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Blood, Vol. 91 No. 4 (February 15), 1998:
pp. 1288-1294
Correlation of Thrombosis With Increased Platelet Turnover in
Thrombocytosis
By
Henry M. Rinder,
Judith E. Schuster,
Christine S. Rinder,
Chao Wang,
Helen J. Schweidler, and
Brian R. Smith
From the Department of Laboratory Medicine, Yale University School of
Medicine, New Haven, CT.
 |
ABSTRACT |
There are no readily applicable methods to routinely assess
thrombosis risk and treatment response in thrombocytosis. Reticulated platelets (RP) define the most recently released platelets in the
circulation, and the RP% has been shown to estimate platelet turnover
in thrombocytopenic states. We examined whether increased RP values
were associated with thrombotic complications in thrombocytosis. Platelet count, RP%, and absolute RP count were measured at
presentation in 83 patients with chronic or transient thrombocytosis,
46 patients with deep vein (DVT) or arterial (ART) thrombosis and
normal platelet counts, and 83 healthy controls with normal platelet
counts. Chronic thrombocytosis patients presenting with thrombosis (n
= 14) had significantly higher RP% (14.7% ± 10.1%, mean ± SD)
than asymptomatic chronic thrombocytosis patients (n = 23, RP%
= 3.4% ± 1.8%), healthy controls (3.4% ± 1.3%), DVT
patients (n = 21, 3.8% ± 2.1%), or ART patients (n = 25, 4.5% ± 4.1%, P < .05 for all comparisons). Chronic thrombocytosis patients with thrombosis also had significantly higher absolute RP counts than asymptomatic chronic thrombocytosis patients (98 ± 64 × 109/L [range, 54 to 249 × 109/L] v 30 ± 13 × 109/L
[range, 11 to 51 × 109/L]; P = .0004),
whereas healthy controls, DVT, and ART patients had similarly low
absolute RP counts (6 ± 6 × 109/L, 9 ± 7 × 109/L, and 11 ± 7 × 109/L,
respectively; P > .49). The RP% and absolute RP counts
remained significantly higher in chronic thrombocytosis patients with
thrombosis when patients were further subdivided into primary
myeloproliferative disorders versus secondary thrombocytosis. Similarly
elevated RP percentages and absolute counts were also noted in
transient thrombocytosis patients with thrombosis (n = 6, 11.5% ± 4.4% and 90 ± 46 × 109/L, respectively) when compared
with asymptomatic transient thrombocytosis patients (n = 40, 4.5% ± 2.7% and 35 ± 16 × 109/L, respectively) and to all
control groups (P < .05 for all comparisons). In
addition, 7 of 8 thrombocytosis patients who were studied before developing symptoms of thrombosis had elevated absolute RP counts compared with only 1 of 63 thrombocytosis patients who remained asymptomatic. Follow-up studies in seven chronic thrombocytosis patients showed that successful aspirin treatment of symptomatic recurrent thrombosis significantly reduced the RP% from 17.1% ± 10.9% before therapy to 4.8% ± 2.0% after therapy; absolute RP
counts decreased from 102 ± 67 × 109/L to 26 ± 10 × 109/L (P < .01 for both). We conclude that
thrombosis in the setting of an elevated platelet count is associated
with increased platelet turnover, which is reversed by aspirin therapy.
Measurement of reticulated platelets to assess platelet turnover may be
useful in evaluating both treatment response and thrombotic risk in
thrombocytosis.
