Abstract

Aims

This study aimed to evaluate incidence and correlates for low platelet count after transcatheter aortic valve replacement (TAVR) and to determine a possible association between acquired thrombocytopenia and clinical outcomes.

Methods and results

Patients undergoing TAVR from two medical centres were included in the study. They were stratified according to nadir platelet count post procedure: no/mild thrombocytopenia, ≥100 × 109/L; moderate, 50–99 × 109/L; and severe, <50 × 109/L. A total of 488 patients composed of the study population (age 84.7 ± 7.5 years). At a median time of 2 days after TAVR, 176 patients (36.1%) developed significant thrombocytopenia: 149 (30.5%) moderate; 27 patients (5.5%) severe. Upon discharge, the vast majority of patients (90.2%) had no/mild thrombocytopenia. Nadir platelet count <50 × 109/L was highly specific (96.3%), and a count <150 × 109/L highly sensitive (91.2%), for predicting 30-day death (C-statistic 0.76). Patients with severe acquired thrombocytopenia had a significantly higher mortality rate at 1 year (66.7% for severe vs. 16.0% for no/mild vs. 20.1% for moderate; P < 0.001). In multivariate logistic regression, severe thrombocytopenia was independently associated with 1-year mortality (hazard ratio 3.44, CI: 1.02–11.6; P = 0.046).

Conclusions

Acquired thrombocytopenia was common after TAVR and was mostly resolved at patient discharge. The severity of thrombocytopenia after TAVR could be used as an excellent, easily obtainable, marker for worse short- and long-term outcomes after the procedure.

Introduction

Transcatheter aortic valve replacement (TAVR) is an alternative treatment for high-risk patients with severe aortic stenosis.1,2 Although device implantation is successful in the majority of patients undergoing TAVR, periprocedural complications are frequent.3 Common adverse events such as vascular complications, bleeding, and acute kidney injury adversely affect post-procedure course, prolong hospitalization, and are associated with lower patient survival.4,5 It is therefore widely accepted that for optimal results, TAVR patients require meticulous management after the procedure.6,7

Thrombocytopenia, or low platelet blood count, is common in seriously ill patients.8 A decrease in platelet count (DPC) commonly results from enhanced platelet usage (consumptive coagulopathy), reduced production (manifestation of acute illness), or significant haemodilution (multiple red blood cell transfusions). Thrombocytopenia during an intensive care unit (ICU) stay is multifactorial and is associated with higher patient mortality.9 Thrombocytopenia has been previously reported in patients undergoing cardiovascular procedures and is frequently encountered after cardiac surgery.10,11 Thrombocytopenia after percutaneous coronary intervention (PCI) and transcatheter closure of congenital heart defect is associated with increased bleeding events and death within 1 year.12,13

This study aimed to evaluate the incidence and correlates for development of thrombocytopenia in patients undergoing TAVR, and to examine the possible association between acquired thrombocytopenia and clinical outcomes.

Methods

Study design

Data were collected on consecutive patients with severe, symptomatic aortic valve stenosis undergoing TAVR at MedStar Washington Hospital Center (Washington, DC) and Columbia University Medical Center/New York Presbyterian Hospital (New York, NY) from May 2007 to September 2012. Unfractionated heparin was used in all procedures (50–70 units/kg). Baseline demographics, procedural data, and clinical outcomes were prospectively collected, while the analysis was performed retrospectively. Data were entered into a registry at each medical centre and approved by each hospital's respective ethics committees. For the purpose of the current analysis, data from both medical centres were pooled and a joint database was created. No extramural funding was used to support the study. The authors are solely responsible for the design and conduct of this study and all analyses, drafting, and editing of the article.

Definitions and endpoints

The following definitions were used in accordance with the Valve Academic Research Consortium (VARC-2) standardized endpoint definitions for transcatheter aortic valve implantation consensus document: Device success, vascular complication, bleeding, neurological events, periprocedural myocardial infarction, and acute kidney injury.14 Laboratory evaluation was conducted at least once daily during ICU stay; and at the physician's discretion thereafter. For baseline laboratory results, the last evaluation before the procedure was utilized. Patients with baseline moderate/severe thrombocytopenia (platelet count <100 × 109/L) and those who died during the procedure, before laboratory evaluation was repeated, were excluded. Patients were stratified into three groups according to nadir platelet count: no/mild acquired thrombocytopenia, ≥100 × 109/L; moderate, 50–99 × 109/L; and severe, <50 × 109/L. Additionally, the group of patients with moderate or severe thrombocytopenia was stratified according to the time to nadir: early, <4 days or delayed, ≥4 days and according to the DPC [% DPC = 100 × (baseline platelet count – nadir platelet count)/baseline platelet count]: high DPC, ≥50% or low DPC, <50%. High DPC (≥50%) was determined according to the previous studies.12 Heparin-induced thrombocytopenia (HIT) was evaluated at the discretion of the treating physician in patients who developed significant thrombocytopenia (platelet nadir <100 × 109/L) or DPC ≥50%. Patients with a positive result from the specific platelet serotonin release assay were diagnosed as having HIT.15 Our routine practice is to preload patients with double antiplatelet therapy and to discharge them on aspirin 81-mg daily and clopidogrel 75-mg daily, for 3–6 months.

