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(Chest. 2004;125:2115-2120.)
© 2004 American College of Chest Physicians

Evaluation of Intravascular Hemolysis With Erythrocyte Creatine in Patients With Cardiac Valve Prostheses*

Toshika Okumiya, PhD; Mitsuko Ishikawa-Nishi; Tadafumi Doi; Mikio Kamioka, MD; Hiroaki Takeuchi, PhD; Yoshinori Doi, MD and Tetsuro Sugiura, MD, FCCP

* From the Department of Laboratory Medicine (Drs. Okumiya, Kamioka, Sugiura, Ms. Ishikawa-Nishi, and Mr. T. Doi) and Geriatric Medicine (Dr. Y. Doi), Faculty of Medicine, Kochi Medical School, Nankoku; and the Department of Laboratory Sciences (Dr. Takeuchi), Yamaguchi University School of Medicine, Ube, Japan.

Correspondence to: Toshika Okumiya, PhD, Department of Laboratory Medicine, Faculty of Medicine, Kochi Medical School, Oko-cho, Nankoku, Kochi 783-8505, Japan; e-mail: okumiyat{at}med.kochi-u.ac.jp


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: To detect intravascular hemolysis in patients with cardiac valve prostheses. Erythrocyte creatine, a marker of erythrocyte age that increases with shortening erythrocyte survival, was evaluated with other hemolytic markers and hemodynamic parameters.

Design: Prospective study.

Patients and measurements: Erythrocyte creatine was enzymatically assayed in 33 patients with prosthetic valves, including 15 patients with aortic valve replacement, 13 patients with mitral valve replacement, and 5 patients with double-valve (aortic and mitral) replacement, and 33 control subjects. Blood flow velocity and valvular regurgitation were determined by Doppler echocardiography. Other hemolytic markers (lactate dehydrogenase [LDH], reticulocyte count, and haptoglobin) and cardiac muscle markers (myoglobin and myosin light chain 1) were also measured.

Results: Erythrocyte creatine and LDH levels were significantly higher (p < 0.0001) and the haptoglobin level was lower (p < 0.0001) in patients with a prosthetic valve as compared with control subjects. However, there were no significant differences in these markers between those with (n = 17) and without (n = 16) regurgitation. Patients with high erythrocyte creatine levels (> 1.8 µmol/g hemoglobin) exhibited significantly higher total peak flow velocity (sum of peak flow velocities at mitral and aortic valves) than those with normal erythrocyte creatine levels (p = 0.006). Erythrocyte creatine had a significant correlation with total peak flow velocity (r = 0.64, p < 0.0001), but LDH and haptoglobin had no significant correlation with total peak flow velocity. Patients with high LDH levels (> 460 IU/L) showed significantly higher myoglobin (p = 0.008) and myosin light chain 1 (p = 0.02) than those with normal LDH levels, whereas erythrocyte creatine was not related to cardiac muscle markers.

Conclusions: Erythrocyte creatine is a quantitative and reliable marker for intravascular hemolysis in patients with prosthetic valves. Mild hemolysis is ascribable to valvular flow velocity rather than regurgitation.

Key Words: cardiac valve prosthesis • erythrocyte age • erythrocyte creatine • intravascular hemolysis


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Heart valve replacement with mechanical prostheses is known to induce mild but chronic intravascular hemolysis. Clinically significant anemia caused by intravascular hemolysis was reported in patients with ball-valve prosthesis (eg, Starr-Edwards prosthesis; Baxter Healthcare Corporation; Santa Ana, CA).123 Decompensated hemolytic anemia is, however, currently decreasing with the development of advanced generation of cardiac valve prostheses, including biological, tilting disk, and bileaflet prostheses: Carpentier-Edwards (Baxter Healthcare Corporation), Björk-Shiley (Shiley; Irvine, CA), Medtronic Hall (Medtronic; Minneapolis, MN), and St. Jude Medical prostheses (St. Jude Medical; St. Paul, MN). Even in cases with compensated anemia, unnecessary erythrocyte production following intravascular hemolysis due to abnormal destruction of erythrocytes remains to be improved. Moreover, hemolysis is more pronounced in a malfunctioning prosthesis than that in normally functioning prosthesis,4 and a malfunctioning valve has a potential of thromboembolic events. Therefore, a reliable marker to estimate the severity of intravascular hemolysis from mechanical and shear stresses on erythrocytes is desirable.

