Risk of venous thromboembolism in patients with splenic injury and splenectomy. A nationwide cohort study

Risk of venous thromboembolism in

patients with splenic injury and

splenectomy

A nationwide cohort study

Jiun-Nong Lin1–3; Hsuan-Ju Chen4,5; Ming-Chia Lin6; Chung-Hsu Lai3; Hsi-Hsun

Lin3; Chih-Hui Yang7; Chia-Hung Kao8,9

Introduction

The spleen, located in the upper-left portion of the abdomen

underneath the rib cage, is vulnerable to blunt and penetrating abdominal trauma. The spleen plays critical haematologic and immunologic

roles in humans. For example, it removes old red blood

cells and pools a reserve of blood, including red blood cells, white blood cells, and platelets (1). The stored blood cells can be released into circulation in an emergency, after a splenectomy, or when otherwise required (1, 2).

Approximately 22,000 all-cause splenectomies were performed in the United States in 2005 (3, 4). Haematologic disorders are the most common indications of splenectomy, including haemolytic anaemia, autoimmune haemolytic anaemia, sickle cell disease,

_-thalassaemia, and immune thrombocytopenic purpura (3). Currently, splenectomy is not recommended for managing splenic

trauma. Instead, spleen-preserving nonoperative procedures, such

as transcatheter arterial embolisation, have replaced surgical splenectomy (5–7). However, emergent splenectomy is still recommended

for life-threatening haemorrhage and severe splenic injury

(grade III-V) because of the high failure rate of nonoperative management (6, 8, 9).

Using splenectomy to treat haematologic diseases creates several complications, including bacterial infections, cancer, ischaemic heart disease, stroke, and venous thromboembolism

(VTE) (10–14). However, haematologic disorders can be associated with these vascular complications (3). Little is known regarding

(15–17). Thus, we conducted a nationwide retrospective cohort study to determine the risk of VTE in patients with

splenic injury and splenectomy by analysing the National Health Insurance Research Database (NHIRD) of Taiwan.

Materials and methods

Data source

Taiwan launched a single-payer National Health Insurance (NHI) program on March 1, 1995. The NHI database covers nearly the entire population in Taiwan (> 23 million). The NHIRD, a claims

database, is managed and maintained by the National Health Research Institutes of Taiwan. To protect patient privacy, all data are

anonymised through cryptographic scrambling before release to the public for research. In this study, the hospitalisation claims data of all enrollees in Taiwan were analysed, including information on sex, date of birth, dates of admission and discharge, and

expenditures by admission. The diagnoses and procedures were based on the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes. This study was approved by the Institutional Review Board of China Medical University and Hospital (CMUH104-REC2-115).

Study population

All patients included in this study were aged _ 20 years with newly diagnosed splenic injury (ICD-9-CM code 865.xx), as recorded in the inpatient registry file of the NHIRD from 2000–2006. Patients with diagnoses of VTE or undergoing splenectomy (ICD-9-CM codes for procedure 41.2x, 41.43, and 41.5x) before the date of diagnosed splenic injury were excluded from this study. Among the splenic injury cohort, patients who underwent splenectomy

were classified as the splenectomised group, whereas those who received no splenectomy were classified as the nonsplenectomised

group. The first diagnosis date of splenic injury was regarded as the index date. Patients without splenic injury, splenectomy, and VTE were randomly selected from the registry of inpatients and

frequency-matched with splenic injury patients in a 4:1 ratio according to sex, five-year age interval, and the year of index date.

Outcomes and comorbidities

The primary outcome was VTE, including portal vein thrombosis (ICD-9-CM code 452), pulmonary embolism (ICD-9-CM codes

415.1 and 415.19; excluding 415.11), and other venous embolism and thrombosis (ICD-9-CM code 453.xx). All enrolled patients were followed from the index date to the occurrence of primary outcome, December 31, 2011, death or withdrawal from NHI. The risk of VTE after splenic injury and splenectomy was stratified by the follow-up duration after the index date (_ 90, 91–365, and > 365 days) and length of hospital stay for the splenic injury and splenectomy (_ 8, 9–13, and _ 14 days). According to each inpatient diagnosis, we calculated the Charlson Comorbidity Index

(CCI) as the comorbidity measure. CCI score is the sum of the weighted score of 17 comorbidities. A weight is assigned in each indicated diagnosis and added together to provide a total CCI score. Comorbidities, including myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, dementia, chronic pulmonary disease, rheumatologic disease, peptic ulcer disease, mild liver disease, and diabetes mellitus, were calculated as weighted 1. Moderate to severe renal disease, diabetes

mellitus with chronic complications, hemiplegia or paraplegia, leukaemia, tumour of any type, and malignant lymphoma were

weighted 2. Moderate to severe liver disease was weighted 3. Acquired immune deficiency syndrome and metastatic solid tumour

were weighted 6 (18, 19).

