Heart & Lung 43 (2014) 569e573

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Heart & Lung

journal homepage: www.heartandlung.org

Thrombocytopenia is an independent predictor of mortality

in pulmonary hypertension
Mohammad Khalid Mojadidi, MD *, David Goodman-Meza, MD,
Parham Eshtehardi, MD, FAHA, Mohan Pamerla, MD, Pavlos Msaouel, MD, PhD,
Scott C. Roberts, MD, Jared S. Winoker, MD, Neville M. Jadeja, MD, Ronald Zolty, MD
Division of Cardiology, Department of Medicine, Albert Einstein College of Medicine, Montefiore Medical Center and Jacobi Medical Center,
Bronx, NY, USA

a r t i c l e i n f o a b s t r a c t

Article history: Background: Established prognostic factors for pulmonary hypertension (PH) include brain natriuretic
Received 25 April 2014 peptide, troponins and hemodynamic measures such as central venous pressure and cardiac output. The
Received in revised form prognostic role of thrombocytopenia, however, has yet to be determined in patients with PH. The aim of
21 July 2014
this study was to evaluate effect of thrombocytopenia on mortality in patients with PH.
Accepted 23 July 2014
Available online 29 August 2014
Methods: 521 patients with severe PH, defined by a pulmonary artery systolic pressure >60 mm Hg on
transthoracic echocardiography and a platelet count measured within one month after diagnosis were
enrolled from three hospitals of Montefiore Medical Center. The cohort was divided into two groups:
Keywords:
Thrombocytopenia
mild thrombocytopenia to a normal platelet count (platelet count 100,000e450,000 per uL); and
Pulmonary hypertension moderate to severe thrombocytopenia (platelet count <100,000 per uL). Inpatient and social security
Platelets death records were used to determine 1-year all-cause mortality.
Mortality Results: Mean age was 70.3
15.6 with 40% of patients being male. Overall mortality at 1 year was 30.7%, with
increased mortality in PH patients with mild thrombocytopenia compared to those with moderate to severe
thrombocytopenia (46.5% vs. 27.0%, p < 0.001). In multivariate analysis, moderate to severe thrombocytopenia
remained an independent predictor of mortality (HR 1.798, 95% CI 1.240e2.607, p ¼ 0.002).
Conclusions: Moderate to severe thrombocytopenia is an independent predictor of higher mortality in
patients with severe PH. These findings may support the use of thrombocytopenia as a useful prognostic
indicator in patients with severe PH.
Ó 2014 Elsevier Inc. All rights reserved.

Introduction that facilitate the evaluation of patients with PH in order to guide

appropriate and timely intervention and medical therapy. With no
Pulmonary hypertension (PH) remains a serious debilitating intervention, uncontrolled PH often leads to right-sided heart
condition with increasing incidence of hospitalization and mor- failure and death, occurring within 2e3 years of diagnosis in those
tality in the United States.1 It is usually classified as either pulmo- with pulmonary arterial hypertension.5
nary arterial hypertension or PH secondary to other etiologies such Established prognostic factors that predict mortality in patients
as left ventricular disease, hypoxic lung conditions or pulmonary with PH include brain natriuretic peptide, troponin T and hemody-
thromboembolic disease.2 While the cause of PH may vary from namic measurements such as cardiac output and central venous
one patient to another, early detection and treatment results in a pressure.6,7,8 Thrombocytopenia has previously been associated with
reduction of both morbidity and mortality regardless of etiology or PH9,10 where the severity of certain hemodynamic parameters (i.e.
clinical course.3,4 Thus, it is essential to establish prognostic factors right atrial pressure and mixed venous oxygen saturation) directly
correlated to a drop in platelet count in patients with pulmonary
Abbreviations: PH, Pulmonary hypertension; PASP, Pulmonary artery systolic arterial hypertension.9 It is postulated that changes in hemodynamics
pressure; ACEi, Angiotensin-converting enzyme inhibitor; LVEF, Left ventricular and vascular system architecture facilitate stasis of blood and pre-
ejection fraction. dispose to platelet aggregation and subsequent thrombocytopenia.
Disclosures: None. However, the role of thrombocytopenia as an independent prognostic
* Corresponding author. Department of Medicine, Albert Einstein College of
factor in patients with PH has yet to be determined. The aim of this
Medicine, Jacobi Medical Center, 1400 Pelham Parkway S, Building 1, Rm 3N1,
Bronx, NY 10461, USA. Tel.: þ1 7189185656; fax: þ1 3102670384. study was to investigate the effect of severity of thrombocytopenia on
E-mail address: [email protected] (M.K. Mojadidi). mortality in patients with severe PH.

