Submucosal Esophageal Hematoma: A Rare Hemorrhagic Complication Following Neuroendovascular Therapy

Abstract

Objective: Submucosal esophageal hematoma (SEH) is a rare complication of neuroendovascular therapy, and there are insufficient data on the management of antithrombotic therapy in cases of SEH. We report a case of SEH following flow diverter stenting for an unruptured cerebral aneurysm, successfully managed with conservative treatment, including short-term interruption of antiplatelet therapy.

Case Presentation: An 80-year-old woman on clopidogrel and aspirin underwent Pipeline flow diversion with adjunctive coil embolization for an unruptured right internal carotid-posterior communicating artery aneurysm under general anesthesia without complications. Postoperatively, the patient developed chest pain, and CT revealed wall thickening from the middle to lower esophagus, leading to a diagnosis of SEH. SEH in this case was likely caused by a combination of antiplatelet therapy, anticoagulants, nasogastric tube insertion, and mechanical stimulation from intubation and extubation during the operation. The patient was managed conservatively with fasting and discontinuation of antiplatelet therapy. After CT confirmed hemostasis, antiplatelet therapy was resumed with intravenous ozagrel sodium on postoperative day 3, switching to oral prasugrel on day 7. Upper gastrointestinal endoscopy (UGE) on day 8 showed the submucosal hematoma replaced by ulcers and fistula formation. UGE on day 15 showed improvement, and CT on day 23 confirmed hematoma resolution. The patient was discharged on day 24 without symptoms or complications.

Conclusion: In addition to previously reported cases, the presented case suggests that conservative management with temporary antiplatelet interruption and early resumption after hemostasis can lead to favorable outcomes in SEH cases associated with neuroendovascular therapy requiring antiplatelet therapy.

Introduction

Submucosal esophageal hematoma (SEH) is an uncommon cause of submucosal bleeding in the esophagus and is considered part of the spectrum of esophageal wall injuries, including mucosal tears (e.g., Mallory–Weiss syndrome) and full-thickness perforations (e.g., Boerhaave’s syndrome).¹⁾ Causes of SEH include intrinsic factors such as sudden pressure increases due to vomiting or coughing, antiplatelet²⁾ or anticoagulant therapy, hematologic conditions like idiopathic thrombocytopenic purpura,³⁾ and mechanical injuries, such as those caused by food intake,⁴⁾ nasogastric tube insertion, upper endoscopy, or transesophageal echocardiography,³⁾ as well as obstructive gastrointestinal disorders like achalasia.⁴⁾ Although rare, cases of SEH associated with neuroendovascular therapy have also been reported.^5–12)

Although SEH is generally managed conservatively, it can sometimes become severe and be accompanied by hemorrhagic shock.^8,11,12) Hemostasis should be prioritized after the onset of SEH by discontinuing antithrombotic therapy and, if necessary, performing endoscopic procedures.^8,12) However, insufficient data exist regarding the safe duration of antiplatelet therapy interruption or whether resuming antithrombotic therapy increases the risk of hematoma enlargement in SEH cases associated with neuroendovascular therapy. Thus, clinicians may face the dilemma of simultaneously managing hemorrhagic and ischemic complications in SEH associated with neuroendovascular therapy, particularly when performing procedures requiring potent postoperative antithrombotic therapy, such as flow diverter stenting. We herein report a rare case of SEH following flow diverter stenting with adjunctive coil embolization for an unruptured cerebral aneurysm, successfully managed with conservative treatment, including short-term interruption of antiplatelet therapy. Further, we discuss management strategies for SEH associated with neuroendovascular therapy based on the characteristics of previously reported cases. This case report was conducted in accordance with the ethical guidelines of our institution. Written informed consent was obtained from the patient for the publication of this report.

