From January 2003 to February 2016, the medical records of all consecutive patients who were hospitalized for SISBH at 2 tertiary referral hospitals in Korea (Seoul National University Hospital and Seoul National University Bundang Hospital) were retrospectively reviewed. All patients in whom intramural small intestinal hematoma was detected on the CT scan of the abdomen and pelvis were included in this study. Intramural small bowel hematoma was characterized as circumferential bowel wall thickening, luminal narrowing, and intestinal tract obstruction on the CT scan [6]. Any additional modality for small bowel evaluation including CT enterography, magnetic resonance enterography, capsule endoscopy and enteroscopy was not performed in the study population. Among these patients, those with a history of trauma or iatrogenic interventions including intraabdominal surgery or non-surgical procedures within 4 weeks from the presentation of the intramural hematoma were excluded. This study was approved by the Institutional Review Board Committee at the participating medical centers (SNUH IRB No. 1606-079-771; SNUBH IRB No. B-1608-359-401). The informed consent has been omitted. Because this study was a retrospective review of the patient’s medical records, there was no additional risk to the patient.

Data such as age, sex, body weight, and medical history including diabetes mellitus, hypertension, cardiac arrhythmia, congestive heart failure, coronary heart disease, pulmonary thromboembolism, deep vein thrombosis, peripheral arterial disease, history of heart valve replacement, history of cerebrovascular accidents, and malignancy were collected. The Charlson comorbidity index was calculated to evaluate the severity of comorbidities in the study population. With each elevated level of the Charlson comorbidity index, there are stepwise increases in the cumulative mortality attributable to comorbid diseases [35]. The use of probable offending drugs including anticoagulants (warfarin, heparin, and novel oral anticoagulants such as dabigatran, rivaroxaban, and apixaban) and antiplatelets (aspirin, clopidogrel, ticlopidine, ticagrelor, and cilostazol) were reviewed. The GI symptoms associated with the presentation of SISBH and initial laboratory findings including white blood cell (WBC) count, hemoglobin level, platelet count, PT, aPTT, serum BUN, creatinine, albumin, and high-sensitivity CRP (hs-CRP) at the time of presentation were also collected. The primary outcome was the requirement for surgery. The secondary outcomes were lengths of fasting and hospital stay, and mortality rate. Oral feeding or enteral nutrition was considered according to the physician’s discretion in patients who were willing to try enteral nutrition and who had no obstructive GI symptoms including nausea, vomiting, and abdominal distension.

Baseline characteristics and clinical outcomes according to the location of the hematoma in the small intestine were compared. Continuous variables were compared among the groups using one-way ANOVA with Bonferroni correction. Pearson chi-square test or Fisher exact test was used to calculate the statistical significance of the categorical variables. Continuous variables between prolonged (more than 7 days) and short (7 days or less) hospital stays were also compared using Student t-test. Variables considered predictive factors for prolonged hospital stay were assessed using univariate logistic regression analysis. In addition, variables that were significant in the univariate test were entered into the multivariate logistic regression model to identify independent predictive factors for prolonged hospital stay. P-values less than 0.05 were considered to be statistically significant. All statistical analyses were performed using the SPSS version 21.0 (IBM Corp., Armonk, NY, USA).

From January 2003 to February 2016, a total of 110,698 patients were treated with anticoagulant and/or antiplatelet therapy at the participating medical centers. Among them, a total of 37 consecutive patients with SISBH were enrolled in this study. The annual incidence of SISBH was estimated at 0.003% per year. The study population comprised 19 males (51.4%), and the mean age at presentation with SISBH was 74.1 years (range, 51–89 years). Among these patients, 35 (94.6%) had cardiovascular comorbidities including 22 with hypertension (59.5%), 20 with cardiac arrhythmia (54.1%), 13 with a history of cerebrovascular accidents (35.1%), 10 with congestive heart failure (27.0%), 7 with coronary heart diseases (18.9%), 4 with pulmonary embolism and/or deep vein thrombosis (10.8%), 3 with a history of heart valve replacement (8.1%), and 2 with peripheral arterial diseases (5.4%). Three patients (8.1%) had malignant tumors at the time that SISBH presented, all of whom were being treated with systemic chemotherapy. In total, 29 patients (78.4%) had 2 or more comorbidities, and the mean Charlson comorbidity score was 4.6 points (range, 2–10 points). Warfarin, aspirin, clopidogrel, and LMWH was taken by 30 (81.1%), 5 (13.5%), 1 (2.7%), and 1 (2.7%) patient, respectively. None of the study participants received novel oral anticoagulants. Only 1 patient without any underlying illness, who did not use any anticoagulant or antiplatelet therapies, showed prolongation of PT and aPTT during use of an herbal medication at the time of SISBH presentation. Abdominal pain was the most common complaint at the time of presentation (24 of 37 patients; 64.9%). Nausea and/or vomiting were present in 13 patients (35.1%) and GI bleeding developed in 14 (37.8%). Mean WBC count was 12.9×10³/μL (range, 0.2–31.1×10³/μL), mean hemoglobin level was 11.6 g/dL (range, 4.3–18.3 g/dL), and mean platelet count was 235×10³/μL (range, 19–458×10³/μL). Mean PT was 9.9 INR (range, 0.9–18.2 INR) and mean aPTT was 103 seconds (range, 22.7–180 seconds) (Table 1).

