DIAGNOSTIC DILEMMA Aimee K. Zaas, MD Thomas J. Marrie, MD, Section Editors
Thrombotic Thrombocytopenia Purpura: A Potentially Reversible Cause of Complete Heart Block Andrew Peters, MD,a Hayan Al Maluli, MD,b Mohammed Nayeemuddin, MD,a Arslan Mirza, MD,a Danesh Modi, DO,b Jeffrey Arkles, MD,b Riyaz Bashir, MD, FACC, RVTb a
Department of Medicine; bDivision of Cardiovascular Disease, Department of Medicine, Temple University Hospital, Philadelphia, Pa.
PRESENTATION An 80-year-old Hispanic woman presented to the emergency department via ambulance after a syncopal episode and altered mental status at home. She had no significant cardiac history, with the exception of hypertension. The history obtained from the patient’s family was negative for any recent illness, hospitalization, travel, or tick exposure. There was no family history of cardiac or hematologic disease. The patient was not taking any prescription or overthe-counter medications at the time.
ASSESSMENT The patient’s initial vital signs were significant for a heart rate of 20 beats per minute and a blood pressure of 80/56 mm Hg. Physical examination showed dry mucous Funding: None. Conflict of Interest: None. Authorship: We confirm that the manuscript has been read and approved by all named authors. Requests for reprints should be addressed to Riyaz Bashir, MD, FACC, RVT, Vascular and Endovascular Medicine, Division of Cardiovascular Diseases, Department of Medicine, Temple University Hospital, 3401 N. Broad Street (9 PP), Philadelphia, PA 19140. E-mail address: [email protected]
Figure 1
membranes, clear lungs bilaterally, and a grade 3/6 systolic ejection murmur at the left lower sternal border. She had no edema or rash. Neurological examination did not reveal any focal deficits; however, she was confused, with a decreased level of arousal. Significant laboratory findings included a creatinine of 3.18 mg/dL, hemoglobin of 10 gm/dL, platelets of 128,000/mL, brain natriuretic peptide of 2390 pg/mL, and a mildly elevated cardiac troponin. A chest radiograph showed minimal blunting of costophrenic angles. The electrocardiogram demonstrated complete heart block, with a ventricular escape rhythm (Figure 1). A transthoracic echocardiogram revealed a normal left ventricular ejection fraction with mildly elevated right ventricular pressures, moderate tricuspid regurgitation, and no wall motion abnormalities. The patient received a dose of atropine in the Emergency Department without any response, so transvenous pacing was initiated. During the hospital course, the patient continued to demonstrate a waxing and waning mental status and persistent acute kidney injury. Within 2 days, she developed a worsening thrombocytopenia, with a platelet count of 47,000/mL and hemoglobin of 7.4 gm/dL. Further evaluation of her hematologic abnormalities was notable for an elevated lactate dehydrogenase of 1603 U/L, an undetectable haptoglobin level, and a peripheral blood smear
Electrocardiogram rhythm strip depicting complete heart block.
0002-9343/$ -see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2015.05.047
2
The American Journal of Medicine, Vol -, No -,
Figure 2
2015
Telemetry tracing showing 2:1 atrioventricular conduction.
showing 3-4þ schistocytes. Additionally, her platelet count continued to decrease to a nadir of 23,000/mL. An ADAMTS13 activity assay was sent and returned as normal 1 week later.