0147-9563/$ e see front matter Ó 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.hrtlng.2014.07.006

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Methods Results

Study design Baseline demographic, clinical, medications, electrocardiographic

and echocardiographic data of 521 patients included in this analysis
From January 2009 to January 2011, we retrospectively identified stratified by platelet count are outlined in Table 1. Briefly, mean PASP
patients with severe PH. The inclusion criteria included subjects 18 was 73.8
11.6 mm Hg, left ventricular ejection fraction (LVEF) was
years old, the presence of a transthoracic echocardiogram with a 52.3
18.1 and 29.6% had LVEF of less than 40%. Right heart
pulmonary artery systolic pressure (PASP) greater than 60 mm Hg (or
documentation of PH by a transthoracic echocardiogram), and a Table 1
documented platelet count ordered within one month of diagnosis of Baseline demographic, clinical, electrocardiographic and echocardiographic findings
PH. For the diagnosis of PH in this study, we reviewed the echocar- of patients with pulmonary hypertension stratified by platelet count (n ¼ 521).
diographic findings from multiple studies done for a patient at Platelet count
different time points and if there was a significant discrepancy be-
100,000 Less than p valuea
tween reported PASP, those patients were not included in the study. e450,000 100,000
The study included 521 patients who were admitted to (or seen in the (n ¼ 422) (n ¼ 99)
outpatient clinics of) Montefiore Medical Center’s hospitals (Moses Age (years) 70.2
15.5 70.8
15.9 0.743
Hospital, Weiler Hospital and Wakefield Hospital), which are large Male 168 (39.8) 41 (41.4) 0.770
urban academic tertiary care centers in the Bronx, New York. Patients Race 0.004
Non-Hispanic White 93 (22.0) 37 (37.4)
were identified from the Montefiore Medical Center’s Clinical Infor-
Non-Hispanic Black 165 (39.1) 35 (35.4)
mation System (Emerging Health Information Technology, Yonkers, Hispanic 139 (32.9) 19 (19.2)
New York) using the Clinical Looking Glass, a proprietary query tool Other 25 (5.9) 8 (8.1)
and software application that allows clinicians and researchers to Hypertension 312 (73.9) 70 (70.7) 0.514
identify populations of interest from the Montefiore Medical Centers’ Hyperlipidemia 113 (26.8) 22 (22.2) 0.352
Diabetes 178 (42.2) 42 (42.4) 0.965
database, and to gather information about the demographics, clinical,
Myocardial infarction 41 (9.7) 10 (10.1) 0.908
and outcome data.11e15 The database is combined monthly with the Stroke 26 (6.2) 5 (5.1) 0.674
Social Security Death Registry, which allows extraction of clinical COPD 103 (24.4) 17 (17.2) 0.124
outcomes including mortality and hospitalization rates. Patients were Liver disease 29 (6.9) 21 (21.2) <0.001
evaluated for platelet counts and, based on prior studies,16,17 subse- Rheumatologic disease 9 (2.1) 0 (0.0) 0.143
Medications
quently divided into two groups based on the severity of thrombo- Aspirin 97 (23.0) 11 (11.1) 0.009
cytopenia: 1) mild thrombocytopenia to a normal platelet count Plavix 35 (8.3) 6 (6.1) 0.458
(100,000e450,000 per uL); 2) moderate to severe thrombocytopenia ACEi 69 (16.4) 9 (9.1) 0.068
(platelet count < 100,000). Patients’ records were reviewed to deter- ARB 4 (0.9) 2 (2.0) 0.368
Beta-blocker 139 (32.9) 15 (15.2) <0.001
mine their baseline characteristics, co-morbidities, medications,
