Increased troponin I is associated with fatal ... - Wiley Online Library

Received: 2 March 2016

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Revised: 7 September 2016

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Accepted: 9 September 2016

DOI 10.1002/jca.21510

RESEARCH ARTICLE

Increased troponin I is associated with fatal outcome in acquired thrombotic thrombocytopenic purpura Jason Brazelton1 | Robert A. Oster2 | Brandi McCleskey1 | Jessica Fuller3 | Jill Adamski4 | Marisa B. Marques1 1

Department of Pathology, University of Alabama at Birmingham (UAB), Birmingham, Alabama

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Department of Medicine, University of Alabama at Birmingham (UAB), Birmingham, Alabama

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Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio

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Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Phoenix, Arizona Correspondence Marisa B. Marques, MD, University of Alabama at Birmingham, WP P230G - 619 19th St. South, Birmingham, AL 35249-7331. Email: [email protected]

Abstract Thrombotic thrombocytopenic purpura (TTP) has >90% mortality without therapeutic plasma exchange (TPE). Despite TPE, approximately 10% of patients still die, presumably from cardiac ischemia. We sought clinical or laboratory parameters associated with death by reviewing the records of all patients hospitalized with acquired TTP in our institution for 10 years, and collect demographics and results for hemoglobin, platelet count, creatinine, lactate dehydrogenase, transaminases, total bilirubin, creatinine kinase (CK), CK-MB, and troponin I. Sixty-eight patients were admitted 88 times, and 11 died. Survivors and non-survivors were similar in terms of sex, ethnicity, thrombocytopenia, and degree of anemia at presentation, while the latter were older, had worse renal function and higher CK, CK-MB, and troponin I (univariate analysis). However, only troponin I remained significant on multivariate analyses. We propose that patients with TTP should be monitored with troponin I to detect significant myocardial ischemia that could predict death despite TPE. KEYWORDS

cardiac ischemia, cardiac markers, death, troponin I, TTP

Funding information Sources of support: None

1 | INTRODUCTION Thrombotic thrombocytopenic purpura (TTP) is a rare disease, characterized by thrombocytopenia and microangiopathic hemolytic anemia, with significant morbidity and mortality. Congenital TTP is due to mutations in the von Willebrand factor cleaving protease gene, a disintegrin and metalloprotease with thrombospondin type 1 motif member 13 (ADAMTS13), resulting in decreased enzymatic activity of ADAMTS13. In acquired TTP, ADAMTS13 deficiency is caused by an autoantibody inhibitor.1 When ADAMTS13 activity is severely decreased, ultra-large von Willebrand factor multimers (ULvWF) normally released from endothelial stores accumulate in the plasma. Consequently, ULvWF-platelet thrombi are lodged in the microvasculature throughout the body leading to end-organ damage from hypoxia.1 Since 1991, therapeutic plasma J. Clin. Apheresis 2016; 00-00

exchange (TPE) is the mainstay of treatment of acquired TTP.2 TPE removes the ULvWF multimers and the ADAMTS13 inhibitor, and replenishes ADAMTS13 from donor plasma. With prompt initiation of TPE, mortality from TTP decreases from 90% to 1 hospitalization: 8 were admitted twice, 3 were admitted 3 times, and 2 were admitted 4 times. However, for the purpose of statistical analysis, we only used data from each patient’s last admission to maximize the number of events (death). All patients were followed to either in-hospital death or discharge. Eleven of the 68

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TABLE 1

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Clinical and laboratory characteristics of patients according to admission outcome (univariate analysis)

Variable

Survivors (n 5 57)a

Non-Survivors (n 5 11)a

P values

Age, mean in years (range)

41.6 6 15.8

49.8 6 8.4

.027

(18–84)

(33–58)

34 (59%)

8 (73%)

Female sex Ethnicity

.51 1.0

White/Other

13 (23%)

2 (18%)

African-American

44 (77%)

9 (82%)

Number of cardiac risk factors(range)

1.3 6 1.3

2.2 6 1.5

(0–5)

(0–4)

.073

[n 5 51] Mean platelet count 3 10 /L (range) 9

Mean hemoglobin in g/dL (range)

Mean creatinine in mg/dL (range)

Mean eGFR in mL/min (range)

Mean LDH in IU/L (range)

17.1 6 12.5

15.8 6 9.1

(4.0–66.0)

(9.0–33.9)

9.2 6 2.2

9.6 6 2.6

(4.9–14.7)

(4.9–13.0)

1.4 6 0.9

2.3 6 1.5

(0.6–6.3)

(0.8–6.1)

74.1 6 33.3

43.9 6 26.9

(12.2–168.1)

(12.2–104.4)