Statistical analysis

Continuous variables are summarized as mean ± standard deviation (SD) or as medians and interquartile range (IQR) as appropriate, and were compared using Student's t-test or Mann–Whitney rank-sum test. Categorical variables were compared using Chi-square or the Fisher exact test. Receiver operating characteristic curves using the C-statistic were used to compare accuracy in predicting 30-day survival according to nadir platelet count and DPC degree and were compared by the bootstrap method. Best estimate had highest summation of sensitivity and specificity. The estimated 30-day survival curve was calculated and displayed by a hazard function for the probability of death for each platelet nadir, based on the current data set. Survival curves were constructed using Kaplan–Meier estimates, while comparisons relied on the log-rank test. The multivariable model was built by selecting baseline variables of clinical interest and/or satisfaction of the entry criterion of P< 0.05 in the univariable analysis: Society of Thoracic Surgeons (STS) score, baseline renal failure, major vascular complication, major or life-threatening bleeding, major stroke, sepsis, acute kidney injury (stage II/III), and severe thrombocytopenia. A two-sided alpha level of 0.05 was used for all superiority testing. All statistical analyses were performed using SAS software version 9.2 (SAS Institute, Cary, NC, USA).

Results

A total of 506 patients who underwent TAVR were examined. Eighteen patients were excluded: 16 of these patients had baseline thrombocytopenia (platelet count 56–99 × 109/L) and 2 expired before follow-up laboratory evaluation. Therefore, a total of 488 patients comprised the study population (age 84.7 ± 7.5 years, 48.2% men). Median baseline platelet count was 192 × 109/L (IQR 160–241 × 109/L, minimum 100 × 109/L, maximum 517 × 109/L) (Figure 1A). Median length of hospital stay was 7 days (IQR 5–9, minimum 2, maximum 86). During post-procedural hospitalization, 176 patients (36.1%) developed significant thrombocytopenia (30.5% moderate, 5.5% severe). Median nadir platelet count was 113.5 × 109/L (IQR 89–144.5, minimum 11, maximum 476) (Figure 1B). The median time to platelet count nadir was 2 days (IQR 2–3). In patients with moderate/severe acquired thrombocytopenia, 145 (81.5%) had platelet nadir by the third post-operative day (early nadir) (Figure 1C). Upon discharge, median platelet count was 166 × 109/L (IQR 127–219). The majority of patients (90.2%) had no/mild thrombocytopenia (platelet count ≥100 × 109/L) at discharge.

Figure 1

(A) Distribution of cases according to the baseline platelet counts. Sixteen cases with baseline moderate thrombocytopenia were excluded from the analysis for acquired thrombocytopenia. (B) Distribution of cases according to the nadir platelet counts (lowest platelet count during post-procedural hospitalization). (C) Distribution of the time to nadir level in patients with moderate or severe acquired thrombocytopenia divided into early acquired thrombocytopenia (time to nadir ≤3 days, white boxes) and delayed (≥4 days, black). TAVR, transcatheter aortic valve replacement.

Figure 1

(A) Distribution of cases according to the baseline platelet counts. Sixteen cases with baseline moderate thrombocytopenia were excluded from the analysis for acquired thrombocytopenia. (B) Distribution of cases according to the nadir platelet counts (lowest platelet count during post-procedural hospitalization). (C) Distribution of the time to nadir level in patients with moderate or severe acquired thrombocytopenia divided into early acquired thrombocytopenia (time to nadir ≤3 days, white boxes) and delayed (≥4 days, black). TAVR, transcatheter aortic valve replacement.

Patients were stratified according to the degree of acquired thrombocytopenia: no/mild (n = 312), moderate (n = 149), and severe (n = 27). Baseline characteristics, as seen in Table 1, were similar between groups. There were no differences in age, sex, or STS score. Laboratory values during hospitalization can be seen in Table 2. Two patients (0.4%) had a positive platelet serotonin release assay and were diagnosed as having HIT after TAVR. Clinical outcomes are described in Table 3. Patients with severe thrombocytopenia had a significantly higher 30-day mortality rate (48.1 vs. 3.5% for no/mild thrombocytopenia and 6.7% for moderate, P < 0.001 for both comparisons), prolonged ICU stay, and higher rates of major vascular complications, life-threatening bleeding, sepsis, acute kidney injury (type II/III), and multiple blood transfusions during hospital stay. There were no differences in device success, major stroke, or post-procedure paravalvular leak (≥+2) rates between groups.

Table 1

Baseline characteristics

  Acquired thrombocytopenia
 
P-value 
No/mild (nadir ≥100 × 109/L), n = 312 Moderate (nadir 50–99 × 109/L), n = 149 Severe (nadir <50 × 109/L), n = 27 
Age (years) 84.4 ± 7.9 85.3 ± 6.4 84.6 ± 8.1 0.51 
Men 147 (47.1%) 72 (48.3%) 16 (59.3%) 0.48 
Logistic EuroSCORE 29.0 ± 17.8 32.9 ± 22.0 29.5 ± 21.4 0.22 
Society of Thoracic Surgeons score 11.1 ± 4.6 11.4 ± 4.1 11.8 ± 6.0 0.62 
Considered a non-surgical candidate 119 (38.1%) 57 (38.3%) 12 (44.4%) 0.81 
Hypertension 236 (86.4%) 124 (91.2%) 22 (84.6%) 0.34 
Diabetes mellitus 90 (32.8%) 39 (29.1%) 7 (28.0%) 0.69 
Renal failurea 151 (55.3%) 86 (64.7%) 18 (72.0%) 0.08 
Chronic obstructive pulmonary disease 87 (31.9%) 33 (25.2%) 10 (40.0%) 0.22 
Liver cirrhosis 3 (1.1%) 3 (2.2%) 0.59 
Previous stroke/transient ischaemic attack 42 (15.6%) 26 (19.5%) 5 (20.0%) 0.57 
Previous percutaneous coronary intervention 94 (35.2%) 29 (22.3%) 6 (24.0%) 0.13 
Prior cardiac surgery 102 (37.5%) 49 (37.1%) 10 (40.0%) 0.96 
Peripheral vascular disease 73 (28.2%) 43 (35.0%) 7 (29.2%) 0.40 
Baseline left ventricle ejection fraction 51.4 ± 14.8 51.6 ± 14.3 47.1 ± 16.5 0.39 
Baseline aortic valve mean gradient (mmHg) 43.1 ± 15.9 43.9 ± 16.7 45.0 ± 19.5 0.81 
Baseline aortic valve area (cm20.61 ± 0.16 0.57 ± 0.17 0.50 ± 0.17 0.01 
Transcatheter aortic valve replacement device 
 Edwards SAPIEN 297 (95.2%) 146 (98.0%) 27 (100%) 0.16 
 CoreValve 15 (4.8%) 3 (2.0%) 
Procedural access 
 Transfemoral 219 (70.2%) 101 (67.8%) 16 (59.3%) 0.47 
 Transapical/direct-aortic 93 (29.8%) 48 (32.2%) 11 (40.7%) 
  Acquired thrombocytopenia
 
