Abstract
Background:
Preoperative thrombocytopenia is associated with inferior outcomes in surgical patients, though concurrent anemia may obfuscate these relationships. This investigation assesses the prevalence and clinical significance of preoperative thrombocytopenia with thorough consideration of preoperative anemia status.
Methods:
This is an observational cohort study of adults undergoing elective surgery with planned postoperative hospitalization from 01/01/2009 to 05/03/2018. Patients were designated into 4 groups: normal platelet and hemoglobin concentrations, isolated thrombocytopenia (i.e. platelet count <100 × 109/L), isolated anemia (i.e. hemoglobin <12 g/dL females, <13.5 g/dL males), and thrombocytopenia with anemia. Thrombocytopenia was further defined as incidental (i.e. previously undiagnosed) or non-incidental. Multivariable regression analyses were utilized to assess the relationships between thrombocytopenia status and clinical outcomes, with a primary outcome of hospital length of stay.
Results:
120,348 patients were included for analysis: 72.3% (95% CI: 72.1%, 72.6%) normal preoperative laboratory values, 26.3% (26.1%, 26.6%) isolated anemia, 0.80% (0.75%, 0.86%) thrombocytopenia with anemia, and 0.52% (0.48%, 0.56%) isolated thrombocytopenia (0.38% [0.34%, 0.41%] non-incidental, 0.14% [0.12%, 0.17%] incidental). Thrombocytopenia was associated with longer hospital length of stay in those with concurrent anemia (multiplicative increase of the geometric mean 1.05 [1.00, 1.09] days; p=0.034) but not in those with normal preoperative hemoglobin concentrations (multiplicative increase of the geometric mean 1.02 [0.96, 1.07] days; p=0.559). Thrombocytopenia was associated with increased odds for intraoperative transfusion regardless of anemia status (non-anemic: 3.39 [2.79, 4.12]; p<0.001 vs. anemic: 2.60 [2.24, 3.01]; p<0.001). Thrombocytopenia was associated with increased rates of ICU admission in non-anemic patients (1.56 [1.18, 2.05]; p=0.002) but not in those with preoperative anemia (0.93 [0.73, 1.19]; p=0.578).
Conclusion:
Preoperative thrombocytopenia is associated with clinical outcomes in elective surgery, both in the presence and absence of concurrent anemia. However, isolated thrombocytopenia is rare (0.5%) and is usually identified prior to preoperative testing. It is unlikely that routine thrombocytopenia screening is indicated for most patients.
INTRODUCTION:
Preoperative thrombocytopenia is associated with inferior outcomes in non-cardiac surgery, including a nearly 2-fold increase in the odds for perioperative red cell transfusion with platelet counts <100 × 109/L 1–3. Thrombocytopenia has also been associated with increased odds for perioperative sepsis, postoperative pulmonary, renal, and thromboembolic complications, and mortality 1–3. However, prophylactic platelet transfusion strategies have not been associated with improved clinical outcomes 2,4. Furthermore, practice guidelines from the American Society of Anesthesiologists state that platelet transfusions are rarely indicated with platelet counts >100 × 109/L but are usually indicated with platelet counts <50 × 109/L in the presence of microvascular bleeding,5 though evidence to support this recommendation is lacking.
Despite the potential clinical significance of thrombocytopenia in surgical patients, there are substantial knowledge gaps. First, thrombocytopenia often occurs concurrently with anemia and is considered to be an indicator of the severity of underlying illness 6,7. The prevalence and clinical importance of isolated preoperative thrombocytopenia (i.e. occurring in the absence of anemia) remain incompletely described. Presumably, patients with isolated thrombocytopenia may experience distinct clinical outcomes from those with combined thrombocytopenia and anemia. Second, thrombocytopenia is often detected through routine preoperative complete blood count (CBC) testing. While the utility of routine CBC testing prior to surgery has been questioned for many years 8–10, it remains highly utilized in contemporary surgical practice. By defining the probability of detecting incidental (i.e. previously unknown) thrombocytopenia (with and without anemia) through routine preoperative testing, we can potentially tailor preoperative testing to those patients predicted to be at highest risk for thrombocytopenia. Conversely, low risk patients may avoid routine preoperative CBC testing or undergo isolated hemoglobin assessment, which may be performed using either low-volume phlebotomy techniques or with non-invasive modalities (e.g. continuous SpHb® technology). Reserving preoperative platelet count testing for those deemed to be at highest risk for clinically-significant platelet abnormalities may reduce iatrogenic blood loss, minimize patient discomfort, and reduce overall costs of care.
The goal of this investigation is to describe the prevalence of thrombocytopenia in a diverse cohort of patients presenting for elective surgery, with novel emphasis on isolated incidental thrombocytopenia, defined by thrombocytopenia occurring in the absence of anemia and without a known diagnosis prior to preoperative testing. Additionally, we assess differences in clinical outcomes based upon the presence and severity of preoperative thrombocytopenia, with or without concomitant anemia. Finally, we provide novel assessment of the interplay between continuous preoperative hemoglobin concentrations, platelet counts, and perioperative clinical outcomes.
