STRUCTURAL CHARACTERIZATION AND FUNCTIONAL-EFFECTS OF A CIRCULATING HEPARAN-SULFATE IN A PATIENT WITH HEPATOCELLULAR-CARCINOMA

A circulating anticoagulant was isolated from the plasma of a 42-year- old man with cirrhosis and hepatocellular carcinoma who had an unusual coagulation test profile. The patient developed a fatal coagulopathy, unresponsive to protamine therapy or plasma exchange following liver biopsy. However, at presentation, routine hemostasis assays were norma l. The patient had mucocutaneous bleeding but the sole laboratory abno rmality was a prolonged thrombin time (TT = 99 s, normal 25-35 s). Pro tamine titration indicated activity equivalent to a heparin concentrat ion of 6-7 U/ml. Antithrombin III (AT ill) antigen and activity were m arkedly elevated. The anticoagulant activity, purified from plasma by DEAE chromatography, was identified as a glycosaminoglycan (GAG). GAG anti-thrombin activity was completely abolished by heparin lyase ill. Based on the degree of sulfation and HPLC pattern, the GAG was classif ied as heparan sulfate. Low levels (4 mu M) of purified GAG markedly p rolonged the TT (> 120 s) but not the activated partial thromboplastin time (PTT) (31.4 s). In a Factor Xa assay, the GAG exhibited a potenc y equivalent to 0.06 U of low molecular weight heparin per nmol of uro nic acid. Patients with endogenous circulating glycosaminoglycans can present with unusual laboratory coagulation test profiles. These refle ct complex dysfunction of hemostasis, leading to difficulty in providi ng diagnosis and effective care. (C) 1998 Wiley-Liss, Inc.