P-value 
No/mild (nadir ≥100 × 109/L), n = 312 Moderate (nadir 50–99 × 109/L), n = 149 Severe (nadir <50 × 109/L), n = 27 
Age (years) 84.4 ± 7.9 85.3 ± 6.4 84.6 ± 8.1 0.51 
Men 147 (47.1%) 72 (48.3%) 16 (59.3%) 0.48 
Logistic EuroSCORE 29.0 ± 17.8 32.9 ± 22.0 29.5 ± 21.4 0.22 
Society of Thoracic Surgeons score 11.1 ± 4.6 11.4 ± 4.1 11.8 ± 6.0 0.62 
Considered a non-surgical candidate 119 (38.1%) 57 (38.3%) 12 (44.4%) 0.81 
Hypertension 236 (86.4%) 124 (91.2%) 22 (84.6%) 0.34 
Diabetes mellitus 90 (32.8%) 39 (29.1%) 7 (28.0%) 0.69 
Renal failurea 151 (55.3%) 86 (64.7%) 18 (72.0%) 0.08 
Chronic obstructive pulmonary disease 87 (31.9%) 33 (25.2%) 10 (40.0%) 0.22 
Liver cirrhosis 3 (1.1%) 3 (2.2%) 0.59 
Previous stroke/transient ischaemic attack 42 (15.6%) 26 (19.5%) 5 (20.0%) 0.57 
Previous percutaneous coronary intervention 94 (35.2%) 29 (22.3%) 6 (24.0%) 0.13 
Prior cardiac surgery 102 (37.5%) 49 (37.1%) 10 (40.0%) 0.96 
Peripheral vascular disease 73 (28.2%) 43 (35.0%) 7 (29.2%) 0.40 
Baseline left ventricle ejection fraction 51.4 ± 14.8 51.6 ± 14.3 47.1 ± 16.5 0.39 
Baseline aortic valve mean gradient (mmHg) 43.1 ± 15.9 43.9 ± 16.7 45.0 ± 19.5 0.81 
Baseline aortic valve area (cm20.61 ± 0.16 0.57 ± 0.17 0.50 ± 0.17 0.01 
Transcatheter aortic valve replacement device 
 Edwards SAPIEN 297 (95.2%) 146 (98.0%) 27 (100%) 0.16 
 CoreValve 15 (4.8%) 3 (2.0%) 
Procedural access 
 Transfemoral 219 (70.2%) 101 (67.8%) 16 (59.3%) 0.47 
 Transapical/direct-aortic 93 (29.8%) 48 (32.2%) 11 (40.7%) 

aGolmerular filtration rate <60 cc/min.

Table 2

Laboratory values during hospitalization

  Acquired thrombocytopenia
 
P-value 
No/mild (nadir ≥100 × 109/L) n = 312 Moderate (nadir 50–99 × 109/L) n = 149 Severe (nadir <50 × 109/L) n = 27 
Baseline platelet count (109/L) 225.78 ± 63.35 165.42 ± 46.82 176.33 ± 57.43 <0.001 
Nadir platelet count (109/L) 145.73 ± 45.75 81.51 ± 12.68 36.00 ± 10.87 <0.001 
Decrease in platelet count (%) 35.2 ± 13.4 50.1 ± 14.4 78.4 ± 7.9 <0.001 
Days to platelet nadir, median 2 (1,3) 2 (2,3) 2 (2,3) 0.001 
Early acquired moderate/severe thrombocytopenia (%)a NA 133 (89.3%) 12 (44.4%) <0.001 
Discharge platelet count (109/L) 199.53 ± 73.00 159.19 ± 75.93 133.93 ± 113.52 <0.001 
Baseline haemoglobin (g/dL) 14.56 ± 58.15 11.42 ± 1.52 11.71 ± 1.89 0.78 
Nadir haemoglobin (g/dL) 9.00 ± 1.35 8.56 ± 1.48 7.37 ± 1.72 <0.001 
Baseline haematocrit (%) 34.60 ± 4.46 34.87 ± 4.47 36.27 ± 5.21 0.17 
Nadir haematocrit (%) 27.60 ± 3.97 26.01 ± 4.49 22.66 ± 5.13 <0.001 
Baseline leucocytes (109/L) 7.43 ± 2.47 6.96 ± 2.21 9.25 ± 10.77 0.006 
Peak leucocytes (109/L) 13.36 ± 6.06 13.41 ± 5.52 20.81 ± 17.13 <0.001 
Baseline creatinine (mg/dL) 1.17 ± 0.45 1.29 ± 0.65 1.47 ± 0.84 0.051 
Peak creatinine (mg/dL) 1.11 ± 0.48 1.34 ± 0.72 2.06 ± 1.76 <0.001 
  Acquired thrombocytopenia
 