METHODS:
This is a historical observational cohort study approved by the local Institutional Review Board (IRB). All participants had previously granted permission to use their medical records for research (consistent with Minnesota Statute 144.295); thus, the requirement for written informed consent was waived by the IRB. The study was designed and conducted in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology guidelines 11.
The study cohort included all adult patients (age ≥18 years) with scheduled hospital admission following elective surgery performed from 01/01/2009 to 05/03/2018 and with a CBC available (including both hemoglobin and platelet count) as part of routine preoperative screening within 30 days of surgery. Surgeries were performed in the main operating room theaters of 2 hospital campuses at a large tertiary care medical center and were performed under general anesthesia, monitored anesthetic care (MAC), and regional anesthesia techniques. Patients were excluded for the following reasons: surgery performed in outfield locations (i.e. outside of the main operating room theater) or procedures performed under local anesthesia or nurse-administered sedation, absent preoperative CBC testing, outpatient surgery (i.e. hospital length of stay <24 hours), absent research authorization, emergency surgery, American Society of Anesthesiology Physical Status (ASA PS) class 6, and admission to the hospital prior to surgery, given that these patients often have inherent medical and/or surgical complexity that may influence clinical outcomes and the prevalence of anemia and/or thrombocytopenia.
The primary exposure variable of interest was the presence of thrombocytopenia, which was identified utilizing the preoperative platelet count (i.e. the platelet count value obtained closest to the time of surgery and no more than 30 days prior to this event). For our primary analyses, thrombocytopenia was defined as a platelet count <100 × 109/L, recognizing that platelet counts >100 × 109/L are rarely considered clinically actionable in surgical patients. Hemoglobin values from the same preoperative CBC sample were extracted to determine the incidence of isolated thrombocytopenia (i.e. without concurrent anemia, defined by hemoglobin ≥12 g/dL in females, ≥13.5 g/dL in males) versus thrombocytopenia occurring in the presence of anemia. Validated electronic search queries followed by manual chart review verification (LJM, KE) were utilized for all patients with preoperative thrombocytopenia to discern a previous laboratory or clinical diagnosis (i.e. utilizing International Classification of Disease (ICD)-9 code 287.5 and ICD-10 code D69.6) of thrombocytopenia within 5 years of the preoperative CBC. When a previous diagnosis was present, thrombocytopenia was considered non-incidental. Conversely, incidental was utilized to describe thrombocytopenia without a previous diagnosis. Patients were categorized into 4 groups: normal hemoglobin and platelet count, isolated thrombocytopenia, isolated anemia, and combined thrombocytopenia and anemia.
Additional exposure variables of interest included demographic information (age, sex), clinical features (comorbid medical diagnoses, Charlson score, preoperative antiplatelet or anticoagulant therapy), and surgical characteristics (type of anesthetic, ASA PS score, surgery type). Eligible patients were identified using an existing electronic health record (EHR)-based datamart, the Acute Care datamart 12. This validated datamart provides a near real-time feed of the electronic medical record and facilitates the rapid extraction of exposure and outcome data in surgical patients.
Clinical outcomes of interest included: hospital length of stay (primary outcome) and secondary outcomes of intraoperative transfusion (i.e. allogeneic red blood cells (RBCs), plasma, platelets, cryoprecipitate, and cell salvaged blood), postoperative intensive care unit (ICU) admission rates, and reoperation with 72 hours. In-hospital mortality was also assessed for each group, but given limited events, between-group comparisons were not assessed.
Statistical Analyses:
Thrombocytopenia and anemia status are summarized overall as well as according to procedure type and sex as number (percentage). Prevalence of thrombocytopenia and anemia groups are described along with Clopper-Pearson confidence intervals (CI) for the estimated prevalence. Hospital and transfusion outcomes are summarized according to thrombocytopenia and anemia status as number (percentage) for categorical outcomes and median (25th percentile, 75th percentile) for continuous outcomes. To assess the association between outcomes and thrombocytopenia, multivariable linear and logistic regression models were fit as appropriate to estimate the effects of thrombocytopenia, anemia, and the thrombocytopenia by anemia interaction. Estimated effects are reported with 95% confidence limits according to anemia status. P-values assessing the significance of the interaction term as well as the effects of thrombocytopenia within each anemia group are presented. In addition, to assess the relationships between incidental and non-incidental thrombocytopenia separately in both anemic and non-anemic patients, a model with the 3-level (none, incidental, non-incidental) categorical variable for thrombocytopenia, anemia, and interaction between anemia and the 3-level thrombocytopenia variable was fit. Estimates with 95% confidence intervals are reported for both incidental and non-incidental thrombocytopenia in both anemic and non-anemic patients. All models were adjusted for features selected a priori that could influence the relationships between thrombocytopenia and/or anemia status and clinical outcomes, including: demographics (age, sex), comorbid illness (ASA physical status, history of cancer, lymphoma, leukemia, chronic liver disease, chronic kidney disease, myocardial infarction, heart failure, and stroke), surgical features (surgery type, anesthesia type), and medication use (preoperative antiplatelet therapy [i.e. aspirin, clopidogrel within 7 days of surgery] and preoperative anticoagulant use [i.e. warfarin within 5 days of surgery, low-molecular weight heparin within 24 hours of surgery, direct oral anticoagulants within 3 days of surgery]). To account for skewed residuals, hospital length of stay was analyzed using a log transformation, with estimates and corresponding 95% confidence intervals exponentiated to reflect the estimated multiplicative increase of the geometric mean.
