http://www.jhltonline.org
EDITORIAL COMMENTARIES
Hematologic disorders and continuous-flow left ventricular assist devices Jean M. Connors, MD From the Hematology Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts.
The management of end-stage heart failure patients has changed dramatically in the past decade, primarily as a result of the use of mechanical circulatory support devices. In the 5-year period between 2007 and 2012, the number of left ventricular assist devices (LVADs) implanted in the United States has increased almost 10-fold, from 247 in 2007 to 2162 in 2012.1 Both improvements in the technology of the devices as well as expansion of the patient population, including not only those waiting for heart transplant but also those ineligible for transplant for whom the LVAD is used as a destination device, are responsible for this increase. Although overall outcomes have improved significantly, high rates of bleeding and thrombotic complications still occur. Almost 39% of patients will have bleeding complications; 17% will develop neurologic dysfunction, including thromboembolic strokes and intracranial hemorrhage; 5.4% venous thromboembolism (VTE); and 1.3% non-stroke arterial embolic events.1 An increase in early post-implantation device thrombosis for the HeartMate II LVAD, the most commonly used device, has also been reported recently.2 Although device technology continues to be refined, the selection of appropriate patients for use remains critical to maximize good outcomes. In this issue of the journal, Fried and colleagues report on the outcomes of patients with pre-existing hematologic disorders. The necessity of maintaining adequate levels of anti-coagulation to prevent thrombotic events, and the associated risk of bleeding, intuitively suggests that screening and assessment of patients for either bleeding or thrombotic risks before device implantation should be beneficial. Patients can have inherited or acquired disorders that affect coagulation factors or platelets; disorders of either can render patients at risk for bleeding or clotting. Fried et al retrospectively reviewed their single-center continuous-flow LVAD (CF-LVAD) experience over a 5.5-year period between 2008 through 2013.3 Of 286 patients with CF-LAVDs implanted during this time, they identified 12 patients with 5 hematologic conditions that were not due to
malignancy or drug effect, including immune-mediated thrombocytopenia (ITP), Factor V Leiden mutation, elevated Factor VIII activity, heparin-induced thrombocytopenia (HIT) and a strong history of thromboembolism. This group of patients had a significantly higher mortality rate compared with their patient population without hematologic conditions and compared with the INTERMACS registry report CF-LVAD patients during the same period.1 This increase occurred between the first and second year, suggesting that immediate peri-operative bleeding or thrombosis at the time of device implantation was not the cause of the increase in mortality. Survival in this patient group dropped from 81% at 1 year to 49% at 2 years, whereas the remaining population had survival rates of 86.6% at 1 year and 80.5% at 2 years. Patients with hematologic disorders represented just 4.2% of their total patient population and statistical significance could not be determined with such small numbers for each subgroup. The types of coagulation disorders identified by Fried and colleagues are diverse.3 One patient had a true validated inherited thrombophilia— Factor V Leiden mutation (FVL), seen in up to 7% of the Caucasian population in the United States. In the heterozygous state, FVL increases the odds ratio for venous thromboembolism by 4- to 10-fold compared with the normal population, and by 50- to 100-fold in the homozygous state.4,5 Two patients were diagnosed with HIT, an acquired pro-thrombotic state due to antibody formation to heparin–platelet factor 4 (PF4) complexes. HIT can result in catastrophic and fatal thrombosis, but the ability to definitively identify those patients at risk for thrombotic complications versus those with positive antibody tests and thrombocytopenia with no risk of thrombosis remains elusive.6 Given this inherent difficulty in identifying the true thrombotic risk of heparin–PF4 antibodies, management strategies have evolved that are understandably conservative in an effort to prevent thrombosis, as were used by Fried and colleagues in the peri-operative management of patients with HIT in this study.3 These 3 patients
1053-2498/$ - see front matter r 2014 International Society for Heart and Lung Transplantation. All rights reserved. http://dx.doi.org/10.1016/j.healun.2014.08.009
Connors
Hematologic Disorders and Continuous-flow Left Ventricular Assist Devices
with clearly identified increased risks for thrombosis did well; 2 were transplanted and 1 has remained on mechanical circulatory support. The remaining hematologic diagnoses—elevated Factor VIII activity, undefined hypercoagulable state or previous significant VTE history, and ITP—have risks that are more difficult to define and quantitate, due to significant interpatient variability in both disease impact and response to treatment. Increasing data from a number of case-control studies support that elevated Factor VIII levels are associated with thrombosis in a dose-dependent manner, but elevated Factor VIII has not been thoroughly validated as a unique hypercoagulable state.7 Inherent variability from patient to patient, ABO blood type-dependent differences in levels, and increased levels due to inflammation make it hard to verify as a specific risk factor. Although there is clearly a familial component to elevated Factor VIII levels in some patients, no responsible genetic mutations have been identified. Despite dramatic elevation in Factor VIII activity and multiple previous thrombotic episodes, the 1 patient in this study with elevated