Diuretic 7 (1.7) 1 (1.0) 0.637
baseline electrocardiograms and echocardiograms, and any significant Spironolactone 36 (8.5) 5 (5.1) 0.247
laboratory values. This multi-center study was approved by the CCB 54 (12.8) 6 (6.1) 0.059
Institutional Review Board of Albert Einstein College of Medicine of Digoxin 12 (2.8) 6 (6.1) 0.115
Yeshiva University (Protocol Number: 12-10-355). Statin 65 (15.4) 8 (8.1) 0.059
Prostaglandin inhibitor 3 (0.7) 0 (0.0) 0.400
PDE5I 13 (3.1) 5 (5.1) 0.334
Clinical outcomes Heparin exposure 146 (33.9) 44 (44.4) 0.050
Heparin subcutaneous 122 (28.9) 36 (36.4) 0.147
The clinical outcome of this study was 1-year all-cause mortality. Heparin intravenous 36 (8.5) 14 (14.1) 0.091
EKG findings
Atrial fibrillation 190 (45.0) 45 (45.5) 0.938
Statistical analysis RBBB 18 (4.3) 4 (4.0) 0.920
Laboratory findings
Continuous variables were expressed as the mean
standard de- Pro-BNP >100 ng 234 (55.5) 48 (48.5) 0.211
viation. Categorical variables were expressed as number and per- Troponins >0.01 ng 140 (33.2) 46 (46.5) 0.013
Hemoglobin <10.5 g/dl 134 (31.8) 37 (37.4) 0.284
centage. Demographic and clinical characteristics, medications, White blood cell count, 8.9
4.1 9.7
11.2 0.483
electrocardiographic and echocardiographic characteristics, mortality 10^3/mL per mL
variables were compared among those with normal or mild throm- Platelet count, 213.8
78.1 74.6
20.3 <0.001
bocytopenia versus those with moderate to severe thrombocytopenia 10^3/mL per mL
Right heart catheterization 39 (9.2) 8 (8.1) 0.717
using Student’s t-test for continuous variables, or chi-square test for
PAP, median (range) 43 (11e61) 38.5 (32e53) 0.734
categorical variables. Univariate Cox regression models were con- Echocardiography findings
structed to determine predictors of mortality and presented as hazard PASP 73.7 (11.5) 74.2 (12.2) 0.713
ratios (HR) and 95% confidence intervals (CI). All variables with a p Ejection fraction, % 51.7
18.0 54.9
18.3 0.106
value <0.10 in univariate analysis were included as potential con- LVEF <40% 126 (30.5) 28 (28.6) 0.707
Left atrium diameter, mm 44.6
8.1 43.6
7.8 0.322
founders of the relationship of thrombocytopenia and our outcome Right ventricular hypokinesis 0.462
variables in our final multivariate model. Both models were controlled Mild 11 (2.6) 5 (5.1)
for age and race. A two-sided p-value <0.05 was considered statisti- Moderate 11 (2.6) 4 (4.0)
cally significant in our final models. KaplaneMeier curves were used to Severe 8 (1.9) 1 (1.0)
compare mortality outcomes among the groups. A restricted cubic Data are number (%) or mean
standard deviation.
spline plotting the platelet count and the relative log hazard ratio COPD, chronic obstructive pulmonary disease; ACEi, angiotensin-converting-
estimated by Cox regression was performed to demonstrate the non- enzyme inhibitor; ARB, angiotensin-receptor-blocker; CCB, calcium channel
blocker; ERA, endothelin receptor antagonist; LVEF, left ventricular ejection frac-
linear relationship of mortality and platelet count. KaplaneMeier tion; PDE5I, phosphodiesterase type 5 inhibitor; RBBB, right bundle branch block;
curve and restricted cubic spline were plotted in R 3.0.2. All other PAP, pulmonary artery pressure; PASP, pulmonary artery systolic pressure.
a
analyses were performed using SPSS version 21.0 (IBM, Armonk, NY). p values highlighted in bold denote statistical significance at a <0.05 level.

