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Background and Objective: The bleeding manifestations frequently observed in patients with immunoglobulin light chain amyloidosis (AL) have been attributed to different pathogenetic factors: amyloid deposits in several organs and systems leading to failures of these latter, the affinity of amyloid for some clotting factors, and the presence of plasma components interfering with fibrin formation could all induce alterations of clotting tests. This investigation was aimed at defining the prevalence of clotting abnormalities and their clinical manifestations in patients with AL., Design and Methods: Thirty-six consecutive patients with biopsy proven amyloidosis and documented monoclonal gammapathy were enrolled within one year. The following clotting tests were considered in the study: activated partial thromboplastin time (aPTT), prothrombin time (PT), thrombin time (TT), reptilase time (RT), Russell's viper venom time (RVTT), fibrinogen, factor X and alpha-2 antiplasmin., Results: Hemorrhagic manifestations were mild to moderate in nine patients, but severe and untractable in one. The most frequent clotting anomaly was defective fibrinogen conversion to fibrin, as demonstrated by prolongation of both TT (85% of cases) and RT (90% of cases). Low levels of factor X activity were observed in about 1 out of 4 samples, while fibrinogen and alpha2 antiplasmin levels were distributed over a wide range of values. PT was prolonged in 8 and aPTT in 25 patients. The search for lupus anticoagulant was negative in samples showing a prolongation of aPTT and/or RVVT., Interpretation and Conclusions: The prolongation of TT and RT is not dependent on either the presence of a heparin-like substance in the plasma or on fibrinogen levels; furthermore, the prolongation of RVVT is not related to factor X level. The hypothesized presence in the plasma of an inhibitor of fibrin formation could also affect factor X activation by Russell viper venom. The prolongation of TT and RT represents a peculiar feature of amyloidosis. The variability in the behavior of the other clotting times and hemostatic factors studied is mirrored in the heterogeneity of the clinical features observed in this disease.

Intracerebroventricular (i.c.v.) administration of histamine (HA, 0.025-0.1 microM/rat) to arthritic rats induces a dose-related inhibition of the neuronal thalamic firing evoked by peripheral noxious stimuli. To characterize the type(s) of HA receptors involved in this depressing activity of the amine we used electrophysiological techniques to examine the effects of i.c.v. administration of H1 and H2 agonists and antagonists on the spontaneous and evoked nociceptive firing of the thalamic neurons in rats rendered arthritic by Freund's adjuvant. The H1 agonist 2-pyridylethylamine (0.4-1.0 microM/rat, i.c.v.) displayed a dose-dependent antinociceptive effect very similar to that of HA, while the H2 agonist dimaprit (0.05-0.2 microM/rat, i.c.v.) did not modify thalamic firing. Neither mepyramine (H1 antagonist, 0.1 microM/rat, i.c.v.) nor zolantidine (H2 antagonist, 0.01 microM/rat, i.c.v.) modified the evoked firing of rat thalamic neurons. When administered before HA (0.1 microM/rat, i.c.v.) mepyramine but not zolantidine was able to inhibit the antinociceptive effect of HA. On the basis of the present electrophysiological results, we suggest that a specific interaction of histamine with H1 receptors may be important for its antinociceptive effect on afferent peripheral inputs to the thalamus.