Factor VIII did well with mechanical circulatory support. Three patients were identified as having a “hypercoagulable state,” as evidenced by documented episodes of thrombosis but without an identifiable specific known causative factor. One patient was young and had arterial events including left anterior descending coronary artery occlusion with massive myocardial infarction, an embolic cerebrovascular accident (CVA) after LVAD implantation, and subsequent device thrombosis. Despite this history the patient was transplanted and did well. The other 2 patients had had multiple episodes of venous thrombosis before LVAD implantation. Unfortunately, both patients died after device placement, but at significantly different time-points: 1 at 36 days and the other at 3.24 years after CF-LVAD placement. Although all 3 of these patients could be considered hypercoagulable, their individual profiles for a hypercoagulable state are unlikely to be similar. Different pathophysiologic mechanisms are thought to be involved in arterial versus venous thrombosis. The development of venous thrombosis in many cases can be considered a result of the culmination of additive simultaneous risk factors that are often not easily identified or are considered independent but weak individual factors. Heart failure patients often have well-known VTE risk factors, such as immobilization, surgery and acute medical illness, that, when combined with unique individual factors, may tip the balance in favor of thrombosis at a critical time-point. Trying to analyze these patients as a single homogeneous group could lead to inaccurate results as the underlying responsible factors may affect CF-LVAD outcomes in different ways. Although both patients with multiple previous VTE events were of similar age and died with thrombotic complications, 1 survived 1,192 days with CF-LVAD support, significantly longer than the patient who survived only 36 days. Patients with ITP can also be difficult to assess as a homogeneous group, due to wide variation in severity of disease and response to treatment.8 Many patients can have compensated ITP, with platelet counts in the 70,000/μl
1115
range and without the need for treatment, whereas other patients, with platelet counts of 10,000/μl, can be refractory to multiple therapies, including steroids, intravenous IgG, thrombopoietin mimetics and even rituximab. ITP can be a difficult diagnosis to make. It requires excluding a wide number of possible causes of thrombocytopenia as there is no definitive positive laboratory test for ITP. Often, initial response to treatment with steroids or intravenous IgG is the best diagnostic test, although the expected duration of response is short, as neither agent has a high long-term response rate. Given the wide variability in severity of ITP, it is not surprising that patients with a diagnosis of ITP and heart failure treated with CF-LVAD implantation can have very different outcomes. In this cohort of 5 patients diagnosed with ITP before CF-LVAD implantation, only 1 died from a bleeding event, which occurred in the immediate post-operative period. Two died roughly 1.5 years after CF-LVAD implantation: 1 from recurrent device thrombosis complications and the other from unknown causes. Two had good outcome, with 1 transplanted and 1 alive on CF-LVAD support. Fried and colleagues are the first to report results in patients with CF-LVADs who had evidence of coagulation-related disorders before implantation. Although their findings of increased mortality may suggest that patients with hematologic coagulation disorders be excluded from CF-LVAD use, the wide range in outcomes for individual patients in each subgroup or with a distinct hematologic disorder underscores the extremely small number of patients analyzed so far and the descriptive nature of this study. Currently, CF-LVAD use is still an emerging therapy that is rapidly evolving with many undefined aspects. It would be premature to exclude patients from eligibility for LVADs at this time based on a hematologic diagnosis alone. Of the 12 patients with hematologic disorders, only 1 with ITP could possibly be determined to have died as a direct result of the hematologic disorder. In addition, the inherently high rates of bleeding and thrombosis accompanying CF-LVAD use are difficult to separate from the hematologic disorders in any one specific patient, as evidenced by the results presented in Fried et al’s Tables 2 and 3. Almost all patients had both bleeding and thrombotic events, regardless of whether their hematologic disorder predisposed them to bleeding or clotting. Careful history-taking that includes assessment for prior bleeding and thrombotic events for all patients undergoing evaluation for CF-LVADs needs to be emphasized— laboratory testing alone is not enough, as evidenced by this small group of patients in whom only 2 of the 12 patients had a diagnosis identifiable by laboratory testing (FVL and Factor VIII). The approach of Fried and colleagues, as outlined in Figure 3 of their work, serves as a starting point for assessment. Involvement of hematology colleagues when a positive response is found in the patient’s history can help further tailor appropriate hematology evaluation. Although an apparent increase in mortality in this patient population at first glance may be of concern, identification of hematologic disorders does not mandate exclusion from CF-LVAD use if complications can be anticipated and management strategies improved. Going forward, data for
1116
The Journal of Heart and Lung Transplantation, Vol 33, No 11, November 2014
outcomes in patients with well-defined hematologic conditions should be collected prospectively from multiple centers, treatment experience should be shared, and guidelines for the management of hematology disorders should be developed so that these life-saving devices can be used to their fullest potential.