P-value 
No/mild (nadir ≥100 × 109/L) n = 312 Moderate (nadir 50–99 × 109/L) n = 149 Severe (nadir <50 × 109/L) n = 27 
Baseline platelet count (109/L) 225.78 ± 63.35 165.42 ± 46.82 176.33 ± 57.43 <0.001 
Nadir platelet count (109/L) 145.73 ± 45.75 81.51 ± 12.68 36.00 ± 10.87 <0.001 
Decrease in platelet count (%) 35.2 ± 13.4 50.1 ± 14.4 78.4 ± 7.9 <0.001 
Days to platelet nadir, median 2 (1,3) 2 (2,3) 2 (2,3) 0.001 
Early acquired moderate/severe thrombocytopenia (%)a NA 133 (89.3%) 12 (44.4%) <0.001 
Discharge platelet count (109/L) 199.53 ± 73.00 159.19 ± 75.93 133.93 ± 113.52 <0.001 
Baseline haemoglobin (g/dL) 14.56 ± 58.15 11.42 ± 1.52 11.71 ± 1.89 0.78 
Nadir haemoglobin (g/dL) 9.00 ± 1.35 8.56 ± 1.48 7.37 ± 1.72 <0.001 
Baseline haematocrit (%) 34.60 ± 4.46 34.87 ± 4.47 36.27 ± 5.21 0.17 
Nadir haematocrit (%) 27.60 ± 3.97 26.01 ± 4.49 22.66 ± 5.13 <0.001 
Baseline leucocytes (109/L) 7.43 ± 2.47 6.96 ± 2.21 9.25 ± 10.77 0.006 
Peak leucocytes (109/L) 13.36 ± 6.06 13.41 ± 5.52 20.81 ± 17.13 <0.001 
Baseline creatinine (mg/dL) 1.17 ± 0.45 1.29 ± 0.65 1.47 ± 0.84 0.051 
Peak creatinine (mg/dL) 1.11 ± 0.48 1.34 ± 0.72 2.06 ± 1.76 <0.001 

NA, not applicable.

aTime to platelet count nadir ≤4 days.

Table 3

Clinical outcomes

  Acquired thrombocytopenia
 
P-value 
No/mild (nadir ≥100 × 109/L) n = 312 Moderate (nadir 50–99 × 109/L) n = 149 Severe (nadir <50 × 109/L) n = 27 
30 days 
 Death 11 (3.5%) 10 (6.7%) 13 (48.1%) <0.001 
 Cardiovascular death 8 (2.6%) 4 (2.7%) 7 (25.9%) <0.001 
 Device success 287 (94.7%) 139 (93.3%) 23 (85.2%) 0.14 
 Sepsis 18 (5.8%) 6 (4.0%) 9 (33.3%) <0.001 
 Major stroke 8 (2.6%) 4 (2.7%) 2 (8.0%) 0.24 
 Minor stroke/transient ischaemic attack 7 (2.3%) 3 (2.0%) 1.0 
 Major vascular complication 9 (3.4%) 26 (20.2%) 7 (30.4%) <0.001 
 Life threatening bleeding 8 (3.0%) 20 (15.7%) 9 (37.5%) <0.001 
 Major bleeding 26 (10.0%) 10 (8.8%) 3 (15.8%) 0.64 
 Significant anaemiaa 77 (24.7%) 49 (32.9%) 19 (70.4%) <0.001 
 Any blood transfusions 98 (31.8%) 72 (48.3%) 18 (69.2%) <0.001 
 Number of blood transfusions 0 (0,1) 0 (0,2) 2 (0.6) <0.001 
 Multiple blood transfusions 60 (19.2%) 57 (38.3%) 15 (55.6%) <0.001 
 Acute kidney injuryb 25 (9.9%) 15 (12.6%) 11 (55.0%) <0.001 
 Periprocedural myocardial infarction 1 (0.3%) 1 (0.7%) 1 (4.0%) 0.11 
 Pacemaker implantation 15 (4.9%) 9 (6.0%) 0.42 
 Post mean aortic valve gradient (mm Hg) 8.0 ± 4.9 7.7 ± 5.4 7.1 ± 6.2 0.76 
 Post perivalvular leak (≥+2) 49 (15.9%) 20 (13.4%) 5 (19.2%) 0.66 
 Intensive care unit stay (days) 1 (1,2) 2 (1,3) 4 (2.8) <0.001 
1 year 
 Death 50 (16.0%) 30 (20.1%) 18 (66.7%) <0.001 
 Cardiovascular death 34 (10.9%) 17 (11.4%) 8 (29.6%) 0.059 
 Major stroke 7 (3.2%) 5 (4.6%) 3 (13.0%) 0.086 
  Acquired thrombocytopenia
 
