Thrombocytopenia is an independent predictor of mortality in pulmonary hypertension

Thrombocytopenia is an independent predictor of mortality in pulmonary hypertension

Heart & Lung 43 (2014) 569e573 Contents lists available at ScienceDirect Heart & Lung journal homepage: www.heartandlung.org Thrombocytopenia is an...

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Heart & Lung 43 (2014) 569e573

Contents lists available at ScienceDirect

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: Received 25 April 2014 Received in revised form 21 July 2014 Accepted 23 July 2014 Available online 29 August 2014

Background: Established prognostic factors for pulmonary hypertension (PH) include brain natriuretic peptide, troponins and hemodynamic measures such as central venous pressure and cardiac output. The prognostic role of thrombocytopenia, however, has yet to be determined in patients with PH. The aim of this study was to evaluate effect of thrombocytopenia on mortality in patients with PH. 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: mild thrombocytopenia to a normal platelet count (platelet count 100,000e450,000 per uL); and moderate to severe thrombocytopenia (platelet count <100,000 per uL). Inpatient and social security death records were used to determine 1-year all-cause 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.

Keywords: Thrombocytopenia Pulmonary hypertension Platelets Mortality

Introduction Pulmonary hypertension (PH) remains a serious debilitating condition with increasing incidence of hospitalization and mortality in the United States.1 It is usually classified as either pulmonary arterial hypertension or PH secondary to other etiologies such as left ventricular disease, hypoxic lung conditions or pulmonary thromboembolic disease.2 While the cause of PH may vary from one patient to another, early detection and treatment results in a reduction of both morbidity and mortality regardless of etiology or clinical course.3,4 Thus, it is essential to establish prognostic factors Abbreviations: PH, Pulmonary hypertension; PASP, Pulmonary artery systolic pressure; ACEi, Angiotensin-converting enzyme inhibitor; LVEF, Left ventricular ejection fraction. Disclosures: None. * Corresponding author. Department of Medicine, Albert Einstein College of Medicine, Jacobi Medical Center, 1400 Pelham Parkway S, Building 1, Rm 3N1, Bronx, NY 10461, USA. Tel.: þ1 7189185656; fax: þ1 3102670384. E-mail address: [email protected] (M.K. Mojadidi). 0147-9563/$ e see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.hrtlng.2014.07.006

that facilitate the evaluation of patients with PH in order to guide appropriate and timely intervention and medical therapy. With no intervention, uncontrolled PH often leads to right-sided heart failure and death, occurring within 2e3 years of diagnosis in those with pulmonary arterial hypertension.5 Established prognostic factors that predict mortality in patients with PH include brain natriuretic peptide, troponin T and hemodynamic measurements such as cardiac output and central venous pressure.6,7,8 Thrombocytopenia has previously been associated with PH9,10 where the severity of certain hemodynamic parameters (i.e. right atrial pressure and mixed venous oxygen saturation) directly correlated to a drop in platelet count in patients with pulmonary arterial hypertension.9 It is postulated that changes in hemodynamics and vascular system architecture facilitate stasis of blood and predispose to platelet aggregation and subsequent thrombocytopenia. However, the role of thrombocytopenia as an independent prognostic factor in patients with PH has yet to be determined. The aim of this study was to investigate the effect of severity of thrombocytopenia on mortality in patients with severe PH.

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Methods

Results

Study design

Baseline demographic, clinical, medications, electrocardiographic and echocardiographic data of 521 patients included in this analysis stratified by platelet count are outlined in Table 1. Briefly, mean PASP was 73.8  11.6 mm Hg, left ventricular ejection fraction (LVEF) was 52.3  18.1 and 29.6% had LVEF of less than 40%. Right heart