| |
INTRODUCTION |
PATIENTS WITH PRIMARY thrombocytosis
associated with myeloproliferative disorders (MPD) may have
hemorrhagic1,2 and thrombotic complications that are
presumed to relate to either abnormal platelet function,3-6
the increased number of circulating platelets, or both.7-9
Secondary or reactive thrombocytosis has also been linked to thrombotic
complications in various settings, although some investigators believe
that the evidence for a direct association is minimal in this patient
group.7,10-14 However, in either group, specific risk
factors for thrombotic or bleeding complications in the setting of an
increased platelet count are relatively unclear. In at least one study,
higher platelet counts appeared to correlate best with bleeding,
whereas lower (but still elevated) counts tended to be associated with
thrombosis15; nonetheless, threshold counts for
intervention are not well defined. Platelets from primary
thrombocytosis patients show abnormal arachadonic acid metabolism and
agonist response,16-18 but this finding may not predict
either thrombosis or bleeding.16,18 In vivo platelet
activation has been demonstrated during thrombosis in both primary and
secondary thrombocytosis,6,19-21 and both platelet
activation and decreased isotopic platelet half-life have been noted in
MPD patients with erythromelalgia.22,23 However, these
specialized laboratory measurements are not readily accessible; hence,
examination of a simpler measurement of platelet turnover might provide
both mechanistic and clinically valuable information on the occurrence
of thrombosis in the setting of thrombocytosis, regardless of the
underlying cause.
Similar to red blood cell reticulocytes,24 reticulated
platelets (RP) are defined by their increased RNA
content.25,26 In animals, RP appear to be the youngest
circulating platelets,27 and there is evidence in a dog
model that the youngest platelets are also the most functionally
active.28 Thrombocytopenia due to decreased platelet
survival has been shown to result in an increased
RP%.26,29-31 Furthermore, RP may also reflect increased platelet turnover in the setting of a normal platelet count, because women who went on to develop pre-eclampsia had an elevated RP% before
they became symptomatic or developed thrombocytopenia.32 Therefore, RP measurements might provide a rapid and simple measure of
platelet turnover in patients with thrombocytosis. RP values might, in
turn, reflect increased platelet consumption during the evolution of
thrombosis and/or as a prelude to the development of
thrombosis. We examined whether increased reticulated platelet values
were associated with thrombotic complications in patients with
thrombocytosis and compared this group with healthy controls and
patients presenting with deep vein or arterial thrombosis in the
setting of a normal platelet count.
| |
MATERIALS AND METHODS |
Patients.
This study was approved by the Yale University Human Investigation
Committee. All patients were consecutively enrolled. Thrombocytosis patients were included if they had a platelet count greater than 600 × 109/L.1,2 Patients with deep vein
thrombosis (DVT) or arterial thrombosis (ART) were included if their
platelet count was between 150 and 450 × 109/L.
Patients were excluded if they had prolonged coagulation studies or if
they were receiving anticoagulant or cytotoxic therapy, growth factors,
or medications affecting platelet function. A healthy volunteer on no
medications with a platelet count between 150 and 450 × 109/L was included as a simultaneous control in each study.
Ninety-eight thrombocytosis patients, 48 ART patients, and 25 DVT
patients were initially enrolled. Forty-two subjects were subsequently excluded because they were receiving coumadin (n = 5), chemotherapeutic agents (n = 8), recombinant growth factors (n = 6), or aspirin (n = 23)
at enrollment, leaving 83 thrombocytosis patients, 25 ART patients, and
21 DVT patients evaluable for the study.
Patient records were reviewed by an investigator blinded to all
laboratory results. Thrombocytosis was defined as transient if the
platelet count was within the normal range (<450 × 109/L) within 4 months before or after the study sample and
the patient was not receiving cytotoxic therapy. Chronic thrombocytosis
was defined as a platelet count persistently greater than 600 × 109/L over the same time period and was additionally
confirmed by an independent clinical hematology consultant reviewing
the patient's history. Patients with chronic thrombocytosis were
subdivided into (1) primary MPD-associated thrombocytosis due to
polycythemia vera (PV) or essential thrombocythemia (ET)1,9
or (2) secondary thrombocytosis associated with diseases other than
primary hematopoietic disorders.33 All thrombotic events
were confirmed by (1) direct observation at surgery; (2) angiography,
ultrasonography, or magnetic resonance imaging; (3) classic symptoms of
erythromelalgia; or (4) electrocardiogram and creatinine kinase
documentation of a myocardial infarction.
Blood sampling and preparation.