Lastly, a continuous analysis was performed to identify platelet count and hemoglobin concentrations associated with the greatest risk for intraoperative transfusion. In the continuous analysis, flexible functional forms for hemoglobin and platelet count were considered using restricted cubic splines with knots at the 5th, 50th, and 95th percentiles to allow for non-linear relationships with outcomes. The model included spline terms for both hemoglobin and platelet count, all the pairwise interactions between hemoglobin and platelet count restricted cubic spline terms (a tensor restricted cubic spline), and the interactions between sex and the terms for hemoglobin. Results of the tensor spline are reported as adjusted estimates of the multiplicative increase of geometric mean or odds ratios as described for endpoints above, relative to a reference level of 13 g/dL hemoglobin and 150 × 109/L platelet count. Missing data were rare, with 1% missing ASA PS and <1% missing anesthesia type; a missing level was defined missing values of these categorical adjustment variables. All analyses were conducted using SAS software, version 9.4 (SAS Institute Inc., Cary, NC, USA). P <0.05 were considered statistically significant.
RESULTS:
442,945 adult patients presented for elective surgery with postoperative hospital admission during the study period, of which 288,304 patients underwent surgery performed in the main operating room environment; 61% of these patients had preoperative CBC testing available within 30 day of surgery (Figure 1). A total of 120,348 patients were included for analysis, of which 52% were male and with a mean (standard deviation) age of 61.8 years (14.8; Table 1). 72.3% (95% CI: 72.1%, 72.6%) of patients had normal platelet counts and hemoglobin levels prior to surgery, followed by 26.3% (26.1%, 26.6%) with isolated anemia, 0.80% (0.75%, 0.86%) with combined anemia and thrombocytopenia (0.54% [0.50%, 0.58%] non-incidental, 0.26% [0.24%, 0.29%] incidental), and 0.52% (0.48%, 0.56%) with isolated thrombocytopenia (0.38% [0.34%, 0.41%] non-incidental, 0.14% [0.12%, 0.17%] incidental). The distribution of platelet counts for our patient cohort is displayed in a histogram plot (Supplemental Figure). Most patients received general anesthesia (87%) followed by regional anesthesia (11%), with the lowest rates of regional anesthesia use observed in those with thrombocytopenia (range 2–4%). Patients with thrombocytopenia and/or anemia were more likely to be male than female (70% for combined anemia and thrombocytopenia) when compared to those without hemoglobin or platelet abnormalities (49%). Additionally, patients with combined thrombocytopenia and anemia had the highest ASA PS (75% ASA 3–4) and Charlson scores (median 6 [4, 9]). Patients with non-incidental and incidental isolated thrombocytopenia were generally similar with the exception of a higher rate of solid-organ malignancy (36% vs. 27%), a lower rate of liver disease (19% vs. 26%), and higher platelet counts (90 [80, 95] vs. 78 [62, 90]) in those with incidental compared to non-incidental disease.
Figure 1:
Flow diagram of study population. CBC = complete blood count
Table 1 -.