From January 2009 to January 2011, we retrospectively identified patients with severe PH. The inclusion criteria included subjects 18 years old, the presence of a transthoracic echocardiogram with a pulmonary artery systolic pressure (PASP) greater than 60 mm Hg (or documentation of PH by a transthoracic echocardiogram), and a documented platelet count ordered within one month of diagnosis of PH. For the diagnosis of PH in this study, we reviewed the echocardiographic findings from multiple studies done for a patient at different time points and if there was a significant discrepancy between reported PASP, those patients were not included in the study. The study included 521 patients who were admitted to (or seen in the outpatient clinics of) Montefiore Medical Center’s hospitals (Moses Hospital, Weiler Hospital and Wakefield Hospital), which are large urban academic tertiary care centers in the Bronx, New York. Patients were identified from the Montefiore Medical Center’s Clinical Information System (Emerging Health Information Technology, Yonkers, New York) using the Clinical Looking Glass, a proprietary query tool and software application that allows clinicians and researchers to identify populations of interest from the Montefiore Medical Centers’ database, and to gather information about the demographics, clinical, and outcome data.11e15 The database is combined monthly with the Social Security Death Registry, which allows extraction of clinical outcomes including mortality and hospitalization rates. Patients were evaluated for platelet counts and, based on prior studies,16,17 subsequently divided into two groups based on the severity of thrombocytopenia: 1) mild thrombocytopenia to a normal platelet count (100,000e450,000 per uL); 2) moderate to severe thrombocytopenia (platelet count < 100,000). Patients’ records were reviewed to determine their baseline characteristics, co-morbidities, medications, baseline electrocardiograms and echocardiograms, and any significant laboratory values. This multi-center study was approved by the Institutional Review Board of Albert Einstein College of Medicine of Yeshiva University (Protocol Number: 12-10-355). Clinical outcomes The clinical outcome of this study was 1-year all-cause mortality. Statistical analysis Continuous variables were expressed as the mean  standard deviation. Categorical variables were expressed as number and percentage. Demographic and clinical characteristics, medications, electrocardiographic and echocardiographic characteristics, mortality variables were compared among those with normal or mild thrombocytopenia versus those with moderate to severe thrombocytopenia using Student’s t-test for continuous variables, or chi-square test for categorical variables. Univariate Cox regression models were constructed to determine predictors of mortality and presented as hazard ratios (HR) and 95% confidence intervals (CI). All variables with a p value <0.10 in univariate analysis were included as potential confounders of the relationship of thrombocytopenia and our outcome variables in our final multivariate model. Both models were controlled for age and race. A two-sided p-value <0.05 was considered statistically significant in our final models. KaplaneMeier curves were used to compare mortality outcomes among the groups. A restricted cubic spline plotting the platelet count and the relative log hazard ratio estimated by Cox regression was performed to demonstrate the nonlinear relationship of mortality and platelet count. KaplaneMeier curve and restricted cubic spline were plotted in R 3.0.2. All other analyses were performed using SPSS version 21.0 (IBM, Armonk, NY).

Table 1 Baseline demographic, clinical, electrocardiographic and echocardiographic findings of patients with pulmonary hypertension stratified by platelet count (n ¼ 521). Platelet count 100,000 e450,000 (n ¼ 422) Age (years) Male Race Non-Hispanic White Non-Hispanic Black Hispanic Other Hypertension Hyperlipidemia Diabetes Myocardial infarction Stroke COPD Liver disease Rheumatologic disease Medications Aspirin Plavix ACEi ARB Beta-blocker Diuretic Spironolactone CCB Digoxin Statin Prostaglandin inhibitor PDE5I Heparin exposure Heparin subcutaneous Heparin intravenous EKG findings Atrial fibrillation RBBB Laboratory findings Pro-BNP >100 ng Troponins >0.01 ng Hemoglobin <10.5 g/dl White blood cell count, 10^3/mL per mL Platelet count, 10^3/mL per mL Right heart catheterization PAP, median (range) Echocardiography findings PASP Ejection fraction, % LVEF <40% Left atrium diameter, mm Right ventricular hypokinesis Mild Moderate Severe

Less than 100,000 (n ¼ 99)

p valuea

70.2 168

15.5 (39.8)

70.8 41

15.9 (41.4)

93 165 139 25 312 113 178 41 26 103 29 9

(22.0) (39.1) (32.9) (5.9) (73.9) (26.8) (42.2) (9.7) (6.2) (24.4) (6.9) (2.1)

37 35 19 8 70 22 42 10 5 17 21 0

(37.4) (35.4) (19.2) (8.1) (70.7) (22.2) (42.4) (10.1) (5.1) (17.2) (21.2) (0.0)

0.514 0.352 0.965 0.908 0.674 0.124 <0.001 0.143

97 35 69 4 139 7 36 54 12 65 3 13 146 122 36

(23.0) (8.3) (16.4) (0.9) (32.9) (1.7) (8.5) (12.8) (2.8) (15.4) (0.7) (3.1) (33.9) (28.9) (8.5)