Blood samples were drawn at presentation to the hospital or clinic,
before any medical or surgical intervention was begun. Fourteen
patients with chronic thrombocytosis also had follow-up blood studies
performed at the first new visit after their initial study. After
informed consent, venous blood was drawn into EDTA (1.5 mg/mL); a
complete blood count (CBC) was confirmed by manual counts. Platelets
were prepared from blood as previously described.34 Briefly, blood was centrifuged to obtain platelet-rich plasma; platelets were washed with Tyrodes buffer and fixed in 1%
paraformaldehyde at 4°C for 1 hour. After fixation, platelets were
washed and resuspended at 200 × 109/L.
Labeling.
One hundred microliters of the platelet suspension was labeled with
phycoerythrin (PE)-anti-gpIIb/IIIa (P2; Coulter, Hialeah, FL) and then
washed and incubated with thiazole orange (Retic-COUNT; Becton
Dickinson Immunocytometry Systems, San Jose, CA) at 22°C for 60 minutes (final concentration, 90% vol/vol).31,33,35 Platelet samples pretreated with ribonuclease showed loss of thiazole fluorescence, as previously described.
Flow cytometry.
Measurement of platelet thiazole fluorescence was performed on a
FACScan (Becton Dickinson) flow cytometer with compensation settings to
prevent PE fluorescence bleedover into thiazole orange fluorescence;
quantitation of the RP% was performed as previously described.31,34,35 The coefficient of variation for
repeated RP measurements of the same sample was less than 5%. The
absolute RP count was calculated by multiplying the RP% by the
platelet count.
Statistics.
Statistical analysis was performed with Statgraphics Plus (Manugistics,
Rockville, MD). Comparisons between groups were examined for
significance (P < .05) with the Student's t-test or,
if distribution fitting by  2 analysis showed a
non-normal distribution, the Mann-Whitney U-test for nonparametric
values. The strength of associated risk factors for a thrombotic
complication was estimated by calculation of the odds ratio and 95%
confidence intervals (95% CI).
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RESULTS |
Patient demographics.
The 83 thrombocytosis patients studied included 48 women and 35 men
ranging from 18 to 84 years of age, with a median age of 52 years.
There were 37 subjects (24 women and 13 men) with chronic
thrombocytosis; of these, 12 had chronic primary thrombocytosis associated with PV (n = 3) or ET (n = 9;
Table 1). None of the primary
thrombocytosis patients had had a prior thrombotic event, and all were
previously untreated (except for phlebotomy in the 3 patients with PV)
at enrollment. Twenty-five patients had chronic secondary
thrombocytosis associated with sickle cell disease (n = 7),
remote (>1 year) splenectomy (n = 8), or chronic inflammatory diseases (n = 10; Table 1). There were 46 subjects (23 women and 23 men) with transient thrombocytosis (Table 1) associated with acute
infectious or inflammatory disease (n = 24), massive hemorrhage (n = 8), malignancy (n = 9), or recent (<12 weeks) splenectomy for trauma (n = 5), all conditions previously reported to
be associated with thrombocytosis.10,36-41
The 14 chronic thrombocytosis patients with follow-up studies had blood
samples drawn between 4 and 30 weeks after enrollment. One patient with
ET was receiving aspirin and hydroxyurea and was excluded from
follow-up analysis. Of the remaining 13 patients, 5 of 7 patients with
chronic primary thrombocytosis (4 with ET and 1 with PV) and 2 of 6 patients with chronic secondary thrombocytosis (both postsplenectomy)
were receiving aspirin alone; the remaining 6 patients (1 with PV, 1 with ET, 2 with sickle cell disease, and 2 postsplenectomy) were not
receiving any medication at follow-up.
Twenty of the 83 thrombocytosis patients (24%) had thrombotic events;
8 of these patients had blood studies drawn more than 24 hours before
they became symptomatic, whereas 12 had blood studies drawn
simultaneous with or shortly (<24 hours) after the onset of
thrombotic symptoms. Age and gender distribution did not differ
significantly between patients with and without thrombosis in any of
the chronic or transient thrombocytosis groups (P > .27 for
all comparisons). The average age for all thrombocytosis patients with
(n = 20) and without (n = 63) thrombosis was 50 ± 21 (SD) years and
52 ± 17 years, respectively (P = .90).
