Prognostic impact of hypochromic erythrocytes in patients with pulmonary arterial hypertension

doi:10.21203/rs.3.rs-853248/v1

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Prognostic impact of hypochromic erythrocytes in patients with pulmonary arterial hypertension

https://doi.org/10.21203/rs.3.rs-853248/v1

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Background

Iron deficiency affects up to 50% of patients with pulmonary arterial hypertension (PAH) but iron markers such as ferritin and serum iron are confounded by several non-disease related factors like acute inflammation and diet. The aim of this study was to identify a new marker for iron deficiency and clinical outcome in PAH patients.

Methods

In this single-center, retrospective study we assessed indicators of iron status and clinical parameters specifying the time to clinical worsening (TTCW) and survival in PAH patients at time of initial diagnosis and at 1-year follow-up using univariable and multivariable analysis.

Results

In total, 150 patients were included with an invasively confirmed PAH and complete data on iron metabolism. The proportion of hypochromic erythrocytes > 2% at initial diagnosis was identified as an independent predictor for a shorter TTCW (p = 0.0001) and worse survival (p = 0.002) at initial diagnosis as well as worse survival (p = 0.016) at 1-year follow-up. Only a subset of these patients (64%) suffered from iron deficiency. Low ferritin or low serum iron neither correlated with TTCW nor survival. Only severe hemoglobin deficiency at baseline was significantly associated with a shorter TTCW (p = 0.001).

Conclusions

The presence of hypochromic erythrocytes > 2% was a strong and independent predictor of mortality and shorter TTCW in this cohort of PAH patients. Thus, it can serve as a valuable indicator of iron homeostasis and prognosis even in patients without iron deficiency or anemia. Further studies are needed to confirm the results and to investigate therapeutic implications.

Pulmonology

Evolutionary Genetics

Translational Medicine

Pediatrics

Oncology

Iron deficiency

anemia

hypochromic erythrocytes

pulmonary arterial hypertension

In the last decade, increasing attention has been paid to the role of iron metabolism in cardiovascular diseases (Chopra and Anker 2020; Vinchi et al. 2020). Iron deficiency can affect up to 50% of patients with pulmonary arterial hypertension (PAH) (Rhodes et al. 2010; Ruiter et al. 2011). Moreover, iron deficiency in PAH patients correlated with more severe disease, including reduced exercise capacity and worse survival (Rhodes et al. 2011; Ruiter et al. 2015; Soon et al. 2011). While PAH guidelines suggest iron supplementation when needed (Galiè et al. 2019; Galiè et al. 2015), iron supplementation trials in PAH patients provided inconclusive results in three smaller studies with around 22 PAH patients (Olsson et al. 2020; Ruiter et al. 2015; Viethen et al. 2014). Only in two of these three studies the 6-minute walking distance increased significantly in previously iron deficient patients (Olsson et al. 2020; Viethen et al. 2014). Nevertheless, all studies presented improvements of study specific measurements such as quality of life (Viethen et al. 2014), exercise endurance time (Ruiter et al. 2015) or right ventricular fractional area change (Olsson et al. 2020). In these studies, the definition of iron deficiency was based on the three parameters serum ferritin, transferrin saturation (TSAT), and serum iron or hemoglobin concentration. Furthermore, treatment of iron deficiency should be managed with extreme caution since underlying conditions, such as infection and inflammation, that alter iron handling put the patient at risk of having detrimental effects due to iron treatment.

Routinely, iron deficiency diagnosis relies on the TSAT and serum ferritin levels. However, these parameters can be altered by concomitant conditions such as inflammation and infections and, thus, not always accurately reflect the iron status (Sonnweber et al. 2020). In addition, the measurement of serum iron levels depends on the daytime and food intake (Dale et al. 2002). Thus, these parameters are unreliable if not recorded under standardized conditions such as fasting. Moreover, TSAT is often not part of the routine laboratory assessment. Therefore, readily available, new iron deficiency indices which mirror the clinical status of the patient and which are less affected by inflammation are needed to facilitate therapeutic decisions.

Hypochromic erythrocytes may be such a new “biomarker” because they reflect upon the availability of iron in the previous 120 days and are both an early marker of anemia and an index of response to iron treatment (Goddard et al. 2011). Hypochromic erythrocytes mirror the current iron availability status in the bone marrow and erythropoietic system since they are produced as a consequence of iron deficient erythropoiesis (Goddard et al. 2011). Therefore, they are useful indicators of functional iron deficiency, providing values independent of concomitant inflammatory processes (Macdougall et al. 1992; Navarro and Macia 1997).

