that this platelet heterogeneity is due to aging of circulating platelets. Platelets were thought to change in size, becoming smaller and lighter with aging 770,772 However, it would appear that circulating platelets do not change in size773 or density with senescence774,775 Large platelets may not be younger platelets, but rather platelets with a longer lifespan.773 Platelet heterogeneity may result from the heterogeneity of m eg a k ary o c y te s,774 w hich may be due to pro d u ctio n facto rs in the bone marrow.774,776,777 Platelet volume may also be determined during thrombocytopoie- sis.777 Platelets with a larger mean volume are derived from megakaryocytes with a larger mean cytoplasmic volume,778 and this appears independent of aging.771,779 Platelet size and age both appear to be independent determinants of platelet func tion.771,776,780 Larger platelets, for example, are more reactive than smaller platelets
in virro.781,782 This may be due to quantitative differences based on size rather than qualitative differences due to aging and other factors.773,783 The response of platelets to the aggregating agents thrombin and collagen increases in proportion to their M py 776 The release of arachidonic acid metabolites is also quantitatively related to their size,783 and the ability of platelets to incorporate arachidonic acid, convert it to active metabolites, and release these metabolites, is related to their volume.783 The ability of platelets to release unmetabolised arachidonic acid varies inversely with the M py 783 There is a linear relationship between TXB2 production and MPV.784
F u rth erm o re , fo llo w in g in d u ctio n o f th ro m b o cy to p e n ia , the m ean cy to p lasm ic volum e increases in m egakaryocyte populations with a higher than norm al mean polidy num ber. Such m egakaryocytes generate m ore TX B 2 per volum e and the larger platelets derived from the large m egakaryocytes are m ore reactive. In addi tion, these platelets produce more TXB2 per unit platelet volume.784
An increase in platelet reactivity associated with increased platelet volume has been confirmed by other methods used to assess platelet reactivity.776,785,786 The inhibitory effects o f PGI2 on aggregation are dependent on both platelet volum e and platelet co u n t.786 This in h ib ito ry effect decreases with an increase in p latelet m ass and is independent o f w hether it resulted from increased volum e or platelet count.786 F ur thermore, a decrease in the inhibitory effectiveness of PGI2 on both aggregation and the release reaction occurs in the presence o f a greater m ass.786 This is also in d e p e n d e n t o f w h e th er th e in c re a se d m ass is due to in c re a se d p la te le t v o lu m e or number.786
Larger platelets appear to have both increased m etabolic as well as functional cap a b ilitie s. In c re ase d g ly co g en o ly sis, glycogen and p ro tein sy n th esis, and g reater contents o f orthophosphate and nucleotides have been noted in larger and heavier p latelets.772 Furtherm ore, larger platelets m anifest increased clot retraction ability, greater adherence to collagen, increased aggregation with ADP and greater release o f granule contents in response to ADP.771,781
It is possible that these d ifferences are due to the physical properties o f different sized p articles.785 Large platelets may aggregate m ore readily than sm all platelets because increased in vitro reactivity may reflect, not differences in platelet function, but m ore frequent co llisio n o f larg er p latelets.785 H ow ever, given the preceeding discussion, this sim ple physical proposal is unlikely to be the solitary explanation. Platelets separated into size dependent populations also show no differences in the rate and extent o f clum ping in response to ristocetin.776 Furtherm ore, the absolute amounts o f ADP and BTG are greater within larger platelets and the amounts secret ed in the release reaction have a close correlation with platelet size.776
In summary, even though it is well established that different sized platelets have dif ferent m etabolic cap ab ilities, and different physical and functional properties, the relevance of platelet volume to platelet physiology and pathology remains controver sial. The cause o f these differences also remains uncertain, although the quantitative differences are well established.771
7.1.1.2 The relationship between platelet count and platelet size. An inverse linear relationship betw een platelet count and size is well docum ented.787 The pro p o rtio n o f la rg e r p la te le ts (volum es >8 fl) is g reater in norm al in d iv id u als w ith low er p latelet co u n ts, and there are proportionally m ore sm all platelets (<8 fl) as the platelet count increases.788 Platelet count and volume appear to be inversely but not linearly related in norm al subjects.779,789,790 This relationship exists in patients w ith low or high platelet counts. Levin and B essm an found that the product o f the p latelet count and size varies substantially w ithin the norm al range, although the platelet mass increased as platelet count increased.779 At platelet counts less than 450 109/1, any groups w ith a difference in platelet count o f >80 109/1 had significantly
different volumes.779 W ith progressively lower counts the MPV increases. The most m arked difference in MPV occurs when the platelet count is below 100 1 09/1 and there is no difference in MPV w ith a platelet count above 450 109/1. The platelet mass increases in a non-linear manner as the platelet count increases,779 although the platelet mass is constant for counts betw een 100 to 450 109/1 when correcting for splenic sequestration o f larger platelets and inherent errors in electronic m easure m ent of MPV.771 In the absence o f haem ostatic "stress" both the platelet count and MPV remain constant over time in a given individual.771