Patient Characteristics
A total of 92 subjects were included in the study, 33 (36%) of whom were female. The average age at the time of complete blood count measurement was 24.0 ± 8.9 years, and the average age at Fontan was 4.1 ± 4.1 years. Demographic and clinical characteristics of the cohort are detailed in Table 1.
Table 1. General Characteristics
Variable
|
All Patients (N = 92)
|
Thrombocytopenia
|
P-value
|
Demographics
|
|
No (N = 60)
|
Yes (N = 32)
|
|
Sex (female)
|
33 (36%)
|
27 (44%)
|
6 (19%)
|
0.02
|
Age at the time of platelet count measurement (y)
|
24.0 ± 8.9
|
22.8 ± 9.3
|
26.5 ± 7.6
|
0.06
|
Age at Fontan (y)
|
4.1 ± 4.1
|
4.1 ± 4.8
|
4.0 ± 2.7
|
0.87
|
Diagnosis
|
|
|
|
0.02
|
Hypoplastic Left Heart Syndrome
|
29 (32%)
|
14 (24%)
|
15 (46%)
|
|
Tricuspid Atresia
|
17 (19%)
|
16 (27%)
|
1 (3%)
|
|
Double Inlet Left Ventricle
|
16 (17%)
|
9 (15%)
|
7 (21%)
|
|
Double Outlet Right Ventricle
|
10 (11%)
|
8 (13%)
|
2 (6%)
|
|
Pulmonary Atresia
|
6 (7%)
|
4 (7%)
|
2 (6%)
|
|
Transposition of the Great Arteries
|
4 (4%)
|
1 (2%)
|
3 (9%)
|
|
AV Septal Defect
|
4 (4%)
|
2 (3%)
|
2 (6%)
|
|
Double Inlet Right Ventricle
|
2 (2%)
|
1 (2%)
|
1 (3%)
|
|
Ebstein’s Anomaly
|
1 (1%)
|
1 (2%)
|
0 (0%)
|
|
Other
|
3 (3%)
|
3 (5%)
|
0 (0%)
|
|
Type of Fontan Circulation
|
|
|
|
0.12
|
Extracardiac Conduit
|
62 (67%)
|
43 (73%)
|
19 (58%)
|
|
Lateral Tunnel
|
23 (32%)
|
16 (27%)
|
13 (39%)
|
|
Other
|
1 (1%)
|
0 (0%)
|
1 (3%)
|
|
Ventricular morphology
|
|
|
|
0.27
|
Left Ventricle Dominant
|
44 (48%)
|
33 (54%)
|
11 (36%)
|
|
Right Ventricle Dominant
|
33 (36%)
|
19 (31%)
|
14 (45%)
|
|
Balanced or Mixed
|
15 (16%)
|
9 (15%)
|
6 (19%)
|
|
Function
|
|
|
|
|
Ventricular Function, moderately depressed or worse
|
26 (28%)
|
14 (24%)
|
12 (36%)
|
0.23
|
AV valve insufficiency, moderate or worse
|
10 (11%)
|
6 (10%)
|
4 (12.5%)
|
0.73
|
Anti-coagulation/Anti-platelet
|
|
|
|
0.39
|
Aspirin
|
74 (80%)
|
49 (83%)
|
25 (76%)
|
|
Warfarin
|
9 (10%)
|
6 (10%)
|
3 (9%)
|
|
Direct Oral Anticoagulant (DOAC)
|
4 (4%)
|
3 (5%)
|
1 (3%)
|
|
Clopidogrel
|
1 (1%)
|
0 (0%)
|
1 (3%)
|
|
Other
|
1 (1%)
|
0 (0%)
|
1 (3%)
|
|
None
|
3 (3%)
|
1 (1%)
|
2 (6%)
|
|
Results are presented as mean ± standard deviation or as proportions as appropriate; AV = atrioventricular
Complete Blood Count
The average platelet count was 183.0 ± 70.2/µL. There were 32 patients (35%) with thrombocytopenia. The average platelet count among those with thrombocytopenia was 111.1 ± 26.3/µL, while the average platelet count among those without thrombocytopenia was 222.2 ± 53.5/µL (Table 2).