The aim of the current study was to correlate routinely measured iron related parameters including the percentage of hypochromic erythrocytes with clinical data at baseline and during follow-up in particular with time to clinical worsening (TTCW) and survival in a large cohort of PAH patients.

Study design

This was a single-center, retrospective study analyzing TTCW and survival during yearly follow-up in PAH patients diagnosed and treated in the Centre for Pulmonary Hypertension between 04/2013 and 08/2017 at the Thoraxklinik Heidelberg gGmbH at Heidelberg University Hospital, Germany. This study evaluated data from incident PAH patients with at least one follow-up examination.

TTCW was defined as death, transplantation, hospitalization due to PAH, worsening of World Health Organization (WHO) functional class of at least one stage or 6-minute walking distance (6MWD) deterioration ≥ 15% compared to baseline. Clinical worsening was recorded either with date and type of worsening or death with date, cause and circumstances. The ethics committee of the Medical Faculty of Heidelberg University Hospital had no objection against the conduct of the study (internal number S-317/2020). The study complied with the Declaration of Helsinki in its current version.

Study Population

Inclusion criteria were incident patients aged ≥ 18 years with PAH (defined according to the European Society of Cardiology / European Respiratory Society pulmonary hypertension guidelines) (Galiè et al. 2015) diagnosed by right heart catheterization, defined as a mean pulmonary arterial pressure ≥ 25 mmHg, pulmonary arterial wedge pressure ≤ 15 mmHg and pulmonary vascular resistance > 3 Wood Units. Patients with significant left heart disease or lung disease were excluded.

Study investigations

The variables to investigate the clinical significance of iron deficiency were derived from routine laboratory assessments (ferritin, serum iron, hemoglobin, mean erythrocyte corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration and percentage of hypochromic erythrocytes, which contained less than 28 g/dl hemoglobin). Clinical parameters for characterization included demographic data, comorbidities, hospitalization data, vital signs, echocardiography, hemodynamics measured by right heart catheterization, spirometry, blood gas analysis, lung function, WHO functional class, 6-minute walking distance, as well as the laboratory parameters for the assessment of renal function (creatinine, glomerular filtration rate).

Statistical methods

Data including patient characteristics and the clinical parameters were presented using descriptive statistics with mean ± standard deviation and frequency tables. Frequency data, presented as n and %, were analyzed using the chi-square test. Survival was analyzed with Kaplan-Meier statistics and Cox regression analysis. For survival, date of initial diagnosis (i.e. right heart catheterization) was used as baseline and date of death due to any cause, date of lung transplantation or date of last patient contact when the patient was still alive were used for follow-up.

The prognostic value for survival and TTCW at initial diagnosis and survival one year after initial diagnosis were investigated by univariable and multivariable analysis with hemoglobin deficiency, ferritin < 40 ng/ml, hypochromic erythrocytes > 2% and low iron as outcome variable. Hemoglobin deficiency was defined as < 12 g/dl in women and < 13 g/dl in men and low serum iron as < 12 µmol/l in women and < 13 µmol/l in men. Reference values are based on internal laboratory reference ranges or clinical routine cut-offs for iron supplementation. All variables identified with the univariable log rank tests as being significantly associated with survival (p < 0.05) were further analyzed using a multivariable Cox model.

Clinical characteristics between patient groups with better and worse survival for independent prognostic predictors were compared with Mann-Whitney U-Test. P values <0.05 were considered statistically significant. All analyses were performed with IBM SPSS V 25.0 (IBM Corp. Released 2017. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp.).

Baseline characteristics

Among 1522 right heart catheterizations performed at the Center for Pulmonary Hypertension, Thoraxklinik Heidelberg between April 2013 and August 2017, 150 patients had an invasively confirmed PAH diagnosis and a concomitant iron metabolism assessment. Table 1 shows baseline characteristics of the whole study cohort. Out of 150 PAH patients, 93 were female (62%) with a mean age of 63.3 ± 14.5 years. Forty-four patients were included with idiopathic PAH (29%), 4 with heritable PAH (3%), 50 patients with associated PAH (33%) and 52 with other PAH forms (35%). Right heart catheterization revealed severely increased pulmonary pressures with high pulmonary vascular resistances. Patients showed an enlarged right heart with mild impairment of right ventricular systolic function. On average patients displayed a normal renal function.

