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Ventricular assist device thrombosis: A wide spectrum of clinical presentation
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RESEARCH CORRESPONDENCE Ventricular assist device thrombosis: A wide spectrum of clinical presentation Edo Y. Birati, MD,a Ylenia Quiaoit, MSN, ACNP-BC,a Joyce Wald, DO,a James N. Kirkpatrick, MD,a Lee R. Goldberg, MD, MPH,a Pavan Atluri, MD,b Kenneth B. Margulies, MD,a and J. Eduardo Rame, MD, MPhila From the aDivision of Cardiology; and the b Cardiovascular Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Ventricular assist device (VAD) thrombosis is associated with substantial morbidity and mortality,1 usually requiring replacement of the device. Since 2011 there has been a sharp increase in the incidence of VAD thrombosis, from 2.2% before 2011 to 8.4% in 2013.1 The exact reason for this increase is unknown, with many studies aiming to identify the risk factors and pathophysiology for this complication. Increased reports of VAD thrombosis have heightened the awareness of this entity. Diagnostic markers, including increased plasma lactate dehydrogenase (LDH), plasma free hemoglobin, or abnormal responses to programmed increments in pump speed (ramp test),2 should allow earlier and more accurate diagnosis.3 To date, VAD thrombosis has been described as the reason for pump
Table 1
failure leading to acute decompensated heart failure, and has also been associated with embolic complications. In this study, we describe a broader range of clinical and echocardiographic presentations associated with proven VAD thrombosis. We included all patients treated with a HeartMate II (Thoratec Corporation) left ventricular assist device (LVAD) at our center since 2011 who developed confirmed VAD thrombosis, defined as a thrombus detected on the rotor of the device, its inflow cannula or outflow conduit, at time of device replacement.3 Only cases with pump thrombosis confirmed by the manufacturer are included in this report. Patients’ medical records, echocardiographic tests, hemodynamic variables and laboratory parameters were reviewed. A total of 11 patients with confirmed VAD thrombosis were identified. Table 1 summarizes the baseline clinical characteristics of the patients observed. All but 1 patient received LVAD support as a permanent “destination therapy.” Table 2 presents the clinical and hemodynamic variables before pump exchange, and Table S1 (refer to Supplementary Material available online at www.jhltonline. org) summarizes the laboratory results and VAD parameters of all patients. All patients had elevated LDH levels. Shortness of breath was the most frequent presenting symptom, occurring in 72.7% of patients. As highlighted in Figure 1, clinical and echocardiographic parameters varied substantially, ranging from completely asymptomatic with unchanged functional status, normal filling pressures and 2 negative ramp tests (Patient 10) to cardiogenic shock
Baseline Characteristics of Patients
Pt
Age
Gender
Race
DT/BTT
BMI
HF etiology
DM
GFR (ml/min)
1 2 3 4 5 6 7 8 9 10 11 Mean ⫾ SD
77 51 56 66 66 65 69 56 70 55 61 63 ⫾ 7
M M M M F M M M F F M
C AA C C C C C AA AA C AA
DT DT DT DT DT DT DT BTT DT DT DT
27 30 21 36 34 33 21 35 27 24 32 31 ⫾ 5
I-CMP Non-I-CMP Non-I-CMP I-CMP Non-I-CMP I-CMP I-CMP Non-I-CMP Non-I-CMP Non-I-CMP Non-I-CMP
Yes Yes No Yes Yes No No Yes Yes No Yes
29 63 103 35 68 54 66 66 34 98 104 66 ⫾ 25
AA, African-American; BMI, body mass index; BTT, bridge to transplant; C, Caucasian; DM, diabetes mellitus; DT, destination therapy; F, female; GFR, glomerular filtration rate; HF, heart failure; I-CMP, ischemic cardiomyopathy; M, male; Non-I-CMP, non-ischemic cardiomyopathy; Pt, patient. 1053-2498/$ - see front matter r 2015 International Society for Heart and Lung Transplantation. All rights reserved. http://dx.doi.org/10.1016/j.healun.2014.12.007
614 Table 2
The Journal of Heart and Lung Transplantation, Vol 34, No 4, April 2015 VAD Thrombosis—Symptoms, Arrhythmias and Hemodynamic Presentation
Pt
Chest pain
SOB
Palpitation
VT
Cardiogenic shock
RAP (mm Hg)
1 2 3 4 5 6 7 8 9 10 11
No No No No No No No No No No No
Yes Yes Yes Yes No Yes Yes Yes Yes No No
No No No No No No No No No No No
No No No No No Yes Yes No No No No
No No Yes No No No Yes No No No No
20 23 17 24 19 18 19 14 14 12 17
PAP (mm Hg) 60/40
30/15 65/30 38/20 55/40 48/30 50/30
Pulmonary congestion on X-ray No No Yes Yes No Yes Yes Yes No No No
Other CVA, ischemic
CVA, cerebrovascular accident; LVEDD, left ventricular end-diastolic diameter; PAP, pulmonary artery pressure; Pt, patient; RAP, right atrial pressure; SOB, shortness of breath; VAD, ventricular assist device; VT, ventricular tachycardia.
