Inhibition of arterial thrombosis by a soluble tissue factor mutant and active site-blocked factors IXa and Xa in the guinea pig.

The substrate recognition region of tissue factor contains two residues, Lys165 and Lys166, which are important for macromolecular substrate activation by the tissue factor:factor VIIa complex. Replacement of these two residues with alanine in a soluble version of human tissue factor resulted in a mutant, hTFAA, which can bind factor VIIa but forms an enzymatically inactive complex. We found that hTFAA inhibits the activity of guinea pig factor VIIa, allowing us to evaluate hTFAA's effects on thrombosis and hemostasis in a guinea pig model of recurrent arterial thrombosis.

A human antibody that binds to the gamma-carboxyglutamic acid domain of factor IX is a potent antithrombotic in vivo.

10C12, a human antibody F(ab')2, which specifically binds to the Gla domain of factor IX, interfered with all known coagulation processes that involve factor IX/IXa. These include the function of the intrinsic Xase complex and the activation of zymogen factor IX by factor XIa and by the tissue factor:factor VIla complex. Furthermore, 10C12 potently inhibited activated partial thromboplastin clotting times (APTT) in plasma of guinea pig and rat, thus enabling in-vivo evaluation.

Hyperalgesia in spontaneous and experimental animal models of diabetic neuropathy.

Hyperactivity of nociceptive C-fibers has been recently described in diabetic BB/Wistar rats. This study assesses the association of hyperalgesia, using an analgesy-meter, with elevated glycosylated haemoglobin levels in three animal models of diabetic and nutritional neuropathies: Psammomys obesus (sand rat), streptozotocin-treated and galactose-fed rats. Pain threshold measurements (paw pressure test) and motor nerve conduction velocities were recorded in controls (n = 75), hyperinsulinaemic (n = 16), insulin-deficient (n = 46) und galactosaemic (n = 12) animals.