Statistical analysis

Differences among cohorts were examined using the Chi-square test for categorical variables and Student’s t-test for continuous variables. Cumulative incidences of VTE in the splenectomised, nonsplenectomised, and comparison cohorts were explored using the Kaplan-Meier method, and the differences were determined using log-rank tests. Cox proportional hazards regression models were used to assess the association of VTE with splenic injury and splenectomy after adjustments for sex, age, and CCI score. Hazard ratios (HRs) and 95 % confidence intervals (CIs) were calculated to quantify the risk of VTE. All analyses were performed using SAS software Version 9.3 (SAS Institute, Cary, NC, USA). Differences were considered statistically significant if the two-tailed p-value was < 0.05.

Results

comparison patients were enrolled in this study (

_

Table 1). In the splenic injury cohort, 3,033 patients received splenectomy, and 3,129 patients did not receive splenectomy. The age of the patients with splenic injury was 41.93 ± 16.44 years (mean ± standard deviation, SD), and 83.33 % of patients were younger than 60 years.

Men accounted for approximately 71 % of the patients in each cohort. A higher CCI score was found in the splenic injury cohort

than in the comparison cohort (0.32 ± 0.91 vs 0.16 ± 0.65, p < 0.001). The mean ± SD follow-up periods were 7.08 ± 3.18 and

7.7 ± 2.64 years in the splenic injury and comparison cohorts, respectively (p < 0.001). Splenectomised patients had a shorter

follow-up duration than did nonsplenectomised patients (6.98 ± 3.45 vs 7.18 ± 2.90 years; p = 0.01).

Among the 6,162 splenic injury patients, 44 patients, including 19 nonsplenectomised and 25 splenectomised patients, developed

VTE (incidence density rate, 10.08 per 10,000 person-years). Additionally, 99 patients had VTE among the 24,648 comparison patients

(incidence density rate, 5.21 per 10,000 person-years)

(

_

Table 2). Compared with patients in the comparison cohort, splenic injury patients with and without splenectomy exhibited a 2.21-fold and 1.71-fold increased risk of VTE (95 % CI, 1.43–3.43;

95 % CI, 1.05–2.80, respectively). The risk of VTE was 1.97-fold higher in the splenic injury cohort than in the comparison cohort,

irrespective of splenectomy status (95 % CI, 1.38–2.81). Among patients with splenic injury, splenectomised patients had a 1.35-fold greater risk of VTE compared with nonsplenectomised patients; however, the difference was not significant (95 % CI, 0.74–2.45).

The Kaplan-Meier analysis revealed that splenic injury patients had a significantly higher cumulative incidence of VTE than did the patients in the comparison cohort (log-rank test, p < 0.001;

_

Figure 1 A). Significant differences in the cumulative incidences of VTE were detected among these three cohorts (

_

Figure 1 B; p < 0.001), and the cumulative incidence of VTE was the highest in splenic injury patients with splenectomy.

We analysed the effect of sex, age, and CCI score on the risk of VTE after splenic injury and splenectomy (

_

Table 3). The incidence density rates of VTE in female and male splenic injury patients

were 6.30 and 11.63 per 10,000 person-years, respectively;

both incidence density rates were higher than that in the comparison cohort (3.34 and 5.96 per 10,000 person-years, respectively).

Among the splenic injury patients, men, but not women, exhibited a significant 1.97-fold (95 % CI, 1.33–2.92) higher risk of developing

VTE than did male patients in the comparison cohort. Further analysis showed that the risk of VTE was only significant in male

splenectomised patients (adjusted HR, 2.24; 95 % CI, 1.39–3.63). Age-specific analysis revealed that the incidence density rates of VTE increased with age in each cohort. The risk of VTE was significant in splenic injury patients aged < 60 years compared with in

patients in the nonsplenic injury cohort. Among the splenic injury patients, only those aged < 60 years who underwent splenectomy had significantly increased risks of VTE. Splenic patients in all age groups who did not receive splenectomy had no increased risk for VTE. With regard to CCI score, we observed that both splenectomised and nonsplenectomised splenic injury patients with a CCI

score of 0 had a significantly higher risk of VTE compared with the nonsplenic injury cohort. However, the risk of VTE after splenic injury did not increase in patients with a CCI score _ 1. The simultaneous comorbidities of patients with VTE events during the follow-up periods were analysed (Suppl. Table 1, available online at www.thrombosis-online.com). Among the 44 VTE patients in

the splenic injury cohort, liver cirrhosis (52.27 %) is the most prevalent comorbidity, followed by cancer (40.91 %) and diabetes mellitus

(31.82 %). Hypertension (38.38 %), cancer (33.33 %), and liver cirrhosis (27.27 %) were the leading three comorbidities among the 99 VTE patients in the nonsplenic injury cohort. Liver cirrhosis was the only significantly more prevalent comorbidity in the splenic injury cohort than in the nonsplenic injury cohort (p = 0.006).