(Patients 3 and 7). In the asymptomatic patient, whose negative ramp test is illustrated in Figure 2, progressive increases in LDH (peaking at 1,500 U/liter) and plasma free hemoglobin (peaking at 22.4 mg/dl) ultimately led to pump exchange with device inspection revealing thrombi at the distal part of the rotor (Figure S1 in Supplementary Material). The patient’s LDH returned to normal after the procedure. One patient died from an ischemic stroke before pump exchange. All patients who underwent pump exchange
Figure 1 The clinical spectrum of VAD thrombosis. Patients with VAD thrombosis may be completely asymptomatic. The condition may progress, leading to a variable presentation, ranging from shortness of breath, low cardiac output state, valvular insufficiency, arrhythmias and right ventricular failure. With or without medical therapy, these patients can progress to cardiogenic shock and death. Despite the wide spectrum of presentations highlighted, there is a consistent finding of elevated LDH as a marker of active hemolysis in all patients.
survived the surgery. Three patients had recurrent VAD thrombosis after the initial pump exchange. Of these patients, 1 with recurrent thrombosis died from hemorrhagic stroke and another from heart failure. The third patient underwent repeat pump exchange and has remained alive and well at 8 months. A variety of factors may have contributed to the diverse presentations described. For example, limited nonobstructive thrombus formation may cause hemolysis without pump dysfunction with more extensive thrombus causing significant obstruction with pump failure. The location of the thrombus within the VAD system may also impact the presentation. Patient-associated factors, such as the intrinsic left or right ventricular function, aortic or mitral valve disease, and innate capacity of the patient to tolerate hemodynamic stress, may also affect presentation. Finally, as observed in 3 of our patients, VAD thrombosis may result in acute thromboembolism, affecting any organ, with the potential for catastrophic cerebrovascular accident. It appears that elevated LDH is a sensitive marker of VAD thrombosis. None of our patients with confirmed VAD thrombosis had LDH within the normal range. Uriel et al reported that LDH at 45-fold the normal level was 100% sensitive and 92% specific for the diagnosis of pump thrombosis.2 However, these results only applied to patients with a positive ramp test, so the magnitude of elevated LDH may be greater in this sub-group of patients. Our series included 2 patients with confirmed pump thrombosis, with a o3-fold increase in LDH, so the sensitivity of a 5-fold LDH cut-off would be only 82% in our series. Moreover, other factors, including infection, malignancies, liver injury and aortic insufficiency,4,5 may reduce the specificity of an elevated LDH. The use of a lower LDH threshold would reduce this specificity even further. Nevertheless, both our study and that of Uriel and colleagues2 support the inference that an elevation in LDH above a given patient’s baseline should lead to increased vigilance for other signs of VAD thrombosis. Our series demonstrates that no single symptom, laboratory result, echocardiographic parameter or provocative test is fully reliable for the diagnosis of VAD thrombosis. A patient with VAD thrombosis may be completely asymptomatic with
Research Correspondence
615
Figure 2 Echocardiographic left ventricular end-diastolic diameter (LVEDD) during pump speed change (ramp study) (see Patient 10 in Tables 1, 2 and S1). The pump speed was increased gradually from 8,800 to 10,600 (ramp study), in accordance with the Columbia protocol.6 The LVEDD decreased substantially from 5.2 cm at 8,800 RPM (top left figure) to 2.07 cm at 10,600 (top right figure).
