(Stroke. 1995;26:995-999.)
© 1995 American Heart Association, Inc.
Articles |
From the Department of Medicine for the Elderly, Royal Infirmary of Edinburgh and Liberton Hospital (T.O'M., P.L., C.S.), and the Department of Medical Statistics, University of Edinburgh (R.A.E.), Edinburgh, Scotland.
Correspondence to Dr T. O'Malley, Cardiovascular Research Unit, Hugh Robson Bldg, George Sq, Edinburgh EH8 9XF, Scotland.
| Abstract |
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Methods We studied 58 stroke patients consecutively admitted to a geriatric medical unit. Platelet variables were measured in the acute (<48 hours after stroke) and chronic (>6 months) phases of cerebral ischemia and compared with control variables. Control patients, admitted to the same unit, were of similar age and sex and without evidence of acute vascular events.
Results Mean platelet volume was higher in acute stroke (11.3 compared with 10.1 fL in control subjects; P<.001, Student's t test). In addition, platelet count was reduced in stroke patients (255x109/L) compared with control subjects (299x109/L; P<.01). Repeated measurements of mean platelet volume and platelet count in available survivors showed no significant change from the acute phase. Platelet changes did not relate to outcome measured at 6 months.
Conclusions With the use of more precise methodology, these findings show that an increase in mean platelet volume and a reduction in platelet count are features of both the acute and nonacute phases of cerebral ischemia. It is possible that these changes precede the vascular event, and further studies are warranted.
Key Words: cerebral ischemia platelets risk factors thrombosis
| Introduction |
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Increases in platelet volume have been reported in acute myocardial infarction,11 12 13 14 15 acute cerebral ischemia,16 17 and transient ischemic attack.18 A recent study has shown that an increase in MPV is an independent risk factor for death and recurrent vascular events after myocardial infarction.19 This association was of a magnitude similar to that of better-known risk factors such as elevated fibrinogen, blood viscosity, and white cell count. Studies that have measured platelet volume in acute ischemic stroke have shown inconsistent results that may relate to the highly selected patient populations or to the different methods of measuring MPV.16 17 Our aim was to study a broad spectrum of stroke patients using a more exact methodology for MPV measurement.
| Subjects and Methods |
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Results were compared using Student's paired and unpaired t tests. Multiple logistic regression analysis was applied to determine the relative importance of different factors in predicting stroke.
| Results |
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There was a significant negative (r=-.37,
P<.003; n=58) correlation between platelet count and MPV in
stroke patients. There was no such relation in control subjects
(r=.07, P=.61; n=50). There was no significant
difference in estimated platelet mass (MPVxplatelet count), although
MPV was clearly greater in stroke patients, as shown in Fig 1
. Follow-up blood samples were possible in 29 of
38 (76.3%) survivors. MPV and platelet count did not change
significantly between the acute stroke period and late follow-up
(median, 10 months; range, 6 to 16 months). Fig 2
shows changes in MPV (0.6±1.7; mean±95% confidence interval), and
Fig 3
shows changes in platelet count
(56±101)x109/L.
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| Discussion |
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-granule
proteins,23 thereby indicating platelet activation. Others
have shown that platelet aggregation is not increased in the acute
phase but occurs several days after the event.24 This lack
of activation in the acute phase has been attributed to platelet
consumption during the event. However, the lack of agreement between
these studies may relate to specimen handling and different
methodology. Earlier studies of platelet size relied on microscopic
evaluation of platelet diameters until accurate measurement became
available with the development of aperture-impedance cell counting
systems. Two principal technologies are used to size platelets: aperture impedance of Coulter and Sysmex and flow cytometry laser optics used by Technicon. In the Coulter series, cells are held in fluid suspension and flowed through a small aperture, thereby creating a change in voltage proportional to particle size. A raw histogram is generated, and a log-normal curve is fitted to the data. Platelet count is derived from this together with the MPV, which is calculated by numerical integration. Similarly, the Sysmex measures parameters with cells in fluid suspension, although in addition the cells are hydrodynamically focused, ensuring that cells travel in a straight line through the aperture. This prevents cells flowing through at the edge of the aperture and causing spurious changes in the electrical field. It also differs from Coulter in that the upper and lower discriminators are both mobile. The distribution curve obtained is thus the actual data and not a fitted curve. MPV is calculated from the curve by a formula (see "Subjects and Methods"). In contrast, Technicon instruments use laser-optic technology to measure the size and granularity of cells in suspension. A beam of light is passed through cells, and the amount of forward scatter is proportional to size of particles, whereas side scatter equates to density or granularity. A platelet histogram is derived from the data, and MPV is calculated as the mode. Differences of up to 40% have been found when Coulter and Technicon results have been compared.25 Further differences were noted with regard to anticoagulants used: over a 39-hour period, MPV increased in EDTA by 17% when measured in the Coulter compared with a 22% decrease when the same sample was analyzed by Technicon.25 On exposure to EDTA, the most commonly used anticoagulant, there is an immediate change in shape of platelets from discoid to spherical.25 Furthermore, EDTA is thought to increase intracellular cyclic AMP and change plasma membrane permeability.26 27 This explains the progressive platelet swelling and concomitant reduction in density with time seen with the anticoagulant and explains the differences in MPV values observed between aperture-impedance and light-scattering methods. The effects of EDTA on MPV using the Sysmex autoanalyzer, as we used in this study, have been documented. Similar to Coulter systems, we found time- dependent changes using EDTA, which were maximal in the first 7 hours and stabilized after 24 hours.28 Thus, to standardize methodology in a study, it is imperative to state the anticoagulant used, time from venipuncture, cell-sizing technology, and temperature for storage of bloods.29 30 31