Table 1

Baseline characteristics of the study cohort
		Whole cohort (n = 150) mean ± SD or n and (%)
		Whole cohort (n = 150) mean ± SD or n and (%)			n
Characteristics	Age, years	63.3	±	14.5	150
	Height, cm	166.3	±	8.7	149
	Weight, kg	78.0	±	16.8	150
	Body mass index	28.2	±	5.7	149
	Sex, female	93		(62)	149
	6-minute walking distance	331	±	126	118
	WHO functional class				130
	II	25		(19.2)
	III	90		(69.2)
	IV	15		(11.6)
PAH classification	Idiopathic PAH	44		(29.3)	150
	heritable PAH	4		(2.7)
	Associated PAH	50		(33.4)
	Other PAH	52		(34.7)
Laboratory	Creatinine, mg/dl	1.05	±	0.42	149
	Glomerular filtration rate, %	69.2	±	25.2	143
	Iron, µg/dl	13.9	±	6.7	74
	Hemoglobin, g/dl	14.5	±	1.8	149
	Iron deficiency	40		(54.1)	74
	Hemoglobin deficiency	16		(10.7)	149
	Ferritin < 40, ng/ml	13		(16.0)	81
	MCV < 83, fl	21		(14.1)	149
	MCH < 27, pg/cell	17		(11.4)	149
	MCHC < 30, g/dl	6		(4.0)	149
	Hypochromic erythrocytes > 2%	21		(33.9)	62
Diffusion capacity	DLCO SB, %	48.7	±	22.3	130
	Right atrial area, cm²	20.5	±	6.3	142
Echocardiography	Right ventricular area, cm²	24.4	±	7.1	145
	Systolic pulmonary arterial pressure, mmHg	63.6	±	19.5	147
	Tricuspid annular plane systolic excursion	1.9	±	0.6	146
	Right atrial pressure, mmHg	8.0	±	4.7	111
Right heart catheter	Mean pulmonary arterial pressure, mmHg	43.7	±	12.4	150
	Cardiac output, l/min	4.6	±	1.3	134
	Pulmonary arterial wedge pressure, mmHg	9.7	±	3.1	143
	Pulmonary vascular resistance, dynesseccm^− 1	651	±	323	142
PAH = pulmonary arterial hypertension, MCV = mean corpuscular volume, MCH = mean corpuscular hemoglobin, MCHC = mean corpuscular hemoglobin concentration, DLCO = diffusion capacity of carbon monoxide

Anemia and iron metabolism

In the study cohort, 10.7% of patients presented with anemia, i.e. hemoglobin deficiency, at diagnosis (Table 1 and Fig. 1). The number of anemic patients almost doubled to 21.1% after 1-year of follow-up. Low serum iron was nearly unchanged between baseline (54.1%) and 1-year follow-up (50.5%). Likewise, hypochromic erythrocytes (33.9% at baseline vs 36.5% after 1 year) and serum ferritin levels (16.0% at baseline and 15.7% after 1 year) showed similar values over time.

Survival and clinical worsening

To identify parameters associated with TTCW and survival iron related parameters were assessed by Kaplan-Meier analyses (Table 2). Ferritin levels had no prognostic value for survival or TTCW. Hemoglobin deficiency was significantly associated with a shorter TTCW (p = 0.001) (Fig. 2) and showed a trend towards increased mortality in the group of patients with low hemoglobin at diagnosis (p = 0.093) in the univariable analysis. However, no association with survival and hemoglobin levels 1 year after diagnosis could be detected (Fig. 2).

