A 57-year-old immigrant from Nigeria presents to the emergency department for sudden, severe pain and swelling in her lower extremity. She was at a rehabilitation hospital when her symptoms started. The patient has a medical history of obesity, diabetes, bipolar disorder, and tonic-clonic seizures. Her current medications include metformin, insulin, lisinopril, and valproic acid. The patient has IV drug and alcohol use disorder and has presented to the ED many times for intoxication. Her temperature is 98.6°F (37°C), blood pressure is 115/71 mmHg, pulse is 72/min, and respirations are 12/min. Physical exam reveals anasarca and asymmetric lower extremity swelling. Based on the results of a doppler ultrasound of her swollen lower extremity, heparin is started. The patient is then transferred to the general medicine floor for continued management. Laboratory studies are shown below.

Serum:
Na+: 137 mEq/L
K+: 5.5 mEq/L
Cl-: 100 mEq/L
HCO3-: 24 mEq/L
Urea nitrogen: 22 mg/dL
Ca2+: 5.7 mg/dL
Creatinine: 1.7 mg/dL
Glucose: 70 mg/dL

Which of the following is the most likely diagnosis?
Nephrotic syndrome
Factor V Leiden
Liver failure
Antithrombin III deficiency
Nephrotic syndrome
This patient who presents with a deep venous thrombosis (lower extremity swelling, ultrasound followed by treatment with heparin), anasarca, and asymptomatic hypocalcemia most likely has a diagnosis of nephrotic syndrome.

Nephrotic syndrome occurs when large amounts of protein are lost in the urine. This can lead to hyperlipidemia (due to loss of lipoproteins), hypercoagulable state (due to loss of antithrombin III and protein C/S), and hypoalbuminemia. Most serum calcium is bound to albumin, so when albumin is lost in the urine, it can lead to profound hypocalcemia. The ionized or free portion of calcium remains the same; therefore, these patients do not exhibit symptoms of hypocalcemia. Furthermore, the loss of albumin will reduce the oncotic pressure in the vessels resulting in massive extravasation of fluid and anasarca.

Ambler et al. report a case of a patient who presented with a DVT and was found to have nephrotic syndrome. They discuss how the patient had asymptomatic changes in lab values including calcium. They recommend performing a urine dipstick for protein in cases of suspected nephrotic syndrome.

Incorrect Answers:
Answer A: Antithrombin III deficiency is a common cause of a hypercoagulable state because antithrombin III normally helps to neutralize coagulation factors. This disease is a possible explanation for this patient's DVT as it predisposes patients to thrombotic events; however, it does not explain her profound hypocalcemia. Asymptomatic antithrombin III deficiency does not need to be treated; however, patients should have anticoagulation if they undergo surgery.

Answer B: Factor V Leiden is the most common cause of a hypercoagulable state because this mutation renders factor V unable to be inactivated by proteins C and S. This is a possible explanation for this patient's DVT; however, it does not explain her hypocalcemia. Asymptomatic factor V Leiden mutation does not need to be treated; however, patients should have anticoagulation if they undergo surgery.

Answer D: Liver dysfunction is possible given this patient's history of alcohol use and IV drug abuse, placing her at risk for chronic hepatitis C infection. Despite the anasarca, this patient has no other stigmata of liver failure such as jaundice or ascites, making nephrotic syndrome more likely.

Answer E: Prothrombin gene mutation could explain this patient's hypercoagulable state because high levels of this gene can result in unprovoked thrombotic events. This disease would not explain why the patient has anasarca or hypocalcemia. Asymptomatic patients with this mutation do not require treatment.

Bullet Summary:
Nephrotic syndrome can present with a hypercoagulable state due to loss of antithrombin III and protein C/S and hypocalcemia from loss of albumin in the urine.