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Table 2
Univariate analysis of mortality.

Mortality at 1 year

95% confidence interval

HR Lower Upper p valuea

Age 1.008 0.998 1.019 0.126
Male 0.979 0.836 1.146 0.787
Race
Non-Hispanic White (reference) 1.000 e e e
Non-Hispanic Black 1.203 0.821 1.764 0.343
Hispanic 0.662 0.423 1.035 0.070
Other 1.018 0.510 2.032 0.960
Hypertension 0.992 0.700 1.408 0.966
Hyperlipidemia 0.640 0.433 0.948 0.026
Diabetes 0.970 0.708 1.328 0.848
Myocardial infarction 1.283 0.794 2.071 0.309
Stroke 1.542 0.874 2.719 0.135
COPD 1.071 0.746 1.536 0.710
Liver disease 1.406 0.880 2.246 0.154
Rheumatologic disease 2.121 0.817 5.169 0.098
Medications
Fig. 1. KaplaneMeier Survival curve for all-cause mortality at 1 year stratified by Aspirin 0.706 0.467 1.068 0.100
severity of thrombocytopenia. Overall mortality was increased in those with platelets Plavix 0.641 0.327 1.256 0.195
less than 100,000 per mL (p < 0.001). ACEi 0.518 0.304 0.881 0.015
ARB 1.084 0.269 4.371 0.910
Beta-blocker 0.488 0.330 0.723 <0.001
Diuretic 0.048 0.000 8.457 0.250
catheterization was performed among 9%, and mean pulmonary ar-
Spironolactone 0.554 0.272 1.129 0.104
tery pressure was 41.0
10.8 mm Hg. Mean platelet count was CCB 0.343 0.168 0.698 0.003
187.3
89.4 and 99 patients (19%) had a value less than 100,000 Digoxin 1.287 0.603 2.745 0.514
platelets (moderate to severe thrombocytopenia group). Patients Statin 0.560 0.329 0.953 0.033
with moderate to severe thrombocytopenia were more likely to be ERA 3.275 0.458 23.419 0.237
Prostaglandin inhibitor 0.049 0.000 219.42 0.482
non-Hispanic (p ¼ 0.004), have liver disease (p < 0.001) and abnormal PDE5I 1.000 0.442 2.261 1.000
troponin values (p ¼ 0.013), and to use a beta-blocker (p < 0.001). Heparin exposure 1.006 0.729 1.389 0.969
Overall all-cause mortality at 1 year was 30.7% (160 patients), Heparin subcutaneous 0.992 0.709 1.388 0.992
with increased mortality among those with moderate to severe Heparin intravenous 1.185 0.716 1.959 0.509
EKG findings
thrombocytopenia (46.5% vs. 27.0%, p < 0.001, Fig. 1). Unadjusted
Atrial fibrillation 0.845 0.618 1.157 0.295
HRs are presented in Table 2. Moderate to severe thrombocytopenia RBBB 0.856 0.379 1.935 0.709
(platelet count < 100,000; HR 2.060, 95% CI 1.463e2.902, Laboratory findings
p < 0.001) and platelet count as a continuous variable (per 10,000 Troponin >0.01 ng 1.548 1.133 2.116 0.006
increase, HR 0.967, 95% CI 0.949e0.985, p < 0.001) were significant BNP >100 ng 1.100 0.805 1.503 0.549
Hemoglobin <10.5 g/dl 1.422 1.035 1.955 0.030
predictors of mortality. In multivariate analysis (Table 3), after White blood cell count 1.024 1.001 1.048 0.038
adjusting for other predictors of mortality (significant predictors in (per 1000 increase)
univariate analysis), moderate to severe thrombocytopenia Platelet count 0.967 0.949 0.985 <0.001
(platelet count < 100,000) was an independent predictor of mor- (per 10,000 per mL increase)
Platelet <100,000 per mL 2.060 1.463 2.902 <0.001
tality (HR 1.798, 95% CI 1.240e2.607, p ¼ 0.002).
Right heart catheterization 1.166 0.705 1.927 0.550
Fig. 2 demonstrates the non-linear effect of platelet count on PAP, mm Hg 1.004 0.961 1.049 0.856
survival using estimates from the final Cox regression model Echocardiography findings
(adjusted for age, race, hyperlipidemia, liver disease, rheumatologic PASP, mm Hg 1.009 0.996 1.021 0.169
disease, aspirin, ACE inhibitor, beta-blocker, calcium channel Ejection fraction (per % increase) 1.003 0.994 1.012 0.477
LVEF <40% 0.901 0.636 1.277 0.558
blocker, statin, troponin greater than 0.01 ng, hemoglobin <10.5 g/dl Left atrium diameter 1.003 0.982 1.024 0.777
and white blood cell count). A u-shaped curve plotted as lower and Right ventricular hypokinesis
higher platelet counts had the highest hazard ratio for mortality. Mild 0.377 0.093 1.522 0.171
Moderate 1.127 0.462 2.747 0.793
Severe 1.744 0.646 4.708 0.272
Discussion ACEi, angiotensin-converting-enzyme inhibitor; ARB, angiotensin-receptor-
blocker; CCB, calcium channel blocker; COPD, chronic obstructive pulmonary dis-
The current analysis demonstrates that in patients with severe PH, ease; ERA, endothelin receptor antagonist; HR, hazard ratio; LVEF, left ventricular
ejection fraction; PAP, pulmonary artery pressure; PASP, pulmonary artery systolic
moderate to severe thrombocytopenia is associated with an increase
pressure; PDE5I, phosphodiesterase type 5 inhibitor; RBBB, right bundle branch
in 1-year all-cause mortality. This association is independent of block; SD, standard deviation.
medications, echocardiographic findings, and other patient charac- a
p values highlighted in bold denote statistical significance at a <0.05 level.
teristics and comorbidities. Although there is a potential risk of
thrombocytopenia from any of the medications the patients were
exposed to, this is a relatively low risk of <1e2% with most of these severe PH and a platelet count of <100,000 per uL had significantly
medications. In addition, thrombocytopenia remained an indepen- higher 1-year mortality compared to patients with severe PH and a
dent predictor of mortality after adjustment for medications. We normal platelet count. Other independent predictors of adverse
investigated for the first time the prognostic value of thrombocyto- clinical outcome in our study were age and rheumatologic disease.
penia in patients with severe PH, and found a strong association be- Taguchi et al recently described an association between lower
tween the severity of thrombocytopenia and mortality. Patients with baseline platelet levels and a higher mortality in 65 consecutive