1,235 6 779

2,140 6 1,979

(182–4,071)

(565–7,332)

.79

.46

.015

.006

.12

[n 5 10] 185 6 233

722 6 815

(29–1,098)

(95–2,483)

[n 5 29]

[n 5 10]

1.6 6 1.5

22.9 6 36.6

(0–6.0)

(0.8–106.7)

[n 5 28]

[n 5 10]

Mean CK-MB in IU/L – Peak in the first

1.8 6 1.5

23.9 6 36.5

24-h after initial measurement (range)

(0–6.0)

(1–106.7)

[n 5 28]

[n 5 10]

Mean CK-MB in IU/L – Overall peak

2.2 6 1.9

24.4 6 36.2

(range)

(0–7.1)

(1–106.7)

[n 5 28]

[n 5 10]

3.0 6 4.3

2.8 6 5.4

(0–29.1)

(0–16.7)

[n 5 28]

[n 5 10]

Mean CK in IU/L (range)

Mean CK-MB in IU/L – Initial (range)

Mean days to initial CK-MB (range)

.008

.009

.003

.004

.42

(continues)

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TABLE 1

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(continues)

Variable

Survivors (n 5 57)a

Non-Survivors (n 5 11)a

P values

Mean troponin I in ng/mL –

0.5 6 0.9

51.9 6 82.2

.004

Initial (range)

(0.01–3.9)

(0.03–196.8)

[n 5 30]

[n 5 10]

0.6 6 1.1

53.4 6 81.3

(0.01–5.0)

(0.03–196.8)

[n 5 30]

[n 5 10]

0.7 6 1.1

54.3 6 80.6

(0.01–5.0)

(0.8–196.8)

[n 5 30]

[n 5 10]

3.8 6 4.0

2.4 6 5.4

(0–29.1)

(0–16.7)

[n 5 30]

[n 5 10]

21 (68%)

8 (80%)

[n 5 31]

[n 5 10]

18 (58%)

7 (70%)

[n 5 31]

[n 5 10]

34 6 31

257 6 721

(5–190)

(15–2,431)

Mean troponin I in ng/mL – Peak in the first 24-h after initial measurement (range)

Mean troponin I in ng/mL – Overall peak (range)

Mean days to first troponin I (range)

Number of patients with repeated cardiac markers during admission

Number of patients with cardiac markers within 24-h of initial measurement

Mean ALT in IU/L (range)

.002

10 years, 11 patients died. Excluding one patient who died from metastatic cancer diagnosed during a TTP relapse, all others died as a direct consequence of the disease. As we observed that many patients appeared to have succumbed to cardiac death, we sought to determine if any laboratory or clinical parameters of cardiac ischemia were associated with death from TTP. Our analysis demonstrated that TTP non-survivors had significantly higher levels of troponin I. The availability of multiple troponin I measurements during hospitalization helped strengthen the association between this marker and ongoing cardiac muscle necrosis, presumably due to platelet microthrombi. Our findings are very similar to those of Benhamou and colleagues, who studied patients with TTP enrolled in the French Registry for 10 years. They also found that high troponin I was the only predictor of death in TTP.25 Our study population has some similar demographic parameters including age and female predominance of other published TTP series, while our patients were predominantly African-Americans, which differs from other TTP cohorts. We do not expect this difference to affect the generalizability of our findings. Indeed, there was no difference in ethnicity among survivors and non-survivors. Similar to findings from other TTP cohorts, increasing age, worsening renal function (elevated serum creatinine and reduced eGFR), and increased troponin I serum levels were significantly associated with mortality in our univariate analysis, as were CK, and CK-MB. We propose that the abnormal laboratory parameters correlate with the cumulative burden of microvascular thrombosis. On multivariate analysis, however, only troponin I remained significantly associated with death. Myocardial ischemia, cardiac events immediately prior to death, autopsy confirmation of plateletrich thrombi (as seen in 3 of our patients), and impaired left ventricular systolic function were also noted in previous publications.8–26 The recognition that AMI and heart failure are bad prognostic signs in patients with TTP merits the treatment consideration and potential clinical effectiveness of b-blockers and angiotensin-converting enzyme (ACE) inhibitors. Such measures were proposed by Hawkins and colleagues from the Oklahoma TTP-HUS Registry in 2008.20 Six of our 11 non-survivors had PEA arrests. Ventricular arrhythmias and sudden cardiac death are known complications of AMI and heart failure. As none of our patients was on telemetry, we cannot determine how many developed arrhythmias prior to PEA arrest. If telemetry were to become standard practice in the management of TTP, the observation of arrhythmias might justify b-blockers, electrical shock/defibrillation, or