DIAGNOSIS At this point, the diagnosis of thrombotic thrombocytopenia purpura was entertained. Classically, the diagnosis of thrombotic thrombocytopenia purpura has been associated with the following 5 features: thrombocytopenia, neurological abnormalities, renal impairment, microangiopathic hemolytic anemia, and fevers.1 In clinical practice, there are actually a plethora of systemic manifestations of thrombotic thrombocytopenia purpura due to microvascular thrombi in different organ systems.2 This creates a dilemma, as it may be easy to miss the diagnosis in patients due to the presence of multi-organ dysfunction from the damage that thrombosis may cause. In practice, generally, only microangiopathic hemolytic anemia and thrombocytopeniaewithout any other apparent causeeare required before making the diagnosis of thrombotic thrombocytopenia purpura. Utilization of this narrowed spectrum of features is based upon the principle that early treatment of thrombotic thrombocytopenia purpura with plasmapheresis, often even before a definitive diagnosis is made, is essential to patient survival.3 Cardiac involvement is one of the myriad systemic manifestations of thrombotic thrombocytopenia purpura, which are caused by microthrombi in small coronary vessels leading to ischemia and tissue destruction.4 Even within the heart, the presentation of thrombotic complications are diverse.5-7 A systemic review showed that, of 111 patients with cardiac involvement, 26 had myocardial infarctions, 17 had congestive heart failure, 10 had
Figure 3
-
arrhythmias, 6 had cardiogenic shock, and 8 had sudden cardiac death.8 Cardiac arrhythmias are reported less frequently in thrombotic thrombocytopenia purpura, yet there are reports of a wide range of anomalies. Of the 10 patients with arrhythmias described above, 6 had complete heart block, 2 had supraventricular tachycardia, one had atrioventricular junctional tachycardia, and one had a ventricular arrhythmia.8 Another study reported that 4 of 8 patients with thrombotic thrombocytopenia purpura and myocardial infarctions developed atrial fibrillation, atrial flutter, and supraventricular tachycardias.6 While rarely reported in patients who survive this deadly disorder, cardiac conduction abnormalities have been recognized widely in postmortem studies. Ridolfi et al9 reported on 17 patients with thrombotic thrombocytopenia purpura who died due to disease complications. Ten of these were sent for histological section, and 7 hearts were noted to have microthrombi in the conduction system. These were localized to the atrioventricular node and the bundle of His. On review of one patient’s clinical chart in this study, the authors noted the patient developed atrioventricular dissociation with wide QRS complexes before death.9 In similar fashion, James and Alperin10 reported on 2 cases in which lesions were found in the sinus node, atrioventricular node, and the bundle of His. In our patient, the diagnosis of thrombotic thrombocytopenia purpura initially proved to be a dilemma because she presented with complete heart block and mild thrombocytopenia. Despite this, a falling platelet count along with persistent kidney injury, waxing and waning mental status, and microangiopathic hemolytic anemia confirmed the diagnosis of thrombotic thrombocytopenia purpura. Interestingly, the absence of a decrease in ADAMTS13 activity
Electrocardiogram rhythm strip with 1:1 atrioventricular conduction.
Peters et al
Thrombotic Thrombocytopenia Purpura: Complete Heart Block
Figure 4
3
Electrocardiogram rhythm strip of atrial flutter with 2:1 atrioventricular conduction.
is more common in the elderly, and is associated with more mild anemia and thrombocytopenia and more profound renal injury, as demonstrated in our case.11
abnormalities, and to initiate treatment in an expedited fashion.
References MANAGEMENT Thrombotic thrombocytopenia purpura is a deadly disease with case fatality rate of >90% without treatment. Plasmapheresis should be initiated as soon as the diagnosis is suspected, as the mortality remains as high as 10%-30% even with treatment.12 After initiating plasmapheresis, our patient’s platelet count stabilized and her renal function improved. After 5 sessions, her creatinine decreased to 1.5 mg/dL and her platelet count increased above 150,000/mL. Additionally, her mental status improved to baseline. In addition to improvement in her hematologic, renal, and neurologic function, her cardiac conduction began to recover. After the third session of plasmapheresis, the temporary pacemaker was turned off and she was noted to have 2:1 atrioventricular conduction (Figure 2). After the fifth session, the patient was in sinus rhythm with 1:1 atrioventricular conduction (Figure 3). The patient actually returned to the hospital several weeks later in atrial flutter with 2:1 AV conduction with a ventricular rate of 130 beats per minute, further supporting that her conduction system recovered (Figure 4). This case highlights an unusual presentation of thrombotic thrombocytopenia purpura with a cardiac arrhythmia and its response to plasmapheresis. It is important for physicians to have a high level of suspicion for thrombotic thrombocytopenia purpura in a patient presenting with thrombocytopenia, kidney injury, and neurologic
