jugular venous pressure (JVP) was not elevated. Respiratory examination was normal with no crackles on auscultation. Abdominal examination revealed no palpable hepatosplenomegaly or ascites. The fact that this patient was not on any medication other than long term thyroid supplement makes drug-induced edema unlikely. The finding of normal JVP on clinical examination is against the diagnosis of heart failure. Lymphedema is typically nonpitting. Thus, the most likely differential diagnosis includes nephrotic syndrome and early liver cirrhosis. Patient's hemoglobin level was 19.0 g/dL (normal 11.5–16.5 g/L), platelet count 305,000/mm3 (normal 150,000–400,000/mm3). The blood urea nitrogen was 14.4 mg/dL (normal 7.0–18.0 mg/dL), creatinine 0.93 mg/dL (normal <1.5 mg/dL), albumin 2.0 g/dL (normal 3.5–5.5 g/dL), cholesterol 587 mg/dL (normal <200 mg/dL), and triglyceride 447.1 mg/dL (normal <160 mg/dL). The results of liver function tests were normal. Urinalysis revealed 1+ blood, 3+ protein, and granular casts. Twenty-four hour urine protein excretion was 15,000 mg/d. The combination of heavy proteinuria, minimal hematuria, hypoalbuminemia, and hypercholesterolemia suggests nephrotic syndrome. Nephrotic syndrome may be associated with primary kidney disease, such as minimal change disease, focal segmental glomerulosclerosis, and membranous nephropathy. Systemic diseases including diabetes mellitus, systemic lupus erythematosus, amyloidosis, or Fabry's disease also cause nephrotic syndrome. International normalized ratio (INR) was increased to 2.6 and activated partial thromboplastin time (aPTT) was prolonged to 68 s but thrombin clotting time was normal.Clauss fibrinogen level was slightly elevated at 480 mg/dL (normal range 200–400 mg/dL). D-dimer level was not elevated. In general, patients with nephrotic syndrome are in a hypercoagulable state because of urinary loss of antithrombin III and enhanced platelet reactivity, but this patient's coagulation tests were paradoxically prolonged although there was no bleeding symptom. Simultaneous prolongation of both INR and aPTT suggests common coagulation pathway abnormalities like liver dysfunction, vitamin K deficiency, disseminated intravascular coagulopathy (DIC), primary fibrinolysis or post-thrombolytic therapy. However, the normal thrombin clotting time and borderline high fibrinogen level make abnormalities in the conversion pathway of fibrinogen to fibrin less likely. Normal fibrinogen and D-dimer level are atypical for DIC. A deficiency of multiple coagulation factors in both intrinsic and extrinsic coagulation pathways commonly occurs in vitamin K deficiency or hepatic dysfunction. However, 48 hr after administration of 5 mg oral vitamin K, the coagulation indices remained prolonged with an INR at 2.6 and aPTT at 63 s. To further define the causes of coagulopathy, clotting factor levels were assayed individually. Factor II level was high at 166%, factor VII 179%, but factor VIII:C was low at 7%, factor X 3%, whereas factor XII level was borderline low at 47%. (Normal range of these clotting factors was 50–150%). Although acquired factor XII deficiency has been reported in patients with nephrotic syndrome [1], deficiency of multiple coagulation factors suggests acquired conditions, either due to insufficient production or excessive consumption. Coagulation factors II, V, VII, IX, X, XI, and XII are synthesized in the liver, and in addition factor VIII also undergoes extra-hepatic synthesis. This patient has decreased levels of factor X, XII, and VIII, but the borderline high levels of factors II and VII argues against hepatic coagulopathy. In addition, liver function tests were normal. Low level of factor VIII can be due to coexisting von Willebrand disease, but this patient did not have any past or present history of bleeding. Factor VIII can be low for a variety of preanalytical reasons, including clotting in the specimen, precipitation of factor VIII during specimen transportation as whole blood, prolonged storage, or repeated freezing/thawing. However, these preanalytical issues do not usually cause markedly low factor VIII as is seen in this case. DIC can also decrease factor VIII, but the normal D-dimer is against this possibility. Among the coagulation factors, factor X level was the lowest. Acquired factor X deficiency in the absence of other factor