World J Surg (2023) 47:1174–1183

https://doi.org/10.1007/s00268-023-06899-5

ORIGINAL SCIENTIFIC REPORT

Postoperative Timing of Chemoprophylaxis and Its Impact

on Thromboembolism and Bleeding Following Major Abdominal
Surgery: A Multicenter Cohort Study
PROTECTinG investigators • VERITAS Collaborative1

Accepted: 18 December 2022 / Published online: 18 February 2023

Ó The Author(s) 2023

Abstract
Background Major abdominal surgery is associated with bleeding and venous thromboembolism (VTE) risks.
Chemoprophylaxis prevents VTE but increases bleeding risk. When compared with pre- and intra-operative
chemoprophylaxis, recent evidence suggests that starting chemoprophylaxis postoperatively lowers the risk of
bleeding without compromising VTE protection. This study investigates whether an optimal window exists in the
postoperative period for initiating chemoprophylaxis in patients undergoing major abdominal surgery.
Methods Analysis of pooled data from four multicenter PROTECTinG studies, which investigated the timing of perioperative
chemoprophylaxis on bleeding and VTE outcomes following major abdominal surgery. Patients that commenced chemo-
prophylaxis postoperatively were separated into quartiles based on timing of administration within the first 24 h post-surgery.
Results Overall, 4729 (Abdominal visceral resection N = 668, cholecystectomies N = 573, major ventral hernia repair
N = 1701, antireflux surgery N = 1787) consecutive patients had chemoprophylaxis commenced within 24 h following
elective surgery. Baseline characteristics were comparable between quartiles. Across quartiles and within each procedural
type, the timing of starting chemoprophylaxis was not associated with bleeding (2.6, 1.7, 2.7 and 3.2%, p = 0.130) or
clinical VTE (0.8, 0.2, 0.8 and 0.5%, p = 0.131), and did not predict their occurrences on multivariate analysis.
Conclusion Chemoprophylaxis can be safely started at any time within 24 h post-skin closure in major abdominal
surgery, without affecting bleeding or VTE risks. This finding encourages the standardization of chemoprophylaxis
timing in the postoperative period to pre-defined times during the day to improve workflow efficiency and
chemoprophylaxis compliance.

PROTECTinG investigators are co-authors of this study and are listed

in Appendix S1.
Correspondence to: David S. Liu, General and Gastrointestinal
Surgery Research Group, The University of Melbourne Department of
Surgery, Austin Health, 145 Studley Road, Heidelberg, VIC 3084,
Australia; Division of Surgery, Anaesthesia and Procedural
Medicine, Austin Hospital; and Division of Cancer Surgery, Peter
MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC 3000,
Australia.
Email: liu.davidsh@gmail.com
lTwitter: @Dr.DavidSLiu
1
Division of Surgery, Anaesthesia and Procedural Medicine,
Austin Health, 145 Studley Road, Heidelberg, VIC 3084,
Australia
Introduction
Venous thromboembolism (VTE) is an important pre-
ventable postoperative complication associated with sig-
nificant morbidity, mortality and economic burden [1].
Major abdominal surgery incurs a high risk of VTE [2].
Consequently, it is standard practice to administer chemi-
cal and mechanical thromboprophylaxis in the periopera-
tive setting [3]. Although chemoprophylaxis decreases
VTE risk, it also increases bleeding risk [4]. Thus, when
prescribing chemoprophylaxis, the risk and consequences
of VTE need to be balanced against that of bleeding.
Guidelines exist to facilitate chemoprophylaxis