Case Presentation

An 80-year-old woman (height, 159 cm; body weight, 49 kg) was admitted for endovascular treatment of an unruptured right internal carotid-posterior communicating artery aneurysm that had enlarged over the preceding 2 years (Fig. 1A, arrow). The patient had a medical history of dyslipidemia and had been treated with rosuvastatin at 2.5 mg/day. She had been receiving antiplatelet therapy with clopidogrel at 75 mg/day and aspirin at 100 mg/day for the prevention of perioperative ischemic complications over the preceding 2 weeks. Preoperative laboratory tests showed a normal complete blood count (hemoglobin, 13.2 g/dL; platelet count, 17.8 × 10⁴/μL) and no coagulation disturbance (international normalized ratio, 0.99; fibrinogen level, 246 mg/dL; activated partial thromboplastin time, 26.3 s). Preoperatively, platelet function was assessed using thromboelastography (TEG). The TEG 6s system (Haemonetics, Boston, MA, USA) showed a maximum amplitude in response to adenosine diphosphate (MA-ADP) of 51.5 mm (reference range: 19.8–43.2 mm¹³⁾) and to arachidonic acid (MA-AA) of 15.1 mm (reference range: 18.9–37.7 mm¹³⁾), suggesting the possibility of an excessive antiplatelet effect.

Fig. 1 Intraoperative cerebral angiography. Preoperative cerebral angiography showed a wide-necked, bilobed saccular aneurysm in the C2 segment of the right ICA (A, arrows). After coil embolization, a flow diverter stent (Pipeline Flex Embolization Device with Shield Technology 3.5–16 mm; Medtronic, Dublin, Ireland) was placed from the C1 segment to the C3 segment of the ICA (B, arrows and arrowheads). Postoperative angiography demonstrated partial dome filling of the aneurysm (C, arrows). ICA, internal carotid artery

The patient underwent Pipeline flow diversion with adjunctive coil embolization under general anesthesia on hospital day 2 without any particular intraoperative complications (Fig. 1B, arrows and arrowheads). Tracheal intubation and insertion of the nasogastric tube were achieved without event. The nasogastric tube was left open to room air, and no spontaneous reflux of gastric contents was observed. Intravenous heparin was administered during the procedure to prevent thrombotic complications, aiming to maintain the activated clotting time (ACT) between 250 and 300 s. The initial ACT was 185 s, followed by 268, 304, and 298 s, and was 351 s (1.9 times the preoperative baseline) at the end of surgery. Protamine was not administered. Systolic blood pressure was maintained at around 80–120 mmHg during surgery, and no abnormalities in vital signs were observed. After awakening from anesthesia following extubation, the patient immediately reported anterior chest pain. Contrast-enhanced CT revealed wall thickening in the middle to lower esophagus (Fig. 2A and 2B, arrowheads) and contrast extravasation in the lower esophagus (Fig. 2A and 2B, arrow), leading to a diagnosis of SEH. Laboratory testing showed no abnormal findings, including in the complete blood count and coagulation functions. She was treated conservatively with fasting and discontinuation of antiplatelet therapy, and symptoms gradually improved. During the fasting period, nutritional management was provided through intravenous hyperalimentation. CT on postoperative day 2 showed no expansion of the hematoma (figure not shown), suggesting that hemostasis had been achieved. Intravenous antiplatelet therapy with ozagrel sodium at 80 mg twice daily was initiated on postoperative day 3, switching to oral prasugrel at 3.75 mg on postoperative day 7. Upper gastrointestinal endoscopy (UGE) performed on postoperative day 8 revealed that the submucosal hematoma had resolved, leaving mucosal erosion and multiple ulcerations extending from the thoracic esophagus to the abdominal esophagus, along with a fistula in the distal esophagus (Fig. 3A). Chest pain had almost completely resolved by postoperative day 14. UGE on postoperative day 15 showed improvements in mucosal findings with epithelialization of the previously identified ulcers and fistula (Fig. 3B), and a solid diet was initiated. CT on postoperative day 23 indicated that swelling from the submucosal hematoma in the esophagus had resolved (Supplementary Fig. A and B). Repeated MRI performed postoperatively showed no ischemic complications. The patient was discharged on postoperative day 24 without any symptoms.

