Phenprocoumon-Induced Hepatitis Delaying Precise Diagnosis in a Thrombophilic Patient With Activated Protein C Resistance Due to Factor V R506Q Mutation

Abstract

A 38-year-old woman was admitted to the hospital with signs of deep venous thrombosis in the right calf. Phlebography confirmed the diagnosis. Continuous intravenous heparin was instituted, followed by oral anticoagulation with phenprocoumon. Two months later, symptoms of deep venous thrombosis in the right calf recurred when oral anticoagulation was not in the therapeutic range (thromboplastin time 40% to 50%, INR not available). Four months after having started with phenprocoumon, she developed jaundice and elevated liver enzymes. Alanine aminotransferase (ALT) was 3,330 U/L (normal o37 U/L), aspartate aminotransferase (AST) 2,090 U/ L (normal o36 U/L), alkaline phosphatase (AP) 272 U/L (normal o108 U/L), g-glutamyl-transpeptidase (g-GT) 357 U/L (normal o45 U/L), and bilirubin 526 mmol/L (normal o18.8 mmol/L). Albumin was in the normal range (38 g/L). She had no history of alcohol or drug abuse and had never had blood transfusions. Apart from positive anti-HBc and anti-HBs due to hepatitis B infection 18 years earlier, serological tests revealed no evidence for active hepatitis A, B, or C, or cytomegalovirus or Epstein-Barr virus infection. Anticoagulation was stopped in order to perform a liver biopsy, which was, however, subsequently refused by the patient. Oral anticoagulation was not resumed, and elevated liver enzymes returned to normal values within 3 months. At the age of 43 years she was admitted to the hospital for replacement of her pacemaker, which had been implanted 6 years before because of thirddegree heart block. Two days after hospital discharge she was readmitted with clinical signs of right subclavian vein thrombosis and pulmonary embolism. Duplex sonography and pulmonary perfusion/ ventilation scintigraphy confirmed the diagnosis. Therapy with intravenous heparin was started, accompanied by phenprocoumon. Five weeks later, the patient complained of nausea and fatigue and became jaundiced. Laboratory values were as follows: ALT 1,724 U/L, AST 1,219 U/L, AP 200 U/L, gGT 326 U/L, and bilirubin 128 mmol/L. Again, albumin was in the normal range (37 g/L), and serological tests did not show any signs of recent viral infection. Phenprocoumon was stopped, and oral anticoagulation was continued with acenocoumarol. Three weeks later, the patient had clinically improved, and elevated liver values were decreasing: ALT 672 U/L, AST 591 U/L, AP 196 U/L, g-GT 244 U/L, and bilirubin 88 mmol/L. Acenocoumarol was continued for 2 months. One month after withdrawal of acenocoumarol, the patient was investigated for thrombophilia. At that time, ALT (51 U/L), AST (49 U/L), and bilirubin (28 mmol/L) were still slightly elevated, whereas albumin, AP, and g-GT were in the normal range. Results (Table) showed reduced levels of protein C, protein S, and antithrombin III, as well as a decreased APC sensitivity ratio indicating APC resistance, whereas plasminogen was within normal limits (0.79 U/mL) and anticardiolipin antibodies were not detected. Routine coagulation parameters (thromboplastin time 78%, thrombin time 12 sec, fibrinogen 2.7 g/L, factor V clotting activity [FV:C] 0.88 U/mL, FVII:C 0.75 U/mL, and FX:C 0.70 U/mL) were within the normal range, whereas FII:C (0.53 U/mL) was slightly reduced. During the following months, plasma concentration of FII:C and the coagulation inhibitors returned to normal values (Table). However, the APC sensitivity ratio remained decreased, and genetic analysis revealed heterozygous FV R506Q mutation (factor V Leiden mutation). The patient is now under prophylactic anticoagulation with daily subcutaneous applications of a low molecular weight heparin and has remained well for the last 20 months.