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Table 3 While the exact mechanism of poor outcome in patients with

Multivariate Cox regression model of mortality at 1 year. thrombocytopenia and severe PH is unclear, a number of factors may
95% confidence interval be implicated. It is possible that occult disease processes causing
HR Lower Upper p valuea
thrombocytopenia, may have been present in at least some patients.
In this case, thrombocytopenia may indirectly indicate the presence
Age 1.011 1.000 1.023 0.044
Race of unrecognized disease processes that affect morbidity and mor-
Non-Hispanic White (reference) 1.000 e tality. At the same time, thrombocytopenia itself may also directly
Non-Hispanic Black 1.395 0.925 2.104 0.112 affect outcomes.23 It is now well established that primary PH can be
Hispanic 0.832 0.520 1.332 0.443
accompanied by thrombocytopenia24 and higher tendency of
Other 1.055 0.518 2.152 0.882
Hyperlipidemia 0.724 0.479 1.092 0.123
platelets for activation and aggregation.25,26 The cause of throm-
Liver disease 1.148 0.691 1.906 0.595 bocytopenia in PH remains to be elucidated but may involve both
Rheumatologic disease 2.773 1.113 6.910 0.029 ineffective thrombopoiesis and increased platelet destruction.
Aspirin 1.421 0.850 2.376 0.181 Platelet survival is also reduced in most patients with PH.27 A pre-
ACEi 0.785 0.426 1.446 0.437
vious study showed that right atrial pressure and mixed venous
Beta-blocker 0.642 0.385 1.068 0.088
CCB 0.383 0.186 0.787 0.009 oxygen saturation are associated with thrombocytopenia in patients
Statin 0.769 0.414 1.429 0.406 with severe PH of various etiologies.9 One may thus accordingly
Heparin exposure 0.943 0.669 1.329 0.737 assume that the severity of thrombocytopenia may be a marker of
Troponin >0.01 ng 1.311 0.947 1.815 0.103 more severe right heart failure and abnormal hemodynamics
Hemoglobin <10.5 g/dl 1.241 0.896 1.721 0.194
White blood cell count 1.019 0.998 1.041 0.072
(associated with hepatic congestion and resultant hypersplenism)
(per 1000 per mL increase) and therefore poor clinical outcome. However, in the current study,
Less than 100,000 platelets per mL 1.811 1.246 2.632 0.002 right heart failure indices were not associated with the adverse
95% CI, 95% confidence interval; ACEi, angiotensin-converting-enzyme inhibitor; outcome and the association between thrombocytopenia and the
CCB, calcium channel blocker; HR, hazard ratio. outcome was independent of other covariates. Studies in patients
Variables in model were significant at a <0.10 level on univariate analysis for with heart failure suggest that changes in hemodynamics and
mortality at 1 year or were significantly different between groups at baseline.
a
vascular system architecture facilitate stasis of blood and predispose
p values highlighted in bold denote statistical significance at a <0.05 level.
to platelet aggregation and consumption, and thus the severity of
thrombocytopenia might be a reflection of severity of vascular pa-
thologies that are independent of right heart failure indices.28 While,
patients with idiopathic pulmonary arterial hypertension on com-
a small study showed an association between severity of disease in
bination therapy.18 This study provided insight into baseline
primary PH and increased platelet aggregation,25 in another small
platelet levels as a prognostic indicator in idiopathic pulmonary
study of patients with aortopulmonary transpositions, improve-
arterial hypertension patients already receiving optimal medical
ment in platelet count after corrective surgery despite persisting PH
therapy. However, the sample size of that study was small, it
suggested that hypoxemia and polycythemia may play a more
focused only on one category of PH and did not report the prog-
important role in the pathogenesis of thrombocytopenia than the
nostic value of different levels of thrombocytopenia.
severity of PH.29
While PH remains a fatal disease if not treated early,19,20 estab-
Prior reports have identified an association between thrombocy-
lishing its prognostic factors may aid in understanding disease
topenia and adverse clinical outcomes in several disease states23
progression and determining therapeutic interventions. Recent
including acute coronary syndrome,30,31,32 chronic lymphocytic leu-
studies suggest that brain natriuretic peptide, troponin T and he-
kemia,33 and intensive care unit patients.34 Therefore, the observed
modynamic measurements such as cardiac output and central
association between thrombocytopenia and adverse outcome in our
venous pressure can be used as predictors of poor survival in pa-
study may simply follow the same pathogenesis as the aforemen-
tients with PH.6,7,8 Nevertheless, a number of non-hemodynamic
tioned diseases and may be independent of PH. If this hypothesis is
factors may aid in determining prognosis and predicting mortality
true, then this may lead us to regard thrombocytopenia as a general
in PH. The validity of many such non-hemodynamic factors
marker of illness acuity or severity. Another question that also merits
including age and gender remains controversial. For instance, Benza
further investigation is whether treatment of severe thrombocyto-
and colleagues recently demonstrated that demographic indicators
penia in disease states such as PH improves long-term outcomes.
such as age and gender serve as independent predictors of mortality
Studies suggest that changes in hemodynamics and vascular
in patients with PH.21 Although a recent meta-analysis associated
system architecture facilitate stasis of blood and predispose to
over 100 factors with mortality in PH,22 thrombocytopenia was not
platelet aggregation.28,35 Similarly, altered blood flow leads to a rise
studied as a prognostic factor in PH.
in circulating catecholamines and activation of the renin-
angiotensin system, both of which contribute to platelet activa-
tion.36 Low platelet counts may serve as a surrogate marker of
worsening disease in patients with PH. Nevertheless, the underlying
mechanism of association of thrombocytopenia with poor prognosis
in patients with PH needs to be further investigated in future
translational studies including a broad spectrum of PH etiologies.
Establishing prognostic factors for patients with PH may help in
developing risk stratification models for these patients, evaluation
of disease progression, correction of underlying reversible etiol-
ogies, and determining appropriate therapeutic interventions.