123
World J Surg (2023) 47:1174–1183
prescription but they do not specify the optimal timing of
administration [5].
The PROTECTinG (Perioperative Timing of Elective
Chemical Thromboprophylaxis in General Surgery)
research group within the VERITAS (Victorian-collabora-
tive for Education, Research, Innovation, Training and Audit
by Surgical trainees) collaborative was established to
address this gap in perioperative guidelines. Our studies have
shown that postoperative chemoprophylaxis is favored over
early (preoperative and intraoperative) administration in the
settings of elective cholecystectomy [6], major abdominal
resection [7], ventral hernia repair [8], and anti-reflux sur-
gery. These findings were subsequently validated in patients
with high baseline VTE risk [9], and by meta-analysis of
published literature, which focused on patients undergoing
major abdominal surgery [10]. Together, these studies have
conclusively demonstrated that following major abdominal
surgery, postoperative chemoprophylaxis results in a lower
risk of bleeding without compromising VTE protection
when compared with early administration. Additionally,
other studies have demonstrated that therapeutic anticoag-
ulation (using oral agents for patients with atrial fibrillation)
can be safely restarted 24 h after skin-closure without an
increased bleeding risk [11, 12]. Unfortunately, these studies
do not report on VTE endpoints. Therefore, what remains
unknown is the optimal timing of starting chemoprophylaxis
in the postoperative period following major abdominal
surgery.
The relative paucity of evidence directing timing of
chemoprophylaxis has contributed to considerable varia-
tion in practice between hospitals and surgeons [3]. Fur-
thermore, as identified by the Australian Commission on
Safety and Quality in Health Care, despite internationally
recognized guidelines recommending VTE risk assessment
and provision of thromboprophylaxis, not all patients are
receiving this standard-of-care [13]. As highlighted by
multiple studies, usage rates are consistently suboptimal
[14, 15], with one large study reporting only 62% of at-risk
surgical patients receiving appropriate chemoprophylaxis
[2]. There are many reasons for poor compliance, however,
this is often due to a failure to prescribe or administer
chemoprophylaxis during busy clinical schedules. In this
context, knowledge of an ideal window for initiating
chemoprophylaxis in the postoperative period, if one
exists, taking into account bleeding and VTE risks, will
greatly facilitate guideline development and standardiza-
tion of thromboprophylactic practices. Such a system-wide
approach will help ensure that all patients receive appro-
priate chemoprophylaxis in the postoperative period.
Accordingly, we undertook a multicenter study to
determine whether an optimal window exists in the post-
operative period for commencing chemoprophylaxis in
patients undergoing major abdominal surgery.
1175
Methods
Study design
A retrospective analysis of pooled data from 4 multicenter
studies was conducted by PROTECTinG investigators,
which examined the impact of perioperative timing of
chemoprophylaxis following elective cholecystectomies
[6], abdominal visceral resections [7], major ventral hernia
repairs [8], and anti-reflux surgery. Details of these studies
are summarized in Table S1-2. Patients were identified
from prospectively maintained databases or from each
hospital’s administrative database using the Australian
Classification of Health Interventions procedural codes [3].
All patients had chemoprophylaxis commenced within
24 h postoperatively. Patients were excluded if under
18 years-of-age, who underwent an emergency procedure,
and those who had chemoprophylaxis initiated before skin
closure. This study was approved by the Human Research
Ethics Committee across all centers.
Venous thromboembolism prophylaxis
Thromboprophylaxis included both mechanical and
chemical methods. Mechanical thromboprophylaxis com-
prised sequential compression devices (SCD) and throm-
boembolic deterrent stockings (TEDS). Chemoprophylaxis
included subcutaneous injection of either enoxaparin
(daily), heparin (twice daily), or dalteparin (daily), at doses
adjusted to each patients’ creatinine clearance and weight.
Postoperative chemoprophylaxis refers to administration of
any of the above anticoagulants at prophylactic doses after
skin closure. The type and timing of chemoprophylaxis
across all centers for all operations were at the discretion of
the treating team. Additionally, chemoprophylaxis was not
administered within 12 h of regional anesthesia.
Data collection and quality assurance
Data was pooled from each PROTECTinG study onto a
universal electronic proforma. This included patient
demographics, comorbidities, perioperative parameters,
operative details, postoperative timing of chemoprophy-
laxis, postoperative bleeding, and VTE events. As descri-
bed in each PROTECTinG study, an array of quality
assurance measures was undertaken to maximize data
accuracy and minimize inter-observer discrepancies [6–8].
Consequently, a random audit of 10% of data fields for
each study demonstrated a mean accuracy rate of 98.1%
(range 97.7–98.4%), as outlined in Table S1.
123
1176
Study endpoints and definitions
All study endpoints were stipulated and defined a priori.
Our primary endpoint was postoperative bleeding risk.
Secondary endpoints included rates of major bleeding,
minor bleeding, reintervention for bleeding, hemoglobin
changes post-surgery and 30-day clinical VTE rate. We
used Caprini score to evaluate patients’ risk of VTE (B2:
low, 3–4: moderate, C5: high risk). We defined clinical
VTE as radiologically proven (CTPA, V/Q scintigraphy,
venous ultrasound) symptomatic disease occurring within
30 days post-surgery. The criteria for major bleeding
included either the need for blood transfusion, reinterven-
tion (surgical, endoscopic or radiological), or a [20 g/L
fall in hemoglobin from baseline [6–8]. Minor bleeding
refers to any bleeding event failing to meet major bleeding
criteria. As guided by local hospital policies, oral anti-
platelets and anticoagulants (excluding aspirin) were
withheld 3 to 7 days prior to surgery. For those patients
who required ongoing therapeutic anticoagulation, bridging
enoxaparin was used up to 24 h pre-surgery. There was a
4–6-week follow-up period for all patients following
discharge.
Statistical analysis
To determine whether time to starting chemoprophylaxis
affected bleeding and VTE risk, we analyzed time as a
categorical and continuous variable. For the former, we
separated patients into 6 hourly quartiles post-surgery. For
the latter, we analyzed time as a continuum in a multi-
variate analysis. Continuous variables were assessed using
the Student’s t-test for 2 variables and analysis of variance
(ANOVA) for [2 variables. Categorical variables were
assessed using the Fisher’s exact test for 2 variables and chi
square for [2 variables. To determine independent pre-
dictors of post-operative bleeding and VTE, and account
for differences in Australian state-based practices, a hier-
archical multivariate logistic regression analysis was
undertaken. In this model, covariates were treated as fixed
effects, whereas Australian states were treated as a random
effect. For 2 variable comparison, a two-tailed p \ 0.05
and 95% confidence interval (CI) around the odds ratio
(OR) that did not cross one was considered statistically
significant. For comparison involving [2 variables, a
Bonferroni corrected p value was calculated to account for
multiple comparisons. Statistical analyses were conducted
using Prism v9 (GraphPad Software, San Diego, CA, USA)
and R v4.1.0 (R Foundation for Statistical Computing,
Vienna, Austria).
123
World J Surg (2023) 47:1174–1183
Power calculation
Based on our own data and published studies [3, 4], the
overall risk of bleeding following major abdominal surgery
in patients who receive postoperative chemoprophylaxis is
approximately 3%. We considered a [1.5% absolute risk
difference or [50% relative risk difference between study
groups as clinically significant. Given that our entire study
cohort is divided into quartiles based on the time of starting
chemoprophylaxis postoperatively, and therefore we
assumed a 1:1:1:1 ratio of sample size within each quartile,
the total sample size required was 3200 patients (800
patients per quartile) to detect a 1.5% absolute difference
(50% relative difference) in bleeding events between any
two quartiles with 80% statistical power (alpha \ 0.05).
Results
Baseline patient characteristics
In total, we analyzed 4729 consecutive patients who
underwent major abdominal surgery and had chemopro-
phylaxis initiated within the first 24 h post-surgery. These
patients were separated into quartiles based on their timing
of chemoprophylaxis administration. The median (range)
time for each quartile are as follows; Quartile 1: 4.3
(0.0–6.0) hours, quartile 2: 7.5 (6.3–8.6) hours, quartile 3:
14.0 (12.0–15.7) hours, and quartile 4: 21.2 (18.0–24.0)
hours. Within all four major abdominal surgery cohorts,
anti-reflux surgery (N = 1787), ventral hernia repair
(N = 1701), major visceral resection (N = 668) and elec-
tive cholecystectomy (N = 573), quartiles were largely
comparable in demographic, operative and perioperative
characteristics (Tables S3-6). Minor but statistically sig-
nificant differences between quartiles were found with
respect to chemoprophylaxis type for the anti-reflux sur-
gery population (Table S3), hernia type and location for the
ventral hernia repair population (Table S4), and surgeon
seniority for the major visceral resection population
(Table S5). Notably, Caprini score, antiplatelet, and anti-
coagulant use as well as duration of surgery were similar
between quartiles for all four major abdominal surgery
cohorts.
Postoperative chemoprophylaxis timing
was not associated with bleeding
There were no significant differences in bleeding rates
between quartiles for the overall cohort of patients (2.6%,
1.7%, 2.7% and 3.2%, p = 0.13). Sub-group analysis for
anti-reflux surgery (0.6%, 0.4%, 1.3%, 1.2%, p = 0.373),
ventral hernia repair (3.3%, 2.9%, 3.6%, 3.8%, p = 0.905),
World J Surg (2023) 47:1174–1183 1177