11 6 9 2 15 1 5 6 6 8 0 5 44 36 14

(11.1) (6.1) (9.1) (2.0) (15.2) (1.0) (5.1) (6.1) (6.1) (8.1) (0.0) (5.1) (44.4) (36.4) (14.1)

0.009 0.458 0.068 0.368 <0.001 0.637 0.247 0.059 0.115 0.059 0.400 0.334 0.050 0.147 0.091

190 18

(45.0) (4.3)

45 4

(45.5) (4.0)

0.938 0.920

234 140 134 8.9

(55.5) (33.2) (31.8) 4.1

48 46 37 9.7

(48.5) (46.5) (37.4) 11.2

0.211 0.013 0.284 0.483

213.8

78.1

74.6

20.3

<0.001

(9.2) (11e61)

8 38.5

(8.1) (32e53)

0.717 0.734

(11.5) 18.0 (30.5) 8.1

74.2 54.9 28 43.6

(12.2) 18.3 (28.6) 7.8

0.713 0.106 0.707 0.322 0.462

39 43 73.7 51.7 126 44.6 11 11 8

(2.6) (2.6) (1.9)

5 4 1

0.743 0.770 0.004

(5.1) (4.0) (1.0)

Data are number (%) or mean  standard deviation. COPD, chronic obstructive pulmonary disease; ACEi, angiotensin-convertingenzyme inhibitor; ARB, angiotensin-receptor-blocker; CCB, calcium channel blocker; ERA, endothelin receptor antagonist; LVEF, left ventricular ejection fraction; PDE5I, phosphodiesterase type 5 inhibitor; RBBB, right bundle branch block; PAP, pulmonary artery pressure; PASP, pulmonary artery systolic pressure. a p values highlighted in bold denote statistical significance at a <0.05 level.

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571

Table 2 Univariate analysis of mortality. Mortality at 1 year 95% confidence interval

Fig. 1. KaplaneMeier Survival curve for all-cause mortality at 1 year stratified by severity of thrombocytopenia. Overall mortality was increased in those with platelets less than 100,000 per mL (p < 0.001).

catheterization was performed among 9%, and mean pulmonary artery pressure was 41.0  10.8 mm Hg. Mean platelet count was 187.3  89.4 and 99 patients (19%) had a value less than 100,000 platelets (moderate to severe thrombocytopenia group). Patients with moderate to severe thrombocytopenia were more likely to be non-Hispanic (p ¼ 0.004), have liver disease (p < 0.001) and abnormal troponin values (p ¼ 0.013), and to use a beta-blocker (p < 0.001). Overall all-cause mortality at 1 year was 30.7% (160 patients), with increased mortality among those with moderate to severe thrombocytopenia (46.5% vs. 27.0%, p < 0.001, Fig. 1). Unadjusted HRs are presented in Table 2. Moderate to severe thrombocytopenia (platelet count < 100,000; HR 2.060, 95% CI 1.463e2.902, p < 0.001) and platelet count as a continuous variable (per 10,000 increase, HR 0.967, 95% CI 0.949e0.985, p < 0.001) were significant predictors of mortality. In multivariate analysis (Table 3), after adjusting for other predictors of mortality (significant predictors in univariate analysis), moderate to severe thrombocytopenia (platelet count < 100,000) was an independent predictor of mortality (HR 1.798, 95% CI 1.240e2.607, p ¼ 0.002). Fig. 2 demonstrates the non-linear effect of platelet count on survival using estimates from the final Cox regression model (adjusted for age, race, hyperlipidemia, liver disease, rheumatologic disease, aspirin, ACE inhibitor, beta-blocker, calcium channel blocker, statin, troponin greater than 0.01 ng, hemoglobin <10.5 g/dl and white blood cell count). A u-shaped curve plotted as lower and higher platelet counts had the highest hazard ratio for mortality.

