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The Role of Medical Management for Acute Intravascular Hemolysis in Patients Supported on Axial Flow LVAD

Hasin, Tal*; Deo, Salil; Maleszewski, Joseph J.; Topilsky, Yan*; Edwards, Brooks S.*; Pereira, Naveen L.*; Stulak, John M.; Joyce, Lyle; Daly, Richard; Kushwaha, Sudhir S.*; Park, Soon J.

doi: 10.1097/MAT.0000000000000012
Adult Circulatory Support

Continuous flow left ventricular assist devices (LVADs) are used with good outcome. However, acute intravascular hemolysis due to thrombus in the pump remains a clinical challenge. We screened for LVAD-related intravascular hemolysis among 115 consecutive patients surviving HeartMateII implantation and investigated the role of medical therapy in resolving the hemolysis. Hemolytic events were identified in 7% of patients, 2–26 months after implant, manifested by peak lactate dehydrogenase (LDH) levels >6 times normal. With the institution of heparin and enhanced antiplatelet therapy, LDH levels receded rapidly reaching a stable trough level near baseline within 2 weeks with the resolution of clinical symptoms except in one patient who required additional therapy with tissue plasminogen activator (tPA). Complications included transient renal failure, one splenic infarct, and a cerebrovascular attack after tPA. The acute event of hemolysis resolved with medical therapy, and all were successfully discharged. However, recurrent hemolysis was common (6/8 patients over the next 1–7 months). At the end of follow-up, three patients were transplanted, one patient died refusing LVAD exchange for recurrent hemolysis, and 4 remained alive on LVAD support. Medical treatment with intensification of anticoagulation can be effective in resolving the acute hemolytic event. However, a definitive long-term strategy should be planned because the recurrence rate is high.

From the *Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota; Division of Cardiovascular Surgery, Mayo Clinic, Rochester, Minnesota; and Division of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota.

Submitted for consideration March 2013; accepted for publication in revised form July 2013.

Disclosures: Drs. Hasin, Kushwaha, and Park declare accepting a nonrestricted clinical research grant from Thoratec to study endothelial function post-LVAD. Park declares consulting for Thoratec. Dr. Joyce declares accepting a clinical research grant from Thoratec to study GI bleeding post-LVAD. The remaining authors declare no conflicts of interest to disclose.

Reprint Requests: Soon J. Park, MD, Division of Cardiovascular Surgery, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. Email:

Left ventricular assist devices (LVADs) improve survival when implanted in patients with stage D heart failure.1 Newer continuous flow devices offer better durability compared with pulsatile devices and hence are currently the preferred device model.2 The number of patients treated with LVADs is exponentially growing; many of these are now implanted as destination therapy (DT).3 The HeartMate II LVAD (Thoratec Corp, Pleasanton, CA) is the most commonly used LVAD in the United States and the only one currently approved by the Food and Drug Administration for use as DT.

There is some uncertainty regarding the optimal chronic anticoagulation treatment for patients on axial flow LVAD support. To avoid thrombotic complications, LVAD recipients are treated routinely with anticoagulation (usually with warfarin), as well as with antiplatelet agents (usually aspirin).4 Bleeding complications are often encountered in continuous flow LVAD patients,5,6 often necessitating temporary discontinuation of anticoagulation.7,8 Whether less intensive anticoagulation, aimed at reducing bleeding episodes in LVAD patients, is beneficial is the subject of ongoing investigation ( NCT01477528).

Acute hemolytic events in continuous flow LVAD patients are thought to be related to thrombus formation, abutting the moving components of the device.9 Clinical presentation includes abrupt increases in LVAD power consumption, jaundice, dark colored urine, heart failure exacerbation, and anemia with laboratory evidence of intravascular hemolysis. Echocardiography and catheterization may suggest device malfunction.10,11 The HeartMate II clinical trials have documented hemolytic complications in 4% of patients implanted with extended mechanical support as a bridge to transplant (BTT)6 and LVAD thrombosis in 4% implanted as DT.2 The occurrence may be higher in patients not implanted as part of a clinical trial.

