Cardiac prostheses‐related hemolytic anemia

Abstract Hemolysis is an unintended sequel of temporary or permanent intracardiac devices. However, limited data exist on the characteristics and treatment of hemolysis in patients with cardiac prostheses. This entity, albeit uncommon, often poses significant diagnostic and management challenges to the clinical cardiologist. In this article, we aim to provide a contemporary overview of the incidence, mechanisms, diagnosis, and management of cardiac prosthesis‐related hemolysis.


| INTRODUCTION
Cardiac prosthesis-related hemolytic anemia (CPHA) is a well described but likely an under-recognized phenomenon. This potentially life-threatening complication was first described in the 1950s to 1960s in patients undergoing valve replacement with early generation surgical prostheses. 1,2 The incidence of clinically evident hemolysis after surgical valve replacement has since declined due to the improved valve design and surgical implantation techniques. 3,4 However, interest in CPHA has been recently renewed given the increasing number of studies reporting various rates of clinical and subclinical CPHA with mechanical circulatory support devices and transcatheter valvular interventions. [5][6][7] Nonetheless, the management of CPHA is often challenging due to its atypical presentation, lack of standardized definitions/classifications, and due to the dearth of outcomes data on its various treatment strategies. We sought to provide a contemporary overview of the current literature on the incidence, mechanisms, and management strategies of hemolytic anemia associated with various cardiac prostheses.

| DEFINITION OF HEMOLYTIC ANEMIA
There is no single specific definition of hemolytic anemia. However, the diagnosis of hemolytic anemia is usually established if three major criteria are present: (a) unexplained anemia, and (b) signs of accelerated right blood cells (RBCs) production in the bone marrow (eg, high reticulocyte count), and (c) signs of RBCs destruction (eg, elevated unconjugated bilirubin, lactate dehydrogenase [LDH], low haptoglobin). The term "sub-clinical hemolysis" is used to describe patients who meet the latter two criteria but do not have anemia. In these patients, the bone marrow adequately compensate for the hemolysis, maintaining normal hemoglobin. Prosthesis-related hemolytic anemia can then be assumed if new hemolysis is diagnosed in patients with cardiac prostheses, and/or mechanical assist devices in the absence of other causes of hemolysis.

| INCIDENCE AND ETIOLOGY OF CARDIAC PROSTHESIS-RELATED HEMOLYSIS
The incidence of hemolysis in patients with cardiac prostheses varies widely according to the device type and its indwelling time. Mechanical damage to the RBCs due to increased shear stress is the most widely accepted etiology of CPHA. However, causes of this increased shear stress are device-and diseasespecific.

| Hemolysis after open valve surgery
Hemolytic anemia was a common complication of old generation valves, occurring in up to 15% of surgical valves in the 1960s to 1970s. 8,9 However, this incidence decreased to <1% with modern valve designs. In a study of 301 patients who underwent On-X mechanical valve replacement, clinical hemolysis at long-term occurred in 0% and 0.2% of patients who had aortic and mitral valve replacement, respectively. 3 Several other studies confirmed the rarity of clinical hemolysis after valve replacement with contemporary prostheses. 4,10,11 Nonetheless, subclinical hemolysis is not uncommon, occurring in 18% to 51% and in 5% to 10% of contemporary mechanical tissue prostheses, respectively. 12,13 The main mechanism of hemolysis after surgical valve replacement is paravalvular leak (PVL), which may result from suture dehiscence due to heavy annular calcifications, endocarditis, chronic steroids, or suboptimal surgical techniques. [14][15][16][17] Other less common etiologies of hemolysis related to surgical prostheses are listed in Table 1. [18][19][20][21] Hemolysis also complicates a small percentage (<1%) of mitral valve repair and annular ring placement surgeries. [22][23][24][25] Although ring dehiscence appears to be the main mechanism of CPAH in this group, other reported mechanisms include: protruding of the paravalvular suture material, "whiplash motion" of residual free-floating chordae in hyperkinetic ventricles, and small but turbulent eccentric residual regurgitation jet (Table 1). In this large series, valve replacement led to the resolution of hemolysis in the vast majority of cases. 26,27 3.2 | Hemolysis after transcatheter valve replacement The incidence of hemolysis after transcatheter aortic valve replacement (TAVR) is unknown because routine surveys are not performed in these patients. Although clinical hemolysis is not commonly seen, subclinical hemolysis following TAVR may not be uncommon. 17,28 In a study of 122 patients who had TAVR with balloon-expandable valves, subclinical hemolysis occurred in 15%. The strongest predictor of hemolysis was patient-prosthesis mismatch, rather than the degree of PVL. 7 This intriguing finding, albeit requires confirmation in additional studies, suggests that transcatheter (vs surgical) prostheses may be associated with less hemolysis given their lower reported incidence of patient-prosthesis mismatch. 29 In another study of 64 TAVR patients, 37.5% had evidence of subclinical hemolysis 6 months after the procedure. 30 Moderate to severe PVL and bicuspid valve morphology independently predicted hemolysis ( Figure 1A,B), and hemolysis was associated with a 4-fold increase in hospital readmissions at 1 year.
Of note, 21% of patients had evidence of sub-clinical hemolysis before TAVR; supporting the notion that severe native aortic stenosis can lead to hemolysis due to flow acceleration across the stenotic valve. 31,32 Other TAVR-specific mechanisms of CPAH are related to the remaining native leaflets and their potential impact on red cell shear stress (Table 1). 7 The field of transcatheter mitral valve replacement (TMVR) is rapidly evolving. 33 However, given the small number of TMVRs performed worldwide, data on TMVR associated hemolysis are limited. In the early feasibly trial of the Tendyne valve (Abbott, Roseville, Minnesota), only 1 of 30 patient (3.3%) developed severe hemolysis. 34 The main mechanism of hemolysis after TMVR is PVL due to incomplete sealing, device undersizing, or progressive left ventricular remodeling ( Figure 1C,D). Cases of severe clinical hemolysis have also been reported following transcatheter mitral valve in valve/ring implantation. 35