Of the 21 DVT patients, there were 12 women and 9 men with a median age
of 53 years (range, 22 to 76 years), which was not different from all
thrombocytosis patients (P = .74). All 21 DVT patients
presented within 36 hours after developing symptoms of thrombosis, and
all had blood studies drawn at presentation before therapy was begun.
Of the 25 ART patients, there were 12 women and 13 men with a median
age of 62 years (range, 27 to 81 years), which did not differ from the
thrombocytosis group (P = .61). Ten ART patients had myocardial
infarction, whereas 15 had thrombosis involving the middle cerebral,
iliac, femoral, or popliteal arteries; all ART patients had blood
studies drawn less than 12 hours after developing symptoms and before
therapy was begun.
Chronic thrombocytosis (n = 37).
Seven of the 12 individuals (58%) with chronic primary
(MPD-associated) thrombocytosis had arterial/arteriolar thrombotic complications, including 5 patients (4 ET and 1 PV) with
erythromelalgia and 2 patients (ET) with brachial and superior
mesenteric artery thromboses, respectively. Seven of 25 patients (28%)
with chronic secondary thrombocytosis had acute thrombotic events;
these included DVT in 1 of 7 sickle cell (SS) disease patients;
thromboses of the brachial and middle cerebral arteries, respectively,
in 2 of 8 patients with remote splenectomy; and thromboses of the
femoral, popliteal, and splenic arteries, and infrarenal aorta,
respectively, in 4 of 10 patients with chronic inflammatory diseases.
These inflammatory disease patients carried diagnoses of iron
deficiency anemia (n = 1), rheumatoid arthritis (n = 1), and diabetes
mellitus (n = 2).
The 14 chronic thrombocytosis patients with thrombotic events had a
significantly higher RP% (14.7% ± 10.1%, mean ± SD) than both asymptomatic chronic thrombocytosis subjects (n = 23, 3.4% ± 1.8%) and normal controls (3.4% ± 1.3%, P < .002 for both comparisons); the RP% in asymptomatic chronic
thrombocytosis patients did not differ significantly from control
values (P = .82). Patients with thrombosis also had a
significantly higher absolute RP count, without any overlap, than those
without thrombosis, 98 ± 64 × 109/L (range, 54 to
249 × 109/L) versus 30 ± 13 × 109/L (range, 11 to 51 × 109/L; P = .0004). When chronic thrombocytosis patients were further subdivided
into primary and secondary causes of thrombocytosis (Table 2 and
Fig 1), both the RP% and the absolute
RP counts remained significantly higher in patients with thrombosis
than in asymptomatic subjects. Furthermore, when symptomatic chronic thrombocytosis patients (primary and secondary) were subdivided into
those with erythromelalgia and those with larger arterial or venous
events, both the RP% and absolute RP counts remained higher in these
subsets compared with asymptomatic chronic thrombocytosis patients
(P < .05 for all comparisons).
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| Fig 1.
Absolute RP counts (RP% × platelet count) in
thrombocytosis. Thrombocytosis patients include those who
presented with symptomatic thrombosis ( ), those studied more than 24 hours before developing thrombosis ( ), and those who remained
asymptomatic ( ), as well as normal controls () with
normal platelet counts. Thrombocytosis patients are further subdivided
into those with (1) transient thrombocytosis; (2) chronic secondary
thrombocytosis; and (3) chronic primary (MPD-associated)
thrombocytosis. The mean and mean + 2 SD values for
normal controls are shown as solid and dotted lines,
respectively.
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There was a trend towards significantly higher platelet counts in all
chronic thrombocytosis subjects with thrombosis (871 ± 218 × 109/L) compared with patients who did not have thrombosis
(729 ± 131 × 109/L; P = .08). This trend
was due to the platelet counts being significantly higher in chronic
secondary thrombocytosis patients with thrombosis (range, 625 to 1,250 × 109/L) than in asymptomatic patients (range, 600 to
843 × 109/L; P = .045; Table 2); platelet
counts did not differ significantly between chronic primary
thrombocytosis patients with and without thrombosis (range, 653 to 851 × 109/L v 688 to 1,120 × 109/L, respectively; P = .91; Table 2).