Discussion The current analysis demonstrates that in patients with severe PH, moderate to severe thrombocytopenia is associated with an increase in 1-year all-cause mortality. This association is independent of medications, echocardiographic findings, and other patient characteristics 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 medications. In addition, thrombocytopenia remained an independent predictor of mortality after adjustment for medications. We investigated for the first time the prognostic value of thrombocytopenia in patients with severe PH, and found a strong association between the severity of thrombocytopenia and mortality. Patients with

Age Male Race Non-Hispanic White (reference) Non-Hispanic Black Hispanic Other Hypertension Hyperlipidemia Diabetes Myocardial infarction Stroke COPD Liver disease Rheumatologic disease Medications Aspirin Plavix ACEi ARB Beta-blocker Diuretic Spironolactone CCB Digoxin Statin ERA Prostaglandin inhibitor PDE5I Heparin exposure Heparin subcutaneous Heparin intravenous EKG findings Atrial fibrillation RBBB Laboratory findings Troponin >0.01 ng BNP >100 ng Hemoglobin <10.5 g/dl White blood cell count (per 1000 increase) Platelet count (per 10,000 per mL increase) Platelet <100,000 per mL Right heart catheterization PAP, mm Hg Echocardiography findings PASP, mm Hg Ejection fraction (per % increase) LVEF <40% Left atrium diameter Right ventricular hypokinesis Mild Moderate Severe

Upper

p valuea

HR

Lower

1.008 0.979

0.998 0.836

1.000 1.203 0.662 1.018 0.992 0.640 0.970 1.283 1.542 1.071 1.406 2.121

e 0.821 0.423 0.510 0.700 0.433 0.708 0.794 0.874 0.746 0.880 0.817

e 1.764 1.035 2.032 1.408 0.948 1.328 2.071 2.719 1.536 2.246 5.169

0.343 0.070 0.960 0.966 0.026 0.848 0.309 0.135 0.710 0.154 0.098

0.706 0.641 0.518 1.084 0.488 0.048 0.554 0.343 1.287 0.560 3.275 0.049 1.000 1.006 0.992 1.185

0.467 0.327 0.304 0.269 0.330 0.000 0.272 0.168 0.603 0.329 0.458 0.000 0.442 0.729 0.709 0.716

1.068 1.256 0.881 4.371 0.723 8.457 1.129 0.698 2.745 0.953 23.419 219.42 2.261 1.389 1.388 1.959

0.100 0.195 0.015 0.910 <0.001 0.250 0.104 0.003 0.514 0.033 0.237 0.482 1.000 0.969 0.992 0.509

0.845 0.856

0.618 0.379

1.157 1.935

0.295 0.709

1.548 1.100 1.422 1.024

1.133 0.805 1.035 1.001

2.116 1.503 1.955 1.048

0.006 0.549 0.030 0.038

0.967

0.949

0.985

<0.001

2.060 1.166 1.004

1.463 0.705 0.961

2.902 1.927 1.049

<0.001 0.550 0.856

1.009 1.003 0.901 1.003

0.996 0.994 0.636 0.982

1.021 1.012 1.277 1.024

0.169 0.477 0.558 0.777

0.377 1.127 1.744

0.093 0.462 0.646

1.522 2.747 4.708

0.171 0.793 0.272

1.019 1.146

0.126 0.787 e

ACEi, angiotensin-converting-enzyme inhibitor; ARB, angiotensin-receptorblocker; CCB, calcium channel blocker; COPD, chronic obstructive pulmonary disease; ERA, endothelin receptor antagonist; HR, hazard ratio; LVEF, left ventricular ejection fraction; PAP, pulmonary artery pressure; PASP, pulmonary artery systolic pressure; PDE5I, phosphodiesterase type 5 inhibitor; RBBB, right bundle branch block; SD, standard deviation. a p values highlighted in bold denote statistical significance at a <0.05 level.

severe PH and a platelet count of <100,000 per uL had significantly higher 1-year mortality compared to patients with severe PH and a normal platelet count. Other independent predictors of adverse clinical outcome in our study were age and rheumatologic disease. Taguchi et al recently described an association between lower baseline platelet levels and a higher mortality in 65 consecutive

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Table 3 Multivariate Cox regression model of mortality at 1 year. 95% confidence interval

Age Race Non-Hispanic White (reference) Non-Hispanic Black Hispanic Other Hyperlipidemia Liver disease Rheumatologic disease Aspirin ACEi Beta-blocker CCB Statin Heparin exposure Troponin >0.01 ng Hemoglobin <10.5 g/dl White blood cell count (per 1000 per mL increase) Less than 100,000 platelets per mL

HR

Lower

Upper

p valuea

1.011

1.000

1.023

0.044

1.000 1.395 0.832 1.055 0.724 1.148 2.773 1.421 0.785 0.642 0.383 0.769 0.943 1.311 1.241 1.019

0.925 0.520 0.518 0.479 0.691 1.113 0.850 0.426 0.385 0.186 0.414 0.669 0.947 0.896 0.998