| Hemolysis with left ventricular assist devices
The reported incidence of hemolysis with the HeartMate II (HMII; Thoratec, Pleasanton, California) is approximately 13% to 18%. 5,36,37 However, early experience with the third generation magnetically levitated left ventricular assist devices (LVAD) (HeartMate III) revealed very low (<1%) rates of hemolysis. 38,39 Similarly, the novel TORVAD toroidal-flow LVAD has shown negligible rates of hemolysis in preclinical testing. 40 A unique aspect of hemolysis in LVAD patients is its strong relationship with thrombotic complications. Local thrombosis increases shear stress and leads to local destruction of the red cells. 41 However, other mechanisms may be implicated such as increased inlet velocities due to dehydration and under-filling of the left ventricle, transfusion-associated hemolysis, and cannula kinks or malposition (Table 1). [41][42][43] In current practice, an increase in LDH and plasma free hemoglobin levels in LVAD patients is viewed as a possible early cannula thrombosis. 5 Clinical hemolysis in surgical LVAD patients is associated with significant morbidity and mortality. 44 Mild hemolysis occurs in 10% to 30% of patients who receive short-term percutaneous LVAD support with the Impella device (Abiomed Inc., Danvers, Massachusetts). [47][48][49] However, the incidence increases to 60% with device indwelling times >6 hours. 6 In a study of patients undergoing veno-arterial extracorporeal membrane oxygenation, concomitant Impella use was associated with higher incidence of hemolysis (76% vs 33%, P = .004). 50 Clinically significant hemolysis may also occur unexpectedly due to device malfunction or improper placement. [51][52][53] To the best of our knowledge, no cases of clinical hemolysis due to intra-aortic balloon pumps have been reported.  (Figure 2). 28,54 Higher profile devices (eg, ventricular septal occluders) are more associated with more hemolysis than the lower profile Amplatzer vascular plugs. 55,56 Severe hemolysis has also been reported following percutaneous closure of septal defects and peri-MitraClip regurgitation mostly due to residual peridevice shunt. 57 Table 1.

| Hemolysis after transcatheter shunt closure
(a) Blood smear examination: erythrocyte fragments (eg, Schistocytes) are common in "mechanical" hemolytic anemia. These fragments, however, are not specific to CPHA (

| Establishing the relationship between cardiac prostheses and hemolysis
Once the hemolysis diagnosis is confirmed, establishing its relationship with cardiac prostheses is essential to guide therapy. Although this can be challenging due to the absence of a specific test for CPHA, the following steps may be helpful in elucidating the etiology of hemolysis.

| MANAGEMENT OF CARDIAC PROSTHESIS-RELATED HEMOLYSIS
The optimal treatment strategy of cardiac prosthesis-related hemolysis is determined by the degree of hemolysis, clinical symptoms, severity of prosthetic dysfunction, and the predicted risk and success of surgical or percutaneous interventions.

| Medical therapy
Medical therapy with close follow-up is appropriate for patients with mild hemolysis that is not significantly interfering with the quality of life. • Folic acid: Folate deficiency is common in chronic hemolysis due to the increased consumption from accelerated erythropoiesis. 67 In persistent hemolysis, prophylactic oral folic acid supplementation is recommended to avoid substantial folate deficiency.

T A B L E 2 Markers of hemolysis
• Iron supplementation and blood transfusion: Oral ± intravenous iron supplements may be sufficient to treat stable degrees of hemolysis. However, blood transfusion is often needed is severe hemolysis until mechanical corrective measures are undertaken.
• Beta-blocker: Beta-blockers can reduce shear forces in patients with PVL-related hemolysis reducing blood pressure and heart rate.
Oral beta-blockers led to significant improvement in hemolytic anemia in several retrospective series. [68][69][70] • Pentoxifylline: Pentoxifylline improves blood viscosity and erythrocyte deformability. The use of pentoxifylline may subside mild hemolysis in patients with LVAD or mechanical valves. 71 has been shown to be a more effective method in treating severe hemolysis than percutaneous repair. 82 In one study, persistence of or worsening hemolysis was responsible for 50% of crossovers to surgery in patients initially treated with transcatheter techniques. 64 However, redo surgery is associated with significant morbidity and mortality, and the choice of transcatheter or surgical intervention requires a collaborative interdisciplinary approach weighting the risks and potential success of each procedure. 78 Refractory LVAD-related hemolysis: Intensification of antithrombotic therapy is able to improve or resolve hemolysis in the majority of LVAD patients. However, persistent hemolysis despite maximally tolerated anticoagulation is associated with a substantial increase in the risk of stroke and death. 5,77 Hence, pump exchange through various surgical techniques (subxiphoid ± thoracotomy or redo sternotomy) should be considered early in these patients. 41 Occluder devices-induced hemolysis: Severe hemolysis that developed or worsened after transcathter shunt closure is often due to the residual peri-device shunt. Those residual shunts can be often ameliorated with additional occluder devices, and/or intra-device coil deployment within the Nitinol cage of the occluder. 79,83 However, replacement of the involved prosthesis with a different device or conversion to surgical repair is often required.

| SUMMARY
CPHA is an uncommon but important source of morbidity and mortality in patients undergoing valve surgery, transcatheter structural heart interventions, and mechanical circulatory support device implantations. Knowledge of the incidence, etiologies, and the various treatment strategies is key for effective management of this rare but potentially life-threatening entity.

CONFLICT OF INTEREST
The authors declare no potential conflict of interests.