Patient and procedural characteristics according to hemoglobin and platelet status (N=120,348)*
| Isolated thrombocytopenia |
|||||
|---|---|---|---|---|---|
| Normal (n=87,046) | Isolated anemia (n=31,709) | Non-incidental (n=454) | Incidental (n=171) | Thrombocytopenia and anemia (n=968) | |
| Patient and procedural characteristics | |||||
| Age (years) | 61 (51, 70) | 65 (53, 74) | 63 (51, 71) | 62 (52, 71) | 64 (54, 73) |
| Sex | |||||
| Male | 42,490 (49%) | 18,419 (58%) | 264 (58%) | 111 (65%) | 680 (70%) |
| Female | 44,556 (51%) | 13,290 (42%) | 190 (42%) | 60 (35%) | 288 (30%) |
| ASA PS (n=118,872) | |||||
| 1–2 | 51,582 (60%) | 12,654 (40%) | 143 (32%) | 58 (34%) | 231 (24%) |
| 3–4† | 34,463 (40%) | 18,599 (60%) | 307 (68%) | 112 (66%) | 723 (76%) |
| Procedure type | |||||
| Orthopedic | 27,943 (32%) | 7,814 (25%) | 94 (21%) | 36 (21%) | 165 (17%) |
| General | 16,601 (19%) | 8,866 (28%) | 134 (30%) | 57 (33%) | 359 (37%) |
| Cardiac | 8,987 (10%) | 2,989 (9%) | 68 (15%) | 21 (12%) | 91 (9%) |
| Vascular | 1,596 (2%) | 976 (3%) | 10 (2%) | 3 (2%) | 38 (4%) |
| Transplant | 1,430 (2%) | 1,092 (3%) | 13 (3%) | 1 (1%) | 70 (7%) |
| Other procedure type | 30,489 (35%) | 9,972 (31%) | 135 (30%) | 53 (31%) | 245 (25%) |
| Type of anesthetic | |||||
| General | 74,750 (86%) | 27,976 (88%) | 418 (92%) | 161 (94%) | 881 (91%) |
| Regional | 10,736 (12%) | 2,752 (9%) | 19 (4%) | 4 (2%) | 28 (3%) |
| Monitored anesthesia care | 1,073 (1%) | 692 (2%) | 7 (2%) | 6 (4%) | 51 (5%) |
| Comorbidities | |||||
| Charlson score | 4 (2, 5) | 5 (3, 7) | 5 (3, 7) | 5 (3, 7) | 6 (4, 9) |
| Cancer | 24,704 (28%) | 11,841 (37%) | 124 (27%) | 61 (36%) | 366 (38%) |
| Renal disease | 3,137 (4%) | 4,822 (15%) | 40 (9%) | 8 (5%) | 176 (18%) |
| Cerebrovascular accident | 3,024 (3%) | 1,998 (6%) | 28 (6%) | 4 (2%) | 53 (5%) |
| Myocardial infarction | 2,829 (3%) | 2,146 (7%) | 28 (6%) | 10 (6%) | 71 (7%) |
| Chronic heart failure | 2,137 (2%) | 1,722 (5%) | 23 (5%) | 6 (4%) | 61 (6%) |
| Lymphoma | 1,297 (1%) | 1,086 (3%) | 36 (8%) | 7 (4%) | 157 (16%) |
| Liver disease | 812 (1%) | 699 (2%) | 116 (26%) | 33 (19%) | 234 (24%) |
| Leukemia | 441 (1%) | 372 (1%) | 24 (5%) | 9 (5%) | 93 (10%) |
| Pre-operative laboratory values and medications | |||||
| Hemoglobin (g/dL) | 14.1 (13.4, 14.9) | 11.6 (10.7, 12.5) | 14.0 (13.2, 14.7) | 14.3 (13.5, 15.0) | 11.0 (9.9, 12.1) |
| Platelet count (×109 per μL) | 231 (194, 274) | 239 (190, 305) | 78 (62, 90) | 90 (80, 95) | 77 (59, 90) |
| Creatinine (mg/dL; n=101,340) | 0.9 (0.8, 1.1) | 1.0 (0.8, 1.2) | 0.9 (0.8, 1.1) | 0.9 (0.8, 1.1) | 1.0 (0.8, 1.3) |
| INR (n=35,659) | 1.0 (1.0, 1.1) | 1.1 (1.0, 1.2) | 1.1 (1.0, 1.3) | 1.1 (1.0, 1.3) | 1.1 (1.1, 1.3) |
| Anti-platelets‡ | 46,897 (54%) | 16,264 (51%) | 169 (37%) | 74 (43%) | 358 (37%) |
| Anticoagulants¥ | 12,514 (14%) | 6,811 (21%) | 88 (19%) | 31 (18%) | 211 (22%) |
Values are number (percentage) for categorical variables and median (25th percentile, 75th percentile) for continuous variables. When not all data are available, numbers with complete data are presented. Anesthetic type missing for 1% (1,452).
Twenty-four patients were classified as ASA PS 5 or 6.
Includes aspirin and clopidogrel
Includes warfarin, unfractionated and low molecular weight heparin, factor Xa inhibitors, direct thrombin inhibitors,
Abbreviations: ASA PS = American society of anesthesiologists physical status; INR = International normalized ratio
Hospital length of stay was greatest in the combined thrombocytopenia and anemia group (4 [2, 7] days; Supplemental Table). Lengths of stay were similar for isolated anemia (4 [2, 6] days) and isolated incidental (3 [2, 6] days) and non-incidental thrombocytopenia (3 [2, 5] days), with the shortest length of stay in those with normal hemoglobin and platelet count (3 [2, 4] days). Similarly, reoperation (5%) and intraoperative transfusion (54%) rates were highest for patients with combined thrombocytopenia and anemia. Patients without anemia or thrombocytopenia were least likely to require intraoperative transfusion (19%), followed by incidental isolated thrombocytopenia (33%), isolated anemia (34%), and non-incidental isolated thrombocytopenia (43%). Patients without anemia or thrombocytopenia had the lowest rates of ICU admission (5%), followed by isolated anemia (7%), combined anemia and thrombocytopenia (8%), and both incidental and non-incidental isolated thrombocytopenia (10%). Mortality was low, ranging from 0.2% to 1.3% across groups, with the highest rate observed in those with combined thrombocytopenia and anemia (1.3%).