major visceral resection (8.6%, 3.5%, 7.9%, 6.2%,
p = 0.243) and cholecystectomy (0.2%, 0.2%, 0.0%, 3.0%,
p = 0.064) also did not show significant differences in
bleeding rates between quartiles (Table 1). Furthermore,
there was no significant difference in major bleeding,
minor bleeding, reintervention for bleeding or hemoglobin
changes between quartiles in any of these four major
abdominal surgery cohorts. Patients with postoperative
bleeding had a significantly longer length of stay (mean
(SD), 13.3 (18.9) versus 4.2 (9.8) days, p \ 0.001) com-
pared to non-bleeders. The mean (SD) time to commence
chemoprophylaxis post-skin closure was 814.9 (777.8)
minutes for bleeders and 689.0 (503.4) minutes for non-
bleeders (p = 0.058). Overall and within each procedural
type, an optimal time for commencing postoperative
chemoprophylaxis in which bleeding was significantly
lower was not observed.
Postoperative chemoprophylaxis timing
was not associated with thromboembolism
There was no significant difference in VTE rates between
quartiles for postoperative timing of chemoprophylaxis.
Clinical VTE occurred in 10 (0.8%), 2 (0.2%), 9 (0.8%)
and 6 (0.5%) patients for each quartile (p = 0.131). There
was similarly no significant variability amongst quartiles

Table 1 Bleeding outcomes by surgery type

Surgery and outcomes Time from skin closure to postoperative chemoprophylaxis p value
Quartile 1 Quartile 2 Quartile 3 Quartile 4

Anti-reflux surgery N = 530 N = 465 N = 387 N = 405

All bleeding, n (%) 3 (0.6) 2 (0.4) 5 (1.3) 5 (1.2) 0.373
Major bleeding, n (%) 2 (0.4) 2 (0.4) 2 (0.5) 3 (0.7) 0.879
Minor bleeding, n (%) 1 (0.2) 0 (0.0) 3 (0.8) 2 (0.5) 0.217
Reintervention for bleeding, n (%) 2 (0.4) 1 (0.2) 1 (0.3) 1 (0.2) 0.965
Hemoglobin drop, g/L, mean (SD) -35.7 (33.0) -13.5 (0.7) -11.2 (12.1) -30.8 (23.6) 0.359
Ventral hernia repair N = 389 N = 384 N = 449 N = 479
All bleeding, n (%) 13 (3.3) 11 (2.9) 16 (3.6) 18 (3.8) 0.905
Major bleeding, n (%) 6 (1.5) 7 (1.8) 3 (0.7) 9 (1.9) 0.409
Minor bleeding, n (%) 7 (1.8) 4 (1.0) 13 (2.9) 9 (1.9) 0.280
Reintervention for bleeding, n (%) 5 (1.3) 7 (1.8) 1 (0.2) 6 (1.3) 0.160
Hemoglobin drop, g/L, mean (SD) -19.0 (20.1) -12.2 (20.2) -4.6 (8.7) -17.5 (17.2) 0.302
Major visceral resection N = 163 N = 171 N = 140 N = 194
All bleeding, n (%) 14 (8.6) 6 (3.5) 11 (7.9) 12 (6.2) 0.243
Major bleeding, n (%) 11 (6.7) 5 (2.9) 10 (7.1) 11 (5.7) 0.336
Minor bleeding, n (%) 3 (1.8) 1 (0.6) 1 (0.7) 1 (0.5) 0.535
Reintervention for bleeding, n (%) 4 (2.5) 2 (1.2) 6 (4.3) 3 (1.5) 0.259
Hemoglobin drop, g/L, mean (SD) -23.8 (15.6) -25.7 (15.6) -25.5 (29.4) -26.9 (18.0) 0.986
Cholecystectomy N = 111 N = 153 N = 210 N = 99
All bleeding, n (%) 1 (0.2) 1 (0.2) 0 (0.0) 3 (3.0) 0.064
Major bleeding, n (%) 1 (0.2) 1 (0.2) 0 (0.0) 2 (2.0) 0.257
Minor bleeding, n (%) 0 (0.0) 0 (0.0) 0 (0.0) 1 (1.0) 0.187
Reintervention for bleeding, n (%) 1 (0.2) 1 (0.2) 0 (0.0) 0 (0.0) 0.482
Hemoglobin drop, g/L, mean (SD) -15.0 (0.0) -31.0 (0.0) - -15.0 (0.0) -
Overall cohort N = 1193 N = 1173 N = 1186 N = 1177
All bleeding, n (%) 31 (2.6) 20 (1.7) 32 (2.7) 38 (3.2) 0.130
Major bleeding, n (%) 22 (1.8) 15 (1.3) 15 (1.3) 25 (2.1) 0.259
Minor bleeding, n (%) 9 (0.8) 5 (0.4) 17 (1.4) 13 (1.1) 0.064
Reintervention for bleeding, n (%) 12 (1.0) 11 (0.9) 8 (0.7) 10 (0.8) 0.837
Hemoglobin drop, g/L, mean (SD) -22.8 (18.8) -19.5 (16.5) -11.2 (31.3) -24.2 (19.0) 0.156
SD: standard deviation, -: Not applicable. Drop in hemoglobin are absolute numbers