Table 2. Complete blood count findings in patients with and without thrombocytopenia.
Variable
|
All Patients (N = 92)
|
Thrombocytopenia
|
P-value
|
No (N = 60)
|
Yes (N = 32)
|
|
|
|
|
|
Platelet Count (/µL)
|
186.0 ± 70.7
|
223.9 ± 53.7
|
111.5 ± 27.1
|
N/A
|
White Blood Cells (/µL)
|
6.55 ± 2.77
|
7.47 ± 2.9
|
4.96 ± 1.6
|
< 0.01
|
Hemoglobin (/µL)
|
15.3 ± 1.9
|
15.1 ± 1.9
|
15.8 ± 1.9
|
0.44
|
Absolute Lymphocytes (/µL)
|
1.27 ± 0.7
|
1.47 ± 0.7
|
0.89 ± 0.4
|
< 0.01
|
Absolute Neutrophils (/µL)
|
4.59 ± 2.3
|
5.09 ± 2.5
|
3.63 ± 1.5
|
0.01
|
Results are presented as mean ± standard deviation.
Cardiac Catheterization
Of the study population, 59 patients had cardiac catheterization data. The average time from Fontan completion to cardiac catheterization testing was 15.0 ± 16.6 years. There was a significant inverse correlation between platelet count and Fontan pressure (r = -0.38, p = 0.003).
Twenty-one (N = 21, 36%) patients had elevated Fontan pressure ³ 15 mmHg. Patients with thrombocytopenia had an odds ratio of 4.3 (95% CI 1.4–13.5, p = 0.009) to have elevated Fontan pressure ³ 15 mmHg. Patients with thrombocytopenia had significantly higher Fontan pressure (14.8 ± 3.6 mmHg versus 12.5 ± 2.7 mmHg, p = 0.007), as seen in Figure 1.
After adjusting for time from Fontan to lab draw, sex, and diagnosis, patients with thrombocytopenia had an odds ratio of 8.1 (95% CI 1.3–52.7, p = 0.03) to have Fontan pressure ³ 15 mmHg.
Patients with thrombocytopenia had significantly higher end-diastolic pressure (10.3 ± 5.2 mmHg versus 8.5 ± 2.6 mmHg, p = 0.03). There was no significant difference between the groups in pulmonary vascular resistance (PVR) or systemic output (Qs) (Table 3).
Table 3. Catheterization findings in patients with and without thrombocytopenia.
Variable
|
All Patients (N = 59)
|
Thrombocytopenia
|
P-value
|
No (N = 33)
|
Yes (N = 26)
|
|
Fontan pressure (mmHg)
|
13.3 ± 3.0
|
12.5 ± 2.6
|
14.9 ± 3.7
|
0.006
|
End Diastolic Pressure (mmHg)
|
9.2 ± 4.0
|
8.5 ± 2.6
|
10.3 ± 5.2
|
0.03
|
PVR (mmHg)
|
1.77 ± 1.0
|
1.81 ± 1.0
|
1.71 ± 1.0
|
0.65
|
Qs (L/min/m2)
|
3.15 ± 1.2
|
3.17 ± 1.3
|
3.12 ± 1.1
|
0.86
|
Results are presented as mean ± standard deviation.
Liver Function
Of the study population, 83 patients had a liver ultrasound. Of the patients that had an ultrasound, 52 (62%) had normal platelet counts and 32 (38%) had thrombocytopenia.
Patients with thrombocytopenia had an odds ratio of 4.1 (95% CI 1.6–10.6, p = 0.003) to have advanced FALD (Figure 2). On multivariable analysis adjusted for age and sex, thrombocytopenia continued to show positive association with advanced FALD, with an odds ratio of 3.3 (95% CI 1.2 – 9.2, p = 0.02).
Patients with thrombocytopenia had an odds ratio of 2.9 (95% CI 1.1-7.6, p = 0.03) to have splenomegaly. There was no association between thrombocytopenia and any other specific finding on liver ultrasound.
Patients with thrombocytopenia had significantly higher levels of bilirubin (1.15 ± 0.69 mg/dL versus 0.84 ± 0.60 mg/dL, p= 0.03). There was no difference in ALT, AST, GGTP, or albumin levels between the thrombocytopenia and normal platelet groups (Table 4).