_

Table 4 shows the risk of VTE in different vessels. The risk of portal vein thrombosis was significantly elevated in patients with splenic injury (adjusted HR, 3.05; 95 % CI, 1.70–5.45), either in splenectomised patients (adjusted HR, 2.53; 95 % CI, 1.15–5.54) and in nonsplenectomised patients (adjusted HR, 3.58; 95 % CI, 1.78–7.20). There was no significant difference of portal vein

thrombosis between splenectomised and nonsplenectomised cohorts. The risk of pulmonary embolism was not significantly different

following splenic injury (adjusted HR, 1.04; 95 % CI,

0.39–2.77), irrespective of splenectomy status. The risk of VTE other than portal vein thrombosis and pulmonary embolism was elevated in the splenic injury cohort compared with the nonsplenic injury cohort (adjusted HR, 1.75; 95 % CI, 1.04–2.96). This VTE

risk was significantly increased in the splenectomised patients (adjusted HR, 2.25; 95 % CI, 1.22–4.16), but not in the nonsplenectomised

patients (adjusted HR, 1.24; 95 % CI, 0.56–2.75).

We analysed the relationship between VTE risk and length of hospital stay for splenic injury and splenectomy (

_

Table 5). The hospitalisation days were classified into _ 8, 9–13, and _ 14 days according to tertiles. Compared with the comparison cohort, the HRs of VTE increased as the length of hospital stay increased (p for trend < 0.001). Among those who were hospitalised for more than 14 days, the risk of VTE significantly increased following splenic injury (adjusted HR, 2.43; 95 % CI, 1.52–3.59).

When stratified by follow-up periods, the risk of VTE was significantly increased in the splenic injury cohort within 90 days

(adjusted HR, 24.94; 95 % CI, 2.99–208) and more than 365 days after the index date (adjusted HR 1.72; 95 % CI 1.16–2.56)

(

_

Table 6). The VTE risk was substantially increased within 90 days after the index date in the splenectomised patients (adjusted HR, 43.35; 95 % CI, 5.05–372). However, the VTE risk did not increase during 91–365 days after splenic injury. When the followup

duration was more than 365 days after the index date, both splenectomised (adjusted HR, 1.70; 95 % CI, 1.01–2.86) and nonsplenectomised

patients (adjusted HR, 1.75; 95 % CI, 1.04–2.95) remained at a higher risk of VTE.

_Discussion

Recently, a large retrospective study reported the long-term complications of all-cause splenectomy, revealing that splenectomy increases

the risks of pulmonary embolism and deep-vein thrombosis (11). However, an older study showed no correlation between

the occurrence of deep vein thrombosis and splenectomy in patients with Hodgkin disease (12). The present study, which included

only trauma patients, revealed that splenic injury elevated

the risk of VTE (adjusted HR, 1.97; 95 % CI, 1.38–2.81), irrespective of whether the patients underwent splenectomy. A large Australian

study reported a VTE rate of 130 per 10,000 person-years after all-cause splenectomy (20). The incidence density rate of VTE following splenectomy in splenic trauma patients was 11.81 per 10,000 person-years in this study. Our VTE rate is much lower than that in the Australian study (20). The prevalence of VTE varies among different races and ethnicities. Asians have a lower prevalence of VTE than do African Americans, Caucasians, and Hispanics (21–23).

Although the incidence of VTE in women of childbearing age is higher than that in men, the incidence in postmenopausal women is lower than that in men (10, 21). Studies have revealed an association between VTE and increasing age (10, 21). Comorbidities

such as cancer, respiratory failure, myocardial infarction, and congestive heart failure were also shown to increase the risk of VTE

(10). Among the VTE patients in our study, there was no significant difference in the prevalence of comorbidities between the

splenic injury cohort and nonsplenic injury cohort except liver cirrhosis. Epidemiological studies inspecting the association between

liver cirrhosis and VTE demonstrated conflicting results (24). The role of liver cirrhosis in the pathogenesis of VTE in splenic injury patients remains unclear.