Transient thrombocytosis (n = 46).
Six patients with transient thrombocytosis had acute thrombotic events.
One patient with underlying inflammatory disease had a large arterial
thrombosis, and two patients with inflammatory disease and malignancy,
respectively, had myocardial infarctions. DVT occurred in 2 patients
with malignancy and in 1 patient postsplenectomy. Similar to chronic
thrombocytosis, patients with transient thrombocytosis and thrombosis
had significantly higher RP% and absolute RP counts than asymptomatic
patients (Table 2) or normal controls (P < .01 for both). By
contrast, platelet counts did not differ (P = .17) between
thrombotic and asymptomatic patients with transient thrombocytosis
(Table 2), and the RP% in asymptomatic transient thrombocytosis
subjects was also not significantly different (P = .48) from
normal controls (Table 2).
Reticulated platelet studies drawn before thrombosis.
Seventy-one of the 83 thrombocytosis patients had blood studies drawn
when they were asymptomatic (Fig 1), and 8 of 71 (11%) subsequently
developed thrombotic complications (all within 16 days of blood
sampling). Six of these 8 (75%) symptomatic patients had an RP%
greater than 6.0% (the mean + 2 SD value for normal controls), whereas only 10 of 63 patients (16%) who remained
asymptomatic had an RP% greater than 6%; therefore, the odds ratio
for developing a thrombosis with an RP% greater than 6% was 10.3 (3.83 to 46.2, 95%CI). By contrast, only 1 of 8 (13%) thrombosis
patients had a platelet count greater than 1,000 × 109/L compared with 13 of 63 (21%) asymptomatic patients,
yielding an odds ratio of 0.51 (0.07 to 3.81, 95% CI). For an absolute RP count greater than 60 × 109/L (the product of an
RP% >6% and a platelet count >1,000 × 109/L), 7 of 8 (88%) thrombocytosis patients who subsequently developed thrombosis exceeded this value compared with only 1 of 63 (2%) asymptomatic patients (Fig 1). The odds ratio for thrombosis with an
absolute RP count greater than 60 × 109/L was 56.0 (7.89 to 398, 95% CI).
DVT and ART patients with normal platelet counts.
The 21 patients with DVT and the 25 patients with ART had platelet
counts (272 ± 87 × 109/L and 286 ± 95 × 109/L), RP% (3.8% ± 2.1% and 4.5% ± 4.1%), and absolute RP counts (9 ± 7 × 109/L and
11 ± 7 × 109/L), respectively, that did not
differ from healthy controls (P > .49 for all comparisons;
Table 3). Furthermore, the RP% of both DVT
and ART patients was similar to asymptomatic thrombocytosis patients
(P > .30 for all comparisons); by contrast, the RP% in both
DVT and ART patients was significantly lower than the RP% in all
symptomatic thrombocytosis subgroups (Table 2) as well as in the
subgroup of all thrombocytosis patients with localized venous or
arterial thrombosis (n = 15, 14.9% ± 10.1%; P < .05 for
all comparisons).
Follow-up studies in chronic thrombocytosis (n = 13).
At follow-up, the 7 patients receiving aspirin had a significant
decrease in their RP% from 17.1% ± 10.9% to 4.8% ± 2.0%
(P = .006), and the absolute RP counts decreased from
102 ± 67 × 109/L to 26 ± 10 × 109/L (Fig 2A; P = .007), despite platelet counts remaining unchanged (687 ± 211 × 109/L to 635 ± 191 × 109/L;
P = .42). Of note, after the inititation of aspirin, the
absolute RP counts in treated patients ranged from 7 to 35 × 109/L, below the arbitrary risk level of 60 × 109/L; erythromelalgia resolved in 3 MPD patients treated
with aspirin, and none of the aspirin-treated patients had thrombosis
during the follow-up period. By contrast, platelet counts, RP%, and
absolute RP counts did not change in 4 of the 6 untreated patients (Fig 2B) who were asymptomatic at follow-up. However, 2 untreated patients with sickle cell disease and PV suffered from subsequent pulmonary embolism and superior mesenteric artery thrombosis, respectively. Although follow-up studies were not obtained before becoming
symptomatic, absolute RP counts on admission had increased dramatically
in both patients (Fig 2B).