1. Amorosi E, Ultmann J. Thrombotic thrombocytopenic purpura: report of 16 cases and review of the literature. Medicine. 1966;45:139-160. 2. Vesely SK, George JN, Lammle B, et al. ADAMTS13 activity in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: relation to presenting features and clinical outcomes in a prospective cohort of 142 patients. Blood. 2003;102:60-68. 3. George JN. Clinical practice. Thrombotic thrombocytopenic purpura. N Engl J Med. 2006;354:1927-1935. 4. James TN, Monto RW. Pathology of the cardiac conduction system in thrombotic thrombocytopenic purpura. Ann Intern Med. 1966;65:37-43. 5. Hughes C, McEwan JR, Longair I, et al. Cardiac involvement in acute thrombotic thrombocytopenic purpura: association with troponin T and IgG antibodies to ADAMTS 13. J Thromb Haemost. 2009;7:529-536. 6. Gandhi K, Aronow WS, Desai H, et al. Cardiovascular manifestations in patients with thrombotic thrombocytopenic purpura: a single-center experience. Clin Cardiol. 2010;33:213-216. 7. Wahla AS, Ruiz J, Noureddine N, Upadhya B, Sane DC, Owen J. Myocardial infarction in thrombotic thrombocytopenic purpura: a single-center experience and literature review. Eur J Haematol. 2008;81: 311-316. 8. Hawkins BM, Abu-Fadel M, Vesely SK, George JN. Clinical cardiac involvement in thrombotic thrombocytopenic purpura: a systematic review. Transfusion. 2008;48:382-392. 9. Ridolfi RL, Hutchins GM, Bell WR. The heart and cardiac conduction system in thrombotic thrombocytopenic purpura. A clinicopathologic study of 17 autopsied patients. Ann Intern Med. 1979;91:357-363. 10. James TN, Alperin JB. Apoptotic myocardial degeneration in thrombotic thrombocytopenic purpura. Apoptosis. 1997;2:384-394. 11. Kremer Hovinga JA, Vesely SK, Terrell DR, Lammle B, George JN. Survival and relaspse in patients with thrombotic thrombocytopenia purpura. Blood. 2010;115:1500-1511. 12. Allford SL, Hunt BJ, Rose P, Machin SJ. Guidelines on the diagnosis and management of the thrombotic microangiopathic haemolytic anaemias. Br J Haematol. 2003;120:556-573.
Thrombotic Thrombocytopenia Purpura: A Potentially Reversible Cause of Complete Heart Block Andrew Peters, MD,a Hayan Al Maluli, MD,b Mohammed Nayeemuddin, MD,a Arslan Mirza, MD,a Danesh Modi, DO,b Jeffrey Arkles, MD,b Riyaz Bashir, MD, FACC, RVTb a
Department of Medicine; bDivision of Cardiovascular Disease, Department of Medicine, Temple University Hospital, Philadelphia, Pa.
PRESENTATION An 80-year-old Hispanic woman presented to the emergency department via ambulance after a syncopal episode and altered mental status at home. She had no significant cardiac history, with the exception of hypertension. The history obtained from the patient’s family was negative for any recent illness, hospitalization, travel, or tick exposure. There was no family history of cardiac or hematologic disease. The patient was not taking any prescription or overthe-counter medications at the time.
ASSESSMENT The patient’s initial vital signs were significant for a heart rate of 20 beats per minute and a blood pressure of 80/56 mm Hg. Physical examination showed dry mucous Funding: None. Conflict of Interest: None. Authorship: We confirm that the manuscript has been read and approved by all named authors. Requests for reprints should be addressed to Riyaz Bashir, MD, FACC, RVT, Vascular and Endovascular Medicine, Division of Cardiovascular Diseases, Department of Medicine, Temple University Hospital, 3401 N. Broad Street (9 PP), Philadelphia, PA 19140. E-mail address: [email protected]
Figure 1
membranes, clear lungs bilaterally, and a grade 3/6 systolic ejection murmur at the left lower sternal border. She had no edema or rash. Neurological examination did not reveal any focal deficits; however, she was confused, with a decreased level of arousal. Significant laboratory findings included a creatinine of 3.18 mg/dL, hemoglobin of 10 gm/dL, platelets of 128,000/mL, brain natriuretic peptide of 2390 pg/mL, and a mildly elevated cardiac troponin. A chest radiograph showed minimal blunting of costophrenic angles. The electrocardiogram demonstrated complete heart block, with a ventricular escape rhythm (Figure 1). A transthoracic echocardiogram revealed a normal left ventricular ejection fraction with mildly elevated right ventricular pressures, moderate tricuspid regurgitation, and no wall motion abnormalities. The patient received a dose of atropine in the Emergency Department without any response, so transvenous pacing was initiated. During the hospital course, the patient continued to demonstrate a waxing and waning mental status and persistent acute kidney injury. Within 2 days, she developed a worsening thrombocytopenia, with a platelet count of 47,000/mL and hemoglobin of 7.4 gm/dL. Further evaluation of her hematologic abnormalities was notable for an elevated lactate dehydrogenase of 1603 U/L, an undetectable haptoglobin level, and a peripheral blood smear
Electrocardiogram rhythm strip depicting complete heart block.