Our results do not agree with the earlier studies that have suggested that platelet changes occur as a result of acute stroke.16 17 Moreover, these studies may have failed to recognize time-dependent changes in MPV that occur with both EDTA and citrate anticoagulants.31 D'Erasmo et al16 measured MPV within 2 hours of venesection, when changes in platelet volume are likely to be greatest and therefore most unpredictable. A second study found a decrease in platelet count, MPV, and platelet crit (percentage volume of platelets, MPVxplatelet count) in patients with lacunar infarction.17 These authors postulated a selective loss of large active platelets to explain the decreased MPV. This study did not specify the time after venipuncture at which samples were analyzed or the temperature at which they were stored. We have used a methodology with a fixed time of analysis after venipuncture, and we maintained samples at room temperature. D'Erasmo et al16 have further suggested that the reduction in platelet count may be an early predictor of poor outcome, although the results in our less selective population do not agree with this. We found no relationship with outcome but acknowledge that our numbers are too small to provide accurate data on mortality.
Circulating platelet count shows a wide range, which was previously
interpreted as indicating that platelet production might not be tightly
regulated. In 1974, it was first observed that platelet count and MPV
were inversely related.32 Further studies confirmed this
and showed little variability in both variables over time, suggesting
that platelet production is regulated to maintain a constant platelet
mass (the product of platelet count and MPV).3 33 34 A
rise in MPV and a reduction in platelet count have been described
previously in acute myocardial infarction, persisting for up to 6 weeks
after infarct.11 12 These abnormalities have been related
to changes at the bone marrow level.11 Our findings
indicate that similar changes may occur in acute cerebral infarction,
which persist for at least 6 months after infarct. Our results also
suggest that stroke patients show a significant change in the
relationship that exists between MPV and platelet count,35
even though the total platelet mass did not change. We found no
difference in platelet mass, unlike a previous study that showed a
reduction,17 but we did see a clear increase in MPV
compared with the reference population (Fig 1
). We have shown changes
in this axis in stroke patients and have further demonstrated by
multiple logistic regression analysis that MPV is the most
important significant variable of the factors associated with stroke.
It has been suggested that MPV and platelet count are under independent
hormonal control,10 although control of platelet
production remains obscure. Some have suggested a role for
interleukin-6, interleukin-3, thrombopoietin, and colony-stimulating
factors.36 37 38 39 It is, however, generally accepted that
platelet volume and count are determined at
thrombopoiesis,8 9 and as in ischemic heart disease, these
findings may implicate primary changes occurring at the bone marrow
(megakaryocyte) level. Moreover, an increase in megakaryocyte size and
ploidy (DNA content) coincides with an increase in MPV.40
This direct association suggests the possibility that activation of
megakaryocytes, as heralded by an increase in MPV, is a feature of
ischemic stroke.
There is indirect evidence that the changes in MPV and platelet count are likely to have preceded the vascular event and are unlikely to be due to platelet consumption at the infarct site. Because the average life span of the platelet is about 8 days, the elevated MPV seen within the first 48 hours after stroke probably represents platelets released before infarction. Furthermore, it is unlikely that platelet consumption due to localized thrombosis would affect peripheral venous estimations of platelet variables. The observation that there was no difference in MPV between large cortical strokes and smaller lacunar infarctions also lends support to this view. In addition, the fact that the observed increase in MPV and reduction in platelet count have remained unchanged in poststroke survivors is further evidence that changes are likely to precede the acute event. We suggest that large platelets may promote the thrombotic event in a susceptible individual. We suggest that the increase in MPV may have contributed to the development of the stroke rather than simply being a consequence of the acute event itself.
In conclusion, this study has shown an elevation of MPV and reduction of platelet count in acute stroke that persist long after the acute event. Within this relationship and confounding for other significant variables in univariate analysis, an increase in MPV is independently associated with stroke. The observations here suggest a role for larger platelets in the genesis of cerebral thrombosis and are likely to represent changes occurring at thrombopoiesis. Further research is required into the role of platelet volume in stroke pathology, outcome, and, most importantly, in individuals at risk for stroke.
| Acknowledgments |
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Received August 13, 1994; revision received December 20, 1994; accepted February 20, 1995.
| References |
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