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| Fig 2.
Absolute RP counts (RP% × platelet count) in chronic
thrombocytosis patients (A) before and after treatment with aspirin
() and (B) at baseline and follow-up in untreated chronic
thrombocytosis patients ( ). Initial (baseline) values were drawn at
enrollment into the study; follow-up studies were drawn at the first
new visit after enrollment. The interval between studies ranged from 4 to 23 weeks and 7 to 30 weeks in treated and untreated subjects, respectively.
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| |
DISCUSSION |
This study has used a rapid and accessible method of evaluating
platelet kinetics to show that increased percentages and absolute numbers of RP are highly associated with thrombosis in patients with
thrombocytosis. All subsets of thrombocytosis patients with thrombosis
had significantly higher RP% compared with patients without
thrombosis, and all chronic thrombocytosis patients with thrombosis had
a greater absolute number of RP than the highest value observed in
asymptomatic subjects. Treatment with aspirin uniformly caused a
decrease in the RP% and absolute RP counts concomitant with complete
symptomatic improvement in patients with erythromelalgia and the
absence of recurrent thrombosis in all treated patients. These data
suggest that changes in platelet turnover in the setting of an elevated
platelet count may be reflected by RP values, and such changes could be
correlated with successful antithrombotic therapy. Moreover, when
asymptomatic thrombocytosis patients were studied, an elevated RP% and
absolute RP count were more often associated with subsequent
development of a thrombotic complication, with respective odds ratios
of 10.3 and 56.0. The positive predictive values for developing
symptomatic thrombosis with an RP% greater than 6% or an absolute RP
count greater than 60 × 109/L were 38% and 88%,
respectively. Therefore, although our patient numbers are small and
require confirmation in a prospective manner, these data further
suggest that changes in RP values might reflect increased thrombotic
risk in thrombocytosis. A larger prospective study is required to
determine whether observing serial RP measurements over time in
asymptomatic thrombocytosis patients would reliably produce an adequate
interval between an increase in RP values and the development of
symptomatic thrombotic events that would allow for earlier, and
possibly more successful, intervention.42-44
Reticulated platelets have been shown to be the youngest circulating
platelets in animals,27,45 and increased RP percentages appear to reflect increased platelet turnover in humans with
destructive thrombocytopenia.26,29,30,35 Although RP have
not been formally studied with respect to platelet survival in
thrombocytosis, this study's findings of normal RP% in asymptomatic
thrombocytosis patients is consistent with previous reports of normal
platelet survival in asymptomatic patients with reactive thrombocytosis or ET.22 Furthermore, thrombosis in thrombocytosis patients has been associated with increased platelet turnover; MPD patients with
erythromelalgia had decreased isotopic platelet survival that improved
after aspirin therapy, suggesting that enhanced platelet
activation has a role in this phenomenon.22,23 In fact,
increased levels of circulating activated platelets or platelet
aggregates have been noted in MPD patients with
thrombosis.6,17,20,23 Our current study would support the
hypothesis that an aspirin-sensitive platelet pathology is partly
responsible for the simultaneous occurrence of thrombosis and increased
platelet turnover, because we demonstrated a decrease in the RP% and
absolute RP count in those patients who received aspirin therapy. Thus,
RP measures may provide a noninvasive, readily applicable means of
monitoring the response to therapy in thrombocytosis.