In adjusted analyses (Table 2), preoperative anemia had significant interactions on the relationships between thrombocytopenia and clinical outcomes of intraoperative transfusion (p=0.029), and ICU admission (p=0.006) but not reoperation (p=0.269). In those with normal preoperative hemoglobin concentrations, there was no association between thrombocytopenia and the primary outcome of hospital length of stay (multiplicative increase of the geometric mean 1.02 [0.96, 1.07]; p=0.559). In patients with preoperative anemia, thrombocytopenia was associated with increased hospital length of stay (1.05 [1.00, 1.09] multiplicative increase of the geometric mean; p=0.034). However, the interaction between thrombocytopenia and anemia for length of stay outcomes was not statistically significant (p=0.37) suggesting insufficient evidence to conclude the relationship differs by anemia status. Thrombocytopenia was associated with increased odds for intraoperative transfusion regardless of anemia status, though this association was more robust in non-anemic (3.39 [2.79, 4.12]; p<0.001) than anemic patients (2.60 [2.24, 3.01]; p<0.001). Thrombocytopenia was associated with increased rates of ICU admission in non-anemic patients (1.56 [1.18, 2.05]; p=0.002) but not in those with preoperative anemia (0.93 [0.73, 1.19]; p=0.578). Thrombocytopenia was not associated with reoperation irrespective of preoperative anemia status.
Table 2 –
Associations between thrombocytopenia and outcomes in anemic and non-anemic patients*
| Effect of ITCP in non-anemic patients |
Effect of TCP in anemic patients |
||||
|---|---|---|---|---|---|
| Interaction P | Estimate (95% CI) | P | Estimate (95% CI) | P | |
| Hospital length of stay† | 0.365 | 1.02 (0.96, 1.07) | 0.559 | 1.05 (1.00, 1.09) | 0.034 |
| Perioperative transfusion‡ | 0.029 | 3.39 (2.79, 4.12) | <.001 | 2.60 (2.24, 3.01) | <.001 |
| Re-operation within 72 hours‡ | 0.269 | 0.90 (0.52, 1.54) | 0.698 | 1.27 (0.92, 1.75) | 0.139 |
| ICU admission within 24 hours‡ | 0.006 | 1.56 (1.18, 2.05) | 0.002 | 0.93 (0.73, 1.19) | 0.578 |
Results are from multivariable linear or logistic regression adjusting for age, sex, ASA physical status, procedure type, anesthesia type, history of cancer, lymphoma, leukemia, liver disease, renal disease, MI, CHF, stroke, pre-operative antiplatelet therapy, and pre-operative anticoagulant. The interaction p-value tests for equality in effect of TCP between anemic and non-anemic patients.
Hospital length of stay is modelled on the log scale and estimates are for the multiplicative increase of the geometric mean associated with TCP in the given patient population.
Estimates are odds ratios and represent the increased risk of the given outcome associated with TCP in the given patient population.
Comparison of outcomes for incidental and non-incidental thrombocytopenia are summarized in Table 3. In non-anemic patients, thrombocytopenia had differential associations with hospital length of stay (p=0.042) and intraoperative transfusion (p=0.048) based upon whether it was incidental or non-incidental. Incidental isolated thrombocytopenia was associated with longer hospital length of stay (1.11 [1.00, 1.22] multiplicative increase of the geometric mean; p=0.042), while non-incidental isolated thrombocytopenia was not associated with length of stay (0.98 [0.92, 1.05]; p=0.583). Both incidental and non-incidental isolated thrombocytopenia were associated with increased odds for intraoperative transfusion, though this relationship was strongest in those with non-incidental (3.83 [3.06, 4.79]; p<0.001) rather than incidental thrombocytopenia (2.44 [1.66, 3.6]; p<0.001). Only non-incidental thrombocytopenia was associated with postoperative ICU admission (1.53 [1.11, 2.11]; p=0.009) in non-anemic patients. Similarly, in anemic patients, a differential relationship existed between thrombocytopenia and intraoperative transfusion (p<0.001) such that non-incidental thrombocytopenia (3.18 [2.66, 3.8]; p<0.001) was associated with a greater increase in the odds for transfusion than incidental thrombocytopenia (1.73 [1.34, 2.22]; p<0.001). While there was not a significant interaction between incidental or non-incidental thrombocytopenia and hospital length of stay or ICU admission in anemic patients, only non-incidental thrombocytopenia was significantly associated with longer hospital length of stay in this group (multiplicative increase of the geometric mean 1.07 [1.02, 1.13]; p=0.010).