Table 2

Uni- and multivariable analysis of predictors for survival and time to clinical worsening
		TTCW	Survival	Survival
Univariate Analysis		baseline	baseline	1 year
	Hemoglobin deficiency	0.001	0.093	0.932
	Ferritin < 40, ng/ml	0.140	0.932	0.410
	Hypochromic erythrocytes > 2%	< 0.0001	0.001	0.015
	Iron low	0.900	0.722	0.030
		TTCW	Survival	Survival
Multivariate Analysis		baseline	baseline	1 year
	Hemoglobin deficiency	-	-	-
	Ferritin < 40, ng/ml	-	-	-
	Hypochromic erythrocytes > 2%	0.0001	0.002	0.016
	Iron low	-	-	-

The presence of hypochromic erythrocytes > 2% at baseline resulted in a strong, independent prediction of TTCW (p = 0.0001) and survival (p = 0.001) in the univariable analysis (Fig. 3, Table 2). Likewise, also the presence of hypochromic erythrocytes > 2% detected 1 year after diagnosis was still associated with impaired survival (p = 0.015). Importantly, hypochromic erythrocytes were the only measurement which remained significant for TTCW and survival in the multivariable analysis (Table 2).

Differences between patients with hypochromic erythrocytes ≤ 2% and > 2%

Patients with a higher rate of hypochromic erythrocytes (≤2% vs. >2%), displayed a significant impairment of renal function (glomerular filtration rate 72.8 ± 28.1 vs. 57.4 ± 26.3 ml/min respectively, p = 0.021, Table 3), anemia (19% vs. none), and impairment of lung diffusion capacity (55.7 ± 22.2 vs. 43.4 ± 21.8 %, p = 0.022). No differences were found regarding right heart size or function in transthoracic echocardiography. Hemodynamics were comparable between the two groups except for a slightly higher pulmonary arterial wedge pressure in patients with more hypochromic erythrocytes (9.8 ± 2.2% vs. 11.3 ± 3.1%, p = 0.045).

Table 3

Characteristics of patients with normal and abnormal hypochromic erythrocytes at baseline
		Hypochromic erythrocytes at baseline
		≤ 2%			> 2%
		n = 41			n = 21
		mean ± SD or n (valid %)			mean ± SD or n (valid %)			p-value*
Characteristics	Age, years	62.4	±	14.3	68.1	±	15.2	0.106
	Height, cm	166.9	±	9.8	164.9	±	9.1	0.227
	Weight, kg	80.5	±	16.7	80.9	±	21.1	0.577
	Sex, female	24		(58.5)	12		(57.1)	0.916
PAH classification	Idiopathic PAH	19		(46.3%)	3		(14.3%)	0.036
	Associated PAH connective tissue disease	6		(14.6%)	6		(28.6%)
	Portal hypertension	1		(2.4%)	0
	Congenital heart disease	0			2		(9.5%)
	Other PAH	15		(36.6%)	10		(47.6%)
Laboratory	Creatinine, mg/dl	1.1	±	0.4	1.3	±	0.5	0.054
	Glomerular filtration rate, %	72.8	±	28.1	57.4	±	26.3	0.021
	Iron, µg/dl	15.0	±	5.5	13.2	±	6.7	0.285
	Hemoglobin, g/dl	15.0	±	1.4	14.1	±	1.8	0.048
	Iron deficiency	10		(45.5%)	7		(63.6%)	0.455
	Hemoglobin deficiency	0			4		(19%)	0.004
	Ferritin < 40, ng/ml	3		(8.3)	3		(16.7)	0.380
	MCV < 83, fl	1		(2.4%)	5		(23.8%)	0.007
	MCH < 27, pg/cell	1		(2.4%)	3		(14.3%)	0.072
	MCHC < 30, g/dl	0			1		(4.8%)	0.169
Diffusion capacity	DLCO SB, %	55.7	±	22.2	43.4	±	21.8	0.022
Echocardiography	Right atrial area, cm²	19.8	±	6.5	22.7	±	6.5	0.062
	Right ventricular area, cm²	22.4	±	5.4	24.9	±	7.8	0.211
	Systolic pulmonary arterial pressure, mmHg	61.0	±	20.9	59.5	±	19.7	0.855
	Tricuspid annular plane systolic excursion	2.1	±	0.6	2.0	±	0.7	0.581
Right heart catheter	Right atrial pressure, mmHg	7.1	±	4.2	9.1	±	3.9	0.053
	Mean pulmonary arterial pressure, mmHg	40.2	±	12.0	40.1	±	9.2	0.743
	Cardiac output, l/min	4.6	±	1.2	4.6	±	1.8	0.438
	Pulmonary arterial wedge pressure, mmHg	9.8	±	2.8	11.3	±	3.1	0.045
	Pulmonary vascular resistance, dynesseccm^− 1	600.8	±	363.2	590.6	±	334.3	0.970
*Wilcoxon Mann-Whitney Test or chi-square test for frequency data.
PAH = pulmonary arterial hypertension, MCV = mean corpuscular volume, MCH = mean Corpuscular hemoglobin, MCHC = mean corpuscular hemoglobin concentration, DLCO = diffusion capacity of carbon monoxide

