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Circulation. 1997;95:11-13

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(Circulation. 1997;95:11-13.)
© 1997 American Heart Association, Inc.

Articles

Simply Read: Erythrocytes Modulate Platelet Function

Should We Rethink the Way We Give Aspirin?

Bianca Rocca, MD; Garret A. FitzGerald, MD

the Center for Experimental Therapeutics, University of Pennsylvania, Philadelphia, Pa.

Correspondence to Dr G.A. FitzGerald, Center for Experimental Therapeutics, 905 Stellar Chance Laboratories, University of Pennsylvania, 422 Curie Blvd, Philadelphia, PA 19014. E-mail garret@spirit.gcrc.upenn.edu.


Key Words: platelets • aspirin • erythrocytes • thrombosis • Editorials


*    Introduction
up arrowTop
 *Introduction
down arrowReferences
 
The role of thrombosis in the precipitation of acute clinical syndromes of vascular occlusion, such as myocardial infarction and many strokes, is well established.1 The sequence of plaque fissure, platelet activation, and superimposed thrombogenesis underlies the use of platelet inhibitors, such as aspirin, in the prevention and treatment of such cardiovascular diseases.2 3 Perhaps less well appreciated is the multicellular contribution to thrombogenesis. Among the pioneers of this concept is the group associated with Aaron Marcus.2 3 Not only have they drawn our attention to the presence of erythrocytes (RBCs) and polymorphonuclear leukocytes (PMNs) within the thrombus, but they have provided in vitro evidence for bidirectional modulation of platelet function by these cell types. Whereas PMNs appear to diminish the capacity of platelets to respond to agonists,4 RBCs appear to facilitate platelet activation.5 6 Marcus and colleagues7 8 also provided evidence to suggest that interactions among platelets, RBCs, and PMNs may also facilitate the transcellular metabolism of bioactive lipids to novel species. These may, in part, contribute to the functional consequences of such cellular interactions.9

Santos and colleagues10 have now extended their in vitro observations of RBC-platelet interactions into the clinical domain. Before we consider their contribution, which appears in the current issue of Circulation,10 it is worth providing the context for our present understanding of such phenomena. Almost 90 years ago, Duke11 described measurement of the bleeding time in three patients with anemia and thrombocytopenia. Transfusion raised the platelet count and shortened their prolonged bleeding times to normal. Despite the subsequent decline of the platelet count to pretransfusion levels, the bleeding time remained considerably shorter than before transfusion. Presciently, Duke observed that "since anemia is associated with a delayed bleeding time, this relief might be accounted for by the rise in the red count. In interpreting the beneficial results following transfusion, this point should always be considered."

Several clinical observations have subsequently reinforced the impression that RBCs play a role in disorders of hemostasis.12 The hematocrit has been related in small cross-sectional studies to the incidence of myocardial infarction,13 and the circadian variability in hematocrit also coincides with the variability in the incidence of heart attack.14 Indeed, given the suggestions in vitro that RBCs augment platelet activation,5 6 alterations in hematocrit may have confounded attempts based on ex vivo assays of platelet aggregability to implicate circadian variability in platelet function in the pathogenesis of myocardial infarction and stroke.15 Although the experience is very limited, there have been suggestions that a reduction in hematocrit will augment cerebral blood flow in patients with stroke16 ; hematocrit has also been independently related to the incidence of myocardial infarction in a multivariate analysis.17 Thrombosis may also complicate disorders of RBC function, such as in sickle cell anemia, and the capacity of RBCs to aggregate ex vivo has been related to vascular occlusion in one small study.18 Despite these observations, the actual functional relevance of RBCs in human thrombosis remains obscure. For example, coronary thrombi tend to be composed primarily of platelets at the site of plaque fissure and are enriched in RBCs at their proximal and distal extensions.19 Perhaps paradoxically, at least in rabbit femoral arteries, RBC-enriched thrombi are more susceptible to therapeutic thrombolysis than those thrombi that consist largely of platelets.20

The mechanisms by which RBCs might modulate platelet function have attracted attention. Hellem21 demonstrated that RBCs, on contact with foreign surfaces, released a substance—he called it factor R—that facilitated the adherence of platelets to glass. The nature of this factor remains ill defined; however, it appears that adenosine may contribute, at least in part, to its activity.22 23 In addition to releasing chemical factors, RBCs may also modulate platelet function via physical interactions. The work of Turritto and Weiss24 25 and others has established that RBCs may enhance platelet deposition on the vessel wall by convectional diffusion. Indeed, platelet deposition on the subendothelium in experimental models is directly proportional to the hematocrit.26 27 RBC size and deformability may also contribute to these effects independently of the hematocrit. The interaction of chemical and physical mechanisms of RBC modulation of platelet function would also seem likely. Finally, such interactions are likely to be enhanced under circumstances of exaggerated shear, as has been demonstrated in vitro.28

Santos, Marcus, and colleagues10 describe the application of an assay system of RBC-platelet interactions to humans in the present study. Briefly, platelets are activated with collagen, and the supernatant is then added to autologous platelets to induce aggregation—which the authors call "recruitment"—or release of radiolabeled serotonin and formation of thromboxane (Tx), which they call "activation." Using this approach, they demonstrate that the inclusion of RBCs with platelets before collagen stimulation enhances both recruitment and activation of platelets by the supernatant. This effect of coincubation with RBCs is not observed if they are fixed or depleted of ATP and is not dependent on hemolysis.6