Table 3 –
Comparison of incidental and non-incidental thrombocytopenia according to patient anemia status*
| Incidental TCP |
Non-incidental TCP |
||||
|---|---|---|---|---|---|
| Interaction P | Estimate (95% CI) | P | Estimate (95% CI) | P | |
| Hospital length of stay† | |||||
| Non-anemic patients | 0.042 | 1.11 (1.00, 1.22) | 0.042 | 0.98 (0.92, 1.05) | 0.583 |
| Anemic patients | 0.145 | 1.00 (0.93, 1.08) | 0.949 | 1.07 (1.02, 1.13) | 0.010 |
| Perioperative transfusion‡ | |||||
| Non-anemic patients | 0.048 | 2.44 (1.66, 3.60) | <.001 | 3.83 (3.06, 4.79) | <.001 |
| Anemic patients | <.001 | 1.73 (1.34, 2.22) | <.001 | 3.18 (2.66, 3.80) | <.001 |
| Re-operation within 72 hours ‡ | |||||
| Non-anemic patients | 0.130 | 0.24 (0.03, 1.69) | 0.151 | 1.15 (0.65, 2.01) | 0.633 |
| Anemic patients | 0.636 | 1.41 (0.83, 2.41) | 0.201 | 1.21 (0.82, 1.78) | 0.328 |
| ICU admission within 24 hours‡ | |||||
| Non-anemic patients | 0.862 | 1.62 (0.97, 2.69) | 0.065 | 1.53 (1.11, 2.11) | 0.009 |
| Anemic patients | 0.876 | 0.91 (0.59, 1.40) | 0.658 | 0.94 (0.71, 1.27) | 0.702 |
Results are from multivariable linear or logistic regression adjusting for age, sex, ASA physical status, procedure type, anesthesia type, history of cancer, lymphoma, leukemia, liver disease, renal disease, MI, CHF, stroke, pre-operative antiplatelet therapy, and pre-operative anticoagulant. The interaction p-value tests for equality in effect of incidental and non-incidental TCP in the given patient population.
Hospital length of stay is modelled on the log scale and estimates are for the multiplicative increase in geometric mean associated with TCP in the given patient population.
Estimates are odds ratios for categorical variables and represent the increased risk of the given outcome associated with TCP in the given patient population.
Analysis of the relationships between preoperative platelet count values and hemoglobin concentrations with the odds for intraoperative transfusion are displayed in a heat map (Figure 2) and at representative hemoglobin and platelet count combinations (Table 4). The odds for transfusion are influenced by both hemoglobin and platelet count values, though hemoglobin is the primary driver. For any given platelet count, the odds for transfusion consistently increase with incremental decreases in hemoglobin concentrations. For any given hemoglobin concentration, the odds for transfusion increase consistently, particularly when the platelet count is less than 200 × 109/L.
Figure 2:
Heat map of association between platelet count and hemoglobin concentration with odds for intraoperative transfusion, estimated using a tensor restricted cubic spline and logistic regression. The reference value point is 13 g/dL hemoglobin and 150 × 109/L platelet count. Blue color indicates a lower odds ratio for transfusion, while red color indicates a higher odds ratio for transfusion.
Table 4 -.
Increased odds of perioperative transfusion associated with the given values of hemoglobin and platelets
| Platelet count (per μL) |
|||||
|---|---|---|---|---|---|
| 50×109 | 100×109 | 150×109 | 300×109 | 400×109 | |
| Females | |||||
| Hemoglobin = 8 g/dL | 18.71 (13.95, 25.09) | 16.08 (12.85, 20.11) | 13.82 (11.69, 16.32) | 10.97 (9.61, 12.51) | 11.95 (10.46, 13.65) |
| Hemoglobin = 10 g/dL | 6.50 (5.60, 7.54) | 5.39 (4.80, 6.04) | 4.47 (4.09, 4.88) | 3.39 (3.13, 3.67) | 3.83 (3.53, 4.14) |
| Hemoglobin = 13 g/dL | 1.63 (1.52, 1.75) | 1.28 (1.23, 1.32) | Referent | 0.71 (0.67, 0.75) | 0.85 (0.79, 0.91) |
| Hemoglobin = 15 g/dL | 1.20 (1.02, 1.40) | 0.89 (0.79, 1.01) | 0.66 (0.60, 0.73) | 0.44 (0.40, 0.49) | 0.57 (0.50, 0.65) |
| Males | |||||
| Hemoglobin = 8 g/dL | 16.70 (12.70, 21.97) | 14.35 (11.67, 17.65) | 12.34 (10.55, 14.42) | 9.79 (8.45, 11.34) | 10.67 (9.18, 12.39) |
| Hemoglobin = 10 g/dL | 6.17 (5.36, 7.11) | 5.12 (4.60, 5.71) | 4.25 (3.90, 4.62) | 3.22 (2.96, 3.51) | 3.64 (3.34, 3.96) |
| Hemoglobin = 13 g/dL | 1.63 (1.52, 1.75) | 1.28 (1.23, 1.32) | Referent | 0.71 (0.67, 0.75) | 0.85 (0.79, 0.91) |
| Hemoglobin = 15 g/dL | 1.09 (0.95, 1.24) | 0.81 (0.74, 0.89) | 0.60 (0.57, 0.64) | 0.40 (0.38, 0.43) | 0.52 (0.45, 0.59) |
Estimates are odds ratios and reflect the increased odds of event associated with the given hemoglobin/platelet combination. Estimates are from multivariable logistic regression including the linear and spline terms for hemoglobin and platelet count as well as their interactions, interactions between sex and hemoglobin terms, and ASA PS, procedure type, type of anesthesia, and comorbidities (cancer, lymphoma, leukemia, liver disease, renal disease, MI, CHF, stroke, prior anti-platelet medication, and prior anticoagulation medication). Reference values for hemoglobin and platelet count are 13g/dL and 150×109/L respectively
DISCUSSION:
The main finding of this observational study is that isolated thrombocytopenia is extremely rare (0.52%) in a broad surgical cohort. Most cases are previously identified such that incidental diagnosis by preoperative laboratory testing occurs in only ¼ of isolated thrombocytopenia cases (0.14% of patients). Conversely, preoperative anemia is common, and thrombocytopenia most often occurs concurrently with anemia; yet only 3% of anemic patients are thrombocytopenic. Interestingly, isolated thrombocytopenia is associated with several adverse outcomes, including increased rates of intraoperative transfusion and postoperative ICU admission. However, given the low prevalence of thrombocytopenia, particularly incidental thrombocytopenia, it is unlikely that routine preoperative platelet count testing is indicated for patients without a known diagnosis of thrombocytopenia or a history suggestive of abnormal bleeding.
Preoperative laboratory testing (e.g. CBC) has long been considered non-essential for many surgical patients 8–10,13,14. However, as evident in this study, routine testing is still widely performed. While incidental thrombocytopenia is rarely discovered, preoperative anemia is common and is associated with poor perioperative outcomes 15–18, which would lend support to proponents of testing. However, diagnostic testing can be uncomfortable for patients and may contribute to iatrogenic anemia development and RBC transfusion 19–22. Notably, less than 10% of phlebotomized blood is actually utilized, and conservation of red blood cell mass prior to surgery and hospitalization is important for the prevention and exacerbation of perioperative anemia. Fortunately, there are methods available to assess hemoglobin concentrations utilizing lower phlebotomy volumes 15 or non-invasive technology for estimation (i.e. SpHb, Massimo). While studies regarding the accuracy of non-invasive estimation devices in pediatric, surgical, and trauma patients have shown mixed results 23–26, they may be useful as an anemia screening tool even in the absence of a high-level of accuracy at hemoglobin extremes.
Despite being rarely encountered, thrombocytopenia was associated with several clinical outcomes. This included increased intraoperative transfusion rates in anemic and non-anemic patients, increased ICU admission rates in non-anemic patients, and longer hospital lengths of stay with concurrent anemia, though the clinical significance of a 5% increase in geometric mean length of stay is unclear. Previous investigations have also noted associations between thrombocytopenia and inferior clinical outcomes 1–4, though this study suggests that thrombocytopenia may be problematic even in the absence of anemia. Importantly, patients with combined anemia and thrombocytopenia experienced the greatest rates of intraoperative transfusion and longest hospitalizations. Through novel assessment of the interplay between continuous preoperative hemoglobin concentrations and platelet counts, we discovered that for any given platelet count, the odds for transfusion increase substantially with incremental decreases in preoperative hemoglobin. This suggests that the dynamic relationship between preoperative anemia and thrombocytopenia status has clinical relevance extending beyond the effects of either condition in isolation.
Unique from previous work, this investigation also assessed the relationships between thrombocytopenia and clinical outcomes based upon whether thrombocytopenia was previously recognized (i.e. non-incidental) or diagnosed incidentally. Non-incidental thrombocytopenia in both anemic and non-anemic patients was associated with a greater increase in the odds for intraoperative transfusion, suggesting that incidental thrombocytopenia may not carry the same relevance for intraoperative hemostasis as established thrombocytopenia. While the mechanisms driving this relationship are unknown, it is likely that those with non-incidental thrombocytopenia had established personal or family histories of abnormal bleeding or other hematological disorders, which may have driven early diagnostic evaluations. Hence, known thrombocytopenia at the time of preoperative evaluation may indeed suggest an increased propensity for perioperative bleeding when compared to otherwise asymptomatic individuals who are only noted to have thrombocytopenia through routine preoperative laboratory testing before elective surgery. This information is important for anesthesiologists, surgeons, and other perioperative medical professions involved in preoperative evaluation. Additionally, anemic patients with non-incidental thrombocytopenia also experienced longer hospitalizations and higher odds for postoperative ICU admission than those with incidental thrombocytopenia. However, non-anemic patients with incidental thrombocytopenia had increased hospital lengths of stay compared to their non-incidental counterparts. The mechanism for this relationship is unknown, but it is possible that those with newly discovered thrombocytopenia were more prone to receive diagnostic evaluations for thrombocytopenia during hospitalization, which could theoretically lead to modest prolongation of hospitalization. In the absence of increased rates of perioperative ICU admission, transfusion, or reoperation, it is unlikely that the mechanism driving the observed relationship is mediated by effects on surgical hemostasis.