a “normal” ramp study, despite clinically significant hemolysis and concerning LDH levels. Given that some patients are asymptomatic, we are likely underestimating the true prevalence of thrombosis in VAD patients and/or diagnosing the condition late in many cases. With a growing number of patients treated with VAD support for advanced heart failure, the clinical impact of pump thrombosis will increase without improved preventive and treatment strategies. More complete recognition of this complication and greater understanding of its mechanisms are clearly needed. Nevertheless, it is unknown whether early diagnosis of VAD thrombosis may allow successful medical management and avoidance of the need for pump replacement or whether early pump replacement will improve survival and decrease adverse event rates. Analogous to acute coronary syndromes, the timing of intervention in patients with pump thrombosis is likely to be clinically relevant. Earlier reports have described high recurrence rates and increased mortality with conservative, non-surgical management of VAD thrombosis.1,6 However, those series may not have adequately represented the subgroup of patients who may be captured with earlier diagnosis and the therapeutic efficacy achieved with earlier interventions. Additional studies are necessary to determine the relative merits of a trial of medical therapy versus immediate pump exchange in asymptomatic patients with early diagnosis of VAD thrombosis. For now, decisions about the timing of device replacement must depend on judgments about the potential for immediate and long-term stabilization without pump exchange and the procedural risks of device replacement.
Disclosure statement E.Y.B. and J.E.R. received training and research grant support from Thoratec Corporation and HeartWare. L.R.G. is a consultant
for Thoratec, St. Jude and Respircardia. K.B.M. is on the advisory committees for Novo Nordisk and Astra-Zeneca and received research grant support from Juventis Therapeutics, Celladon, Thoratec, Innolign Biomedical and the U.S. National Institutes of Health (HL105993, HL110338, HL113777). The remaining authors have no conflicts of interest to disclose. The authors thank Dr Michael Acker, Dr Hansie Mathelier, Dr Sourin Banerji, Dr Jeremy A. Mazurek, Christyna M. Justice and Rhondalyn McLean for their contribution to the study. K.B.M. and J.E.R. contributed equally to this work.
Supplementary data Supplementary data associated with this article can be found in the online version at www.jhltonline.org.
References 1. Starling RC, Moazami N, Silvestry SC, et al. Unexpected abrupt increase in left ventricular assist device thrombosis. N Engl J Med 2014;370:33-40. 2. Uriel N, Morrison KA, Garan AR, et al. Development of a novel echocardiography ramp test for speed optimization and diagnosis of device thrombosis in continuous-flow left ventricular assist devices: the Columbia Ramp Study. J Am Coll Cardiol 2012;60:1764-75. 3. Uriel N, Han J, Morrison KA, et al. Device thrombosis in HeartMate II continuous-flow left ventricular assist devices: a multifactorial phenomenon. J Heart Lung Transplant 2014;33:51-9. 4. Gopalan RS, Arabia FA, Noel P, et al. Hemolysis from aortic regurgitation mimicking pump thrombosis in a patient with a HeartMate II left ventricular assist device: a case report. ASAIO J 2012;58:278-80. 5. Adeva-Andany M, López-Ojén M, Funcasta-Calderón R, et al. Comprehensive review on lactate metabolism in human health. Mitochondrion 2014;17:76-100. 6. Hasin T, Deo S, Maleszewski JJ, et al. The role of medical management for acute intravascular hemolysis in patients supported on axial flow LVAD. ASAIO J 2014;60:9-14.
