Platelet activation and inhibition in polycythemia vera
and essential thrombocythemia
Carlo Patrono,1Bianca Rocca,1and Valerio De Stefano2
1Department of Pharmacology and2Institute of Hematology, Catholic University School of Medicine, Rome, Italy
Persistently enhanced platelet activation
has been characterized in polycythemia
vera (PV) and essential thrombocythemia
(ET) and shown to contribute to a higher
risk of both arterial and venous throm-
botic complications. The incidence of
major bleeding complications is also
somewhat higher in PV and ET than in
the general population. Although its effi-
cacy and safety was assessed in just 1
relatively small trial in PV, low-dose
aspirin is currently recommended in prac-
tically all PV and ET patients. Although
for most patients with a thrombosis his-
tory the benefit/risk profile of antiplatelet
therapy is likely to be favorable, in those
with no such history this balance will
depend critically on the level of throm-
botic and hemorrhagic risks of the in-
dividual patient. Recent evidence for a
chemopreventive effect of low-dose aspi-
rin may tilt the balance of benefits and
harm in favor of using aspirin more
broadly, but the potential for additional
benefits needs regulatory scrutiny and
novel treatment guidelines. A clear phar-
macodynamic rationale and analytical
tools are available for a personalized
approach to antiplatelet therapy in ET,
and an improved regimen of low-dose
erly sized randomized trial. (Blood. 2013;
Polycythemia vera (PV), essential thrombocythemia (ET), and
primary myelofibrosis are collectively classified as BCR-ABL 1–
negative myeloproliferative neoplasms (MPNs). Chronic myeloid
neoplasms share a common stem cell–derived clonal heritage of
altered proliferation and differentiation, and theirphenotypicdiversity
is attributed to differences in specific genetic rearrangements or
mutation(s) that underlie the clonal myeloproliferation.1Although
risk of thrombosis, hemorrhage, and myelofibrotic or leukemic
transformation.2-4The aim of current therapy is to reduce the risk
of thrombosis or hemorrhage in PV and ET, and to address the
low-dose aspirin (81-100 mg/d), alone or in combination with
management in practically all PV and ET patients, independently of
risk stratification.5,6Inherent to these treatment recommendations are
2 distinct assumptions: (1) that the benefit/risk profile of antiplatelet
therapy is consistently favorable in PV and ET, also for patients
without prior thrombosis; and (2) that the same aspirin dose and
dosing regimen is appropriate for both PV and ET and is comparable
to that recommended in non-MPN, high-risk patients.
The aims of this perspective are to challenge these assumptions
based on a critical review of the available data, to suggest a
to discuss theneed for new randomized trials of antiplatelet agents in
PV and ET.
Platelet activation, atherothrombosis, and
Enhanced platelet activation has been consistently demonstrated in
PV and ET, by different groups and methods either in vivo7,8or ex
vivo9,10suggesting a pathogenetic link between activated platelets
and thrombotic complications. In particular, markedly enhanced
urinary excretion of thromboxane (TX) A2metabolites characterizes
untreated ET and PV patients.7,8TX metabolite excretion is
a validated index of in vivo platelet activation.11As shown in
Figure 1, the urinary excretion rates of 11-dehydro-TXB2reported in
untreated ET7and PV8patients are at least comparable to unstable
angina12and higher than a variety of clinical settings at increased
cardiovascular risk.13-19Moreover, a role for circulating immature
platelets as contributors to cardiovascular events and/or poor
antiplatelet drug response has been emerging in both ET10and
non-MPN diseases.20,21Interestingly, immature platelets are in-
creased in ET and have been associated with a higher rate of
thrombosis independently of thrombocythosis.10,22-25Moreover,
JAK2 V617F has been associated with a significantly higher number
of immature platelets in ET.24,25
Incidence of arterial thrombosis and venous thromboembolism.
The pathophysiology and incidence of platelet-mediated micro-
vascular disturbances in PV and ET has been reviewed elsewhere26
and will not be addressed here.
The true incidence of major arterial thrombosis (ie, fatal and
nonfatal myocardial infarction [MI] and ischemic stroke) and venous
thromboembolism (ie, deep vein thrombosis [DVT] or pulmonary
embolism [PE]) in BCR-ABL 1–negative MPNs is difficult to
estimate because of several confounding factors across different
studies. Most reports included major thrombotic events together with
microvascular disturbances (migraine, erythromelalgia), transient
ischemic attacks (TIA), and superficial venous thrombosis. More-
over, the incidence of events is rarely expressed as percent per year,
and the majority of the cohorts include patients with different
cytoreductive strategies, with or without previous thrombosis and/or
antiplatelet treatments (mainly aspirin). In addition, the recent
revisions of diagnostic criteria27,28render comparisons across dif-
ferent patient cohorts quite problematic.