Optimal treatment for LVAD-associated acute hemolysis due to suspected thrombosis is unclear, and published literature on this subject is limited. Surgical treatment with pump replacement is associated with morbidity and a higher operative risk. Indeed, pump thrombosis was a major reason for LVAD replacement in the HeartMate II BTT experience (4 of 11 patients needing pump replacement); two subsequently died.6 Thrombolytic therapy has been advocated in case reports and small series for devices, such as the Micromed DeBakey (Micromed Corp, Houston, TX), Jarvik 2000 (JarvikHeart Corp, NY), and HeartWare (HeartWare Corp, Framingham, MA), and despite the reported safety, may result in bleeding or embolic events.12–15 We hypothesized that intensification of anticoagulation and platelet inhibition is a safe and effective treatment for such events. Here, we report our experience with medical treatment for LVAD-associated hemolysis in the axial flow HeartMate II LVAD.

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We conducted a retrospective review of all patients implanted with extended LVAD support at our center between January 2008 and June 2011. Of 137 patients implanted with LVADs, we excluded 10 with devices other than the HeartMate II (six with VentrAssist [Ventrassist Pvt Ltd, Australia], two with HeartMate XVE [Thoratec Corp, Pleasanton, CA], one with a DuraHeart [Terumo Corp, Japan], and one with a HeartWare). Because our aim was to study the occurrence of intravascular hemolysis in successfully implanted individuals, we further excluded 12 patients who did not survive the surgical procedure. The clinical follow-up for our LVAD patients includes prescheduled outpatient visits and telephone follow-up. Visits are scheduled monthly for the first 3 months, 3 monthly until 1 year, 4 monthly for the second year, and every 6 months for the third and fourth years after implant. An evaluation for possible hemolysis including lactate dehydrogenase (LDH) measurement is performed routinely during these visits.

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Hemolytic Events

Left ventricular assist device–related intravascular hemolysis was defined as acute increase in serum LDH levels more than twofold from a stable baseline, presence of free plasma hemoglobin (normal cutoff is 12.4 mg%), and supportive clinical symptoms such as dark urine or unexplained heart failure without other medical reasons for the hemolysis. Presenting symptoms, treatment, laboratory parameters and outcomes, as well as long-term follow-up were recorded. The study was approved by the institutional review board.

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Statistical Analysis

Descriptive analysis was performed by presenting the mean ± SD for numerical data unless markedly non-normal in which case the median and interquartile range (25th and 75th percentile) were used unless otherwise specified. Two-sided Wilcoxon signed rank test was used for comparisons. p< 0.05 was considered significant and adjusted for multiple comparisons using the Bonferroni correction. Data were analyzed using the JMP System software version 8.0 (SAS Institute, Inc, Cary, NC).

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For the 115 patients implanted with the HeartMate II device surviving to discharge, 83% were males; age 59 ± 13 (mean ± SD) years. Most patients (63%) were implanted as DT and 37% as BTT. Ischemic heart disease was the cause in 56 (49%), idiopathic dilated cardiomyopathy in 40 (35%), and 11 patients (10%) were implanted due to restrictive cardiomyopathy.

Patient characteristics for the patients with intravascular hemolysis are summarized in Table 1. Acute hemolytic events were identified in eight patients (7% of patients) of which seven were male and age varied between 19 and 70 years (median 51 years). Five were implanted as DT, and five had an etiology of ischemic heart disease. Six patients had preoperative atrial fibrillation. Pump speeds were 8,800 to 9,800 RPM (median 9,600). None of these parameters differed significantly between patients with and without hemolysis. Some type of bleeding event occurred in six of eight patients after implant but before the index hemolytic event. This resulted in holding off anticoagulation in two patients 6 and 5 months before the index event (for 2 and 1 months, respectively). Another patient’s anticoagulation was temporarily held for a procedure and then resumed 5 days before thrombosis occurred. Earlier events suspicious for hemolysis or LVAD thrombus but not fulfilling our case definition were noted in two of the patients.