RESEARCH CORRESPONDENCE Ventricular assist device thrombosis: A wide spectrum of clinical presentation Edo Y. Birati, MD,a Ylenia Quiaoit, MSN, ACNP-BC,a Joyce Wald, DO,a James N. Kirkpatrick, MD,a Lee R. Goldberg, MD, MPH,a Pavan Atluri, MD,b Kenneth B. Margulies, MD,a and J. Eduardo Rame, MD, MPhila From the aDivision of Cardiology; and the b Cardiovascular Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Ventricular assist device (VAD) thrombosis is associated with substantial morbidity and mortality,1 usually requiring replacement of the device. Since 2011 there has been a sharp increase in the incidence of VAD thrombosis, from 2.2% before 2011 to 8.4% in 2013.1 The exact reason for this increase is unknown, with many studies aiming to identify the risk factors and pathophysiology for this complication. Increased reports of VAD thrombosis have heightened the awareness of this entity. Diagnostic markers, including increased plasma lactate dehydrogenase (LDH), plasma free hemoglobin, or abnormal responses to programmed increments in pump speed (ramp test),2 should allow earlier and more accurate diagnosis.3 To date, VAD thrombosis has been described as the reason for pump
Table 1
failure leading to acute decompensated heart failure, and has also been associated with embolic complications. In this study, we describe a broader range of clinical and echocardiographic presentations associated with proven VAD thrombosis. We included all patients treated with a HeartMate II (Thoratec Corporation) left ventricular assist device (LVAD) at our center since 2011 who developed confirmed VAD thrombosis, defined as a thrombus detected on the rotor of the device, its inflow cannula or outflow conduit, at time of device replacement.3 Only cases with pump thrombosis confirmed by the manufacturer are included in this report. Patients’ medical records, echocardiographic tests, hemodynamic variables and laboratory parameters were reviewed. A total of 11 patients with confirmed VAD thrombosis were identified. Table 1 summarizes the baseline clinical characteristics of the patients observed. All but 1 patient received LVAD support as a permanent “destination therapy.” Table 2 presents the clinical and hemodynamic variables before pump exchange, and Table S1 (refer to Supplementary Material available online at www.jhltonline. org) summarizes the laboratory results and VAD parameters of all patients. All patients had elevated LDH levels. Shortness of breath was the most frequent presenting symptom, occurring in 72.7% of patients. As highlighted in Figure 1, clinical and echocardiographic parameters varied substantially, ranging from completely asymptomatic with unchanged functional status, normal filling pressures and 2 negative ramp tests (Patient 10) to cardiogenic shock
Baseline Characteristics of Patients
Pt
Age
Gender
Race
DT/BTT
BMI
HF etiology
DM
GFR (ml/min)
1 2 3 4 5 6 7 8 9 10 11 Mean ⫾ SD
77 51 56 66 66 65 69 56 70 55 61 63 ⫾ 7
M M M M F M M M F F M
C AA C C C C C AA AA C AA
DT DT DT DT DT DT DT BTT DT DT DT
27 30 21 36 34 33 21 35 27 24 32 31 ⫾ 5
I-CMP Non-I-CMP Non-I-CMP I-CMP Non-I-CMP I-CMP I-CMP Non-I-CMP Non-I-CMP Non-I-CMP Non-I-CMP
Yes Yes No Yes Yes No No Yes Yes No Yes
29 63 103 35 68 54 66 66 34 98 104 66 ⫾ 25
AA, African-American; BMI, body mass index; BTT, bridge to transplant; C, Caucasian; DM, diabetes mellitus; DT, destination therapy; F, female; GFR, glomerular filtration rate; HF, heart failure; I-CMP, ischemic cardiomyopathy; M, male; Non-I-CMP, non-ischemic cardiomyopathy; Pt, patient. 1053-2498/$ - see front matter r 2015 International Society for Heart and Lung Transplantation. All rights reserved. http://dx.doi.org/10.1016/j.healun.2014.12.007
614 Table 2
The Journal of Heart and Lung Transplantation, Vol 34, No 4, April 2015 VAD Thrombosis—Symptoms, Arrhythmias and Hemodynamic Presentation
Pt
Chest pain
SOB
Palpitation
VT
Cardiogenic shock
RAP (mm Hg)
1 2 3 4 5 6 7 8 9 10 11
No No No No No No No No No No No
Yes Yes Yes Yes No Yes Yes Yes Yes No No
No No No No No No No No No No No
No No No No No Yes Yes No No No No
No No Yes No No No Yes No No No No
20 23 17 24 19 18 19 14 14 12 17
PAP (mm Hg) 60/40
30/15 65/30 38/20 55/40 48/30 50/30
Pulmonary congestion on X-ray No No Yes Yes No Yes Yes Yes No No No
Other CVA, ischemic
CVA, cerebrovascular accident; LVEDD, left ventricular end-diastolic diameter; PAP, pulmonary artery pressure; Pt, patient; RAP, right atrial pressure; SOB, shortness of breath; VAD, ventricular assist device; VT, ventricular tachycardia.