Erythrocyte survival with a 51Cr-labeling method was utilized to estimate the severity of intravascular hemolysis in patients with prosthetic valves and valvular heart disease, and shortened erythrocyte survival was demonstrated in those patients.567 The 51Cr-labeling method is, however, not suitable for routine clinical use, because it requires exclusive equipment for radioactive materials and a prolonged examination period with series of blood drawing from the patient. However, erythrocyte creatine is regarded as a sensitive and quantitative marker of mean age of the erythrocyte population, because young erythrocytes contain considerably higher creatine levels than older erythrocytes,8 and creatine contents in erythrocytes decrease gradually with advancing cell age.9 Thus, an increase in erythrocyte creatine quantitatively reflects the degree of shortened erythrocyte survival. In practice, erythrocyte creatine is closely correlated with 51Cr-labeled erythrocyte survival in patients with hemolytic anemia.10 In contrast to the 51Cr-labeling method, measurement of erythrocyte creatine is simple, rapid, and economically favorable to determine the erythrocyte age by a single blood sample measurement. Several assay methods have been used for erythrocyte creatine measurement1011121314; however, these methods have some disadvantages on specificity and sensitivity, stability of the reagents, and applicability to automated analyzers. Accordingly, we developed a sensitive and specific enzymatic assay method for erythrocyte creatine measurement,15 which is applicable to automated analyzers, and applied to several pathologic situations associated with abnormal erythrocyte destruction to estimate abnormally decreased hemoglobin A1c in patients with shortened erythrocyte age,16 erythropoietic status in patients with functional copper deficiency17 and in patients with maintenance hemodialysis therapy,18 and degree of hypersplenism in patients with liver cirrhosis.19 This marker has a potential to assess turnover of circulating erythrocytes in various pathologic situations other than above mentioned, eg, drug reaction, infection, and hemoglobin and vascular abnormalities. In this study, we measured erythrocyte creatine by means of the enzymatic method with other hemolytic markers to compare their characteristics in patients with cardiac valve prostheses, and examined the relation between intravascular hemolysis and hemodynamic parameters in these patients.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects
Thirty-three patients with prosthetic valves were enrolled. The study population consisted of 15 patients with aortic valve replacement (11 St. Jude Medical, 3 Björk-Shiley, and 1 ATS Medical prostheses [ATS Medical; Minneapolis, MN]), 13 patients with mitral valve replacement (6 St. Jude Medical, 5 Björk-Shiley, and 2 Carpentier-Edwards prostheses) and 5 patients with double valve (aortic and mitral) replacement (3 patients with both St. Jude Medical prostheses, 1 patient with St. Jude Medical (aortic valve) and Björk-Shiley (mitral valve) prostheses, and 1 patient with both Björk-Shiley prostheses). Time from final operation (mean ± SD) was 2,921 ± 2,177 days (2,352 ± 2,146 days for aortic valve replacement, 3,646 ± 2,129 days for mitral valve replacement, and 3,065 ± 2,350 days for double valve replacement). Ejection fraction of the 33 patients was 65 ± 10%. No patient showed schistocytes on blood smear or bilirubinemia. To avoid possible interference with other pathogenic processes including abnormality in production or destruction of erythrocytes, patients with hematologic, immunologic, hepatic, and renal diseases were excluded. Thirty-three healthy volunteers were used as a control group. There was no significant difference in age and gender distributions between patient and control groups (Table 1 ). Written informed consent was obtained from all subjects, and all samples from these subjects were prepared and analyzed in accordance with the ethical recommendations of the responsible committee of the hospital.


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  		Table 1. Hematologic Profiles of the Patients With Prosthetic Valves*

 
Measurement of Erythrocyte Creatine and Other Hemolytic Markers
Erythrocyte creatine was assayed enzymatically in accordance with a previous report.15 Briefly, blood was collected in ethylenediamine tetra-acetic acid-containing tubes and centrifuged to remove plasma and buffy coat. After lysis and deproteinization of packed erythrocytes, supernatant was obtained by centrifugation and filtration. Creatine concentration in the supernatant was measured with the enzymatic assay method involving creatine amidinohydrolase, sarcosine oxidase, and peroxidase. Measured data were expressed as micromole per gram of hemoglobin. Hematologic examinations were carried out with an automated analyzer (Sysmex SE-9000; TOA Medical Electronics; Kobe, Japan). Reticulocyte counts were performed with an automated analyzer (Sysmex R-3000; TOA Medical Electronics). Lactate dehydrogenase (LDH), haptoglobin, myoglobin, and cardiac myosin light chain 1 isoform in serum were determined with commercially available kits [LD(L)-L reagent; International Reagent; Kobe, Japan], HPT-Array System (Beckman Coulter; Fullerton, CA), Myoglobin Kit "Daiichi" III (Daiichi Radioisotope Laboratories; Tokyo, Japan), and Myosin LI Kit Yamasa (Yamasa Corporation; Choshi, Japan), respectively.

