A 55-year-old Caucasian woman presented with a 5week 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 druginduced 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/mm (normal 150,000– 400,000/mm). 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 11 blood, 31 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
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Open Access
May 1, 2021
Katrina A Williamson + 2
