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J Thorac Cardiovasc Surg 2002;123:550-556
© 2002 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology (CSP)

Intravascular hemolysis in patients with new-generation prosthetic heart valves: A prospective study

From the Divisions of Cardiac Surgery^a and Cardiology^b, Cardio-Thoracic Department, University of Pisa Medical School, Pisa, Italy.

Received for publication June 21, 2001; revisions requested Aug 25, 2001; revisions received Sept 4, 2001; accepted for publication Sept 10, 2001. Address for reprints: U. Bortolotti, MD, U.O. Cardiochirurgia, Ospedale Cisanello, Via Paradisa 2, 56124 Pisa, Italy (E-mail: u.bortolotti{at}cardchir.med.unipi.it).

	Abstract

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Objective: A prospective clinical study was designed to assess the frequency and severity of intravascular hemolysis in patients with new-generation, normally functioning prosthetic heart valves.
Methods: Hemolysis was evaluated in 172 patients with a mechanical prosthesis (53 CarboMedics and 119 Sorin Bicarbon) and in 106 patients with a bioprosthesis (15 St Jude Medical Toronto, 19 Baxter Perimount, and 72 Medtronic Mosaic) in the aortic position, mitral position, or both. Aortic valve replacement was performed in 206 patients, mitral valve replacement in 59 patients, and double valve replacement in 13 patients. The presence of hemolysis was assessed on the basis of the level of serum lactic dehydrogenase and serum haptoglobin and the presence and amount of reticulocytes and schistocytes in the peripheral blood. Severity of intravascular hemolysis was estimated on the basis of serum lactic dehydrogenase. Clinical, echocardiographic, and hematologic evaluations were performed 1, 6, and 12 months after discharge.
Results: None of the 278 patients experienced decompensated anemia, whereas at 12 months, mild subclinical hemolysis was identified in 49 patients, 44 (26%) with a mechanical prosthesis and 5 (5%) with a bioprosthesis (P < .001). At multivariate analysis, independent predictors of the presence of subclinical hemolysis were mitral valve replacement (P < .001), use of a mechanical prosthesis (P = .002), and double valve replacement (P = .02). Frequency of hemolysis in patients with stented aortic bioprostheses was 3%, whereas it was absent in those with stentless valves. Among mechanical valve recipients, double versus single valve replacement (P = .04) and mitral versus aortic valve replacement (P = .05) were correlated with the presence of hemolysis; double valve recipients also showed a more severe degree of hemolysis (P = .03). In patients with a Sorin Bicarbon prosthesis, hemolysis was less frequent (22% vs 34%, P = .09) and severe (P < .001) than in those with a CarboMedics prosthesis.
Conclusions: In normally functioning prosthetic heart valves, subclinical hemolysis is a frequent finding. A low incidence of hemolysis is found in stented biologic prostheses, and it is absent in stentless aortic valves. Modifications of valve design may contribute to minimize the occurrence of hemolysis in mechanical prostheses.

	Introduction

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Since the implantation of the first mechanical prosthesis by Hufnagel in 1956, ¹ traumatic hemolysis has been recognized as a potentially serious problem after heart valve replacement. This complication, reported to occur in 5% to 15% of patients with a ball-caged valve, is rarely observed with current normally functioning prostheses but is still encountered in the setting of prosthetic valve dysfunction and regurgitation. ^2,3 However, it has been demonstrated that chronic subclinical hemolysis may be present in patients with mechanical or biologic valve prostheses. ^4-6 Turbulence of flow with high shear-stress forces and abnormal flow jets through the prosthetic valve are thought to be causes of hemolysis. ^7-9 Accordingly, modifications of valve design may contribute to the minimization of the occurrence of such complications by enhancing hemodynamic performance. The aim of this study was to evaluate prospectively the presence of hemolysis in patients with new-generation prosthetic valves and to correlate the frequency and severity of hemolysis to prosthesis number, type, size, and position.

	Materials and methods

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Patient population
From January 1997 to December 1998, a total of 434 patients who underwent mitral valve replacement (MVR), aortic valve replacement (AVR), or both were discharged with normally functioning prosthetic valves. Patients with renal, hepatic, or pulmonary disease were excluded from the study. Informed consent to be enrolled in this study was obtained from 300 patients. However, a complete set of clinical, hematologic, and echocardiographic assessments was available for only 280 of them. Two patients showing paraprosthetic leak at follow-up echocardiography were removed from the study, and the remaining 278 patients form the basis of the present report.