Echocardiography
The valve function was assessed with hemodynamic parameters at rest using a Sequoia echocardiography system (Acuson; Mountain View, CA), equipped with a 3.5-MHz sector transducer. Blood flow velocity and valvular regurgitation were determined by Doppler echocardiography. Flow velocity parameters were calculated by means of the meter-per-second scale on the vertical axis, and the time scale on the horizontal axis. Valvular regurgitation was assessed with color-flow imaging technique in accordance with previously defined criteria for prosthetic valvular regurgitation: regurgitant jet area > 2 cm2 and jet length > 2.5 cm in the mitral position, or jet area > 1 cm2 and length > 1.5 cm in the aortic position.20 Peak flow velocities at the mitral and aortic valves were summed up and expressed as total peak flow velocity, because intravascular hemolysis in patients with a prosthetic valve is ascribable to the total damage of erythrocytes at cardiac valves, including prosthetic and intact valves.

Statistical Analysis
The measured values are expressed as mean ± SD. Two-sample, independent-group t tests was used for data comparison between the two groups. Data comparison among three or more groups was based on analysis of variance, with respective all-pairwise, multiple comparison, post hoc analysis utilizing the Sheffe method. Categorical variables were compared with {chi}2 analysis. Correlation between two variables was determined by a linear regression analysis. Results were considered to be significant at p < 0.05.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Hemolysis in Patients With Prosthetic Valves
There were no significant differences in erythrocyte count, hemoglobin, hematocrit, and platelet and reticulocyte counts between the patients with prosthetic valves and control subjects (Tables 1, 2 ). Erythrocyte creatine and LDH levels were significantly higher (p < 0.0001) and haptoglobin was lower (p < 0.0001) in the patients with prosthetic valves as compared with control subjects (Table 2).


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  		Table 2. Comparison of Hemolytic Markers in Patients With Prosthetic Valves*

 
Effect of the Site of the Prosthetic Valve on Hemolysis
The patients with double-valve replacement showed significantly higher erythrocyte creatine levels (2.83 ± 0.94 µmol/g hemoglobin) than those with mitral valve replacement (1.92 ± 0.49 µmol/g hemoglobin, p = 0.05). There were no significant differences in hemoglobin, LDH, and haptoglobin levels among the patients with aortic, mitral, and double-valve replacement. Total peak flow velocity (4.65 ± 1.23 m/s) in patients with double-valve replacement was significantly higher than those with mitral valve replacement (3.41 ± 0.62 m/s, p = 0.02).

Effect of Regurgitation on Hemolysis
Thirty-three patients with prosthetic valves were classified into two groups in accordance with presence (n = 17; 13 transvalvular and 4 paravalvular) or absence (n = 16) of regurgitation at aortic and/or mitral valves. There were no significant differences in erythrocyte creatine, LDH, and haptoglobin levels between patients with and without regurgitation (2.30 ± 0.61 µmol/g hemoglobin vs 2.02 ± 0.77 µmol/g hemoglobin, p = 0.26; 568 ± 169 IU/L vs 517 ± 107 IU/L, p = 0.31; and 21 ± 29 mg/L vs 66 ± 217 mg/L, p = 0.42, respectively).

Comparison of Hemolytic Markers With Peak Flow Velocity
Twenty patients with high erythrocyte creatine levels (> 1.8 µmol/g hemoglobin) had significantly higher total peak flow velocity than 13 patients with normal erythrocyte creatine levels (4.04 ± 1.06 m/s vs 3.22 ± 0.52 m/s, p = 0.006). However, there was no significant difference in total peak flow velocity between 22 patients with high LDH levels (> 460 IU/L) and 11 patients with normal LDH levels (3.69 ± 1.05 m/s vs 3.78 ± 0.82 m/s). Thirty-two of 33 patients with prosthetic valves showed abnormally low haptoglobin values. Erythrocyte creatine showed significant correlation with total peak flow velocity (r = 0.64, p < 0.0001), but LDH and haptoglobin were not related to total peak flow velocity (r = 0.11, p = 0.54; and r = 0.03, p = 0.86, respectively) [Fig 1 ].



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  		Figure 1. Correlation of erythrocyte creatine (left, A), LDH (LD) [middle, B], and haptoglobin (Hpt) [right, C] with total peak flow velocity.

 
Comparison of Hemolytic Markers With Cardiac Markers
The patients with high LDH levels had significantly higher myoglobin levels (64.2 ± 27.8 µg/L vs 45.3 ± 7.6 µg/L, p = 0.008) and myosin light chain 1 isoform (number of patients with > 1.0 µg/L, 8 of 22 patients vs 0 of 11 patients, p = 0.02) than those with normal LDH levels. However, no significant difference was observed in the cardiac muscle markers between patients with high erythrocyte creatine and normal erythrocyte creatine (myoglobin, 58.5 ± 26.1 µg/L vs 58.6 ± 24.6 µg/L, p = 0.98; and myosin light chain 1 isoform, number of patients with > 1.0 µg/L, 5 of 20 patients vs 3 of 13 patients, p = 0.51). There were no significant differences in ejection fraction and left ventricular end-diastolic volume between the patients with high LDH and normal LDH levels.