The increased RP values in thrombocytosis patients with thrombus may
reflect increased platelet turnover due to loss of platelets into large
arterial or smaller, but more widespread, arteriolar clots
(erythromelalgia).46 Alternatively, increased RP
measurements may reflect an abnormal platelet physiology3,38
(perhaps aspirin-sensitive) causing increased platelet adhesion to endothelium, leukocytes,47,48 or other platelets and
subsequent removal of those platelets from the circulation without
necessarily forming a true clot. Indeed, the latter explanation has
been previously cited in studies showing increased platelet turnover in
asymptomatic ET patients.22 Although the fact that some
thrombocytosis patients in the current study showed increased RP values
before becoming symptomatic similarly suggests the latter mechanism, it
is also possible that the increase in platelet turnover in these
patients was the result of subclinical thrombosis. However, against
this possibility is the fact that we did not find increased RP
percentages in symptomatic patients presenting with DVT or ART and
normal platelet counts as compared with normal controls. Nonetheless, an alternate explanation for this finding may be that the
arteriolar/arterial platelet deposition in thrombocytosis is widespread
enough to produce increased platelet turnover, as compared with the
relatively localized venous or arterial thrombosis associated with
normal platelet counts. Even with these caveats, we favor the
explanation that thrombocytosis patients who are predisposed to
thrombosis13 have an underlying platelet pathology
associated with increased platelet turnover that is correctable by
aspirin therapy. This latter hypothesis has been suggested by several
other studies49,50 and is further supported by our finding
that localized venous or arterial thrombosis in thrombocytosis patients
was associated with a higher RP% than in DVT or ART patients with
normal platelet counts.
We found a 58% incidence of arterial/arteriolar thrombotic events in
untreated MPD patients, whereas patients with chronic secondary
thrombocytosis had a 28% incidence of thrombotic phenomena that
occurred primarily in the large arterial circulation. Most studies
would suggest that MPD platelets have an abnormal
physiology,3 whereas in reactive thrombocytosis, thrombotic
risk may be based more on the specific setting associated with the
elevated platelet count.10 The incidence of thrombotic
complications in all patients with thrombocytosis (including both
primary and secondary causes) has been reported to range from 11% to
80%,2,5,51 and some series report as high as a 20%
incidence of fatal thrombotic events,16,52 suggesting that
there are patient subsets with a high risk of thrombotic complications.
The current study was not designed a priori as an epidemiologic survey
and hence cannot formally address the question of whether secondary
thrombocytosis is significantly prothrombotic. Patients in this study
were identified sequentially on the basis of CBC with platelet counts
 600 × 109/L received by our hematology
laboratory; it is relevant to note that less than 25% of the CBC
studies in our laboratory are from outpatients, and more than 80% of
these outpatient samples are from specialty referral clinics. Thus, our
laboratory sampling is biased toward a more ill and complicated patient
population, and this bias may be responsible for the high incidence of
thrombotic complications in chronic secondary thrombocytosis patients.
However, regardless of the pathophysiology responsible for symptomatic thrombosis, this study found that increased platelet turnover in all
subsets of thrombocytosis patients was associated with thrombosis.
In summary, thrombocytosis is associated with normal percentages of
reticulated platelets when patients are free of thrombotic complications; in the perithrombotic period and specifically in a
subset of asymptomatic patients who subsequently developed thrombosis, the percentage and absolute number of reticulated platelets were elevated, consistent with increased platelet turnover. By contrast, increased RP values were not seen in venous or arterial thrombosis patients with normal platelet counts. An aspirin-sensitive
pathophysiology may be responsible for the association of increased
platelet turnover with symptomatic thrombocytosis, because aspirin
therapy resulted in lower RP values and correlated with symptomatic
improvement. Reticulated platelet measurements may prove useful for
monitoring therapeutic responses in patients with thrombocytosis and
perhaps in stratifying those patients at risk for thrombotic
complications.
| |
FOOTNOTES |
Submitted April 2, 1997;
accepted September 29, 1997.
Supported by National Institutes of Health Grants No. HL02668 (H.M.R.)
and HL47193 (B.R.S.) and by an American Heart Association Clinician-Scientist Award (C.S.R.).
Address reprint requests to Henry M. Rinder, MD, Department of
Laboratory Medicine, Yale University School of Medicine, PO Box 208035, New Haven, CT 06520-8035.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section 1734 solely
to indicate this fact.
| |
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Abstract
Introduction
Abstract