Maria Rita Milani

Non-enzymatic glycation reduces heparin cofactor II anti-thrombin activity.

SummaryThe effects of non-enzymatic glycation on heparin cofactor II activity, at glucose concentrations which might be expected in physiological or diabetic conditions have been evaluated in this study. Radiolabelled glucose incorporation was associated with a loss of heparin cofactor anti-thrombin activity. The heparin cofactor heparin and dermatan sulfatedependent inhibition of thrombin was significantly reduced, showing a remarkable decrease of the maximum second order rate constant. This study shows that heparin cofactor can be glycated at glucose concentrations found in the blood, and that this phenomenon produces a loss of heparin cofactor-antithrombin activity. These data suggest, furthermore, a possible link between heparin cofactor glycation and the pathogenesis of thrombosis in diabetes mellitus.

Pharmacology of Desmin (low molecular weight Dermatan sulphate) in healthy volunteers following intravenous bolus administration of different dosages (200, 400, 800 mg)

Eight healthy volunteers (6 males, 2 females, mean age 31.6 yrs), were administered--on three separate days--200, 400 and 800 mg of a new low molecular weight Dermatan sulphate (Desmin), given as a single i.v. bolus (2 min.) injection. Before each administration and 10, 20, 30 min., 1, 2, 4, 8, 12, 24 hours after, blood samples were drawn and the following coagulative assays performed: aPTT (activated Partial Thromboplastin Time), TT (Thrombin Time), anti Xa (Xa Factor inhibition), Heptest, Stachrom D.S.. Furthermore, a kinetic analysis was performed on the activity curves calculated on the Heptest and Stachrom data. Plasma peak values and half lives of the parameters checked showed a clear dose-effect relationship. aPTT and TT showed very short-lasting variations and the inhibition of Factor Xa was moderate, but significant. The most evident and specific effects of Desmin were those on Heptest and Stachrom D.S.: both tests were influenced in a clear-cut and dose-dependent way, mainly as a consequence of the action of Desmin on HCII, with partially different kinetic patterns. A series of in vitro experiments proved an anti Xa effect of Desmin, mediated by antithrombin III, well above the possible interference of the small (< 1%) heparin contaminants in Desmin. An even more marked anti Xa activity was seen in the in vivo study, an observation so far unrecognized for this type of drug: some possible interpretations of this fact are discussed.

Pharmacodynamics of a new low-molecular-weight dermatan sulfate after a single subcutaneous injection in elderly patients with chronic venous disorders: A phase I trial

Abstract Fourteen patients, aged older than 65 years, with chronic venous disorders, underwent a Phase I pharmacodynamic study of the single subcutaneous (SC) administration of a new low-molecular-weight dermatan sulfate. Immediately before and 1, 2, 4, 6, 8, 12, and 24 hours after the SC injection of 100 mg of the drug, the following coagulation and fibrinolysis variables were checked: activated partial thromboplastin time, thrombin time, activated factor X (Xa) inhibition, global anticoagulant activity, as measured by Heptest, selected anti-IIa activity, as measured by Stachrom DS, functional and antigenic plasminogen-activator inhibitor, and functional tissue plasminogen activator. Routine laboratory blood and urine tests to monitor systemic tolerability of the drug were performed. The local tolerability and the occurrence of adverse events were also monitored. Results show anti-Xa and anti-IIa activity, as measured by Heptest and Stachrom DS, increased significantly after administration of the drug, thus suggesting an antithrombotic action. Functional and antigenic PAI concentrations were unchanged. Both systemic and local tolerability of a single SC dose of low-molecular-weight dermatan sulfate were very good.

Evidence for a reduced heparin cofactor II biological activity in diabetes

A reduction of heparin cofactor II (HCII) biological activity, despite its normal plasma concentration, is reported in insulin-dependent diabetic patients. A good linear correlation between HCII activity and concentration is present in normal controls but not in diabetics. In these subjects HCII activity correlates inversely with fasting blood glucose and glycated proteins but not with Hb A1. These data demonstrate the presence of a depressed HCII activity in the presence of its normal plasma concentration in insulin-dependent diabetics and suggest a role for short-term metabolic control in conditioning this phenomenon.