Portal vein thrombosis is a well-known complication after splenectomy indicated for haematologic diseases (25, 26). The process

of haematologic diseases and the presence of splenomegaly were identified as the most important risk factors for portal vein thrombosis after splenectomy (25). In our study, we observed that the

risk of portal vein thrombosis was significantly elevated in the splenic injury cohort, either in splenectomised and nonsplenectomised

patients. However, no statistical difference of portal vein

thrombosis was identified between splenectomised and nonsplenectomised patients. Our findings suggest that splenic injury per

se might increase the risk of portal vein thrombosis beyond the splenectomy.

Van Haren et al. (27) assessed the risk of VTE in trauma patients who hospitalised in intensive care unit. They found that patients with more surgeries, longer intensive care unit stay, and abdominal injury with a higher Abbreviated Injury Scale score were

similar result. In our study, the information of injury severity is not available in the NHIRD. We used length of hospital stay as a proxy for severity of splenic injury. Our results showed that the VTE risk increased along with hospitalisation days. When the length of hospital stay was more than 14 days, splenic injury patients exhibited

a 2.43-fold increased risk of VTE.

Long-term risks of VTE have been rarely described in the literature (11, 29). Thomsen et al. (29) reported a 32.6-, 7.1-, and

3.4-fold higher risks of VTE within 90 days, 91–365 days, and > 365 days after all-cause splenectomy compared with the general population. Among the splenic injury patients, the VTE risk > 365 days post-splenectomy was 3.1-fold higher (95 % CI, 1.8–5.4) than in the normal comparisons (29). Our results showed an increased risk of VTE within 90 days and > 365 days after splenic injury and splenectomy. But the VTE risk did not increase during 91–365

days following splenic injury. The exact reason for the partial inconsistency between our results and the study by Thomsen et al. is

unclear. Race and ethnicity differences may play a role in the variation of VTE risk.

Our study revealed increased short-term and long-term risks of VTE in splenic injury patients than in the control patients. Severe splenic injury could result in hyposplenism or splenic dysfunction. Surgery has been shown to increase the risk of VTE within 30 days of operation (30–32). The mechanisms for VTE after surgery are multifactorial, including blood stasis resulting from immobility, vessel endothelial damage, and upregulation of P-selectin and local

prothrombotic microparticles (30). However, the postprocedural or postoperative risks for VTE are short-term. The increased longterm risk of VTE was less likely caused by only the surgical procedures. In other words, our results suggested that the increased

risk for VTE was due to the splenic injury or splenectomy. Some mechanisms have been proposed for VTE after splenic injury and splenectomy, including reactive thrombocytosis, platelet activation, hypercoagulability, activation of the endothelium, decreased

levels of protein C and protein S, elevated thrombin generation, altered lipid pro_les, leukocytosis, and increased C-reactive

protein levels (33–36). Further studies to understand the pathogenesis of VTE after splenic injury and splenectomy are warranted.

The major strengths of this study include the large number of

cases (N = 6,162), single indication for splenectomy, and long duration of follow-up. However, several limitations should be noted.

First, a paucity of information was identified regarding various risk factors for VTE, such as smoking, obesity, and socioeconomic status. In addition, no haematologic information, such as platelet counts, prothrombin time, and partial thromboplastin time, was contained in the NHIRD. These factors were possible confounding factors in this study. Second, the present study is a retrospectively observational cohort study. Despite the meticulous design and analysis of comorbidity, we cannot prove the real etiology of VTE. Third, the severity of splenic injury is not included in the NHIRD. We cannot evaluate the risk of VTE according to the severity of splenic trauma. However, we used length of hospital stay as a

proxy for severity of splenic injury. Fourth, the NHIRD lack information on pharmacologic prophylaxis and inferior vena cava

filters. These factors could influence the occurrence of VTE. Fifth, the diagnoses of VTE were based on the ICD-9-CM diagnostic

codes. We only classified the sites of VTE into portal vein thrombosis, pulmonary embolism, and other venous embolism and

thrombosis. More detailed classification of venous thrombosis is not available based on the ICD-9-CM. Finally, the diagnoses of VTE, spleen injury, and splenectomy could not be validated using the NHIRD data. Misclassification of diseases may have caused

bias in our study, even though several studies have proven the accuracy of the NHIRD (37, 38).

In conclusion, our study showed that splenic injury was significantly associated with an increased risk of VTE. Among patients

with splenic injury, splenectomised patients had a 1.35-fold increased risk of VTE compared with nonsplenectomised patients;

however, the difference was not statistically significant. This study may alert physicians and patients to the severe complications of splenic injury and splenectomy. Additional trials may be required to investigate prophylactic management of these complications.