Disclosure statement The author has no conflicts of interest to disclose.
References 1. INTERMACS Quarterly Statistical Report, September 30, 2013. http:// www.uab.edu/medicine/intermacs/images/Federal_Quarterly_Report/ Federal_Partners_Report_2013_Q3.pdf. Accessed September 11, 2014.
2. 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. 3. Fried J, Levin AP, Mody KM, et al. Prior hematologic conditions carry a high morbidity and mortality in patients supported with continuousflow left ventricular assist devices. J Heart Lung Transplat 2014;33: 1119-25. 4. Kalafatis M, Bertina RM, Rand MD, et al. Characterization of the molecular defect in Factor VR506Q. J Biol Chem 1995;270:4053-7. 5. Koster T, Rosendaal FR, de Ronde H, et al. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden thrombophilia study. Lancet 1993;342:1503-6. 6. Lo GK, Sigouin CS, Warkentin TE. What is the potential for over diagnosis of heparin-induced thrombocytopenia? Am J Hematol 2007; 82:1037-43. 7. Jenkins PV, Rawley O, Smith OP, et al. Elevated factor VIII levels and risk of venous thrombosis. Br J Haematol 2012;157:653-63. 8. Cines DB, Bussel JB, Liebman HA, et al. The ITP syndrome: pathogenic and clinical diversity. Blood 2009;113:6511-21.
EDITORIAL COMMENTARIES
Hematologic disorders and continuous-flow left ventricular assist devices Jean M. Connors, MD From the Hematology Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts.
The management of end-stage heart failure patients has changed dramatically in the past decade, primarily as a result of the use of mechanical circulatory support devices. In the 5-year period between 2007 and 2012, the number of left ventricular assist devices (LVADs) implanted in the United States has increased almost 10-fold, from 247 in 2007 to 2162 in 2012.1 Both improvements in the technology of the devices as well as expansion of the patient population, including not only those waiting for heart transplant but also those ineligible for transplant for whom the LVAD is used as a destination device, are responsible for this increase. Although overall outcomes have improved significantly, high rates of bleeding and thrombotic complications still occur. Almost 39% of patients will have bleeding complications; 17% will develop neurologic dysfunction, including thromboembolic strokes and intracranial hemorrhage; 5.4% venous thromboembolism (VTE); and 1.3% non-stroke arterial embolic events.1 An increase in early post-implantation device thrombosis for the HeartMate II LVAD, the most commonly used device, has also been reported recently.2 Although device technology continues to be refined, the selection of appropriate patients for use remains critical to maximize good outcomes. In this issue of the journal, Fried and colleagues report on the outcomes of patients with pre-existing hematologic disorders. The necessity of maintaining adequate levels of anti-coagulation to prevent thrombotic events, and the associated risk of bleeding, intuitively suggests that screening and assessment of patients for either bleeding or thrombotic risks before device implantation should be beneficial. Patients can have inherited or acquired disorders that affect coagulation factors or platelets; disorders of either can render patients at risk for bleeding or clotting. Fried et al retrospectively reviewed their single-center continuous-flow LVAD (CF-LVAD) experience over a 5.5-year period between 2008 through 2013.3 Of 286 patients with CF-LAVDs implanted during this time, they identified 12 patients with 5 hematologic conditions that were not due to
malignancy or drug effect, including immune-mediated thrombocytopenia (ITP), Factor V Leiden mutation, elevated Factor VIII activity, heparin-induced thrombocytopenia (HIT) and a strong history of thromboembolism. This group of patients had a significantly higher mortality rate compared with their patient population without hematologic conditions and compared with the INTERMACS registry report CF-LVAD patients during the same period.1 This increase occurred between the first and second year, suggesting that immediate peri-operative bleeding or thrombosis at the time of device implantation was not the cause of the increase in mortality. Survival in this patient group dropped from 81% at 1 year to 49% at 2 years, whereas the remaining population had survival rates of 86.6% at 1 year and 80.5% at 2 years. Patients with hematologic disorders represented just 4.2% of their total patient population and statistical significance could not be determined with such small numbers for each subgroup. The types of coagulation disorders identified by Fried and colleagues are diverse.3 One patient had a true validated inherited thrombophilia— Factor V Leiden mutation (FVL), seen in