There were 157 men and 121 women, with a mean age of 67 ± 9 years (range, 27-86 years). The main preoperative characteristics are summarized in Table 1.

Study protocol
Patients were evaluated preoperatively and postoperatively at 1, 6, and 12 months. Every follow-up examination consisted of (1) clinical evaluation with investigation for other possible causes of hemolytic anemia, (2) assessment of prosthetic valve function by means of transthoracic or transesophageal echocardiography, and (3) hematologic evaluation of hemolysis, as measured by total blood hemoglobin level, serum lactic dehydrogenase (LDH) level, serum haptoglobin level, reticulocyte count, and presence of schistocytes on a peripheral blood smear. All tests were performed in the same laboratory.

Criteria for hemolysis
As suggested by Skoularigis and colleagues, ¹⁰ patients were considered to have intravascular hemolysis under the following conditions:

1. Serum LDH levels were greater than 460 U/L (normal, 230-460 U/L).
   
2. Any 2 of the following 4 criteria were present: (1) blood hemoglobin level of less than 13.8 g/dL for male patients (normal, 13.8-17.9 g/dL) and less than 12.4 g/dL for female patients (normal, 12.4-15.5 g/dL); (2) serum haptoglobin levels of less than 0.5 g/L (normal, 0.5-3.2 g/L); (3) reticulocyte count of greater than 2% (normal, <2%); or (4) presence of schistocytes in the peripheral blood smear (normally absent).
   

Frequency of hemolysis has been reported only at 12 months. Severity of intravascular hemolysis was estimated on the basis of serum LDH levels at 12 months.

Statistical analysis
Data are presented as means ± SD and as simple percentages. A separate analysis was performed to identify the variables associated with the presence of subclinical hemolysis in the overall population, in aortic valve recipients, in mitral valve recipients, in mechanical valve recipients, and in bioprosthesis recipients. The variables analyzed were the following: sex; age; heart rhythm; use of mechanical or biologic prosthesis; prosthetic model, size, and site of implantation; single valve replacement or DVR; aortic and mitral peak and mean transprosthetic gradients; and left ventricular ejection fraction. Univariate analysis was performed with the ² test or the Fisher test, as appropriate, for discrete variables and with the paired t test or the Mann-Wilcoxon test for continuous variables. All parameters showing a P value of less than .10 at univariate analysis were introduced in a stepwise logistic regression for multivariate analysis. Only variables associated with hemolysis with P values of less than .20 at univariate or multivariate analysis were reported in Table 2.

	Results

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Overall population
All 278 patients underwent clinical, hematologic, and echocardiographic evaluation at 1, 6, and 12 months after the operation. All patients showed a significant clinical improvement during follow-up in terms of mean New York Heart Association functional class. Echocardiographic examination ruled out prosthetic dysfunction and the presence of periprosthetic leaks in all cases. Patients with a mechanical prosthesis showed mean LDH levels at 12-month follow-up that were significantly higher than those of patients with a bioprosthesis (535 ± 140 U/L vs 431 ± 138 U/L, P < .001). None of the 278 patients had decompensated anemia caused by intravascular hemolysis, whereas at 12 months, mild subclinical hemolysis was identified in 49 patients, 44 (26%) with a mechanical prosthesis and 5 (5%) with a bioprosthesis. At multivariate analysis, independent predictors of the presence of subclinical hemolysis at 12 months were MVR (P < .001; odds ratio [OR], 3.4; 95% confidence interval [CI], 1.7-7.0), use of a mechanical prosthesis (P = .002; OR, 4.9; 95% CI, 1.8-13), and DVR (P = .02; OR, 3.9; 95% CI, 1.2-13;Table 2).

Considering only patients with subclinical hemolysis at 1 year, mean levels of LDH were 593 ± 104 U/L for patients undergoing AVR versus 654 ± 134 U/L for patients undergoing MVR (P = .05), 641 ± 134 U/L for mechanical valve recipients versus 535 ± 75 U/L for bioprosthesis recipients (P = .04), and 809 ± 195 U/L for patients undergoing DVR versus 621 ± 122 U/L for patients undergoing single valve replacement (P = .002).

In the subgroup of patients with AVR, multivariate analysis indicated the use of a mechanical prosthesis as the only independent predictor of subclinical hemolysis at 12 months (P = .001; OR, 9.3; 95% CI, 1.6-53;Table 2). In the subgroup of patients with MVR, multivariate analysis was not performed because no variables were associated with subclinical hemolysis at 12 months with a P value of .10 or less at univariate analysis(Table 2).