Fig. 2. Restricted cubic spline demonstrating the relationship of platelet count as a Study limitations
continuous variable and the log relative hazard ratio for overall mortality at 1 year
adjusted for age, race, hyperlipidemia, liver disease, rheumatologic disease, aspirin,
ACE inhibitor, beta-blocker, calcium channel blocker, statin, heparin exposure, troponin A number of limitations should be considered when interpreting
greater than 0.01 ng, hemoglobin <10.5 g/dl and white blood cell count. the results of the present study. First, the observational design of the

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 M.K. Mojadidi et al. / Heart & Lung 43 (2014) 569e573 573

study hinders determination of causality. A second limitation is the 15. Yoon AJ, Melduni RM, Duncan SA, Ostfeld RJ, Travin MI. The effect of beta-
blockers on the diagnostic accuracy of vasodilator pharmacologic SPECT
use of echocardiography in diagnosing PH. Cardiac catheterization to
myocardial perfusion imaging. J Nucl Cardiol. 2009;16:358e367.
measure an elevated mean pulmonary arterial pressure remains the 16. Li P, Chen F, Zhao X, et al. Occurrence and clinical significance of in-hospital
most accurate method for diagnosis of PH, and also allows accurate acquired thrombocytopenia in patients undergoing transcatheter device
determination of pulmonary hemodynamics and assessment of PH closure for congenital heart defect. Thromb Res. 2012;130:882e888.
17. Williamson DR, Albert M, Heels-Ansdell D, et al. Thrombocytopenia in critically
severity.37,38 On the other hand, transthoracic echocardiography, ill patients receiving thromboprophylaxis: frequency, risk factors, and out-
employed in our study to diagnose PH, has a reported sensitivity of comes. Chest. 2013;144:1207e1215.
0.79e1.00 and a specificity of 0.60e0.98.37,39,40 While these values are 18. Taguchi H, Kataoka M, Yanagisawa R, et al. Platelet level as a new prognostic
factor for idiopathic pulmonary arterial hypertension in the era of combination
greatly influenced by the minimum set criteria used to confirm a therapy. Circ J. 2012;76:1494e1500.
diagnosis of PH, the accuracy of echocardiography in diagnosis of PH 19. Barst RJ, Gibbs JS, Ghofrani HA, et al. Updated evidence-based treatment
increases with increased hemodynamic severity of PH.41,42 Because algorithm in pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54:
S78eS84.
our study population only consisted of patients with severe PH (PASP 20. Galie N, Rubin L, Hoeper M, et al. Treatment of patients with mildly symp-
>60 mm Hg), the use of transthoracic echocardiography (versus tomatic pulmonary arterial hypertension with bosentan (EARLY study): a
cardiac catheterization) should not significantly influence the accu- double-blind, randomised controlled trial. Lancet. 2008;371:2093e2100.
21. Benza RL, Miller DP, Gomberg-Maitland M, et al. Predicting survival in pul-
racy of our results. In addition, mean pulmonary pressures, measured monary arterial hypertension: insights from the registry to evaluate early and
by cardiac catheterization, were available for 9% (47/521) of patients; long-term pulmonary arterial hypertension disease Management (REVEAL).
catheterization results confirmed that these patients had significant Circulation. 2010;122:164e172.
22. Swiston JR, Johnson SR, Granton JT. Factors that prognosticate mortality in
PH. In addition, we did not stratify our analysis based on the etiology
idiopathic pulmonary arterial hypertension: a systematic review of the liter-