There are important limitations of this investigation. First, it is retrospective data with inherent concerns for residual confounding. This limitation was attenuated by a priori selection of covariates with the potential to confound exposure-outcome relationships and through careful predefined adjustment. Second, we were unable to reliably assess underlying causes of thrombocytopenia. Thrombocytopenia etiologies may influence clinical outcomes, but given the overall infrequency of thrombocytopenia in this large cohort, any analyses for differences in clinical outcomes by etiology of thrombocytopenia would be particularly limited. Third, presented findings represent associations; they should not be considered causal. Fourth, different thresholds could be explored to define thrombocytopenia, though we chose a commonly utilized threshold that is often clinically actionable. Additionally, we assessed the interplay between continuous platelet count values and hemoglobin concentrations, noting that risk for transfusion increases steadily for any given hemoglobin concentration when the platelet count value falls below 200 × 109/L. Further investigation is clearly indicated to establish platelet and hemoglobin concentrations associated with the greatest risk for adverse perioperative outcomes. Fifth, nearly 40% of patients did not have preoperative testing available, which reflects the clinical reality of our high-volume elective surgical practice. It is possible that those without testing could represent a healthier group of patients, which would likely result in overestimation in the prevalence of thrombocytopenia, or those undergoing very low bleeding risk procedures. Additionally, it is possible that some patients without available testing may have indeed undergone preoperative testing at another institution, though their values may have not been available in our electronic record. In any case, the interpretation of results from this investigation should be limited to those with available testing. Sixth, perioperative thrombocytopenia has previously been associated with other adverse events, including sepsis and pulmonary, renal and thromboembolic complications; these outcomes were not assessed in this investigation. Additionally, intraoperative transfusions were utilized as an outcome, but it is possible that transfusions may mediate the relationship between thrombocytopenia and outcomes such as hospital length of stay, ICU admission, and reoperation. Finally, this data represents the experience of a single large tertiary care medical center. Generalizability to other practice environments is uncertain.
CONCLUSIONS:
Isolated thrombocytopenia is rare in elective surgery, occurring in approximately 1 out of every 200 adult patients with routine preoperative laboratory testing. Furthermore, only 1 out of every 1000 patients is discovered to have incidental isolated thrombocytopenia. While preoperative thrombocytopenia is associated with several adverse clinical outcomes in both anemic and non-anemic patients, these outcomes are generally more prominent in the presence of non-incidental rather than incidental thrombocytopenia. Taken together, it is unlikely that routine preoperative testing for thrombocytopenia will improve clinical decision-making and intraoperative management for most patients without a history of anemia or thrombocytopenia, though future studies are needed to confirm these relationships and assess optimal perioperative management strategies.
Supplementary Material
Supplemental Figure: Histogram of platelet count values for the study cohort. Vertical line marked at 100 × 109/L to denote thrombocytopenia. A) Histogram of all patients in the cohort B) Histogram limited to non-anemic patients C) Histogram limited to anemic patients
Key Points:
Question: In patients undergoing elective surgery with postoperative hospital admission, what is the prevalence of isolated thrombocytopenia (platelet count <100 ×109/L) and is it associated with clinical outcomes?
Findings: Thrombocytopenia is rare (0.5% isolated thrombocytopenia, 0.8% thrombocytopenia with anemia), is usually identified prior to preoperative laboratory testing, and is associated with clinical outcomes including hospital length of stay, perioperative transfusion, and ICU admission; importantly, these outcome relationships are influenced by anemia status and known history of thrombocytopenia.
Meaning: Thrombocytopenia is clinically relevant yet infrequently discovered on routine preoperative laboratory testing.
Acknowledgments
Funding: This study was supported by NIH R01 grant (HL121232) to Dr. Kor and by CTSA Grant Number KL2 TR002379 to Dr. Warner from the National Center for Advancing Translational Science (NCATS). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.
Glossary:
- ASA
American Society of Anesthesiologists
- CBC
complete blood count
- ICU
intensive care unit
- MAC
monitored anesthetic care
- RBC
red blood cells
Footnotes
Conflicts of Interest: The authors declare no conflicts of interest.
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Associated Data
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Supplementary Materials
Supplemental Figure: Histogram of platelet count values for the study cohort. Vertical line marked at 100 × 109/L to denote thrombocytopenia. A) Histogram of all patients in the cohort B) Histogram limited to non-anemic patients C) Histogram limited to anemic patients