2.104 1.332 2.152 1.092 1.906 6.910 2.376 1.446 1.068 0.787 1.429 1.329 1.815 1.721 1.041

e 0.112 0.443 0.882 0.123 0.595 0.029 0.181 0.437 0.088 0.009 0.406 0.737 0.103 0.194 0.072

1.811

1.246

2.632

0.002

95% CI, 95% confidence interval; ACEi, angiotensin-converting-enzyme inhibitor; CCB, calcium channel blocker; HR, hazard ratio. Variables in model were significant at a <0.10 level on univariate analysis for mortality at 1 year or were significantly different between groups at baseline. a p values highlighted in bold denote statistical significance at a <0.05 level.

patients with idiopathic pulmonary arterial hypertension on combination therapy.18 This study provided insight into baseline platelet levels as a prognostic indicator in idiopathic pulmonary arterial hypertension patients already receiving optimal medical therapy. However, the sample size of that study was small, it focused only on one category of PH and did not report the prognostic value of different levels of thrombocytopenia. While PH remains a fatal disease if not treated early,19,20 establishing its prognostic factors may aid in understanding disease progression and determining therapeutic interventions. Recent studies suggest that brain natriuretic peptide, troponin T and hemodynamic measurements such as cardiac output and central venous pressure can be used as predictors of poor survival in patients with PH.6,7,8 Nevertheless, a number of non-hemodynamic factors may aid in determining prognosis and predicting mortality in PH. The validity of many such non-hemodynamic factors including age and gender remains controversial. For instance, Benza and colleagues recently demonstrated that demographic indicators such as age and gender serve as independent predictors of mortality in patients with PH.21 Although a recent meta-analysis associated over 100 factors with mortality in PH,22 thrombocytopenia was not studied as a prognostic factor in PH.

Fig. 2. Restricted cubic spline demonstrating the relationship of platelet count as a 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 greater than 0.01 ng, hemoglobin <10.5 g/dl and white blood cell count.

While the exact mechanism of poor outcome in patients with thrombocytopenia and severe PH is unclear, a number of factors may be implicated. It is possible that occult disease processes causing thrombocytopenia, may have been present in at least some patients. In this case, thrombocytopenia may indirectly indicate the presence of unrecognized disease processes that affect morbidity and mortality. At the same time, thrombocytopenia itself may also directly affect outcomes.23 It is now well established that primary PH can be accompanied by thrombocytopenia24 and higher tendency of platelets for activation and aggregation.25,26 The cause of thrombocytopenia in PH remains to be elucidated but may involve both ineffective thrombopoiesis and increased platelet destruction. Platelet survival is also reduced in most patients with PH.27 A previous study showed that right atrial pressure and mixed venous oxygen saturation are associated with thrombocytopenia in patients with severe PH of various etiologies.9 One may thus accordingly assume that the severity of thrombocytopenia may be a marker of more severe right heart failure and abnormal hemodynamics (associated with hepatic congestion and resultant hypersplenism) and therefore poor clinical outcome. However, in the current study, right heart failure indices were not associated with the adverse outcome and the association between thrombocytopenia and the outcome was independent of other covariates. Studies in patients with heart failure suggest that changes in hemodynamics and vascular system architecture facilitate stasis of blood and predispose to platelet aggregation and consumption, and thus the severity of thrombocytopenia might be a reflection of severity of vascular pathologies that are independent of right heart failure indices.28 While, a small study showed an association between severity of disease in primary PH and increased platelet aggregation,25 in another small study of patients with aortopulmonary transpositions, improvement in platelet count after corrective surgery despite persisting PH suggested that hypoxemia and polycythemia may play a more important role in the pathogenesis of thrombocytopenia than the severity of PH.29 Prior reports have identified an association between thrombocytopenia and adverse clinical outcomes in several disease states23 including acute coronary syndrome,30,31,32 chronic lymphocytic leukemia,33 and intensive care unit patients.34 Therefore, the observed association between thrombocytopenia and adverse outcome in our study may simply follow the same pathogenesis as the aforementioned diseases and may be independent of PH. If this hypothesis is true, then this may lead us to regard thrombocytopenia as a general marker of illness acuity or severity. Another question that also merits further investigation is whether treatment of severe thrombocytopenia in disease states such as PH improves long-term outcomes. Studies suggest that changes in hemodynamics and vascular system architecture facilitate stasis of blood and predispose to platelet aggregation.28,35 Similarly, altered blood flow leads to a rise in circulating catecholamines and activation of the reninangiotensin system, both of which contribute to platelet activation.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 etiologies, and determining appropriate therapeutic interventions. Study limitations A number of limitations should be considered when interpreting the results of the present study. First, the observational design of the