This is the first study identifying the biomarker “hypochromic erythrocytes higher than 2%” at baseline as a strong independent predictor for shorter TTCW (p = 0.0001) and worse survival (p = 0.002) in PAH patients. Increased numbers of hypochromic erythrocytes one year after initial diagnosis were also predictive of worse survival (p = 0.016). By contrast, ferritin and low serum iron were not able to predict mortality in PAH patients, although these parameters are commonly used in clinical routine to assess iron metabolism and to indicate iron supplementation therapy. Only severe hemoglobin deficiency at baseline was significantly associated with a shorter TTCW (p = 0.001).

Clinical impact of iron deficiency in PAH

Various combinations of iron markers, such as ferritin, TSAT or the soluble transferrin receptor are commonly used to define iron deficiency (Sonnweber et al. 2018). According to Sonnweber and colleagues, depending on the definition the prevalence of iron deficiency ranged from 11–75% in a cohort of 153 precapillary PH patients (Sonnweber et al. 2018). The lowest prevalence was based on the lowest cut-off values of TSAT together with serum ferritin while the highest prevalence resulted from less stringent, but routinely used cut-off values (Sonnweber et al. 2018). In the cohort analyzed here, 54% and 16% of PAH patients showed low iron and ferritin levels, respectively. Consistent with previous studies (Rhodes et al. 2011; Sonnweber et al. 2018) ferritin failed to predict TTCW or mortality in PAH. Overall, 10.7% of patients presented with anemia at diagnosis. The rate of anemic patients almost doubled to 21.1% after 1-year of follow-up, whereas hypochromic erythrocytes (33.9% at baseline vs 36.5% after 1 year) showed similar values over time. We speculate that ferritin, a marker for systemic iron availability, does not correlate with TTCW or mortality due to falsely high serum ferritin levels as result of inflammation and chronic kidney failure (Uehata et al. 2012). Impaired renal function often occurs in PAH and can increase ferritin levels due to a reduced renal excretion of the iron hormone hepcidin (Uehata et al. 2012). Hepcidin binds to the iron exporter ferroportin and triggers its degradation. This process significantly contributes to iron deficiency in serum as it diminishes dietary iron absorption and blocks iron release from macrophages that recycle aging red blood cells. As a consequence, ferritin levels rise despite diminished iron availability in the circulation (Muckenthaler et al. 2017). This can falsely signal a normal iron status in PAH patients with impaired renal function.

Hypochromic erythrocytes as new “biomarker” reflecting iron status

Being less affected by inflammation status (Urrechaga et al. 2011), hypochromic erythrocytes may provide crucial information for PAH patients since PAH is frequently associated with inflammatory conditions such as systemic sclerosis, HIV and porto-pulmonary hypertension (Simonneau et al. 2019). The percentage of hypochromic erythrocytes has been previously suggested as a reliable marker of iron deficiency in kidney disease patients that is more reliable compared to TSAT and serum ferritin (Macdougall et al. 1992; Urrechaga et al. 2016). This study showed for the first time that increased numbers of hypochromic erythrocytes reliably reflected iron deficiency even in PAH patients with normal ferritin. While only 64% of the patients with > 2% hypochromic erythrocytes showed low ferritin levels and only 19% were diagnosed with anemia, a worse survival could be identified in this cohort. Thus, hypochromic erythrocytes could be a reliable parameter of iron homeostasis and outcome even in the absence of anemia. Another advantage of hypochromic erythrocytes as new “biomarker” is its availability in the routine clinical practice. Hypochromic erythrocytes might therefore be useful as a future therapeutic target in the context of iron supplementation therapy indication, outcome and monitoring.

Limitations

Our study is limited by its retrospective nature. TSAT and soluble transferrin receptor levels were not measured in our patients within the routine work-up and could therefore not be included in the analysis. Moreover, no assessment of patients’ diet and nutrition was performed. However, we could analyze a large, clinically very well characterized cohort of PAH patients. Currently we are performing a prospective study aimed at better characterizing iron metabolism in PAH patients and its correlation with clinical parameters (NCT04086537).