123
1178 World J Surg (2023) 47:1174–1183

Table 2 Venous thromboembolism by surgery type

Surgery and outcomes Time from skin closure to postoperative chemoprophylaxis P value
Quartile 1 Quartile 2 Quartile 3 Quartile 4

Anti-reflux surgery 530 465 387 405

Venous thromboembolism, n (%) 7 (1.3) 1 (0.2) 3 (0.8) 4 (1.0) 0.286
Deep vein thrombosis, n (%) 4 (0.8) 0 (0.0) 2 (0.5) 1 (0.2) 0.262
Pulmonary embolism, n (%) 4 (0.8) 1 (0.2) 1 (0.3) 4 (1.0) 0.345
Ventral hernia repair 389 384 449 479
Venous thromboembolism, n (%) 2 (0.5) 1 (0.3) 2 (0.4) 0 (0.0) 0.490
Deep vein thrombosis, n (%) 1 (0.3) 1 (0.3) 2 (0.4) 0 (0.0) 0.574
Pulmonary embolism, n (%) 1 (0.3) 1 (0.3) 1 (0.2) 0 (0.0) 0.753
Major visceral resection 163 171 140 194
Venous thromboembolism, n (%) 1 (0.6) 0 (0.0) 3 (2.1) 2 (1.0) 0.243
Deep vein thrombosis, n (%) 0 (0.0) 0 (0.0) 1 (0.7) 2 (1.0) 0.362
Pulmonary embolism, n (%) 1 (0.6) 0 (0.0) 3 (2.1) 1 (0.5) 0.162
Cholecystectomy 111 153 210 99
Venous thromboembolism, n (%) 0 (0.0) 0 (0.0) 1 (0.5) 0 (0.0) -
Deep vein thrombosis, n (%) 0 (0.0) 0 (0.0) 1 (0.5) 0 (0.0) -
Pulmonary embolism, n (%) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) -
Overall cohort 1193 1173 1186 1177
Venous thromboembolism, n (%) 10 (0.8) 2 (0.2) 9 (0.8) 6 (0.5) 0.131
Deep vein thrombosis, n (%) 5 (0.4) 1 (0.1) 6 (0.5) 3 (0.3) 0.276
Pulmonary embolism, n (%) 6 (0.5) 2 (0.2) 5 (0.4) 5 (0.4) 0.583
-: Not applicable

when VTE outcomes were separated into DVT and PE
(Table 2). Additionally, on subgroup analysis, no associa-
tion was found between each quartile and VTE risk for
anti-reflux surgery (1.3%, 0.2%, 0.8% and 1.0%,
p = 0.286), ventral hernia repair (0.5%, 0.3%, 0.4% and
0.0%, p = 0.490) and major visceral resection (0.6%, 0.0%,
2.1% and 1.0%, p = 0.243). A p-value was not derived for
the cholecystectomy cohort as a VTE event (DVT)
occurred in only 1 of the 573 patients. The occurrence of
VTE was associated with an extended hospital stay (mean
(SD), 12.4 (14.7) versus 4.4 (10.2) days, p \ 0.001). The
mean (SD) time to commence chemoprophylaxis post-skin
closure was 713.0 (630.4) minutes for patients who
developed VTE and 692.1 (511.8) minutes for those free
from VTE (p = 0.833). Overall and within each procedural
type, an optimal time for commencing postoperative
chemoprophylaxis in which VTE rates were significantly
lower was not observed.
Predictor of postoperative bleeding
Univariate analysis identified the following factors to be
significantly associated with postoperative bleeding: older
age, male gender, higher Caprini score, anesthesia type,
surgical approach, higher ASA score, longer surgical
duration, pre-existing antiplatelet or anticoagulant use, and
repeated chemoprophylaxis dosing (Table 3). Of these,
multivariate analysis identified older age (OR 1.02, 95% CI
1.01–1.04, p = 0.002), longer surgical duration (OR 1.89,
95% CI 1.29–2.77, p = 0.001), and pre-existing anti-platelet
use (OR 1.69, 95%CI 1.09–2.62, p = 0.020) to be inde-
pendent predictors of postoperative bleeding following
major abdominal surgery. Importantly, chemoprophylaxis
timing expressed as a categorical or continuous variable was
not associated with, or predictive of, postoperative bleeding
on univariate or multivariate analysis, respectively.
Predictor of postoperative venous thromboembolism
Factors that were significantly associated with postopera-
tive VTE on univariate analysis included older age, higher
Caprini score, higher ASA score, longer surgical duration,
and repeated chemoprophylaxis dosing (Table 4). Multi-
variate analysis demonstrated higher Caprini score (OR
1.20, 95% CI 1.07–1.33, p = 0.001) and longer surgical
duration (OR 2.20, 95% CI 1.16–4.17, p = 0.016) to be
independent predictors of clinical VTE following major
abdominal surgery. Similarly, chemoprophylaxis timing