deficiency is rare, but it can occur with systemic amyloidosis. Serum protein electrophoresis with immunofixation revealed free monoclonal lambda light chains; the levels of free kappa light chain was 12.5 mg/L (normal 3.3–19.4 mg/L), free lambda level 40.7 mg/L (normal 5.65–26.25 mg/L) with a κ/ι ratio of 0.307 (normal 0.25–1.65). IgM level was normal at 89 mg/dL (normal 41–207 mg/dL); both IgA and IgG were low at 62 mg/dL (normal 70–352 mg/dL) and 77 mg/dL (635–1465 mg/dL), respectively. Bone marrow aspirates showed normal lymphocyte population. Flow cytometry of marrow showed polyclonal B and T cells. Although the number of plasma cell was not increased (2%), these cells expressed CD138+, CD19- and lambda light chain suggesting monoclonal plasma cell dyscrasia. Abdominal fat pad biopsy was negative for Congo red stain. Bone marrow biopsy showed small blood vessels with eosinophilic deposits, which was stained positive with Congo red and green birefringent on polarization (see Fig. 1). Imunohistochemistry stain for AA was negative; thus, the amyloid deposit in the blood vessel was most likely AL type. Micrograph demonstrating a small perivascular amyloid deposit (arrow) with congo red staining in a bone marrow biopsy. Shown at x400 original magnification. Amyloid protein refers to a family of 15–20 precursor proteins that polymerizes to form insoluble amyloid fibrils. These fibrils share a characteristic secondary structure, a β-pleated sheet conformation, thus allowing them to bind Congo red dye. Congo red stain is the most widely used histochemical stain to differentiate amyloid from other hyaline deposits, such as collagen, fibrin. Under ordinary light microscope, the Congo red stain imparts a red color to tissue deposits. However, under polarizing microscopy, the deposits show apple green birefringence, which is diagnostic of amyloid. This green appearance is due to β-pleated sheet conformation so that Congo red dye refracts the light from the polarizing microscope. In this case, immunohistochemical staining for amyloid A (AA) protein was negative. Serum AA protein is an acute phase protein synthesized in the liver; it is associated with chronic inflammation. In contrast, because immunohistochemical staining for amyloid proteins other than AA type is usually unreliable, the diagnosis of AL amyloidosis is by exclusion. The causative protein of AL amyloidosis is immunoglobulin light chains or light-chain fragments produced by clonal plasma cells. In a case series, 9.7% of patients with non-AA amyloidosis were found to have amyloidogenic mutations [2]. Some mutations have low penetrance; therefore, absence of a family history cannot rule out hereditary systemic amyloidosis. It is important to look for a genetic cause in the cases when AL-amyloidosis cannot be confirmed with definite tests. The management and prognosis are dependent on the characterization of these causative amyloid proteins. The patient was referred for assessment of autologous stem cell transplant. Given the patient's coagulopathy, this procedure would be exceedingly risky. Therefore, chemotherapy was preferred. To date, the patient has received five cycles of melphalan and dexamethasone. Although serum free light chains have normalized (free kappa level 10.5 mg/L, free lambda level 8.5 mg/L, with a κ/ι ratio of 1.23) factor X levels remain low at 6%. Amyloidosis is characterized by extracellular deposition of insoluble fibrils in organs and tissues. Over 20 precursor proteins have been identified as components of amyloid fibrils [3]. In AL-amyloidosis, amyloid fibrils consist of monoclonal immunoglobulin light chains forming β-pleated sheets. The accumulation of amyloid fibrils in organs results in progressive structural and functional damages. Up to 85% of patients with amyloidosis have one or more abnormal coagulation tests [4]. Five cohort series of patients with systemic amyloidosis were found using Medline© search [4-8], and the number of patients with abnormal coagulation tests were pooled (Table I). Prolonged thrombin clotting times and reptilase times are the most common coagulation abnormalities in AL-amyloidosis [4, 6]. Both thrombin clotting time and reptilase time measure the conversion of fibrinogen to fibrin. Generally, the causes of prolonged thrombin clotting time and reptilase time may include reduced fibrinogen