of PH or by cause of mortality as such information was not available. ature. Respir Med. 2010;104:1588e1607.
Another limitation of our study was the lack of available hemody- 23. Msaouel P, Lam AP, Gundabolu K, et al. Abnormal platelet count is an inde-
namic measures such as central venous pressure or cardiac output, pendent predictor of mortality in the elderly and is influenced by ethnicity.
Haematologica. 2014;99:930e936.
which are known prognostic factors in PH. 24. Edwards BS, Weir EK, Edwards WD, Ludwig J, Dykoski RK, Edwards JE. Coex-
istent pulmonary and portal hypertension: morphologic and clinical features.
Conclusions J Am Coll Cardiol. 1987;10:1233e1238.
25. Nakonechnicov S, Gabbasov Z, Chazova I, Popov E, Belenkov Y. Platelet ag-
gregation in patients with primary pulmonary hypertension. Blood Coagul
This study demonstrates for the first time an association be- Fibrinolysis. 1996;7:225e227.
tween thrombocytopenia and worse clinical outcomes in patients 26. Varol E, Uysal BA, Ozaydin M. Platelet indices in patients with pulmonary
with severe PH. Moderate to severe thrombocytopenia was an in- arterial hypertension. Clin Appl Thromb Hemost. 2011;17:E171eE174.
27. Steele PP, Weily HS, Davies H, Genton E. Platelet survival in patients with
dependent predictor of higher mortality in these patients. Further rheumatic heart disease. N Engl J Med. 1974;290:537e539.
investigations are needed to determine the mechanisms underly- 28. Chung I, Lip GY. Platelets and heart failure. Eur Heart J. 2006;27:2623e2631.
ing these associations. 29. Terai M, Nakazawa M, Takao A, Imai Y. Thrombocytopenia in patients with
aortopulmonary transposition and an intact ventricular septum. Br Heart J.
1987;57:371e374.
References 30. Harrington RA, Sane DC, Califf RM, et al. Clinical importance of thrombocyto-
penia occurring in the hospital phase after administration of thrombolytic
1. Hyduk A, Croft JB, Ayala C, Zheng K, Zheng ZJ, Mensah GA. Pulmonary hyper- therapy for acute myocardial infarction. The Thrombolysis and Angioplasty in
tension surveillanceeUnited States, 1980-2002. MMWR Surveill Summ. Myocardial Infarction Study Group. J Am Coll Cardiol. 1994;23:891e898.
2005;54:1e28. 31. McClure MW, Berkowitz SD, Sparapani R, et al. Clinical significance of throm-
2. Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of bocytopenia during a non-ST-elevation acute coronary syndrome. The platelet
pulmonary hypertension. J Am Coll Cardiol. 2013;62:D34eD41. glycoprotein IIb/IIIa in unstable angina: receptor suppression using integrilin
3. Benza RL, Miller DP, Barst RJ, Badesch DB, Frost AE, McGoon MD. An evaluation therapy (PURSUIT) trial experience. Circulation. 1999;99:2892e2900.
of long-term survival from time of diagnosis in pulmonary arterial hyperten- 32. Wang TY, Ou FS, Roe MT, et al. Incidence and prognostic significance of
sion from the REVEAL Registry. Chest. 2012;142:448e456. thrombocytopenia developed during acute coronary syndrome in contempo-
4. Galie N, Manes A, Negro L, Palazzini M, Bacchi-Reggiani ML, Branzi A. A meta- rary clinical practice. Circulation. 2009;119:2454e2462.
analysis of randomized controlled trials in pulmonary arterial hypertension. 33. Rozman C, Montserrat E, Feliu E, et al. Prognosis of chronic lymphocytic
Eur Heart J. 2009;30:394e403. leukemia: a multivariate survival analysis of 150 cases. Blood. 1982;59:
5. D’Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pul- 1001e1005.