123
World J Surg (2023) 47:1174–1183 1179

Table 3 Predictors of postoperative bleeding

Characteristics Bleeding N = 121 No Bleeding N = 4608 p value OR 95% CI p value

Demographics
Age, mean (SD) 65.5 (14.0) 59.4 (14.7) <0.001 1.02 1.01–1.04 0.002
Gender, male, n (%) 67 (55.4) 1934 (42.0) 0.004 - - -
Body mass index, kg/m2, mean (SD) 30.0 (7.5) 30.5 (6.4) 0.377 - - -
Caprini score, median (IQR) 6 (4–7) 5 (4–6) <0.001 - - -
Operative details
Anesthesia type, n (%) <0.001 - - -
General only 102 (84.3) 4377 (95.0)
Regional only 1 (0.8) 9 (0.2)
General and regional 18 (14.9) 222 (4.8)
Operation type, n (%) <0.001
Major ventral hernia repair 58 (47.9) 1643 (35.7) 5.29 2.92–9.57 \0.001
Major visceral resection 43 (35.5) 625 (13.6) 5.80 3.11–10.8 \0.001
Cholecystectomy 5 (4.1) 568 (12.3) 1.14 0.32–4.05 0.800
Anti-reflux surgery 15 (12.4) 1772 (38.5) - - -
Operative approach, n (%) <0.001 - - -
Open 73 (60.3) 1669 (36.2)
Laparoscopic 46 (38.0) 2902 (63.0)
Open conversion 2 (1.7) 37 (0.8)
Surgeon seniority, n (%) 0.596 - - -
Consultant 84 (69.4) 2985 (64.8)
Fellow 15 (12.4) 771 (16.7)
Registrar 21 (17.4) 795 (17.3)
Not documented 1 (0.8) 57 (1.2)
Perioperative details
ASA score, median (IQR) 3 (2–3) 2 (2–3) <0.001 - - -
Surgical duration, min, mean (SD) 209.3 (159.2) 146.0 (89.1) <0.001 1.89 1.29–2.77 0.001
Length-of-stay, days, mean (SD) 13.3 (18.9) 4.2 (9.8) <0.001 - - -
Antiplatelet agent use, yes, n (%) 30 (24.8) 585 (12.7) <0.001 1.69 1.09–2.62 0.020
Anticoagulant agent use, yes, n (%) 12 (9.9) 197 (4.3) 0.011 - - -
Mechanical thromboprophylaxis, yes, n (%) 117 (96.7) 4469 (97.0) 0.786 - - -
Chemoprophylaxis type, LMWH, n (%) 102 (84.3) 4009 (87.0) 0.411 - - -
Repeated chemoprophylaxis dosing, yes, n (%) 106 (87.6) 3249 (70.5) <0.001 - - -
Time to first postop chemoprophylaxis, n (%) 0.130
Quartile 1 31 (25.6) 1162 (25.2) - - -
Quartile 2 20 (16.5) 1153 (25.0) 0.68 0.38–1.21 0.200
Quartile 3 32 (26.4) 1154 (25.0) 1.09 0.65–1.82 0.700
Quartile 4 38 (31.4) 1139 (24.7) 1.03 0.63–1.69 0.999
Time to first postop chemoprophylaxis, 814.9 (777.8) 689.0 (503.4) 0.058 - - -
min, mean (SD)
Bold indicates significance at p \ 0.05
ASA American Society of Anesthesiology, CI confidence interval, IQR Interquartile range, LMWH Low molecular weight heparin, OR odds ratio,
SD Standard deviation