P-value 
No/mild (nadir ≥100 × 109/L) n = 312 Moderate (nadir 50–99 × 109/L) n = 149 Severe (nadir <50 × 109/L) n = 27 
30 days 
 Death 11 (3.5%) 10 (6.7%) 13 (48.1%) <0.001 
 Cardiovascular death 8 (2.6%) 4 (2.7%) 7 (25.9%) <0.001 
 Device success 287 (94.7%) 139 (93.3%) 23 (85.2%) 0.14 
 Sepsis 18 (5.8%) 6 (4.0%) 9 (33.3%) <0.001 
 Major stroke 8 (2.6%) 4 (2.7%) 2 (8.0%) 0.24 
 Minor stroke/transient ischaemic attack 7 (2.3%) 3 (2.0%) 1.0 
 Major vascular complication 9 (3.4%) 26 (20.2%) 7 (30.4%) <0.001 
 Life threatening bleeding 8 (3.0%) 20 (15.7%) 9 (37.5%) <0.001 
 Major bleeding 26 (10.0%) 10 (8.8%) 3 (15.8%) 0.64 
 Significant anaemiaa 77 (24.7%) 49 (32.9%) 19 (70.4%) <0.001 
 Any blood transfusions 98 (31.8%) 72 (48.3%) 18 (69.2%) <0.001 
 Number of blood transfusions 0 (0,1) 0 (0,2) 2 (0.6) <0.001 
 Multiple blood transfusions 60 (19.2%) 57 (38.3%) 15 (55.6%) <0.001 
 Acute kidney injuryb 25 (9.9%) 15 (12.6%) 11 (55.0%) <0.001 
 Periprocedural myocardial infarction 1 (0.3%) 1 (0.7%) 1 (4.0%) 0.11 
 Pacemaker implantation 15 (4.9%) 9 (6.0%) 0.42 
 Post mean aortic valve gradient (mm Hg) 8.0 ± 4.9 7.7 ± 5.4 7.1 ± 6.2 0.76 
 Post perivalvular leak (≥+2) 49 (15.9%) 20 (13.4%) 5 (19.2%) 0.66 
 Intensive care unit stay (days) 1 (1,2) 2 (1,3) 4 (2.8) <0.001 
1 year 
 Death 50 (16.0%) 30 (20.1%) 18 (66.7%) <0.001 
 Cardiovascular death 34 (10.9%) 17 (11.4%) 8 (29.6%) 0.059 
 Major stroke 7 (3.2%) 5 (4.6%) 3 (13.0%) 0.086 

aHaemoglobin <8 (g/dL).

bType II/I.

An estimation of 30-day mortality according to the nadir platelet count revealed an inflection for increased 30-day mortality at a nadir platelet count of 50–70 × 109/L (Figure 2). A decrease in nadir platelet count from 100 × 109 to 50 × 109 per L was associated with a 2.8× increase in 30-day death rate: 19.9% (CI 12.9–29.3%) vs. 7.1% (4.9–10.0%). Receiver operating characteristic curve analysis for predicting 30-day mortality using nadir platelet count showed good performance (C-statistic 0.76) (see Supplementary material online, Figure S1 and Appendix). A nadir platelet count of 88 × 109/L had the best combined results: 68% sensitivity and 78% specificity. A nadir platelet count below 50 was very specific (96.3%) and a nadir below 150 was very sensitive (91.2%) in predicting 30-day mortality.

Figure 2

Estimated probability of 30-day death according to the nadir platelet level. An inflection for having increased 30-day mortality is observed at nadir platelet count of 50–70 × 109/L. A decrease in platelet nadir count from 100 × 109 to 50 × 109/L was associated with a 2.8× higher death rate: 19.9% (CI 12.9–29.3%) vs. 7.1% (CI 4.9–10.0%).

Figure 2

Estimated probability of 30-day death according to the nadir platelet level. An inflection for having increased 30-day mortality is observed at nadir platelet count of 50–70 × 109/L. A decrease in platelet nadir count from 100 × 109 to 50 × 109/L was associated with a 2.8× higher death rate: 19.9% (CI 12.9–29.3%) vs. 7.1% (CI 4.9–10.0%).

One-year mortality rates were similar in patients with no/mild thrombocytopenia (16.0%, CI 12.7–21.4%) and in those with moderate thrombocytopenia (20.1%, CI 14.4–27.8%, P = 0.38) (Figure 3A), whereas patients with severe thrombocytopenia had higher rates of mortality (66.7%, CI 48.9–84.4%, P < 0.001). In addition, a landmark analysis showed that in patients who survived for 1 month after TAVR, those with severe thrombocytopenia had higher 1-year mortality rates than those with lower degrees of thrombocytopenia (Figure 3B). Median DPC level was 38.6% (IQR 29.6–50.0%). Patients with high DPC (≥50%) had lower survival rates than those with low DPC (<50, 65.8 vs. 83.9%, P< 0.001) (Figure 3C). Patients who developed moderate/severe thrombocytopenia with a longer time to nadir (≥4 days) had more sepsis events and higher acute kidney injury rates resulting in higher 30-day mortality rates when compared with those with early nadir (<4 days) (Figure 3D, Table 4). The cause of death was mainly cardiovascular in those with early nadir (76.9%) vs. non-cardiovascular (90%) in those with delayed nadir.

Table 4

Thirty-day clinical outcomes according to the time to platelet nadir counta

 Time to nadir ≤3 days (n = 145) Time to nadir ≥4 days (n = 31) P-value 
Death 13 (9.0%) 10 (32.3%) 0.002 
Cardiovascular death 10 (6.9%) 1 (3.2%) 0.40 
Sepsis 4 (2.8%) 11 (35.5%) <0.001 
Major stroke 4 (2.8%) 2 (6.7%) 0.28 
Major vascular complication 24 (19.0%) 9 (34.6%) 0.08 
Life threatening bleeding 20 (16.0%) 9 (34.6%) 0.051 
Multiple blood transfusions 55 (37.9%) 17 (54.8%) 0.08 
Acute kidney injuryb 11 (9.7%) 15 (57.7%) <0.001 
 Time to nadir ≤3 days (n = 145) Time to nadir ≥4 days (n = 31) P-value 
Death 13 (9.0%) 10 (32.3%) 0.002 
Cardiovascular death 10 (6.9%) 1 (3.2%) 0.40 
Sepsis 4 (2.8%) 11 (35.5%) <0.001 
Major stroke 4 (2.8%) 2 (6.7%) 0.28 
Major vascular complication 24 (19.0%) 9 (34.6%) 0.08 
Life threatening bleeding 20 (16.0%) 9 (34.6%) 0.051 
Multiple blood transfusions 55 (37.9%) 17 (54.8%) 0.08 
Acute kidney injuryb 11 (9.7%) 15 (57.7%) <0.001 

aIn patients with moderate or severe acquired thrombocytopenia (nadir platelet count <100 × 109/L).

bType II/III.