monary hypertension. Results from a national prospective registry. Ann Intern 34. Vanderschueren S, De Weerdt A, Malbrain M, et al. Thrombocytopenia and
Med. 1991;115:343e349. prognosis in intensive care. Crit Care Med. 2000;28:1871e1876.
6. Fijalkowska A, Kurzyna M, Torbicki A, et al. Serum N-terminal brain natriuretic 35. Yamamoto K, Ikeda U, Furuhashi K, Irokawa M, Nakayama T, Shimada K. The
peptide as a prognostic parameter in patients with pulmonary hypertension. coagulation system is activated in idiopathic cardiomyopathy. J Am Coll Cardiol.
Chest. 2006;129:1313e1321. 1995;25:1634e1640.
7. Raymond RJ, Hinderliter AL, Willis PW, et al. Echocardiographic predictors of 36. Anfossi G, Trovati M. Role of catecholamines in platelet function: pathophys-
adverse outcomes in primary pulmonary hypertension. J Am Coll Cardiol. iological and clinical significance. Eur J Clin Invest. 1996;26:353e370.
2002;39:1214e1219. 37. Barst RJ, McGoon M, Torbicki A, et al. Diagnosis and differential assessment of
8. Torbicki A, Kurzyna M, Kuca P, et al. Detectable serum cardiac troponin T as a pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43:40Se47S.
marker of poor prognosis among patients with chronic precapillary pulmonary 38. Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and
hypertension. Circulation. 2003;108:844e848. treatment of pulmonary hypertension: the Task Force for the Diagnosis and
9. Chin KM, Channick RN, de Lemos JA, Kim NH, Torres F, Rubin LJ. Hemody- Treatment of Pulmonary Hypertension of the European Society of Cardiology
namics and epoprostenol use are associated with thrombocytopenia in pul- (ESC) and the European Respiratory Society (ERS), endorsed by the Interna-
monary arterial hypertension. Chest. 2009;135:130e136. tional Society of Heart and Lung Transplantation (ISHLT). Eur Heart J. 2009;30:
10. Jubelirer SJ. Primary pulmonary hypertension. Its association with micro- 2493e2537.
angiopathic hemolytic anemia and thrombocytopenia. Arch Intern Med. 39. Janda S, Shahidi N, Gin K, Swiston J. Diagnostic accuracy of echocardiography
1991;151:1221e1223. for pulmonary hypertension: a systematic review and meta-analysis. Heart.
11. Abramowitz M, Muntner P, Coco M, et al. Serum alkaline phosphatase and 2011;97:612e622.
phosphate and risk of mortality and hospitalization. Clin J Am Soc Nephrol. 40. Zhang RF, Zhou L, Ma GF, Shao FC, Wu XH, Ying KJ. Diagnostic value of
2010;5:1064e1071. transthoracic Doppler echocardiography in pulmonary hypertension: a meta-
12. Das R, Feuerstadt P, Brandt LJ. Glucocorticoids are associated with increased analysis. Am J Hypertens. 2010;23:1261e1264.
risk of short-term mortality in hospitalized patients with clostridium difficile- 41. Gorcsan 3rd J, Edwards TD, Ziady GM, Katz WE, Griffith BP. Transesophageal
associated disease. Am J Gastroenterol. 2010;105:2040e2049. echocardiography to evaluate patients with severe pulmonary hypertension
13. Southern WN, Nahvi S, Arnsten JH. Increased risk of mortality and readmission for lung transplantation. Ann Thorac Surg. 1995;59:717e722.
among patients discharged against medical advice. Am J Med. 2012;125:594e602. 42. Kim WR, Krowka MJ, Plevak DJ, et al. Accuracy of Doppler echocardiography in
14. Stein EG, Haramati LB, Bellin E, et al. Radiation exposure from medical imaging in the assessment of pulmonary hypertension in liver transplant candidates. Liver
patients with chronic and recurrent conditions. J Am Coll Radiol. 2010;7:351e359. Transpl. 2000;6:453e458.

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