123
1180 World J Surg (2023) 47:1174–1183

Table 4 Predictors of venous thromboembolism

Characteristics VTE No VTE p value OR 95% CI p value
N = 27 N4702

Demographics
Age, mean (SD) 65.1 (15.5) 59.5 (14.7) 0.048 - - -
Gender, male, n (%) 14 (51.9) 1987 (42.3) 0.334 - - -
Body mass index, kg/m2, mean (SD) 31.2 (6.4) 30.5 (6.4) 0.603 - - -
Caprini score, median (IQR) 6 (5–8) 5 (4–6) <0.001 1.20 1.07–1.33 0.001
Operative details
Anesthesia type, n (%) 0.067 - - -
General only 23 (85.2) 4456 (94.8)
Regional only 0 (0.0) 10 (0.2)
General and regional 4 (14.8) 236 (5.0)
Operation type, n (%) 0.080 – - -
Major ventral hernia repair 5 (18.5) 1696 (36.1)
Major visceral resection 6 (22.2) 662 (14.1)
Cholecystectomy 1 (3.7) 572 (12.2)
Anti-reflux surgery 15 (55.6) 1772 (37.7)
Operative approach, n (%) 0.893 - - -
Open 10 (37.0) 1732 (36.8)
Laparoscopic 17 (63.0) 2931 (62.3)
Open conversion 0 (0.0) 39 (0.8)
Surgeon seniority, n (%) 0.423 - - -
Consultant 20 (74.1) 3049 (64.8)
Fellow 3 (11.1) 783 (16.7)
Registrar 3 (11.1) 813 (17.3)
Not documented 1 (3.7) 57 (1.2)
Perioperative details
ASA score, median (IQR) 3 (2–3) 2 (2–3) 0.045 - - -
Surgical duration, min, mean (SD) 205.0 (129.4) 147.3 (91.7) 0.001 2.20 1.16–4.17 0.016
Length-of-stay, days, mean (SD) 12.4 (14.7) 4.4 (10.2) <0.001 - - -
Antiplatelet agent use, yes, n (%) 2 (7.4) 613 (13.0) 0.568 - - -
Anticoagulant agent use, yes, n (%) 3 (11.1) 206 (4.4) 0.115 - - -
Mechanical thromboprophylaxis, yes, n (%) 26 (96.3) 4560 (97.0) 0.565 - - -
Chemoprophylaxis type, LMWH, n (%) 23 (85.2) 4087 (86.9) 0.773 - - -
Repeated chemoprophylaxis dosing, yes, n (%) 25 (92.6) 3330 (70.8) 0.010 - - -
Time to first postop chemoprophylaxis, n (%) 0.131
Quartile 1 10 (37.0) 1183 (25.2) - - -
Quartile 2 2 (7.4) 1171 (24.9) 0.22 0.05–1.03 0.055
Quartile 3 9 (33.3) 1177 (25.0) 1.03 0.41–2.58 0.999
Quartile 4 6 (22.2) 1171 (24.9) 0.60 1.16–4.17 0.300
Time to first postop chemoprophylaxis, 713.0 (630.4) 692.1 (511.8) 0.833 - - -
min, mean (SD)
Bold indicates significance at p \ 0.05
ASA American Society of Anesthesiology, CI confidence interval, IQR Interquartile range, LMWH Low molecular weight heparin, OR odds ratio,
SD Standard deviation