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study hinders determination of causality. A second limitation is the use of echocardiography in diagnosing PH. Cardiac catheterization to measure an elevated mean pulmonary arterial pressure remains the most accurate method for diagnosis of PH, and also allows accurate determination of pulmonary hemodynamics and assessment of PH severity.37,38 On the other hand, transthoracic echocardiography, employed in our study to diagnose PH, has a reported sensitivity of 0.79e1.00 and a specificity of 0.60e0.98.37,39,40 While these values are greatly influenced by the minimum set criteria used to confirm a diagnosis of PH, the accuracy of echocardiography in diagnosis of PH increases with increased hemodynamic severity of PH.41,42 Because our study population only consisted of patients with severe PH (PASP >60 mm Hg), the use of transthoracic echocardiography (versus cardiac catheterization) should not significantly influence the accuracy of our results. In addition, mean pulmonary pressures, measured by cardiac catheterization, were available for 9% (47/521) of patients; catheterization results confirmed that these patients had significant PH. In addition, we did not stratify our analysis based on the etiology of PH or by cause of mortality as such information was not available. Another limitation of our study was the lack of available hemodynamic measures such as central venous pressure or cardiac output, which are known prognostic factors in PH. Conclusions This study demonstrates for the first time an association between thrombocytopenia and worse clinical outcomes in patients with severe PH. Moderate to severe thrombocytopenia was an independent predictor of higher mortality in these patients. Further investigations are needed to determine the mechanisms underlying these associations. References 1. Hyduk A, Croft JB, Ayala C, Zheng K, Zheng ZJ, Mensah GA. Pulmonary hypertension surveillanceeUnited States, 1980-2002. MMWR Surveill Summ. 2005;54:1e28. 2. Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013;62:D34eD41. 3. Benza RL, Miller DP, Barst RJ, Badesch DB, Frost AE, McGoon MD. An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from the REVEAL Registry. Chest. 2012;142:448e456. 4. Galie N, Manes A, Negro L, Palazzini M, Bacchi-Reggiani ML, Branzi A. A metaanalysis of randomized controlled trials in pulmonary arterial hypertension. Eur Heart J. 2009;30:394e403. 5. D’Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med. 1991;115:343e349. 6. Fijalkowska A, Kurzyna M, Torbicki A, et al. Serum N-terminal brain natriuretic peptide as a prognostic parameter in patients with pulmonary hypertension. Chest. 2006;129:1313e1321. 7. Raymond RJ, Hinderliter AL, Willis PW, et al. Echocardiographic predictors of adverse outcomes in primary pulmonary hypertension. J Am Coll Cardiol. 2002;39:1214e1219. 8. Torbicki A, Kurzyna M, Kuca P, et al. Detectable serum cardiac troponin T as a marker of poor prognosis among patients with chronic precapillary pulmonary hypertension. Circulation. 2003;108:844e848. 9. Chin KM, Channick RN, de Lemos JA, Kim NH, Torres F, Rubin LJ. Hemodynamics and epoprostenol use are associated with thrombocytopenia in pulmonary arterial hypertension. Chest. 2009;135:130e136. 10. Jubelirer SJ. Primary pulmonary hypertension. Its association with microangiopathic hemolytic anemia and thrombocytopenia. Arch Intern Med. 1991;151:1221e1223. 11. Abramowitz M, Muntner P, Coco M, et al. Serum alkaline phosphatase and phosphate and risk of mortality and hospitalization. Clin J Am Soc Nephrol. 2010;5:1064e1071. 12. Das R, Feuerstadt P, Brandt LJ. Glucocorticoids are associated with increased risk of short-term mortality in hospitalized patients with clostridium difficileassociated disease. Am J Gastroenterol. 2010;105:2040e2049. 13. Southern WN, Nahvi S, Arnsten JH. Increased risk of mortality and readmission among patients discharged against medical advice. Am J Med. 2012;125:594e602. 14. Stein EG, Haramati LB, Bellin E, et al. Radiation exposure from medical imaging in patients with chronic and recurrent conditions. J Am Coll Radiol. 2010;7:351e359.

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