Figure 3

Kaplan–Meier 1-year survival curves. (A) Survival according to the severity of acquired thrombocytopenia after TAVR. There was no significant difference between patients with mild/no acquired thrombocytopenia and those with moderate thrombocytopenia (84.0 vs. 79.9%, P = 0.38). Patients with severe thrombocytopenia had the worst survival (33.3%, P< 0.001). (B) One-year survival with 1-month landmark analysis: comparison of 1-year survival of only patients who survived 1-month after the procedure. The survival of patients with severe thrombocytopenia remained worse than others (P = 0.039). (C) Stratification according to the level of decrease in platelet count (DPC) during hospitalization. DPC = (baseline count−nadir count)/baseline count. Patients with high DPC (≥50%) had worse survival than those with low DPC (<50, 83.9 vs. 65.8%, P < 0.001). (D) Stratification of patients with moderate/severe thrombocytopenia according to the time to nadir count. Patients with delayed nadir (time to nadir ≥4 days, black boxes) had worse 1-year survival than those with early nadir (<4 days, 78.5 vs. 41.3%, P < 0.001).

Figure 3

Kaplan–Meier 1-year survival curves. (A) Survival according to the severity of acquired thrombocytopenia after TAVR. There was no significant difference between patients with mild/no acquired thrombocytopenia and those with moderate thrombocytopenia (84.0 vs. 79.9%, P = 0.38). Patients with severe thrombocytopenia had the worst survival (33.3%, P< 0.001). (B) One-year survival with 1-month landmark analysis: comparison of 1-year survival of only patients who survived 1-month after the procedure. The survival of patients with severe thrombocytopenia remained worse than others (P = 0.039). (C) Stratification according to the level of decrease in platelet count (DPC) during hospitalization. DPC = (baseline count−nadir count)/baseline count. Patients with high DPC (≥50%) had worse survival than those with low DPC (<50, 83.9 vs. 65.8%, P < 0.001). (D) Stratification of patients with moderate/severe thrombocytopenia according to the time to nadir count. Patients with delayed nadir (time to nadir ≥4 days, black boxes) had worse 1-year survival than those with early nadir (<4 days, 78.5 vs. 41.3%, P < 0.001).

Predictors for severe thrombocytopenia are shown in Table 5. Table 6 includes univariable and multivariable logistic regression analysis results for 1-year mortality. Severe thrombocytopenia was a significant predictor for 1-year mortality (odds ratio 3.44, confidence interval 1.02–11.6, P = 0.046). Additional predictors were high STS score and acute kidney injury (stage II/III).

Table 5

Predictors for severe acquired thrombocytopenia in patients undergoing transcatheter aortic valve replacement

 Odds ratio P-value 
Baseline 
 Platelet count (109/L), per 10 unit decrease 0.91 (0.84–0.99) 0.02 
 Leucocyte count (109/L), per 1 unit increase 1.08 (1.00–1.16) 0.048 
 Creatinine level (mg/dL), per 1 unit increase 1.74 (0.90–3.36) 0.09 
Early post-procedure 
 Major vascular complication 4.50 (1.73–11.7) 0.002 
 Major/life threatening bleeding 5.13 (2.20–11.9) <0.001 
 Multiple blood transfusions 3.68 (1.67–8.08) 0.001 
Late post-procedure 
 Sepsis 9.10 (3.70–22.4) <0.001 
 Acute kidney injurya 10.1 (3.95–25.9) <0.001 
 Odds ratio P-value 
Baseline 
 Platelet count (109/L), per 10 unit decrease 0.91 (0.84–0.99) 0.02 
 Leucocyte count (109/L), per 1 unit increase 1.08 (1.00–1.16) 0.048 
 Creatinine level (mg/dL), per 1 unit increase 1.74 (0.90–3.36) 0.09 
Early post-procedure 
 Major vascular complication 4.50 (1.73–11.7) 0.002 
 Major/life threatening bleeding 5.13 (2.20–11.9) <0.001 
 Multiple blood transfusions 3.68 (1.67–8.08) 0.001 
Late post-procedure 
 Sepsis 9.10 (3.70–22.4) <0.001 
 Acute kidney injurya 10.1 (3.95–25.9) <0.001 

aType II/III.

Table 6

Predictors for 1-year all-cause mortality in patients undergoing transcatheter aortic valve replacement