Hypochromic erythrocytes > 2% independently predicted a reduced TTCW and survival. This new biomarker may be useful to assess the occurrence of functional iron deficiency with greater reliability compared to other routinely used parameters of iron status, such as ferritin, serum iron or hemoglobin. A parameter, which mirrors iron deficiency largely independent of an inflammatory state and shows prognostic capacity for TTCW and survival even in the absence of anemia could become a useful indicator of iron status and a valuable tool for indicating the need of iron supplementation and monitoring supplementation effects. Further studies are needed to confirm the results and to investigate therapeutic implications.

DLCO diffusion capacity of carbon monoxide

HIV Human immunodeficiency virus

PAH Pulmonary arterial hypertension

MCH mean corpuscular hemoglobin

MCHC mean corpuscular hemoglobin concentration,

MCV mean corpuscular volume

TSAT transferrin saturation

TTCW Time to clinical worsening

WHO World Health Organization

6MWD 6-minute walking distance

Ethics Approval: All data were anonymised and the study was approved by the ethics committee of the medical faculty of Heidelberg University Hospital (internal number S-317/2020). The study complies with the Declaration of Helsinki in its current version.

Consent for publication:

Not applicable.

Availability of data and materials:

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

PX has received personal fees from MSD and OMT outside the submitted work.

VT, MK, MS, DC, AC, AD, MM and CAE declare that they have no competing interests related to this study.

AMM has received personal fees from Bayer, outside the submitted work.

NB received speaker fees from Actelion pharmaceuticals / Janssen Medical, Bayer HealthCare and MSD, outside the submitted work.

EG has received grants and personal fees from Actelion, Bayer AG, and MSD; grants from GSK, Novartis, and United Therapeutics; and personal fees from SCOPE, OrPha Swiss GmbH, and Zurich Heart House, outside the submitted work.

BE received travel fees, consulting fees, speaking fees, and/or honoraria from Actelion, MSD, Bayer and OMT, outside the submitted work.

Funding information

No funding

Authors’ contributions

PX: Substantial contributions to the acquisition, analysis and interpretation of data, drafting of the work

VT: this is a part of doctorate thesis of VT: Substantial contributions to the acquisition, analysis and interpretation of data, drafting of the work

NB: Substantial contributions to the conception, acquisition, data analysis and interpretation of data, drafting of the work.

AMM: Substantial contributions to the acquisition and interpretation of data, drafting of the work

CAE: Substantial contributions to the acquisition of data, drafting of the work

AD: Substantial contributions to the acquisition and interpretation of data, drafting of the work.

BE: Substantial contributions to the acquisition and interpretation of data of the work.

MS: Substantial contributions to the acquisition and interpretation of data of the work.

DC: Substantial contributions to the acquisition and interpretation of data of the work.

AC: Substantial contributions to the acquisition and interpretation of data of the work.

EB: Substantial contributions to the acquisition and interpretation of data of the work.

MK: Substantial contributions to the acquisition and interpretation of data of the work.

EG: Substantial contributions to the conception, acquisition, analysis and interpretation of data of the work.

MM: Substantial contributions to the conception, acquisition, analysis and interpretation of data of the work.

CAE: Substantial contributions to the acquisition and interpretation of data, coordination of the work.

All authors read and approved the manuscript and agree to all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Acknowledgements

We would like to thank all patients who participated in the study. This work was a part the doctoral thesis of VT.

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Editorial decision: Major revision
13 Sep, 2021
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Review #1 received at journal
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Review #3 received at journal
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Reviewer #3 agreed at journal
02 Sep, 2021
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Prognostic impact of hypochromic erythrocytes in patients with pulmonary arterial hypertension

Status:

Version 1

Abstract

Background

Methods

Results

Conclusions

Figures

Background

Methods

Study design

Study Population

Study investigations

Statistical methods

Results

Baseline characteristics

Anemia and iron metabolism

Survival and clinical worsening

Differences between patients with hypochromic erythrocytes ≤ 2% and > 2%

Discussion

Clinical impact of iron deficiency in PAH

Hypochromic erythrocytes as new “biomarker” reflecting iron status

Limitations

Conclusions

Abbreviations

Declarations

References

Status:

Version 1