Rationale for antiplatelet agents in diabetic vascular disease.

Studies summarized in this paper indicate that some diabetics have increased sensitivity to platelet aggregating agents. The problem is in the platelet release reaction and may reflect increased synthesis of prostaglandins or their precursors. An interaction of plasma factor such as von Willebrand factor with platelets may also be involved. Based on these and other considerations, a prospective study on the use of aspirin and dipyridamole on diabetic lower extremity vascular disease is underway as a Veterans Administration Cooperative Study.

Relation between growth hormone levels and Von Willebrand factor activity.

The relationship between growth hormone and von Willebrand factor activity was studied in fasting plasma samples, nocturnal samples, and after intramuscular injection of growth hormone. A significant correlation was seen between the two levels in fasting samples. During sleep, peaks of growth hormone were associated with peaks of von Willebrand factor activity. A subject with isolated growth hormone deficiency had no peaks of either. Intramuscular injection of growth hormone produced a rise of von Willebrand factor activity in all subjects studied. These results indicate that there is a relationship between growth hormone and von Willebrand factor activity.

The effect of oral glucose on von Willebrand factor activity in normal and diabetic subjects.

We have previously noted increased platelet aggregation and high von Willebrand factor activity in patients with chemical diabetes. In this paper we have studied platelet aggregation, plasma glucose, insulin, free fatty acids, growth hormone, and von Willebrand factor activity during the glucose tolerance test in six normal and six chemical diabetic subjects. The results suggest that von Willebrand factor activity is suppressed coincident with the rise of glucose and insulin and provide further evidence of hormonal and metabolic control of levels of von Willebrand factor activity.

The effects of dopamine on human platelet aggregation, in vitro.

An unexpected inhibition of human platelet aggregation by dopamine -- the precursor of epinephrine and norepinephrine -- is presented. Human platelet-rich plasma was incubated in an aggregometer for 120 seconds at 37 degrees C, with either dopamine or saline control. Adenosine diphosphate, epinephrine or collagen was added as the aggregating agent. Dopamine inhibits induction of platelet aggregation by all three agents and causes platelet disaggregation. At low doses (400 mug/ml or less), dopamine induces platelet aggregation and enhances ADP-induced aggregation. In addition, a concentration of dopamine of 40 mug/ml induces aggregation, enhances ADP-induced aggregation and inhibits epinephrine aggregation. Phentolamine is able to block dopamine enhancement of ADP aggregation, but propranolol and haloperidol fail to prevent dopamine inhibition of epinephrine aggregation. These observations are explained neither by the currently known intracellular actions of dopamine which involve competition with serotonin nor by a single mediator such as cyclic adenosine 3':5'-monophosphate. It appears that dopamine may exert its effects via the platelet membrane.

Nature of von Willebrand factor: a new assay and a specific inhibitor.

Platelet-active "von Willebrand factor" is a poorly characterized activity of a plasma-protein macromolecular complex. A new simple assay for von Willebrand factor is based on the dose response relation of the factor and the ristocetin platelet aggregation time. This assay uses the "snowstorm" macroscopic endpoint. A multiply transfused subject with von Willebrand's disease was observed to have a circulating inhibitor that blocks normal ristocetin aggregation of platelets, but not ADP-, epinephrine-, or collagen-induced aggregation. The inhibitor was not adsorbed by normal platelets, and was stable to heating at 56 degrees for 30 min and to repeated freezings and thawings. This inhibitor also prevents action on human platelets by platelet-aggregating factor of bovine plasma, indicating this bovine factor activity is a function of von Willebrand factor. Three inhibitors were compared: (1) the von Willebrand factor inhibitor specifically blocked von Willebrand factor activity, (2) a human antibody from a hemophiliac inhibited only antihemophilic factor activity, and (3) a rabbit antiserum to a preparation of human antihemophilic factor inhibited both activities. The active site for von Willebrand factor on the macromolecular complex appears to be spaced some distance from the antihemophilic factor site.