What are the mechanisms by which RBCs amplify platelet recruitment and activation? Santos et al first considered the role of platelet cyclooxygenase (COX). This enzyme is the target of aspirin action and catalyzes the formation of PGH2 from arachidonic acid.29 A separate enzyme,30 Tx synthase, then converts the endoperoxide to TxA2, which, in turn, may activate platelets and cause vasoconstriction. Enhanced formation of TxA2 might result from RBCs' affording a physical stimulus to phospholipase A2 activation and arachidonic acid release. Alternatively, arachidonate might be delivered in concentrated form in microvesicles released from the membranes of the activated cells for platelet metabolism to Tx.31

To address the role of COX, Santos et al10 examined the effects of aspirin administration in vitro and ex vivo on their assay system. Short-term administration of low doses of aspirin incompletely blocks the formation of platelet TxA2; they also find minimal effects on recruitment or serotonin release. However, this is hardly surprising. It has long been known that the relationship between inhibition of platelet Tx formation and Tx-dependent platelet activation is nonlinear; a residual 10% capacity to synthesize TxA2 will fully sustain platelet activation via this pathway.32 A more interesting observation was made when the dosing period was extended. Patrignani et al33 and others34 have previously shown that the capacity of platelets to form TxA2 is cumulatively inhibited when low doses of aspirin are administered long-term. Under just these circumstances (4, 8, and 15 days of aspirin 50 mg/d), Santos et al observe complete inhibition of platelet TxB2, as expected. However, some RBC-dependent recruitment ({approx}20% to 25% of control values) and serotonin release ({approx}50% of control values) is still observed. Platelets alone exhibit some ability to sustain serotonin release (about half that observed when they are coincubated with RBCs) but not recruitment under long-term dosing conditions with low-dose aspirin. Acute administration of a higher dose of aspirin (500 mg) will suppress these residual indexes of RBC-facilitated platelet function. The authors postulate an action of aspirin independent of COX inhibition to account for these actions. Furthermore, they have extended their observations by following an acute dose of aspirin 500 mg with daily doses of 50 mg/d. Under these circumstances, the suppressive effect of the acute dose on the indexes of RBC-platelet interactions is sustained for at least 3 weeks, after which it begins to recover. On the basis of these observations, the authors suggest that long-term administration of aspirin 50 mg/d should be augmented with single doses of 500 mg at 2-week intervals in cardiovascular indications for aspirin therapy.

What is the message of these studies for clinicians treating patients with cardiovascular disease? First, they prompt some interesting questions. For example, they raise the possibility that we have neglected the multicellular nature of thrombosis to the detriment of therapy. Aspirin reduces the incidence of vascular death by {approx}25% in patients with established coronary or cerebrovascular disease.35 36 These effects may be explained entirely in terms of inhibition of platelet COX.33 The magnitude of benefit seems to be encouraging, given the potential for redundancy in the pathways of platelet activation, rather than disappointing, as the authors imply. The results of Santos et al suggest the possibility of additional, COX-independent mechanisms of aspirin action. Many of these have been described in vitro, including modulation of thrombolysis,37 effects on membrane fluidity,38 and most recently, modulation of the formation of lipid bodies in leukocytes from which eicosanoids may be released.39 Indeed, although Santos et al draw our attention to RBCs, it is important not to neglect the potential effects of aspirin on PMNs and the vessel wall. For example, although platelets express the constitutive COX-1,40 PMNs and vascular tissue may be induced to express COX-2 by inflammatory cytokines. Aspirin interaction with COX-2 but not with COX-1 results in formation of 15-R-HETE coincident with prostaglandin inhibition.41 15-HETE has previously been shown to augment RBC adherence to endothelial cells; the functional consequences of this aspect of aspirin action in vivo is unknown.42 Alternatively, aspirin may modulate the effects of inflammatory stimuli via inhibition of nuclear factor-{kappa}B mobilization.43 44 Finally, the effects of aspirin on these multicellular interactions may be indirect. Thus, inhibition of COX may redirect the arachidonic acid substrate toward metabolism by lipoxygenase enzymes. Santos et al5 and Valles et al6 have already implicated the products of platelet 12-lipoxygenase in blocking the inhibitory effects of PMNs on platelet activation and in augmenting or mediating the facilitatory effects of RBCs. However, although these mechanisms are intriguing, their clinical importance remains to be established.

At present, the observations of Santos et al10 frame a hypothesis rather than provide the basis for an alteration in therapy. Low doses of aspirin achieve effective inhibition of platelet COX-1 and are well tolerated. No clinical advantage of higher doses has yet been demonstrated, as recently emphasized in the case of the secondary prevention of stroke.45 Rather than "laboratory indexes of prothrombotic potential," the clinical relevance of the ex vivo assays developed by Santos et al10 46 remains to be established. This is particularly important, given the absence of variables such as flow and shear from the system27 47 and the relatively modest size of the residual signal in patients taking a conventional regimen of low-dose aspirin. However, the authors have developed an interesting hypothesis that may be tested readily by prospective evaluation of the "pulse-chase" regimen of aspirin in clinical trials. Perhaps the impressive effects of low-dose aspirin in the treatment of cardiovascular disease can be augmented and our understanding of its mechanism of action broadened as we move toward the second century of our experience with this remarkable drug.


*    Footnotes
 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.


*    References
up arrowTop
 up arrowIntroduction
 *References
 

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