up to 7% of the Caucasian population in the United States. In the heterozygous state, FVL increases the odds ratio for venous thromboembolism by 4- to 10-fold compared with the normal population, and by 50- to 100-fold in the homozygous state.4,5 Two patients were diagnosed with HIT, an acquired pro-thrombotic state due to antibody formation to heparin–platelet factor 4 (PF4) complexes. HIT can result in catastrophic and fatal thrombosis, but the ability to definitively identify those patients at risk for thrombotic complications versus those with positive antibody tests and thrombocytopenia with no risk of thrombosis remains elusive.6 Given this inherent difficulty in identifying the true thrombotic risk of heparin–PF4 antibodies, management strategies have evolved that are understandably conservative in an effort to prevent thrombosis, as were used by Fried and colleagues in the peri-operative management of patients with HIT in this study.3 These 3 patients
1053-2498/$ - see front matter r 2014 International Society for Heart and Lung Transplantation. All rights reserved. http://dx.doi.org/10.1016/j.healun.2014.08.009
Connors
Hematologic Disorders and Continuous-flow Left Ventricular Assist Devices
with clearly identified increased risks for thrombosis did well; 2 were transplanted and 1 has remained on mechanical circulatory support. The remaining hematologic diagnoses—elevated Factor VIII activity, undefined hypercoagulable state or previous significant VTE history, and ITP—have risks that are more difficult to define and quantitate, due to significant interpatient variability in both disease impact and response to treatment. Increasing data from a number of case-control studies support that elevated Factor VIII levels are associated with thrombosis in a dose-dependent manner, but elevated Factor VIII has not been thoroughly validated as a unique hypercoagulable state.7 Inherent variability from patient to patient, ABO blood type-dependent differences in levels, and increased levels due to inflammation make it hard to verify as a specific risk factor. Although there is clearly a familial component to elevated Factor VIII levels in some patients, no responsible genetic mutations have been identified. Despite dramatic elevation in Factor VIII activity and multiple previous thrombotic episodes, the 1 patient in this study with elevated Factor VIII did well with mechanical circulatory support. Three patients were identified as having a “hypercoagulable state,” as evidenced by documented episodes of thrombosis but without an identifiable specific known causative factor. One patient was young and had arterial events including left anterior descending coronary artery occlusion with massive myocardial infarction, an embolic cerebrovascular accident (CVA) after LVAD implantation, and subsequent device thrombosis. Despite this history the patient was transplanted and did well. The other 2 patients had had multiple episodes of venous thrombosis before LVAD implantation. Unfortunately, both patients died after device placement, but at significantly different time-points: 1 at 36 days and the other at 3.24 years after CF-LVAD placement. Although all 3 of these patients could be considered hypercoagulable, their individual profiles for a hypercoagulable state are unlikely to be similar. Different pathophysiologic mechanisms are thought to be involved in arterial versus venous thrombosis. The development of venous thrombosis in many cases can be considered a result of the culmination of additive simultaneous risk factors that are often not easily identified or are considered independent but weak individual factors. Heart failure patients often have well-known VTE risk factors, such as immobilization, surgery and acute medical illness, that, when combined with unique individual factors, may tip the balance in favor of thrombosis at a critical time-point. Trying to analyze these patients as a single homogeneous group could lead to inaccurate results as the underlying responsible factors may affect CF-LVAD outcomes in different ways. Although both patients with multiple previous VTE events were of similar age and died with thrombotic complications, 1 survived 1,192 days with CF-LVAD support, significantly longer than the patient who survived only 36 days. Patients with ITP can also be difficult to assess as a homogeneous group, due to wide variation in severity of disease and response to treatment.8 Many patients can have compensated ITP, with platelet counts in the 70,000/μl
1115