Table 4. Hepatic imaging and laboratory data for patients with and without thrombocytopenia.
Variable
|
All Patients (N=83)
|
Thrombocytopenia
|
P-value
|
Ultrasound
|
|
No (N= 54)
|
Yes (N=29)
|
|
Cirrhosis
|
22 (27%)
|
11 (20%)
|
11 (38%)
|
0.08
|
Ascites
|
5 (6%)
|
2 (4%)
|
3 (10%)
|
0.23
|
Median Sheer Wave Speed (m/s)
|
1.86 ± 0.3
|
1.93 ± 0.4
|
1.83 ± 0.3
|
0.24
|
Hepatomegaly
|
10 (12%)
|
7 (13%)
|
3 (10%)
|
0.73
|
Splenomegaly
|
25 (30%)
|
12 (22%)
|
13 (45%)
|
0.03
|
Heterogenous Parenchyma
|
43 (52%)
|
24 (44%)
|
19 (66%)
|
0.07
|
Hyperechoic Lesions
|
14 (17%)
|
10 (19%)
|
4 (14%)
|
0.58
|
Surface Nodularity
|
19 (23%)
|
12 (22%)
|
7 (24%)
|
0.84
|
Advanced FALD
|
35 (42%)
|
18 (33%)
|
17 (59%)
|
0.03
|
Labs
|
|
|
|
|
Alanine Aminotransferase (units/L)
|
35.4 ± 16.5
|
36.2 ± 18.9
|
33.9 ± 11.0
|
0.55
|
Aspartate Aminotransferase (units/L)
|
27.0 ± 10.7
|
27.8 ± 10.6
|
25.7 ± 10.8
|
0.39
|
Gamma-Glutamyl Transferase (units/L)
|
80.6 ± 53.2
|
79.3 ± 56.5
|
83.1 ± 47.2
|
0.76
|
Total Bilirubin (µmol/L)
|
0.95 ± 0.6
|
0.84 ± 0.6
|
1.15 ± 0.69
|
0.04
|
Albumin (g/dL)
|
4.20 ± 0.7
|
4.14 ± 0.7
|
4.24 ± 0.7
|
0.54
|
Results are presented as mean ± standard deviation or as proportions as appropriate.
Morbidity
Our patients were followed for a total of 1129 patient-years. There were no deaths. Although 97% of our sample were on anti-coagulation or anti-platelet medications, there were no major bleeding events. One patient received a transplant, and that patient was not in the thrombocytopenia group.
Patients with thrombocytopenia had a significantly higher rate of unscheduled admissions (361.8 ± 576.7 versus 115.4 ± 185.4 admissions per 1000 patient-years, p = 0.02) and specifically admissions for heart failure (116.4 ± 223.0 versus 21.5 ± 73.1 admissions per 1000 patient-years, p = 0.02). Patients with thrombocytopenia had a higher rate of admission for arrhythmia, although it was not statistically significant (36.0 ± 86.9 versus 9.3 ± 29.1 admissions per 1000 patient-years, p = 0.10) (Table 5, Figure 3).
Table 5. Morbidity/Mortality in patients with and without thrombocytopenia.
Variable
|
All Patients
|
Thrombocytopenia
|
P-value
|
No (N = 60)
|
Yes (N = 32)
|
Total Patient Years
|
1129
|
715
|
414
|
|
Total Admissions (per 1,000 patient years)
|
204.7 ± 392.7
|
115.4 ± 185.4
|
361.8 ± 576.7
|
0.02
|
Heart Failure Admissions (per 1,000 patient years)
|
55.9 ± 152.2
|
21.5 ± 73.1
|
116.4 ± 223.0
|
0.02
|
Arrhythmia Admissions (per 1,000 patient years)
|
19.0 ± 58.2
|
9.3 ± 29.1
|
36.0 ± 86.9
|
0.10
|
Transplant
|
1 (1%)
|
1 (1%)
|
0 (0%)
|
|
Deaths
|
0 (0%)
|
0 (0%)
|
0 (0%)
|
|
Results are presented as mean ± standard deviation or as proportions as appropriate.