Duodenal intramural hematoma was detected in 4 patients (10.8%), jejunal intramural hematoma in 16 (43.2%), and ileal intramural hematoma in 17 (45.9%). Cardiac arrhythmia occurred significantly more frequently in patients with jejunal intramural hematoma (81.3%) than in those with ileal (35.3%) and duodenal intramural (25.0%) hematomas (P =0.012). All 3 patients who were treated with systemic chemotherapy for malignancy had duodenal involvement. The Charlson comorbidity index in patients with duodenal intramural hematoma (6.8±2.5) was significantly higher than in patients with ileal intramural hematoma (3.9±1.9) (P =0.025). Patients who used warfarin had a predominance of jejunoileal involvement, although the difference among the locations of SISBH was not statistically significant. Compared to jejunal and ileal involvement, duodenal intramural hematoma was significantly associated with low levels of WBC, hemoglobin, and platelets in the blood (Table 1).

The clinical characteristics and treatment outcomes of the 4 patients with SISBH with duodenal involvement are shown in Supplementary Table 1. Among them, only 1 patient (25.0%; No. 4) had duodenal intramural hematoma related to coagulopathy, with a prolongation of PT and aPTT because of warfarin use. The 3 remaining patients with malignancy (No. 1-3) had duodenal intramural hematoma that developed in relation to thrombocytopenia within the normal range of PT and aPTT. Cytarabine and idarubicin had been administrated for the treatment of acute myeloid leukemia in 2 patients (patients No. 1 and 2) before presenting with a duodenal intramural hematoma. Patient No. 1 presented with sudden onset abdominal pain on the ninth day of the induction chemotherapy. At presentation, the patient’s platelet count was 66×10³/μL, and the low platelet count persisted for about 4 weeks thereafter. Patient No. 2 presented with vomiting and hematemesis on the 62nd day of the induction chemotherapy. This patient’s initial platelet count was 28×10³/μL. On the 5th day after admission, he was discharged without any remaining clinical signs or symptoms. Neither patient used any anticoagulant or antiplatelet therapies. Patient No. 3 had pancreatic cancer, which had been treated with gemcitabine and cisplatin, and had been on maintenance LMWH for 8 months to treat pulmonary thromboembolism. He visited the emergency department for vomiting with melena the 34th day after his last administration of chemotherapeutic agents. His initial platelet count was 19×10³/μL. His symptoms subsided after discontinuing LMWH and correction of severe thrombocytopenia.

All patients were treated successfully with conservative therapy including fasting, blood component transfusion, and/or vitamin K injections. None of the patients underwent surgical therapy for SISBH-related complications. Overt GI bleeding was detected in 14 (37.8%) patients with SISBH. Among them, GI bleeding in all patients improved spontaneously by conservative therapy, except 1 patient who underwent angiographic embolization for ileal angiodysplasias although there was no evidence of active bleeding at the time of angiography. Multi-segmental hematoma in proximal to mid-jejunum was detected only in 1 patient (2.7%) with SISBH, an 80-year-old woman who had been taking warfarin for a cerebral infarction and cardiovascular disease. She complained of abdominal pain and nausea, and the initial laboratory findings showed prolonged PT (9.99 INR). She also improved without any complication by conservative therapy including fasting, parenteral nutrition, a transfusion of fresh frozen plasma and a vitamin K injection within 7 days of hospitalization. Moreover, there was no disease-related mortality in the study population. The mean length of fasting and the hospital stay were 3.38 days (range, 0–22 days) and 9.35 days (range, 1–70 days), respectively. Fourteen patients (37.8%) were hospitalized for more than 7 days (Table 2).

Among the 30 patients who were treated with warfarin, 26 (86.7%) continued warfarin after clinical improvement of the SISBH. Warfarin was switched to dual antiplatelet therapy with aspirin and clopidogrel in 2 patients, and to a novel oral anticoagulant (rivaroxaban and dabigatran) in 2 other patients. During the mean follow-up duration of 49.9 months (range, 5–153 months), recurrent SISBH developed in only 1 patient (2.7%) who was on warfarin therapy for a prosthetic heart valve 12 years after the presentation of the first SISBH.

Prolonged hospital stay of more than 7 days was significantly associated with female gender (P =0.045), lower body weight (P =0.011), a history of cerebrovascular accidents (P =0.039), lower WBC counts (P =0.017), lower hemoglobin level (P =0.016), and lower albumin level (P =0.013), respectively (Supplementary Table 2). The multivariate analysis revealed that body weight less than 60 kg (OR, 12.213; 95% CI, 1.755–84.998; P =0.011) and a history of cerebrovascular accident (OR, 6.667; 95% CI, 1.121–39.650; P =0.037) were independent predictors for prolonged hospital stay (Table 3).