Essential thrombocythemia, thrombosis and enhanced platelet regeneration: Is once daily dose of aspirin enough?

Patients with essential thrombocythemia and other myeloproliferative disorders have an increased incidence of arterial thrombotic events, and the therapy generally used to treat these patients has been once-daily low-dose aspirin in addition to cytoreduction. The dosing regimens in these diseases have been largely extrapolated from other arterial diseases, even though there is limited evidence from studies in myeloproliferative disorders.

Recently published studies by Dragani and colleagues provided new insights into platelet biology in essential thrombocythemia that raise important questions regarding antiplatelet therapy and dosing of aspirin in essential thrombocythemia and in other states associated with increased platelet generation.

Platelet thromboxane production is increased in essential thrombocythemia patients, as revealed by enhanced excretion of the urinary metabolite of thromboxane A_2. Cyclooxygenase (Cox)-1 and -2 isozymes catalyze the conversion of arachidonic acid to prostaglandin H2 (PGH2), the initial step in prostanoid synthesis that leads to the formation of several products, including thromboxane A₂, PGI₂ and PGE₂. Under physiologic conditions, platelet thromboxane production is driven primarily by Cox-1 and endogenous PGI₂ by Cox-2. Fewer than 10% of normal platelets have Cox-2. However, Cox-2 is present in megakaryocytes, up-regulated during megakaryopoiesis, and expressed in young platelets. These observations draw attention to the potential contribution of Cox-2 to thromboxane production in diverse clinical conditions characterized by increased platelet production.

From a therapeutic perspective, this has relevance. Aspirin acetylates Ser529 in human Cox-1 and Ser516 in human Cox-2. When given once daily at low doses, aspirin almost completely inhibits Cox-1 in platelets, cells that do not have the ability to replenish the irreversibly inactivated enzyme. Substantially higher doses of aspirin are needed to inhibit Cox-2. Moreover, Cox-2 is an inducible enzyme and the inhibitory effect of aspirin is influenced also by the ability of nucleated cells to rapidly regenerate the enzyme.

Studies by Dragani and colleagues show convincingly that younger thiazole-staining reticulated platelets are increased in essential thrombocythemia patients, indicating enhanced platelet generation. They also show that platelet Cox-2 expression is upregulated in essential thrombocythemia patients. Both of these features have been described in other states associated with increased platelet generation.

Dragani et al show that aspirin, at doses that almost completely suppress thromboxane production in healthy patients, is not as effective in essential thrombocythemia. In an open-label randomized study in essential thrombocythemia patients who are taking daily aspirin, they showed that the addition of a Cox-2 inhibitor to aspirin decreases both urinary excretion of a thromboxane metabolite (marker of endogenous production) and ex-vivo thromboxane production in serum (measure of total synthetic capacity) by about 30%. These studies corroborate that Cox-2 contributes to endogenous thromboxane production in essential thrombocythemia. However, it is important to note, the addition of the Cox-2 inhibitor did not abolish thromboxane production, suggesting the role of additional mechanisms contributing to thromboxane production.

The increased number of reticulated platelets in essential thrombocythemia draws attention to another potentially major mechanism, namely, the enhanced Cox-1 activity in newly released platelets not inhibited by the once-daily low-dose aspirin. The attenuated inhibition derives from the relatively short half-life of aspirin in plasma.

Aspirin is rapidly absorbed from stomach and intestines with peak levels at 30 to 40 minutes after ingestion. It is cleared from plasma with a short half-life of 15 to 20 minutes. In states with rapid platelet generation, a once-daily dose of low-dose aspirin may be insufficient because of the rapid clearance of aspirin and the immense capacity of bone marrow to accelerate platelet production (even 10-fold of basal rate). Dragani and colleagues also showed that the addition of aspirin (50 mcM) to blood in vitro abolishes thromboxane production in essential thrombocythemia patients already receiving aspirin. This is consistent with aspirin’s effect on Cox-1 not acetylated by the single dose administered 24 hours earlier.

Cardiovascular considerations

Studies by other investigators in normal patients and patients with ischemic heart disease also point to similar considerations. In a study of 60 healthy patients, Guthikonda and colleagues found increased thromboxane production in patients with higher reticulated platelets; whereas ex-vivo addition of Cox-1 or Cox-2 inhibitor to blood attenuated the thromboxane production, the effect was greater with a Cox-1 inhibitor. They found decreased inhibitory effects of aspirin and clopidogrel in patients with coronary artery disease with higher number of reticulated platelets.

An important question is whether aspirin-resistant thromboxane production is of clinical relevance with respect to arterial events. The evidence for this comes from studies in patients with ischemic heart disease. Eikelboom and colleagues have shown an association between failure of suppression of thromboxane generation and cardiovascular risk in a well-defined cohort of aspirin-treated patients at high risk for cardiovascular events. Higher baseline urinary concentrations of 11-dehydro thromboxane B2 in patients assigned aspirin were associated with an increasing risk for myocardial infarction and cardiovascular death.

The recent report by Dragani and colleagues raises important issues regarding optimum regimen to suppress thromboxane production not only in essential thrombocythemia, but other states as well. What is clear is that low-dose aspirin administered once daily may be inadequate to fully suppress thromboxane production in essential thrombocythemia, and that may likely be the case in other disorders with increased platelet production.

The addition of a Cox-2 inhibitor may not be the complete answer — because of the persistent thromboxane production observed by them despite a seven-day dual drug therapy with a Cox-2 antagonist and aspirin. The short plasma half-life of aspirin argues against added benefits of higher doses at same dosing interval. These studies advanced a rationale for a dosing interval shorter than the traditional once daily aspirin. This remains to be tested in disease states with rapid platelet turnover using thrombotic events as endpoints.

If indeed the thromboembolic events are driven by thromboxane production, and as also suggested by the researchers, there may be a role for thromboxane receptor antagonists that inhibit thromboxane generated by multiple mechanisms. It may be time to re-think the optimum antithrombotic regimens and the well-entrenched strategy of once-daily dosing of aspirin in essential thrombocythemia and other states with accelerated platelet generation.

A. Koneti Rao, MD, is Sol Sherry Professor of Medicine, Director, Sol Sherry Thrombosis Research Center, and Chief of the Hematology Section at Temple University School of Medicine. He is also a member of the HemOnc Today Editorial Board.

Dragani A. Blood. 2010;115:921-922.

Eikelboom JW. Circulation. 2002;105:1650-1655.

Guthikonda S. J Am Coll Cardiol. 2008;52:743-749.

Guthikonda S. J Thromb Haemost. 2007;5:490-496

Rocca B. Proc Natl Acad Sci USA. 2002;99:7634-7639.

This important editorial gains even more credence in view of older (and somewhat ignored) studies of Harker and co-workers that demonstrated need for thrice-daily aspirin — rather than once-daily — to fully inhibit platelet aggregation in vivo. Their rigorous baboon model assayed attachment of radiolabeled platelets to intravascular teflon implants (J Clin Invest. 1985;75:1591).

– Harry S. Jacob, MD

HemOnc Today Chief Medical Editor