 Odds ratio 95% Confidence interval P-value 
Univariable analysis 
 Age (years) 1.01 0.98–1.04 0.48 
 Men 1.28 0.82–1.99 0.28 
 Society of thoracic surgeons score (%) 1.05 1.00–1.11 0.045 
Baseline renal failurea 1.85 1.12–3.04 0.016 
 Chronic obstructive pulmonary disease 0.98 0.59–1.63 0.94 
 Peripheral vascular disease 1.06 0.63–1.79 0.82 
 Baseline left ventricular ejection fraction (%) 0.99 0.98–1.01 0.34 
 Baseline aortic valve area (cm20.97 0.17–5.48 0.97 
 Transapical access 0.73 0.46–1.16 0.18 
 Perivalvular leak (≥ +2) 1.75 0.99–3.07 0.052 
Major vascular complication 3.38 1.72–6.62 <0.001 
Major/life threatening bleeding 2.92 1.68–5.07 <0.001 
Major stroke 5.79 1.96–17.1 <0.001 
Sepsis 5.62 2.72–11.6 <0.001 
Acute kidney injuryb 5.63 3.02–10.5 <0.001 
Severe acquired thrombocytopeniac 9.52 4.13–22.0 <0.001 
Multivariable logistic regression 
Society of thoracic surgeons score (%) 1.07 1.00–1.14 0.046 
 Baseline renal failurea 1.42 0.74–2.75 0.29 
 Major vascular complication 1.90 0.63–5.79 0.26 
 Major/life threatening bleeding 1.35 0.61–2.98 0.46 
 Major stroke 4.82 0.57–40.9 0.15 
 Sepsis 4.31 0.81– 33.4 0.11 
Acute kidney injuryb 3.71 1.62–8.45 0.002 
Severe acquired thrombocytopeniac 3.44 1.02–11.6 0.046 
 Odds ratio 95% Confidence interval P-value 
Univariable analysis 
 Age (years) 1.01 0.98–1.04 0.48 
 Men 1.28 0.82–1.99 0.28 
 Society of thoracic surgeons score (%) 1.05 1.00–1.11 0.045 
Baseline renal failurea 1.85 1.12–3.04 0.016 
 Chronic obstructive pulmonary disease 0.98 0.59–1.63 0.94 
 Peripheral vascular disease 1.06 0.63–1.79 0.82 
 Baseline left ventricular ejection fraction (%) 0.99 0.98–1.01 0.34 
 Baseline aortic valve area (cm20.97 0.17–5.48 0.97 
 Transapical access 0.73 0.46–1.16 0.18 
 Perivalvular leak (≥ +2) 1.75 0.99–3.07 0.052 
Major vascular complication 3.38 1.72–6.62 <0.001 
Major/life threatening bleeding 2.92 1.68–5.07 <0.001 
Major stroke 5.79 1.96–17.1 <0.001 
Sepsis 5.62 2.72–11.6 <0.001 
Acute kidney injuryb 5.63 3.02–10.5 <0.001 
Severe acquired thrombocytopeniac 9.52 4.13–22.0 <0.001 
Multivariable logistic regression 
Society of thoracic surgeons score (%) 1.07 1.00–1.14 0.046 
 Baseline renal failurea 1.42 0.74–2.75 0.29 
 Major vascular complication 1.90 0.63–5.79 0.26 
 Major/life threatening bleeding 1.35 0.61–2.98 0.46 
 Major stroke 4.82 0.57–40.9 0.15 
 Sepsis 4.31 0.81– 33.4 0.11 
Acute kidney injuryb 3.71 1.62–8.45 0.002 
Severe acquired thrombocytopeniac 3.44 1.02–11.6 0.046 

aGolmerular filtration rate <60 cc/min.

bType II/III.

cPlatelet nadir <50 × 109/L.

P-value is Bold font is statistically significant (P < 0.05).

Discussion

The current study is the first, large, systematic evaluation of thrombocytopenia after TAVR. The main findings are: (i) transient thrombocytopenia was common after the procedure; >1/3 of patients undergoing TAVR had platelet nadir <100 × 109/L, which was mostly resolved at patient discharge; (ii) thrombocytopenia after TAVR was strongly associated with baseline- (e.g. low platelet count, leucocyte count), procedural-, and post-procedural adverse events but rarely with HIT; and (iii) severe thrombocytopenia (<50 × 109/L) after TAVR was a strong predictor for both early- and long-term mortality. Hence, significant thrombocytopenia after TAVR could be viewed as an excellent marker for worse clinical outcomes after the procedure.

Thrombocytopenia after transcatheter aortic valve replacement and other cardiovascular procedures

A recently published study found an average DPC of 34 ± 15% after TAVR, similar to the median DPC level in the current study of 38.6%.16 That study was underpowered to evaluate the significance of thrombocytopenia post-procedure since only three patients had developed severe thrombocytopenia post-TAVR. The incidences of significant thrombocytopenia post-TAVR seen in the current study, 30.5% moderate and 5.5% severe, are higher than would be expected after most other percutaneous cardiovascular procedures but are similar to those seen after cardiac surgery.10,11,17,18 Cardiac surgery using cardiopulmonary bypass commonly results in a 30–60% fall in platelet count, mainly secondary to haemodilution, platelet consumption, and blood loss. The rate of thrombocytopenia after PCI, reported in large clinical studies, is lower (0.7–13.0%).19–23 After percutaneous closure of congenital heart defects, moderate/severe thrombocytopenia (nadir <100 × 109/L) occurred in 11.7%.13

Aetiologies for early vs. late acquired thrombocytopenia after transcatheter aortic valve replacement

Thrombocytopenia occurring early after TAVR (<4 days) is directly related to procedural/early post-procedural adverse events, such as vascular complication, bleeding, and multiple blood transfusions. The physiological reaction to thrombocytopenia is an increase in bone marrow production of platelets.24 In contrast, a delayed nadir in platelet count (≥4 days) is not directly related to procedural adverse events but rather related to the presence of several co-morbidities such as renal failure,8,25,26 sepsis, or disseminated intravascular coagulation.27 Our study results are in agreement with these previous studies, and show an association between delayed thrombocytopenia post TAVR, acute kidney injury, and sepsis. Patients with delayed time to nadir had lower survival rates than those with early nadir, mostly secondary to non-cardiovascular death events. Interestingly, severe thrombocytopenia was associated with both baseline leucocytosis and post-procedural sepsis. Hypothetically, patients with latent infectious disease before the procedure, manifested only by leucocytosis, might suffer from sepsis and significant thrombocytopenia after TAVR.