concentration, dysfibrinogenemia or presence of inhibitor. Patients with AL-amyloidosis generally have normal fibrinogen level. Elevated fibrinogen level from an acute phase reaction can cause a prolonged reptilase time but thrombin time is typically normal [9]. In contrast, heparin or direct thrombin inhibitors such as argatroban, hirudin, and bivalirudin prolong the thrombin time but not the reptilase time. Increased primary fibrinolysis has been reported in patients with systemic AL-amyloidosis [10]. Endothelium damaged by amyloid protein may release plasminogen activator [10]. Alternatively, amyloid fibrils selectively adsorb fibrinolysis inhibitory factor(s), thus increases fibrinolysis [10]. Vascular infiltration by amyloid fibrils also prolong bleeding time and increase capillary fragility [11]. Acquired factor deficiencies have been reported in patents with AL-amyloidosis and less so with other types of amyloidosis [12]. In patients with amyloidosis, factor X deficiency is the most commonly reported factor deficiency [5], with a frequency between 7% [7] and 14% [8]. Among the patients with acquired factor X deficiency, over two-thirds have systemic amyloidosis [13]. Of 368 patients with factor X deficiency, majority had prolonged INR and less than one third had prolonged aPTT [5]. However, neither INR nor aPTT correlated well with the factor X levels [5]. Deficiencies of other coagulation factor deficiencies may coincide; these include factor IX deficiency [14], factor XII deficiency [15], von Willebrand factor deficiency [16], and factor V deficiency [17]. The mechanisms for coagulation factor deficiency in systemic AL-amyloidosis are likely multifactorial. One of the proposed mechanisms is adsorption of coagulation factors to amyloid deposits [13, 18]. When 131I-labeled factor X was infused in a patient with AL-amyloidosis; the rapid disappearance of labeled factor X in the plasma was not explained by rapid degradation or urinary excretion, but by immobilization in the vasculature [18]. When investigators evaluated the amyloid load and correlated with the degree of coagulopathy, the results were conflicting. 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 [8]. Splenectomy may correct factor X deficiency [19, 20]. Although splenectomy removes the bulk amyloid protein, this procedure also arrests the progress of underlying disease leading to normalization of factor X level. Admittedly, factor X deficiency in patients with systemic amyloidosis is not caused by hepatocellular dysfunction because the levels of other hepatic coagulation factors are normal. Furthermore, factor X deficiency has been reported in cases with minimal hepatic involvement [13]. Majority of the bleeding manifestations in patients with systemic AL-amyloidosis are mild to modest [4, 21]. Bleeding manifestations include easy bruising, spontaneous ecchymosis, purpura or bleeding from mucosal membranes [10]. Choufani et al. found that significant bleeding events occurred in 56% of patients with systemic amyloidosis, and 75% of patients with factor X deficiency [5]. However, in another case series, factor X level was not associated with postprocedural bleeding [21]. Generally, renal biopsy is avoided in patients with amyloidosis and abnormal coagulation indexes because of noncompressible bleeding site and amyloid angiopathy. Nevertheless, one retrospective study found that the postrenal biopsy bleeding rate was not increased in patients with amyloidosis [22]. Although coagulopathy is commonly reported in patients with systemic amyloidosis, thromboembolic complications also occur [23]. The treatment of patients with amyloidosis and coagulopathy involves supportive measures, but the coagulopathy generally does not respond well to vitamin K or plasma infusion [11, 18]. Level of factor X may improve spontaneously [24], or increase after treatments such as plasma exchange [25], melphalan and prednisone [26], splenectomy [19, 20], or autologous stem cell transplantation [5]. Our patient had AL-amyloidosis confirmed with immunohistochemical stains and monoclonal plasma cells in bone marrow examination. This patient also had prolonged INR and aPTT with combined deficiencies of factor X, XII, and VIII. The mechanisms for coagulopathy in patients with systemic amyloidosis is likely multifactorial.

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