0002-9343/$ -see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2015.05.047
2
The American Journal of Medicine, Vol -, No -,
Figure 2
2015
Telemetry tracing showing 2:1 atrioventricular conduction.
showing 3-4þ schistocytes. Additionally, her platelet count continued to decrease to a nadir of 23,000/mL. An ADAMTS13 activity assay was sent and returned as normal 1 week later.
DIAGNOSIS At this point, the diagnosis of thrombotic thrombocytopenia purpura was entertained. Classically, the diagnosis of thrombotic thrombocytopenia purpura has been associated with the following 5 features: thrombocytopenia, neurological abnormalities, renal impairment, microangiopathic hemolytic anemia, and fevers.1 In clinical practice, there are actually a plethora of systemic manifestations of thrombotic thrombocytopenia purpura due to microvascular thrombi in different organ systems.2 This creates a dilemma, as it may be easy to miss the diagnosis in patients due to the presence of multi-organ dysfunction from the damage that thrombosis may cause. In practice, generally, only microangiopathic hemolytic anemia and thrombocytopeniaewithout any other apparent causeeare required before making the diagnosis of thrombotic thrombocytopenia purpura. Utilization of this narrowed spectrum of features is based upon the principle that early treatment of thrombotic thrombocytopenia purpura with plasmapheresis, often even before a definitive diagnosis is made, is essential to patient survival.3 Cardiac involvement is one of the myriad systemic manifestations of thrombotic thrombocytopenia purpura, which are caused by microthrombi in small coronary vessels leading to ischemia and tissue destruction.4 Even within the heart, the presentation of thrombotic complications are diverse.5-7 A systemic review showed that, of 111 patients with cardiac involvement, 26 had myocardial infarctions, 17 had congestive heart failure, 10 had
Figure 3
-
arrhythmias, 6 had cardiogenic shock, and 8 had sudden cardiac death.8 Cardiac arrhythmias are reported less frequently in thrombotic thrombocytopenia purpura, yet there are reports of a wide range of anomalies. Of the 10 patients with arrhythmias described above, 6 had complete heart block, 2 had supraventricular tachycardia, one had atrioventricular junctional tachycardia, and one had a ventricular arrhythmia.8 Another study reported that 4 of 8 patients with thrombotic thrombocytopenia purpura and myocardial infarctions developed atrial fibrillation, atrial flutter, and supraventricular tachycardias.6 While rarely reported in patients who survive this deadly disorder, cardiac conduction abnormalities have been recognized widely in postmortem studies. Ridolfi et al9 reported on 17 patients with thrombotic thrombocytopenia purpura who died due to disease complications. Ten of these were sent for histological section, and 7 hearts were noted to have microthrombi in the conduction system. These were localized to the atrioventricular node and the bundle of His. On review of one patient’s clinical chart in this study, the authors noted the patient developed atrioventricular dissociation with wide QRS complexes before death.9 In similar fashion, James and Alperin10 reported on 2 cases in which lesions were found in the sinus node, atrioventricular node, and the bundle of His. In our patient, the diagnosis of thrombotic thrombocytopenia purpura initially proved to be a dilemma because she presented with complete heart block and mild thrombocytopenia. Despite this, a falling platelet count along with persistent kidney injury, waxing and waning mental status, and microangiopathic hemolytic anemia confirmed the diagnosis of thrombotic thrombocytopenia purpura. Interestingly, the absence of a decrease in ADAMTS13 activity
Electrocardiogram rhythm strip with 1:1 atrioventricular conduction.