Bioprostheses
At all follow-up intervals, the majority of patients with a bioprosthesis had hemoglobin, LDH, and haptoglobin levels and reticulocyte counts within the range of normality (Table 3). Serum LDH levels showed a small but significant decrease during follow-up (ANOVA F = 3.1, P = .05) and were slightly lower in patients with an aortic than in those with a mitral bioprosthesis (421 ± 115 U/L vs 458 ± 97 U/L at 12-month follow-up, P = .07;Figure 1). Only 5 (5%) patients with a bioprosthesis fulfilled the criteria for intravascular hemolysis, 2 (3%) patients with an aortic stented valve and 3 (23%) with a porcine valve in the mitral position. None of the 15 patients with a stentless aortic bioprosthesis showed signs of intravascular hemolysis. At multivariate analysis, the only independent predictor of subclinical hemolysis at 12 months was MVR (P = .007; OR, 13.6; 95% CI, 2.0-92;Table 2).

View larger version (43K): [in this window] [in a new window]   Fig. 1. Serum LDH (in units per liter) and haptoglobin (in grams per liter) distribution at 1, 6, and 12 months after AVR and MVR with a bioprosthesis. The horizontal gray bandrepresents the range of normality for LDH levels.

View larger version (39K): [in this window] [in a new window]   Fig. 2. Serum LDH (in units per liter) and haptoglobin (in grams per liter) distribution at 1, 6, and 12 months after AVR, MVR and DVR with a mechanical prosthesis. The horizontal gray band represents the range of normality for LDH levels.

View larger version (36K): [in this window] [in a new window]   Fig. 3. Serum LDH (in units per liter) levels at 12 months after AVR, MVR and DVR with a SB or CM prosthesis. The horizontal gray band represents the range of normality for LDH levels.

Considering only patients with subclinical hemolysis at 1 year, mean levels of LDH were 809 ± 195 U/L after DVR, 599 ± 106 U/L after AVR (P < .001 vs DVR), and 633 ± 99 U/L after MVR (P = .004 vs DVR, Figure 4). Serum levels of LDH in patients with an SB were lower than those found in patients with a CM, irrespective of valve position (728 ± 123 U/L vs 580 ± 107 U/L, P < .001).

View larger version (34K): [in this window] [in a new window]   Fig. 4. Serum LDH (in units per liter) and haptoglobin (in grams per liter) levels at 12 months in patients with subclinical hemolysis after AVR, MVR and DVR with a mechanical prosthesis. The horizontal gray band represents the range of normality for LDH levels.

	Discussion

Top Abstract Introduction Materials and methods Results Discussion References

Recently, fluid-dynamic simulation models have identified distinct patterns of regurgitant flow disturbances in patients with mitral mechanical prostheses that were associated with high shear stress and may therefore produce hemolysis. ¹⁴ This observation would indicate that low levels of hemolysis generated by bileaflet valves are probably caused by backflow and closing phenomena rather then forward flow. ²⁴ The SB and CM prostheses are widely used, and many reports have confirmed their excellent hemodynamics and durability, but there are no reported studies comparing the incidence of hemolysis with these 2 prostheses. The results of our study show that in the present series SB prostheses were associated with a lower severity of hemolysis than CM prostheses. Several factors may account for this, but we believe that the peculiar design of the SB prosthesis with the curved profile of the 2 leaflets may play an important role. Indeed, in vitro studies have demonstrated a shorter spatial extension of the turbulent zone in the forward flow phase in this prosthesis when compared with prostheses with 2 flat-surface leaflets. ²⁵ Moreover, experimental studies comparing leakage flow and shear stress within the gap flow of different mechanical bileaflet valves have shown that the SB prosthesis has a lower blood-damage index and hemolysis than the CM prosthesis. ²⁴ Finally, we were not able to identify any possible correlation between the frequency and severity of intravascular hemolysis and cardiac rhythm, left ventricular ejection fraction, prosthetic size, and transprosthetic peak and mean pressure gradients. Furthermore, the low levels of hemolysis observed, particularly in mechanical valve recipients, in the present study were of no clinical relevance at 1-year follow-up, and in our opinion they should not represent a problem in the long term.

In conclusion, in normally functioning prosthetic heart valves subclinical hemolysis is a frequent finding that remains stable during follow-up. A low incidence of hemolysis is found in stented biologic prostheses, whereas it is absent in stentless valves after AVR. Modifications of valve design may contribute to a further minimization of the occurrence of hemolysis in mechanical prostheses.

	References

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