123
World J Surg (2023) 47:1174–1183
expressed as a categorical or continuous variable was not
associated with, or predictive of, postoperative VTE on
univariate or multivariate analysis, respectively.
Discussion
This is the first study to investigate the optimal postoperative
timing of chemoprophylaxis in major abdominal surgery.
Our incidence of clinical VTE and bleeding are comparable
to published data on anti-reflux surgery [16–19], ventral
hernia repair [20–23], major visceral resection [24–26],
cholecystectomy [20, 27–32], and elective general surgery
[33–35]. Whilst VTE risk necessitates chemoprophylaxis in
the perioperative setting, strong evidence now exists
demonstrating that chemoprophylaxis confers a clinically
significant risk of bleeding [4]. Multiple studies now show
that postoperative commencement of chemoprophylaxis is
favored over pre- and intra-operative administration because
of reduced bleeding risk while preserving VTE protection
[24, 26, 36–39]. In this study, our findings indicate that there
is no optimal time window for initiating chemoprophylaxis
in the early postoperative period. As long as it is given within
24 h of skin closure, both VTE and bleeding risks remain
acceptably low.
The significance of this finding is that it informs pro-
tocol development towards standardization of thrombo-
prophylactic practices. The current variability in practice
likely contributes to the recognized suboptimal compliance
with administering chemoprophylaxis prescriptions
[40, 41]. Furthermore, non-compliance has been cited as a
major reason for surgeons prescribing chemoprophylaxis
preoperatively (a practice associated with increased risk of
bleeding and no additional VTE protection) [42]. We
propose that protocolizing chemoprophylaxis on the sur-
gical ward to set times during the day will likely be easier
for nursing staff to manage. With this approach, should an
operation finish after one set time, chemoprophylaxis will
be given at the next designated time point. This method is
different to surgeons requesting chemoprophylaxis to start
at fixed intervals postoperatively, as the latter will result in
multiple inpatients needing chemoprophylaxis adminis-
tered at multiple, and often at odd hours of the day (or
night). Such practices may lead to confusion and neglect,
particularly during periods of high clinical demand, thus
compromising adequate thromboprophylaxis. In contrast,
standardizing postoperative chemoprophylaxis to specific
times during the day fosters routine, enables integration
into pre-existing workflows, and allows nursing staff to
anticipate and plan, which ultimately may improve com-
pliance to thromboprophylaxis, and patient safety.
There are inherent limitations within this retrospective
study. Moreover, we did not search for an optimal
1181
chemoprophylaxis window beyond 24 h of skin closure.
This is because evidence already exist demonstrating the
safety of commencing therapeutic anticoagulation at 24 h
post-surgery [11], and it is uncommon for clinicians to
delay chemoprophylaxis beyond 24 h post-surgery unless
there were specific concerns for bleeding. Additionally, the
incidence of clinical VTE may be underestimated in this
study as patients may present to other health services for
treatment. However, all patients were followed-up between
4–6 weeks post-surgery, and as noted earlier, our reported
rates of clinical VTE are comparable to contemporary
series [33–35]. We are unable to provide 90-day bleeding
or clinical VTE rates as patients were not universally fol-
lowed-up after 6 weeks post-surgery.
Conclusion
The timing of initiating chemoprophylaxis within 24 h
postoperatively is not significantly associated with bleed-
ing and clinical VTE after major abdominal surgery. Given
the low risk of bleeding and clinical VTE associated with
postoperative chemoprophylaxis, our findings advocate for
standardization of chemoprophylaxis timing in the post-
operative period to improve compliance with
administration.
Funding Open Access funding enabled and organized by CAUL and
its Member Institutions.
Declarations
Conflict of interest None declared.
Ethical approval This study was approved by Human Research
Ethics Committee from all participating sites.
Supplementary Information The online version contains
supplementary material available at https://doi.org/10.1007/s00268-
023-06899-5.
Open Access This article is licensed under a Creative Commons
Attribution 4.0 International License, which permits use, sharing,
adaptation, distribution and reproduction in any medium or format, as
long as you give appropriate credit to the original author(s) and the
source, provide a link to the Creative Commons licence, and indicate
if changes were made. The images or other third party material in this
article are included in the article’s Creative Commons licence, unless
indicated otherwise in a credit line to the material. If material is not
included in the article’s Creative Commons licence and your intended
use is not permitted by statutory regulation or exceeds the permitted
use, you will need to obtain permission directly from the copyright
holder. To view a copy of this licence, visit http://creativecommons.
org/licenses/by/4.0/.
123
1182
References
1. Access Economics (2008) The burden of venous thromboem-
bolism in Australia. Report for The Australia and New Zealand
Working Party on the Management and Prevention of Venous
Thromboembolism. Available at: https://www.safetyandquality.
gov.au/publications-and-resources/resource-library/burden-
venous-thromboembolism-australia. Accessed 15 Sept 2022
2. Kakkar AK, Cohen AT, Tapson VF et al (2010) Venous throm-
boembolism risk and prophylaxis in the acute care hospital set-
ting (ENDORSE survey): findings in surgical patients. Ann Surg
251:330–338
3. Liu DS, Stevens S, Wong E et al (2020) Variations in practice of
thromboprophylaxis across general surgical subspecialties: a
multicentre (PROTECTinG) study of elective major surgeries.
ANZ J Surg 90:2441–2448
4. Leonardi MJ, McGory ML, Ko CY (2006) The rate of bleeding
complications after pharmacologic deep venous thrombosis pro-
phylaxis: a systematic review of 33 randomized controlled trials.
Arch Surg 141:790–797; discussion 797–799
5. Gould MK, Garcia DA, Wren SM et al (2012) Prevention of VTE
in nonorthopedic surgical patients: antithrombotic therapy and
prevention of thrombosis, 9th ed: American College of Chest
Physicians Evidence-Based Clinical Practice Guidelines. Chest
141:e227S-e277S
6. Liu DS, Stevens S, Wong E et al (2020) Pre-operative and intra-
operative chemical thromboprophylaxis increases bleeding risk
following elective cholecystectomy: a multicentre (PROTECT-
inG) study. ANZ J Surg 90:2449–2455
7. Liu DS, Newbold R, Stevens S et al (2022) Early versus post-
operative chemical thromboprophylaxis is associated with
increased bleeding risk following abdominal visceral resections: a
multicenter cohort study. J Gastrointest Surg 26:1495–1502