range and without the need for treatment, whereas other patients, with platelet counts of 10,000/μl, can be refractory to multiple therapies, including steroids, intravenous IgG, thrombopoietin mimetics and even rituximab. ITP can be a difficult diagnosis to make. It requires excluding a wide number of possible causes of thrombocytopenia as there is no definitive positive laboratory test for ITP. Often, initial response to treatment with steroids or intravenous IgG is the best diagnostic test, although the expected duration of response is short, as neither agent has a high long-term response rate. Given the wide variability in severity of ITP, it is not surprising that patients with a diagnosis of ITP and heart failure treated with CF-LVAD implantation can have very different outcomes. In this cohort of 5 patients diagnosed with ITP before CF-LVAD implantation, only 1 died from a bleeding event, which occurred in the immediate post-operative period. Two died roughly 1.5 years after CF-LVAD implantation: 1 from recurrent device thrombosis complications and the other from unknown causes. Two had good outcome, with 1 transplanted and 1 alive on CF-LVAD support. Fried and colleagues are the first to report results in patients with CF-LVADs who had evidence of coagulation-related disorders before implantation. Although their findings of increased mortality may suggest that patients with hematologic coagulation disorders be excluded from CF-LVAD use, the wide range in outcomes for individual patients in each subgroup or with a distinct hematologic disorder underscores the extremely small number of patients analyzed so far and the descriptive nature of this study. Currently, CF-LVAD use is still an emerging therapy that is rapidly evolving with many undefined aspects. It would be premature to exclude patients from eligibility for LVADs at this time based on a hematologic diagnosis alone. Of the 12 patients with hematologic disorders, only 1 with ITP could possibly be determined to have died as a direct result of the hematologic disorder. In addition, the inherently high rates of bleeding and thrombosis accompanying CF-LVAD use are difficult to separate from the hematologic disorders in any one specific patient, as evidenced by the results presented in Fried et al’s Tables 2 and 3. Almost all patients had both bleeding and thrombotic events, regardless of whether their hematologic disorder predisposed them to bleeding or clotting. Careful history-taking that includes assessment for prior bleeding and thrombotic events for all patients undergoing evaluation for CF-LVADs needs to be emphasized— laboratory testing alone is not enough, as evidenced by this small group of patients in whom only 2 of the 12 patients had a diagnosis identifiable by laboratory testing (FVL and Factor VIII). The approach of Fried and colleagues, as outlined in Figure 3 of their work, serves as a starting point for assessment. Involvement of hematology colleagues when a positive response is found in the patient’s history can help further tailor appropriate hematology evaluation. Although an apparent increase in mortality in this patient population at first glance may be of concern, identification of hematologic disorders does not mandate exclusion from CF-LVAD use if complications can be anticipated and management strategies improved. Going forward, data for
1116
The Journal of Heart and Lung Transplantation, Vol 33, No 11, November 2014
outcomes in patients with well-defined hematologic conditions should be collected prospectively from multiple centers, treatment experience should be shared, and guidelines for the management of hematology disorders should be developed so that these life-saving devices can be used to their fullest potential.
Disclosure statement The author has no conflicts of interest to disclose.
References 1. INTERMACS Quarterly Statistical Report, September 30, 2013. http:// www.uab.edu/medicine/intermacs/images/Federal_Quarterly_Report/ Federal_Partners_Report_2013_Q3.pdf. Accessed September 11, 2014.
2. 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. 3. Fried J, Levin AP, Mody KM, et al. Prior hematologic conditions carry a high morbidity and mortality in patients supported with continuousflow left ventricular assist devices. J Heart Lung Transplat 2014;33: 1119-25. 4. Kalafatis M, Bertina RM, Rand MD, et al. Characterization of the molecular defect in Factor VR506Q. J Biol Chem 1995;270:4053-7. 5. Koster T, Rosendaal FR, de Ronde H, et al. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden thrombophilia study. Lancet 1993;342:1503-6. 6. Lo GK, Sigouin CS, Warkentin TE. What is the potential for over diagnosis of heparin-induced thrombocytopenia? Am J Hematol 2007; 82:1037-43. 7. Jenkins PV, Rawley O, Smith OP, et al. Elevated factor VIII levels and risk of venous thrombosis. Br J Haematol 2012;157:653-63. 8. Cines DB, Bussel JB, Liebman HA, et al. The ITP syndrome: pathogenic and clinical diversity. Blood 2009;113:6511-21.