(Patients 3 and 7). In the asymptomatic patient, whose negative ramp test is illustrated in Figure 2, progressive increases in LDH (peaking at 1,500 U/liter) and plasma free hemoglobin (peaking at 22.4 mg/dl) ultimately led to pump exchange with device inspection revealing thrombi at the distal part of the rotor (Figure S1 in Supplementary Material). The patient’s LDH returned to normal after the procedure. One patient died from an ischemic stroke before pump exchange. All patients who underwent pump exchange
Figure 1 The clinical spectrum of VAD thrombosis. Patients with VAD thrombosis may be completely asymptomatic. The condition may progress, leading to a variable presentation, ranging from shortness of breath, low cardiac output state, valvular insufficiency, arrhythmias and right ventricular failure. With or without medical therapy, these patients can progress to cardiogenic shock and death. Despite the wide spectrum of presentations highlighted, there is a consistent finding of elevated LDH as a marker of active hemolysis in all patients.
survived the surgery. Three patients had recurrent VAD thrombosis after the initial pump exchange. Of these patients, 1 with recurrent thrombosis died from hemorrhagic stroke and another from heart failure. The third patient underwent repeat pump exchange and has remained alive and well at 8 months. A variety of factors may have contributed to the diverse presentations described. For example, limited nonobstructive thrombus formation may cause hemolysis without pump dysfunction with more extensive thrombus causing significant obstruction with pump failure. The location of the thrombus within the VAD system may also impact the presentation. Patient-associated factors, such as the intrinsic left or right ventricular function, aortic or mitral valve disease, and innate capacity of the patient to tolerate hemodynamic stress, may also affect presentation. Finally, as observed in 3 of our patients, VAD thrombosis may result in acute thromboembolism, affecting any organ, with the potential for catastrophic cerebrovascular accident. It appears that elevated LDH is a sensitive marker of VAD thrombosis. None of our patients with confirmed VAD thrombosis had LDH within the normal range. Uriel et al reported that LDH at 45-fold the normal level was 100% sensitive and 92% specific for the diagnosis of pump thrombosis.2 However, these results only applied to patients with a positive ramp test, so the magnitude of elevated LDH may be greater in this sub-group of patients. Our series included 2 patients with confirmed pump thrombosis, with a o3-fold increase in LDH, so the sensitivity of a 5-fold LDH cut-off would be only 82% in our series. Moreover, other factors, including infection, malignancies, liver injury and aortic insufficiency,4,5 may reduce the specificity of an elevated LDH. The use of a lower LDH threshold would reduce this specificity even further. Nevertheless, both our study and that of Uriel and colleagues2 support the inference that an elevation in LDH above a given patient’s baseline should lead to increased vigilance for other signs of VAD thrombosis. Our series demonstrates that no single symptom, laboratory result, echocardiographic parameter or provocative test is fully reliable for the diagnosis of VAD thrombosis. A patient with VAD thrombosis may be completely asymptomatic with
Research Correspondence
615
Figure 2 Echocardiographic left ventricular end-diastolic diameter (LVEDD) during pump speed change (ramp study) (see Patient 10 in Tables 1, 2 and S1). The pump speed was increased gradually from 8,800 to 10,600 (ramp study), in accordance with the Columbia protocol.6 The LVEDD decreased substantially from 5.2 cm at 8,800 RPM (top left figure) to 2.07 cm at 10,600 (top right figure).