8. PROTECTinG investigators, VERITAS collaborative, (2022)
Chemical thromboprophylaxis before skin closure increases
bleeding risk after major ventral hernia repair: a multicenter
cohort study. Surgery 172:198–204
9. Liu DS, Stevens SG, Watson DI et al (2022) Optimal timing of
perioperative chemoprophylaxis in patients with high throm-
boembolic risk undergoing major abdominal surgery: a multi-
center cohort study. Ann Surg. https://doi.org/10.1097/SLA.
0000000000005697
10. Klonis C, Ashraf H, Cabalag CS et al (2022) Optimal timing of
perioperative chemical thromboprophylaxis in elective major
abdominal surgery: a systematic review and meta-analysis. Ann
Surg. https://doi.org/10.1097/SLA.0000000000005764
11. Douketis JD, Spyropoulos AC, Duncan J et al (2019) Perioper-
ative management of patients with atrial fibrillation receiving a
direct oral anticoagulant. jama intern med 179:1469–1478
12. Douketis JD, Spyropoulos AC, Murad MH, et al (2022) Periop-
erative Management of Antithrombotic Therapy: An American
College of Chest Physicians Clinical Practice Guideline Execu-
tive Summary. Chest
13. Australian Commission on Safety and Quality in Health Care
(2020) Venous Thromboembolism Prevention Clinical Care
Standard. Available from: https://www.safetyandquality.gov.au/
publications-and-resources/resource-library/venous-thromboem
bolism-prevention-clinical-care-standard-2020. Accessed 15 Sept
2022
14. Otero R, Uresandi F, Cayuela A et al (2001) Use of venous
thromboembolism prophylaxis for surgical patients: a multicentre
analysis of practice in Spain.
15. Yu HT, Dylan ML, Lin J et al (2007) Hospitals’ compliance with
prophylaxis guidelines for venous thromboembolism. Am J
Health Syst Pharm 64:69–76
123
World J Surg (2023) 47:1174–1183
16. Cuschieri A, Hunter J, Wolfe B et al (1993) Multicenter
prospective evaluation of laparoscopic antireflux surgery. Pre-
liminary report Surg Endosc 7:505–510
17. Nguyen NT, Hinojosa MW, Fayad C et al (2007) Laparoscopic
surgery is associated with a lower incidence of venous throm-
boembolism compared with open surgery. Ann Surg
246:1021–1027
18. Schlottmann F, Strassle PD, Patti MG (2017) comparative anal-
ysis of perioperative outcomes and costs between laparoscopic
and open antireflux surgery. J Am Coll Surg 224:327–333
19. Schlottmann F, Strassle PD, Patti MG (2018) Antireflux surgery
in the USA: Influence of surgical volume on perioperative out-
comes and costs-time for centralization? World J Surg
42:2183–2189
20. Alizadeh RF, Sujatha-Bhaskar S, Li S et al (2017) Venous
thromboembolism in common laparoscopic abdominal surgical
operations. Am J Surg 214:1127–1132
21. Helm JH, Helm MC, Kindel TL et al (2019) Blood transfusions
increase the risk of venous thromboembolism following ventral
hernia repair. Hernia 23:1149–1154
22. Pannucci CJ, Basta MN, Fischer JP et al (2015) Creation and
validation of a condition-specific venous thromboembolism risk
assessment tool for ventral hernia repair. Surgery 158:1304–1313
23. Ross SW, Kuhlenschmidt KM, Kubasiak JC et al (2020) Asso-
ciation of the risk of a venous thromboembolic event in emer-
gency vs elective general surgery. JAMA Surg 155:503–511
24. Doughtie CA, Priddy EE, Philips P, et al (2014) Preoperative
dosing of low-molecular-weight heparin in hepatopancreatobil-
iary surgery. Am J Surg 208:1009–1015; discussion 1015
25. Kakkar AK, Agnelli G, Fisher W et al (2014) Preoperative
enoxaparin versus postoperative semuloparin thromboprophy-
laxis in major abdominal surgery: a randomized controlled trial.
Ann Surg 259:1073–1079
26. Zaghiyan KN, Sax HC, Miraflor E et al (2016) Timing of
chemical thromboprophylaxis and deep vein thrombosis in major
colorectal surgery: a randomized clinical trial. Ann Surg
264:632–639
27. Gundogdu RH, Oduncu M, Bozkirli BO et al (2017) Does
thromboprophylaxis cause bleeding after laparoscopic cholecys-
tectomy? Bratisl Lek Listy 118:156–159
28. Henry ML, Abdul-Sultan A, Walker AJ et al (2020) Duration and
magnitude of postoperative risk of venous thromboembolism
after cholecystectomy: a population-based cohort study. Dig Surg
37:32–38
29. Persson G, Stromberg J, Svennblad B et al (2012) Risk of
bleeding associated with use of systemic thromboembolic pro-
phylaxis during laparoscopic cholecystectomy. Br J Surg
99:979–986
30. Rondelli F, Manina G, Agnelli G et al (2013) Venous throm-
boembolism after laparoscopic cholecystectomy: clinical burden
and prevention. Surg Endosc 27:1860–1864
31. Stein PD, Matta F, Sabra MJ (2014) Pulmonary embolism and
deep venous thrombosis following laparoscopic cholecystectomy.
Clin Appl Thromb Hemost 20:233–237
32. Stromberg J, Sadr-Azodi O, Videhult P et al (2015) Incidence and
risk factors for symptomatic venous thromboembolism following
cholecystectomy. Langenbecks Arch Surg 400:463–469
33. Assareh H, Chen J, Ou L et al (2014) Rate of venous throm-
boembolism among surgical patients in Australian hospitals: a
multicentre retrospective cohort study. BMJ Open 4:e005502
34. Mukherjee D, Lidor AO, Chu KM et al (2008) Postoperative
venous thromboembolism rates vary significantly after different
types of major abdominal operations. J Gastrointest Surg
12:2015–2022
World J Surg (2023) 47:1174–1183
35. Sakon M, Kakkar AK, Ikeda M et al (2004) Current status of
pulmonary embolism in general surgery in Japan. Surg Today
34:805–810
36. Altieri MS, Yang J, Hajagos J et al (2018) Evaluation of VTE
prophylaxis and the impact of alternate regimens on post-opera-
tive bleeding and thrombotic complications following bariatric
procedures. Surg Endosc 32:4805–4812
37. Hull RD, Pineo GF, Francis C et al (2000) Low-molecular-weight
heparin prophylaxis using dalteparin in close proximity to surgery
vs warfarin in hip arthroplasty patients: a double-blind, ran-
domized comparison. The North American Fragmin Trial
Investigators. Arch Intern Med 160:2199–2207
38. McAlpine K, Breau RH, Werlang P et al (2021) Timing of
perioperative pharmacologic thromboprophylaxis initiation and
its effect on venous thromboembolism and bleeding outcomes: a
systematic review and meta-analysis. J Am Coll Surg
233(619–631):e614
39. Taghlabi K, Carlson BB, Bunch J et al (2022) Chemoprophylactic
anticoagulation 72 hours after spinal fracture surgical treatment
1183
decreases venous thromboembolic events without increasing
surgical complications. N Am Spine Soc J 11:100141
40. Fanikos J, Stevens LA, Labreche M et al (2010) Adherence to
pharmacological thromboprophylaxis orders in hospitalized
patients. Am J Med 123:536–541
41. Shermock KM, Lau BD, Haut ER et al (2013) Patterns of non-
administration of ordered doses of venous thromboembolism
prophylaxis: implications for novel intervention strategies. PLoS
ONE 8:e66311
42. Liu DS, Wong E, Fong J et al (2020) Perioperative thrombo-
prophylaxis is highly variable in general surgery: results from a
multicentre survey. ANZ J Surg 90:2401–2403
Publisher’s Note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
123