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transcutaneous/transvenous pacing depending on the type of arrhythmias or heart block. Another consideration should be to drugs that decrease platelet function, whose benefit would have to be weighed against the risk of bleeding. Newer agents that specifically block the binding of VWF to the platelet glycoprotein Ib complex such as aurintricarboxylic acid, ARC1779 or nanobodies are current under investigation and may prove useful adjunctive therapies in the future.1,30 For now, increasing the frequency of TPE to twice daily to increase ADAMTS13 in patients with high troponin I may be tried to decrease their risk of death. We recognize a number of limitations in our study. First, the number of patients in the non-survivor group was only 11. However, considering the low prevalence of TTP and the overwhelming response to TPE, we suggest that our cohort is large enough to yield actionable data. Second, our data came from a single institution with a significant proportion of African-American patients, not the ethnic mix of every hospital that treats patients with TTP. Third, our analysis was limited to the availability of results of cardiac markers which had been ordered at the discretion of the treating physician. For this reason, we analyzed their potential role in predicting death at 3 time-points during hospitalization, namely initial measurement, peak in the first 24 h after first measurement, and overall peak. To our surprise, all three behaved similarly in the multivariate analysis. Fourth, laboratory tests significantly associated with death on univariate analysis were not ordered for all patients, subjecting our data to the concept of fragility.31Conversely, as all tests were performed in the same clinical laboratory, the analyses were strengthened by the ability to compare the results of all patients. Fifth, we used the MDRD equation to estimate GFR in predominantly acute renal impairment from TTP, recognizing that the formula was designed for patients with chronic renal insufficiency.28 Next, despite a thorough review of the medical records of every patient during each admission, our ability to assess the presence of cardiac risk factors was limited by the retrospective nature of the data. Lastly, for the patients with more than one TTP episode, having to choose one to include in the analysis may also be a limitation. By choosing the last admission to maximize the number of fatalities, troponin I levels may have been lower than if we had used the initial TTP presentation, considering that the diagnosis of TTP is often made earlier in relapses than when patients first present with TMA. In conclusion, our data confirm recent reports from Europe.22,25 suggesting that serum markers of cardiac damage are predictive of mortality in patients with TTP. We echo previous recommendations that in addition to the use of b-blockers, ACEinhibitors, telemetry, echocardiograms, electrocardiograms, serial troponin I monitoring should be considered. Furthermore, subspecialty consultation with a cardiologist is advisa-

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ble, as clinically indicated. We recognize that only prospective studies will appropriately answer the validity of these management options, and that the rarity of this potentially lethal condition is an impediment to their feasibility. In summary, we agree with the assertion by Blombery and Scully who state that patients with TTP should be quickly referred to specialized centers where efficient and coordinated care are likely to improve outcomes.32 R EFE RE NC ES [1] Sarode R, Bandarenko N, Brecher ME, et al. Thrombotic thrombocytopenic purpura: 2012 American Society for Apheresis (ASFA) consensus conference on classification, diagnosis, management, and future research. J Clin Apher. 2014; 29:148–167. [2] Rock GA, Shumak KH, Buskard NA, et al. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. N Engl J Med. 1991; 325:393–397. [3] Rose M, Eldor A. High incidence of relapses in thrombotic thrombocytopenic purpura. Clinical Study of 38 Patients. Am J Med. 1987; 83:437–444. [4] Lara PN Jr, Coe TL, Zhou H, Fernando L, Holland PV, Wun T. Improved survival with plasma exchange in patients with thrombotic thrombocytopenic purpurahemolytic uremic syndrome. Am J Med. 1999; 107:573– 579. [5] Levandovsky M, Harvey D, Lara P, Wun T. Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS): a 24-year clinical experience with 178 patients. J Hematol Oncol. 2008; 1:23–30. [6] Benhamou Y, Assie C, Boelle PY, et al. Development and validation of a predictive model for death in acquired severe ADAMTS13 deficiency-associated idiopathic thrombotic thrombocytopenic purpura: the French TMA Reference Center experience. Haematologica. 2012; 97: 1181–1186. [7] Chaturvedi S, Carcioppolo D, Zhang L, McCrae KR. Management and outcomes for patients with TTP: analysis of 100 cases at a single institution. Am J Hematol. 2013; 88:560–565. [8] Amorosi EL, Ultmann JE. Thrombotic thrombocytopenic purpura: report of 16 cases and review of the literature. Medicine. 1966; 45:1392159. [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] Ridolfi RL, Bell WR. Thrombotic thrombocytopenic purpura. Report of 25 cases and review of the literature. Medicine. 1981; 60:413–428. [11] Webb JG, Butany J, Langer G, Scott G, Liu PP. Myocarditis and myocardial hemorrhage associated with

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