a “normal” ramp study, despite clinically significant hemolysis and concerning LDH levels. Given that some patients are asymptomatic, we are likely underestimating the true prevalence of thrombosis in VAD patients and/or diagnosing the condition late in many cases. With a growing number of patients treated with VAD support for advanced heart failure, the clinical impact of pump thrombosis will increase without improved preventive and treatment strategies. More complete recognition of this complication and greater understanding of its mechanisms are clearly needed. Nevertheless, it is unknown whether early diagnosis of VAD thrombosis may allow successful medical management and avoidance of the need for pump replacement or whether early pump replacement will improve survival and decrease adverse event rates. Analogous to acute coronary syndromes, the timing of intervention in patients with pump thrombosis is likely to be clinically relevant. Earlier reports have described high recurrence rates and increased mortality with conservative, non-surgical management of VAD thrombosis.1,6 However, those series may not have adequately represented the subgroup of patients who may be captured with earlier diagnosis and the therapeutic efficacy achieved with earlier interventions. Additional studies are necessary to determine the relative merits of a trial of medical therapy versus immediate pump exchange in asymptomatic patients with early diagnosis of VAD thrombosis. For now, decisions about the timing of device replacement must depend on judgments about the potential for immediate and long-term stabilization without pump exchange and the procedural risks of device replacement.
Disclosure statement E.Y.B. and J.E.R. received training and research grant support from Thoratec Corporation and HeartWare. L.R.G. is a consultant
for Thoratec, St. Jude and Respircardia. K.B.M. is on the advisory committees for Novo Nordisk and Astra-Zeneca and received research grant support from Juventis Therapeutics, Celladon, Thoratec, Innolign Biomedical and the U.S. National Institutes of Health (HL105993, HL110338, HL113777). The remaining authors have no conflicts of interest to disclose. The authors thank Dr Michael Acker, Dr Hansie Mathelier, Dr Sourin Banerji, Dr Jeremy A. Mazurek, Christyna M. Justice and Rhondalyn McLean for their contribution to the study. K.B.M. and J.E.R. contributed equally to this work.
Supplementary data Supplementary data associated with this article can be found in the online version at www.jhltonline.org.
References 1. Starling RC, Moazami N, Silvestry SC, et al. Unexpected abrupt increase in left ventricular assist device thrombosis. N Engl J Med 2014;370:33-40. 2. Uriel N, Morrison KA, Garan AR, et al. Development of a novel echocardiography ramp test for speed optimization and diagnosis of device thrombosis in continuous-flow left ventricular assist devices: the Columbia Ramp Study. J Am Coll Cardiol 2012;60:1764-75. 3. Uriel N, Han J, Morrison KA, et al. Device thrombosis in HeartMate II continuous-flow left ventricular assist devices: a multifactorial phenomenon. J Heart Lung Transplant 2014;33:51-9. 4. Gopalan RS, Arabia FA, Noel P, et al. Hemolysis from aortic regurgitation mimicking pump thrombosis in a patient with a HeartMate II left ventricular assist device: a case report. ASAIO J 2012;58:278-80. 5. Adeva-Andany M, López-Ojén M, Funcasta-Calderón R, et al. Comprehensive review on lactate metabolism in human health. Mitochondrion 2014;17:76-100. 6. Hasin T, Deo S, Maleszewski JJ, et al. The role of medical management for acute intravascular hemolysis in patients supported on axial flow LVAD. ASAIO J 2014;60:9-14.