Heterogeneity of the aggregation response of human platelets to arginine vasopressin

Abstract

Previous reports have alluded to variability in the aggregation response of normal human platelets to the neuropeptide arginine vasopressin (AVP). Since it has not been well documented, the current studies were undertaken to characterize this response. AVP (1-100 nM) produced a concentration-dependent aggregation response. Although the aggregation response to 100 nM AVP did not correlate with age or sex, there was a bimodal response distribution based on the presence or absence of a second wave of aggregation. In kinetic studies, the apparent km of AVP was 18.3 +/- 5.4 nM. There was a significant inverse relationship between the maximal aggregation response to 100 nM AVP and the km (r = -0.82). One hundred nanomolar AVP increased the intracellular calcium concentration of platelets by 406 +/- 120 nM in calcium free buffer and by 658 +/- 233 nM in the presence of 1.0 mM CaCl2. The aggregation response to 100 nM AVP correlated most strongly with the transmembrane influx of calcium (r = 0.84). In individuals whom 100 nM AVP was able to generate a second wave of aggregation, the selective protein kinase C inhibitor bis-indolylmaleimide significantly decreased the platelet aggregation response. Thus, there is significant heterogeneity in the aggregation response of normal human platelets to AVP. Based on our kinetic studies and the effects of PKC inhibition on the aggregation response to AVP, we would hypothesize that the variability of the aggregation response of normal human platelets to AVP is related to a polymorphism of the platelet AVP V1 receptor.

Vasopressin and platelets: a concise review

“…The aggregation response to AVP was significantly correlated with the total increase in platelet intracellular calcium concentration (r = 0.88) and the influx of calcium across that platelet membrane (r = 0.84). 17 Lachant et al also dem onstrated a significant inverse correlation between the Km for AVP and the aggregation response (r = ±0.82), suggesting that qualitative differences in the V 1 receptor and/or in the transmem brane/ intracellular signalling pathways m ight account for the observed heterogeneity in AVP-induced aggregation. In support of this hypothesis, AVP-induced platelet aggregation was diminished by the selective protein kinase C inhibitor bisindolylmaleimide in `high-responders' but did not inhibit the platelet response in `lowresponders' .…”

“…In addition, there was a strong correlation between AVP-and DDAVP-induced CD62 expression (rho = 0.62, P = 0.0008, Spearman rank correlation). Finally, parallel to the data of Lachant et al 17 with AVP, subjects could be grouped into `low-activators' or `highactivators' in response to 1 nM DDAVP. Taken together, these data strongly support the hypothe sis that DDAVP directly activates platelets via the V 1 -receptor.…”

Study of V1a vasopressin receptor gene single nucleotide polymorphisms in platelet vasopressin responsiveness

“…AVP has also been reported to stimulate platelet aggregation via its V1a receptor. A genetic regulation of platelet V1a receptors (V1aR) is suggested by the demonstration of a significant heterogeneity in the aggregation response to AVP (17). V1aR comprises 418 amino acids of the open reading frame and its gene is within 6.4 kb with two coding exons separated by a 2.2-kb intron.…”

Lack of vasopressin-induced platelet aggregation in healthy subjects

“…We have previously reported a close relation between maximal percentage aggregation with AVP and AVP binding sites on platelet [6] . Large variations in the functional responsiveness of human platelets to AVP have been observed among individuals [5,13] . However, no detailed data are available on platelet aggregation refractoriness to AVP.…”