A description of the index events is summarized in Table 2. The presenting symptoms were highly suspicious (hemolysis or abrupt increase in LVAD power requirement) in four patients and were more subtle and suggestive of heart failure in four. Two patients had increase in LVAD power (intermittent in one and persistent in the other). Hemolysis occurred as early as 2 months to as late as 2.2 years after implant (median 260 days). All patients were treated with anticoagulation with admission international normalized ratio values of 1.7 ± 0.4, mostly within the preset range (detailed in the table) or slightly lower. All except one patient (with previous gastrointestinal [GI] bleeding) were treated with aspirin at the time of presentation. Lactate dehydrogenase values measured before, during, and after the thrombotic event are depicted in Figure 1A. Baseline LDH levels were about twice the upper limit of normal (similar to levels measured in uncomplicated LVAD patients).16 Peak LDH levels during hemolysis were more than 6 times the upper limit of normal. Serum levels of LDH were noted to track with the extent and duration of the event, as well as the response to treatment, as illustrated in Figure 1B. Most patients reached a trough LDH level within a week to 2 weeks after initiation of medical treatment that was significantly lower than the peak levels, yet significantly elevated compared with baseline (p = 0.0078).

Treatment and outcomes are described in Table 3. For the most part, patients were treated medically with heparin infusion in conjunction with continuing warfarin, and aspirin and clopidogrel were added as a second platelet inhibitor. Four of the patients required blood transfusion during the hospitalization. A patient (7) with concomitant bleeding treated with Eptifibatide was transfused with 12 units. One patient (8) with high-grade hemolysis did not respond to initial therapy. He received an additional therapy of intravenous infusion of tissue plasminogen activator (tPA) 12 days after the initial presentation. Hemolysis resolved, but he unfortunately experienced an embolic stroke causing aphasia 30 minutes after tPA treatment. None of the patients needed a pump change-out operation. Complications in other patients were related to the hemolysis and consisted of transiently worsening renal dysfunction; one patient was identified with a small splenic infarct. Late GI bleeding occurred in three patients 1–2 months after the event. Overall, medical treatment resulted in resolution or significant improvement of symptoms in all patients, and all were discharged home with relatively short hospitalizations after diagnosis and treatment.

However, hemolysis recurred in the majority during the follow-up period. Although two patients had no recurrence of hemolysis (interestingly one of these had to hold warfarin 1 year later for a month because of GI bleeding without adverse effects), recurrent hemolysis was noted in six of eight patients over the next 1 to 7 months. At the end of follow-up, three patients were transplanted (two had ongoing evidence of hemolysis), withdrawal of support was performed in one patient who refused LVAD exchange following recurrent hemolysis in 7 months, and four were on ongoing LVAD support. Pumps were investigated for the presence of thrombus in four patients after explant. A thrombus was identified on the rotor part of the LVAD in all the patients who had signs of hemolysis at the time of LVAD removal (Figure 2), showing the histological features of a platelet-rich thrombus.

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In this analysis, we identified eight patients among our cohort of 115 patients (7%) who presented with intravascular hemolysis thought to be associated with device thrombosis. It is possible that the “true” hemolysis rate is higher because we considered only those who presented with significant clinical symptoms after achieving stable medical condition. This occurrence seems marginally higher than the 4% reported previously among BTT patients.6 This difference may be because of longer follow-up time in our cohort because two thirds of BTT patients were transplanted 6 months after LVAD implantation in the study and hemolytic events may occur later. Other explanations include different patient population as well as less stringent anticoagulation, especially during bleeding events in some of our patients. Stringent anticoagulation may be associated with less thrombosis but with increased bleeding episodes.17