Fig. 2 Postoperative contrast-enhanced CT. A contrast-enhanced CT immediately after onset showed wall thickening of the middle to lower esophagus (arrowheads) and focal contrast extravasation in the lower esophagus (arrow) (A, axial; B, coronal section).

Fig. 3 An UGE on postoperative days 8 and 15. UGE on postoperative day 8 revealed the resolution of the submucosal hematoma, along with multiple ulcerations extending from the thoracic esophagus to the abdominal esophagus, accompanied by fistula formation (A, asterisk). UGE on postoperative day 15 revealed improvements in the mucosal findings, including epithelialization of the ulcers and fistula formation (B, asterisk). UGE, upper gastrointestinal endoscopy

Discussion

In the present case, the development of SEH may have been influenced by multiple factors. First, the effect of antiplatelet therapy is a plausible contributor. The patient had been maintained preoperatively on dual antiplatelet therapy with clopidogrel and aspirin. Notably, while the MA-ADP value was within the reference range, the MA-AA value for aspirin was below the reference range,¹³⁾ suggesting the possibility of an excessive antiplatelet effect. This is the first reported case of SEH associated with neuroendovascular therapy in which platelet aggregation was evaluated using TEG. However, sufficient data on the recommended TEG parameters for antiplatelet therapy in neuroendovascular procedures remain limited. Second, perioperative anticoagulation with heparin may have played a role. No established method with definitive evidence exists regarding anticoagulation protocols for preventing thromboembolic events in neuroendovascular therapy. According to Japanese guidelines, the ACT should be maintained within 250–300 s or 2.0–2.5 times the preoperative value.¹⁴⁾ In this case, we aimed to keep the ACT within this range, but the final ACT extended to 351 s. This slightly exceeded the target, although this prolongation was not considered clinically significant. Third, mechanical stress from insertion of the nasogastric tube could have contributed. Although the tube was inserted and removed without resistance, some stress on the esophageal wall may still have been induced, leading to submucosal bleeding. The fistula observed in the distal esophagus during endoscopic examination may have been caused by mechanical stimulation from the insertion of the nasogastric tube, which is considered the primary contributing factor to the development of SEH. Fourth, the effect of tracheal intubation cannot be ruled out. Both intubation and extubation were performed without complications, but the mechanical stimuli associated with these procedures may have increased intrathoracic and intraesophageal pressures, predisposing the esophagus to minor mucosal injury. Case reports have described SEH associated with neuroendovascular therapy in which heparin was considered the cause.^6,11) However, as various factors in neuroendovascular therapy can contribute to the development of SEH,^7–9) these factors appear likely to interact in a complex manner to induce its occurrence in the present case.