Severe thrombocytopenia: a marker for poor prognosis after transcatheter aortic valve replacement

The degree of platelet nadir after TAVR proved to be a significant correlate for early and late survival. The group with moderate thrombocytopenia (nadir 50–99 × 109/L) had similar survival when compared with those with no/mild thrombocytopenia (nadir >100 × 109/L). In contrast, patients with severe thrombocytopenia (<50 × 109/L) had poor outcomes after the procedure; close to half died within 30 days, and even in those who survived, long-term survival was worse. Severe thrombocytopenia can directly affect patient outcomes through an increase in bleeding events. In the current study, however, the effect of thrombocytopenia on survival was not exclusively related to bleeding. Additionally, bleeding events most commonly occur with very low platelet counts (<20 × 109/L),28 much lower than the cut-off for increased mortality found in the current study (50–70 × 109/L). Alternatively, platelet blood level, rapidly metabolized and consumed during different adverse events, such as vascular complications, bleeding events, and sepsis, can be a very sensitive marker for general clinical state. In addition, since red blood cells are transfused more commonly than platelets, the effect of the decrease in blood cells and the association with patient outcome may be blunted.

Thrombocytopenia after TAVR may be a marker of severe physiological stress and poor prognosis. Rather than being directly implicated in the causal pathway to death, platelet count could be viewed as a ‘final common pathway’ of several death correlates, being an easily obtainable lab result with high predictability, similar to the way in which systemic inflammatory response after TAVR is strongly associated with outcome.29

Clinical implications

In patients being evaluated for TAVR, factors closely related to the occurrence of thrombocytopenia can be identified so that a DPC after TAVR can be anticipated and managed appropriately. Before the procedure, low platelet count and high leucocyte count can be recognized and an attempt to normalize these results may be made in selective cases. Specifically, patients with baseline leucocytosis without a clear aetiology, such as corticosteroid therapy, could be evaluated for latent infectious disease. Study results revalidate the fact that, in TAVR practice, the importance of aiming for a reduction in major vascular complications and bleeding events should not be underestimated.4

After TAVR, platelet counts should be routinely evaluated and nadir count may be used as a marker for patient outcome. Since a nadir <150 × 109/L was very sensitive (91.2%) and a nadir <50 × 109/L very specific (96.3%) in predicting 30-day mortality, a patient without thrombocytopenia after TAVR (platelet count remains >150) will probably have a good outcome, while a patient who reaches severe thrombocytopenia (<50) will most likely die during the post-procedural period. Data gained from platelet counts may be helpful in managing patient and family expectations. Patients with mild–moderate thrombocytopenia after TAVR should be meticulously evaluated and their lab results carefully monitored. Nevertheless, patients who keep their platelet count above 70 × 109/L have good prognosis with common resolution of their platelet count at discharge, and therefore no change in their treatment should be made. Evaluation for HIT should be made according to the recommendations, although the probability of having the full clinical phenomenon (not only elevations of non-specific immunoassay lab results) was low (<1%). Since HIT typically manifests at least 5 days after exposure, suspicion of this severe complication should be higher in cases with delayed thrombocytopenia.14

Limitations

The rate of thrombocytopenia after TAVR reflects the practice of valve implantations in our medical centres starting from the beginning of our learning curve while using early technology. It could be suggested that the degree of thrombocytopenia found in the current study will not reflect TAVR practice in other centres. However, a reduction in adverse events, and presumably in thrombocytopenia after TAVR, may not change the association found between the degree of thrombocytopenia, when it occurs, and clinical outcome.

Since severe thrombocytopenia is not common (5.5%), the study was not powered to fully compare patients' baseline characteristics according to the degree of acquired thrombocytopenia post-TAVR. In addition, previous studies have revealed an association between increased inflammatory markers after TAVR and worse outcome.29 In the current study, leucocyte count was increased in patients who developed significant thrombocytopenia; however, a systematic analysis of more specific markers for inflammation was not made.

Heparin-induced thrombocytopenia was evaluated according to guidelines30 and at the discretion of the treating physician in patients who developed significant thrombocytopenia (nadir <100 × 109/L) or a DPC ≥ 50%. This group comprised 36.1% of the population studied. It is important to interpret the test in the appropriate clinical context since HIT antibodies are detectable by enzyme immunoassays in ∼50% of patients 1 week after cardiac surgery and in these situations diagnostic specificity is low.31

Conclusion

Thrombocytopenia was common after TAVR, occurring in more than one-third of patients at a significant degree (nadir <100 × 109/L), mostly within the first three post-operative days. Nadir platelet count <50 × 109/L was highly specific, and <150 × 109/L highly sensitive, for predicting 30-day mortality. In multivariate logistic regression, severe thrombocytopenia was a strong and significant correlate for both early- and long-term mortality. Low platelet count after the procedure is an excellent, easily obtainable marker for patient outcome after TAVR.

Supplementary material

Supplementary material is available at European Heart Journal online.

Conflict of interest: R.W. disclosures are as follows: Speaker's Bureau: Boston Scientific (>$10,000); Medtronic (>$10,000); AstraZeneca (>$10,000); Biotronik (>$10,000); Abbott Vascular (<$10,000). Non-Royalty Payments: Biotronik (>$10,000). Research Grants: Boston Scientific (>$10,000); Medtronic (>$10,000); Volcano (>$10,000); Lilly Daiichi Sankyo (>$10,000); AstraZeneca (>$10,000); Abbott Vascular (<$10,000). Consultant Fees: Biotronik (>$10,000); Boston Scientific (>$10,000); Abbott Vascular (<$10,000); Volcano (<$10,000).

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Author notes

First two authors contributed equally to this work.

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