Structural characterization and functional effects of a circulating heparan sulfate in a patient with hepatocellular carcinoma

Abstract

A circulating anticoagulant was isolated from the plasma of a 42-year-old man with cir-rhosis 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 normal. The patient had mucocutaneous bleeding but the sole laboratory abnormality was a prolonged thrombin time (TT = 99 s, normal 25-35 s). Protamine titration indicated activity equivalent to a heparin concentration of 6-7 U/ml. Antithrombin III (AT III) antigen and activity were markedly 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 III. Based on the degree of sulfation and HPLC pattern, the GAG was classified as heparan sulfate. Low levels (4 µM) of purified GAG markedly prolonged the TT (>120 s) but not the activated partial thromboplastin time (PTT) (31.4 s). In a Factor Xa assay, the GAG exhibited a potency equivalent to 0.06 U of low molecular weight heparin per nmol of uronic acid. Patients with endogenous circulating glycosaminoglycans can present with unusual laboratory coagulation test profiles. These reflect complex dysfunction of hemostasis, leading to difficulty in providing diagnosis and effective care. Am.

Endogenous heparin‐like activity detected by anti‐Xa assay in infected cirrhotic and non‐cirrhotic patients

“…Endogenous heparinoids have also been detected in portal hypertensive patients after gastrointestinal haemorrhage (24) and in several other conditions (mostly myeloproliferative diseases, but also chronic nephritis, acquired immunodeficiency syndrome, solid carcinomas, suramin treatment and in newborns as a congenital disorder) characterized by the occurrence of bleeding, which can be occasionally fatal, or unexpected prolongation of coagulation tests (25). Endogenous anticoagulants have been characterized in a few cases, showing the properties mostly ascribed to heparan sulphate (24,(26)(27)(28). In one study there were characteristics of a high affinity heparin (29), and in another of dermatan-sulphate (30).…”

Endogenous Heparinoids Detected by anti-Xa Activity are Present in Blood during Acute Variceal Bleeding in Cirrhosis. A Prospective Study

“…Patients with HCC have circulating endogenous GAGs [25], and this is most likely re ected by the detected raised anti-Xa levels. In HCC, there are quantitative and qualitative abnormalities of GAGs in the cancer tissue compared to normal liver [26].…”

An uncommon cause of postoperative bleeding

“…Actually, several endogenous GAGs acting as HLAs have been described, and their dysregulated production can result in a bleeding diathesis previously described as 'heparinoids syndrome' [11].…”

“…Heparin-like anticoagulants have been described in a number of other diseases, including transitional cell carcinomas [6,7], breast cancer [8], multiple myeloma [9], systemic mastocytosis [10] and hepatocellular carcinoma [11].…”