Peters et al
Thrombotic Thrombocytopenia Purpura: Complete Heart Block
Figure 4
3
Electrocardiogram rhythm strip of atrial flutter with 2:1 atrioventricular conduction.
is more common in the elderly, and is associated with more mild anemia and thrombocytopenia and more profound renal injury, as demonstrated in our case.11
abnormalities, and to initiate treatment in an expedited fashion.
References MANAGEMENT Thrombotic thrombocytopenia purpura is a deadly disease with case fatality rate of >90% without treatment. Plasmapheresis should be initiated as soon as the diagnosis is suspected, as the mortality remains as high as 10%-30% even with treatment.12 After initiating plasmapheresis, our patient’s platelet count stabilized and her renal function improved. After 5 sessions, her creatinine decreased to 1.5 mg/dL and her platelet count increased above 150,000/mL. Additionally, her mental status improved to baseline. In addition to improvement in her hematologic, renal, and neurologic function, her cardiac conduction began to recover. After the third session of plasmapheresis, the temporary pacemaker was turned off and she was noted to have 2:1 atrioventricular conduction (Figure 2). After the fifth session, the patient was in sinus rhythm with 1:1 atrioventricular conduction (Figure 3). The patient actually returned to the hospital several weeks later in atrial flutter with 2:1 AV conduction with a ventricular rate of 130 beats per minute, further supporting that her conduction system recovered (Figure 4). This case highlights an unusual presentation of thrombotic thrombocytopenia purpura with a cardiac arrhythmia and its response to plasmapheresis. It is important for physicians to have a high level of suspicion for thrombotic thrombocytopenia purpura in a patient presenting with thrombocytopenia, kidney injury, and neurologic
1. Amorosi E, Ultmann J. Thrombotic thrombocytopenic purpura: report of 16 cases and review of the literature. Medicine. 1966;45:139-160. 2. Vesely SK, George JN, Lammle B, et al. ADAMTS13 activity in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: relation to presenting features and clinical outcomes in a prospective cohort of 142 patients. Blood. 2003;102:60-68. 3. George JN. Clinical practice. Thrombotic thrombocytopenic purpura. N Engl J Med. 2006;354:1927-1935. 4. James TN, Monto RW. Pathology of the cardiac conduction system in thrombotic thrombocytopenic purpura. Ann Intern Med. 1966;65:37-43. 5. Hughes C, McEwan JR, Longair I, et al. Cardiac involvement in acute thrombotic thrombocytopenic purpura: association with troponin T and IgG antibodies to ADAMTS 13. J Thromb Haemost. 2009;7:529-536. 6. Gandhi K, Aronow WS, Desai H, et al. Cardiovascular manifestations in patients with thrombotic thrombocytopenic purpura: a single-center experience. Clin Cardiol. 2010;33:213-216. 7. Wahla AS, Ruiz J, Noureddine N, Upadhya B, Sane DC, Owen J. Myocardial infarction in thrombotic thrombocytopenic purpura: a single-center experience and literature review. Eur J Haematol. 2008;81: 311-316. 8. Hawkins BM, Abu-Fadel M, Vesely SK, George JN. Clinical cardiac involvement in thrombotic thrombocytopenic purpura: a systematic review. Transfusion. 2008;48:382-392. 9. Ridolfi RL, Hutchins GM, Bell WR. The heart and cardiac conduction system in thrombotic thrombocytopenic purpura. A clinicopathologic study of 17 autopsied patients. Ann Intern Med. 1979;91:357-363. 10. James TN, Alperin JB. Apoptotic myocardial degeneration in thrombotic thrombocytopenic purpura. Apoptosis. 1997;2:384-394. 11. Kremer Hovinga JA, Vesely SK, Terrell DR, Lammle B, George JN. Survival and relaspse in patients with thrombotic thrombocytopenia purpura. Blood. 2010;115:1500-1511. 12. Allford SL, Hunt BJ, Rose P, Machin SJ. Guidelines on the diagnosis and management of the thrombotic microangiopathic haemolytic anaemias. Br J Haematol. 2003;120:556-573.