Submitted October 30, 2012; accepted December 6, 2012. Prepublished
online as Blood First Edition paper, January 18, 2013; DOI 10.1182/blood-
© 2013 by The American Society of Hematology
BLOOD, 7 MARCH 2013 x VOLUME 121, NUMBER 101701
For personal use only.on October 21, 2015. by guest
The incidence of major thrombosis in PV and ET derives mainly
fromobservationaland retrospective studies2-4,29-37(Tables 1and 2).
In reviewing these studies, we only considered those that allowed
estimating the annualized incidence of thrombotic and/or hemor-
rhagic events. Thromboses involve arteries in approximately two-
thirds of cases in both disorders. The incidence of major and minor
PV, and from 1.3% to 6.6% per year in ET (Table 1). Such figures
vary mainly accordingtoage and previous thrombosis,which are the
2 main factors consistently identified as predictors of thrombosis and
currently used for risk stratification (Table 2).
The largest prospective data for PV and ET derive from the
European Collaboration on Low-Dose Aspirin in Polycythemia Vera
(ECLAP) study4and from the Primary Thrombocythemia-1 (PT-1)
trial,32respectively. The ECLAP cohort included 1638 PV patients
monitored independently of their inclusion in the randomized trial. In
this cohort, the incidence of thrombosis was 4.9% per year, ranging
from 2.5% to 10.9% according to age and previous thrombosis4
to hydroxyurea (n 5 404, 69% with previous thrombosis) or
of aspirin.32The overall incidence of thrombosis was 2.6% per year,
with more venous thromboses in the hydroxyurea arm and more TIA
in the anagrelide arm. Based on indirect comparison of different
studies, the rate of first major and minor thrombosis in PV seems
higher than in ET, independently of age (Table 2).2-4,29-41Neverthe-
less, the incidence appears similar when only major nonfatal arterial
(MI, ischemic stroke) and venous thromboembolism (DVT, PE) are
considered: major arterial thrombosis ranged between 0.4% and 1.7%
per year in PV and 0.6% and 1.3% in ET (Table 1); major venous
thromboembolism rangedbetween0.3% and 1.5%peryearinPVand
0.2% and 1.5% in ET (Table 1). Moreover, the rate of cardiovascular
death has been reported between 0.43% and 0.72% per year in PV2-4
and 0.47% per year in ET.3
In the general population of the Western countries, the annual
incidence of major venous thromboembolism is between 0.1% and
0.2%.42In patients with PV43or ET30not treated with aspirin, the
incidence of DVT and/or PE seems ;10-fold higher, being 1.5% and
1.0% per year, respectively (Table 1). In the prospective randomized
ECLAP trial43and in the PT-1 trial,32the PV and ET patients
receiving aspirin had an incidence of major venous thromboembolism
of 0.5% and 0.6% per year, respectively.
In a meta-analysis of 6 primary prevention aspirin trials in
;95000 participants, the control annual rate of any major coronary
event and ischemic stroke was 0.34% and 0.36%, respectively.44
Similar control rates (ie, 0.3% and 0.4% per year, respectively) have
been reported in a meta-analysis of randomized trials of cyclo-
oxygenase (COX)–2 inhibitors and traditional nonsteroidal anti-
arm of the ECLAP trial in PV patients, the annual rate of myocardial
infarction and ischemic stroke was 0.2% and 1.1%, respectively.43
Incidence of recurrent arterial and venous thromboembolism.
The risk of recurrence after a first thrombosis is difficult to estimate
because the published cohorts included patients with and without
a previous event.2-4,30-37There is only one retrospective study
investigating the incidence of recurrent thrombosis in 235 PV and
259 ET patients after a first thrombotic event.29Microvascular events,
except for TIA, were not included as a primary outcome. Overall,
Figure 1. Rate of TXB2production in healthy subjects (A) and urinary excretion rates of 11-dehydro-TXB2in clinical settings at high cardiovascular risk. (A) The
metabolic fate of TXA2in vivo and the calculated rate of its production in healthy subjects on the basis of TXB2infusions and measurement of its major urinary metabolite.11,47
(B) Mean (6 standard deviation) or median (interquartile range) urinary excretion rates of 11-dehydro-TXB2in clinical settings characterized by high cardiovascular risk.7,8,12-
19CHD, coronary heart disease; PCI, percutaneous coronary intervention; T2DM, type 2 diabetes mellitus.
1702 PATRONO et alBLOOD, 7 MARCH 2013 x VOLUME 121, NUMBER 10
For personal use only.on October 21, 2015. by guest
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Carlo Patrono, Bianca Rocca and Valerio De Stefano
Platelet activation and inhibition in polycythemia vera and essential
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