Both device and coagulation factors may contribute to LVAD thrombosis. Disturbed flow within the device may play a role. Despite the improved design of the newer pumps, turbulent flow can still occur, especially during periods of unstable hemodynamics (such as early after surgery). Impingement of the inflow cannula or kinking of the outflow might contribute to disturbed flow within the device. Rough textured surfaces within the device,18 as well as heat generation,19 are other possible contributors to device-associated factors. In relation to blood coagulation, both platelet and serum factors may take part. Markers of thrombin activation and fibrinolysis as well as inducible endothelial factors have been found to be elevated in patients with LVADs.20,21 Impaired fibrinolysis due to elevated PAI-1 is also associated with increased thrombosis after LVAD implantation.22 Impaired fibrinolysis can be suggested as a possible contributor to coexisting bleeding and thrombosis such as that occurred in at least one of our patients. Response to treatment may be impaired because anticoagulation is more difficult to regulate in LVAD compared with other patients,23 and a high incidence of aspirin hyporesponsiveness has been documented in these patients.22 As to platelet activation, despite a recent report that did not identify evidence of discernible effect on platelet activation by the HeartMate II LVAD,24 platelet activation has been documented in patients with various LVADs.25 The role of activated platelet in forming thrombus at the rotor seems to be further supported by our finding of platelet-rich white thrombus as shown in Figure 2.

Our treatment approach for acute intravascular hemolysis due to suspected thrombosis included intensification of anticoagulation using heparin in addition to warfarin and of antiplatelet agents using clopidogrel and aspirin. This approach resulted in early resolution of symptoms in seven of eight patients, and only one patient required thrombolytic therapy. Early identification of hemolytic events and intensification of medical treatment allowed in our experience for the successful management of the patients during the acute phase such that none of the patients needed an acute pump change-out operation. Interestingly, two patients did not develop any further recurrence. In most of the remaining six patients, recurrences were noted over the ensuing few weeks to months. One DT patient failed to respond to the medical therapy and refused the surgery to change-out the pump. For the remaining patients, medical therapy was effective in managing them until definitive treatment such as heart transplantation could be rendered.

To the best of our knowledge, this is the largest report describing medical treatment for LVAD-associated hemolysis and suspected thrombosis. Previously published case reports described the additional use of antiplatelet agents to treat VAD thrombosis (clopidogrel with the DeBakey device26 and glycoprotein IIb/IIIa inhibitor in a HeartWare device).27 Treatment by intensification of anticoagulation was also sporadically reported, for example, the effective use of high-intensity heparin7 or hirudin28 in a patient with HeartMate II thrombosis. Using both heparin and IIb/IIIa inhibitor seemed to have an additive benefit against thrombosis in a sheep vascular stent model.29 Therefore, a combined treatment approach using intensified platelet inhibition and anticoagulation may have an additive benefit and be effective in treating intravascular hemolysis due to device thrombosis. This approach may defer the need for urgent pump change-out and should be considered as a first step in patients who are relatively stable. Nevertheless, the likelihood of recurrent hemolysis after the initially successful treatment appears to be rather high as demonstrated in our series as well as by others.13,26,28 Thus, although a more definitive therapy such as transplantation or elective pump exchange needs to be considered, medical therapy has a clear role in the effective management of the acute event.

This study carries the obvious limitations of a retrospective analysis, including a possible underestimation of the incidence of hemolytic events. However, the patients were under stringent clinical surveillance, and we believe significant hemolytic events were noted. We chose to consider only events we thought were clinically significant; hence, the overall incidence of events may be underestimated in this report. Although these limitations may have affected the estimated incidence of hemolytic events, they had no impact on the key findings of this article regarding the outcome of medical treatment for LVAD-associated hemolysis.

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Acute intravascular hemolysis due to suspected pump thrombosis is not infrequent in patients supported on HeartMateII. Medical treatment combining anticoagulation with heparin and antiplatelet agents can be safe and effective as an initial strategy. Recurring thrombosis may occur and necessitate a more definitive therapy.

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heart assist device; hemolysis; thrombosis; management; outcome

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