Time From Operation and Cardiac Rhythm
There were no significant differences in time from the final operation and cardiac rhythm (sinus rhythm or chronic atrial fibrillation) between patients with high erythrocyte creatine and normal erythrocyte creatine levels, and between patients with high LDH and normal LDH levels.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The significant increase in erythrocyte creatine and serum LDH as well as decrease in serum haptoglobin indicates the presence of intravascular hemolysis due to abnormal erythrocyte destruction in patients with prosthetic valves. However, intravascular hemolysis was mild and completely compensated because neither erythrocyte count, hemoglobin, nor hematocrit levels showed any difference between the patients with prosthetic valves and the control group. A previous report21 suggested that paravalvular regurgitation contributed to the severity of intravascular hemolysis. However, there were no significant differences in any of the hemolytic markers including erythrocyte creatine between the patients with and without valvular regurgitation. This discrepancy may be related to the use of a newer generation of prostheses, indicating that regurgitation had minimal effect on mild hemolysis in the patients without apparent anemia.

Several markers including erythrocyte survival, reticulocyte count, schistocyte count, as well as serum levels of hemoglobin, indirect bilirubin, LDH, and haptoglobin have been applied to estimating the severity of intravascular hemolysis.345672122232425262728 Among these markers, serum LDH has been widely used to estimate the severity of intravascular hemolysis in patients with cardiac valve prostheses, because close relation between serum LDH and half-life of 51Cr-labeled erythrocyte was demonstrated in patients with ball-valve prosthesis and valvular disease.722 However, serum LDH is interfered with by other pathologic or artificial processes, including the release of LDH from cardiac muscle, skeletal muscle, and malignant cells. Moreover, hemolysis in vitro during blood preparations (eg, during centrifugation, blood storage, or blood drawing) affects serum LDH levels. To clarify the diagnostic accuracy of various hemolytic markers, hemolytic markers were compared with total peak flow velocity as a shear stress on the erythrocytes. Although the patients with high erythrocyte creatine levels exhibited higher total peak flow velocity as compared to those with normal erythrocyte creatine levels, there was no significant difference in total peak flow velocity between patients with abnormal high LDH levels and normal LDH levels. In contrast to a good correlation between erythrocyte creatine and total peak flow velocity, serum LDH level was not related to total peak flow velocity. Interestingly, high LDH level was associated with elevation of myoglobin and myosin light chain 1 isoform in patients with prosthetic valves. Myoglobin is a cytoplasmic protein found in cardiac and skeletal muscles that binds oxygen. It is not a specific marker for cardiac muscle but can be used as a very sensitive maker of myocardial damage when combined with other specific cardiac muscle markers.29 Myosin light chain 1 isoform is a myocardial contractile protein that is released into circulating blood during myocyte necrosis, and is used as a specific marker of myocardial damage.30 Thus, slight and significant increase in myoglobin and myosin light chain 1 isoform reflects the presence of limited cardiac muscle injury in patients with high LDH level. These findings indicate that an increase in serum LDH is ascribable not only to intravascular hemolysis but also to subtle cardiac muscle damage in patients with prosthetic valves, which compromise the reliability of diagnostic performance of LDH, particularly in the early postoperative stage. In contrast, there was no significant difference in the cardiac muscle markers between patients with high erythrocyte creatine and normal erythrocyte creatine. Considering the fact that erythrocyte creatine is not related to plasma creatine31 and is assayed in packed erythrocytes, erythrocyte creatine is not interfered substantially with cardiac muscle damage and hemolysis in vitro during blood preparations. Haptoglobin is thought to be a sensitive marker for intravascular hemolysis. However, since haptoglobin did not correlate with any of the hemodynamic parameters, it is not favorable for quantitative assessment of intravascular hemolysis in patients with prosthetic valves. Reticulocyte count is also a conventional marker, used as an erythropoietic or hemolytic marker, but it does not have a sufficient sensitivity to detect mild hemolysis.

In conclusion, erythrocyte creatine is a reliable and quantitative maker to estimate the severity of intravascular hemolysis in patients with cardiac valve prostheses. Mild and subclinical hemolysis due to abnormal destruction of erythrocytes caused by prosthetic valve is ascribable to an increase in valvular flow velocity rather than valvular regurgitation.


   Acknowledgements
 
The authors thank Misa Nakagawa and Shigeo Yamanaka of Kochi Medical School (Nankoku, Japan) for technical support.


   Footnotes
 
Abbreviation: LDH = lactate dehydrogenase

This work was supported by grants from Japan Society for the Promotion of Science (Grant-in-Aid for Scientific Research C and Grant-in-Aid for Young Scientists B).

Received for publication August 7, 2003. Accepted for publication December 3, 2003.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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