To the best of our knowledge, 10 cases of SEH occurring during the perioperative period of neuroendovascular therapy have been reported in 8 articles.^5–12) The clinical characteristics of cases, including the present case, are shown in Table 1. Of these, 9 cases underwent coil embolization (including 2 cases of balloon-assisted coil embolization^6,11) and 3 cases of stent-assisted coil embolization^9,12)), and 1 case involved the use of a flow diverter.¹⁰⁾ Preoperative antiplatelet therapy consisted of dual antiplatelet therapy with clopidogrel and aspirin in 6 cases, single antiplatelet therapy with aspirin in 2 cases,^7,9) and no antiplatelet therapy in 2 cases.^5,11) Intraoperative anticoagulation with heparin was administered in all cases, except for 1 case of ruptured aneurysm.¹¹⁾ Two cases also received postoperative anticoagulation with intravenous argatroban,^8,10) while 1 case received intravenous heparin¹¹⁾ to prevent thrombotic complications. Among the 4 cases for which intraoperative ACT values were reported,^6–8,10) the maximum ACT ranged from 254 to 367 s, representing 1.6–2.7 times the preoperative baseline, with no cases showing extreme prolongation. One case exhibited excessive prolongation of activated partial thromboplastin tim (APTT) due to postoperative heparin at the time of onset, which was considered the main cause of SEH.¹¹⁾ However, none of the other cases showed coagulation abnormalities at the time of onset. Conservative treatment was employed in all cases and resulted in favorable outcomes with no residual complications, except for 1 patient who died due to neurological and hemodynamic deterioration caused by subarachnoid hemorrhage.¹¹⁾ However, 3 patients experienced hemorrhagic shock in the acute phase^8,11,12) and required transfusions and hemostatic intervention using a Sengstaken–Blakemore tube^8,12) and endoscopic clipping.¹²⁾ Therefore, it is important to prioritize achieving hemostasis and stabilizing hemodynamics when an SEH occurs. Postoperative antiplatelet therapy was discontinued in 6 of the 8 cases receiving antiplatelet therapy,^7–10,12) resumed after interruption in 3 cases,^9,10,12) and continued at a reduced dose in 1 case.⁹⁾ In 2 of the 3 cases where antiplatelet therapy was resumed, administration was restarted on postoperative days 1 and 3 (details for the other cases were not provided).^10,12) Including the present case, no ischemic complications occurred in patients who temporarily discontinued antiplatelet therapy, indicating that short-term interruption of antiplatelet therapy for a few days may be considered reasonable. In addition, including our case, no enlargement of hematoma was observed in cases where antiplatelet therapy was resumed after interruption or continued at a reduced dose.^9,10,12) Therefore, if imaging confirms that the hematoma has not expanded and hemostasis has been achieved, the risk of hematoma enlargement following resumption of antiplatelet therapy is presumed to be low and early resumption of antiplatelet therapy may be appropriate. This is the first report to discuss the management of antithrombotic treatment for SEH associated with neuroendovascular therapy based on previously reported cases.

Table 1 Clinical characteristics of cases of submucosal esophageal hematoma associated with neuroendovascular therapy

Ref No.	Sex	Age	Height (cm)	BW (kg)	Underlying Disease	EVT	AP	ACT (s) range	ED tube	Symptoms	Timing of onset	Initial diagnostic imaging	Treatment	Cessation of AP	Resumption of AP (PO day)	Initiation of oral intake (PO day)	Hematoma Resolution (PO day)	Prognosis
6)	F	67	NA	NA	Unruptured aneurysm	CE	None	NA	NA	V, H	PO 1st day	CT: hematoma in middle to lower ES	Conservative	NA	–	NA	NA	Good
7)	F	70	146	48	Unruptured aneurysm	BA CE	ASA CPG	137–374	NA	V, EP, BP	3 hrs after surgery	CT: hematoma in middle to lower ES	Conservative	NA	NA	10th day	7th day	Good
8)	F	70	155	52	Unruptured aneurysm	CE	ASA	123–306	Yes	V, EP, CP BP, cold sweats	70 min after surgery	CT: hematoma in middle ES UGE: submucosal hematoma in upper to lower ES	Conservative	Yes	No	5th day	4th day	Good
9)	F	75	154	49	Unruptured aneurysm	CE	ASA CPG	141–316	Yes	V, CP, H, S, retrosternal discomfort	24 min after surgery	CT: hematoma in entire ES UGE: submucosal hematoma in middle to lower ES, laceration with bleeding	Conservative, tracheal intubation, transfusion, SB tube	Yes	No	7th day	7th day	Good
10)	F	65	150.2	48.2	Unruptured aneurysm	DC CE	ASA	NA	Yes	EP, H	Several hrs after surgery	CT: hematoma in middle ES UGE: submucosal hematoma in middle ES	Conservative	Yes	No	6th day	6th day	Good
10)	F	73	151.2	44.8	Unruptured aneurysm	SA CE	ASA CPG	NA	NA	EP, H	NA	NA	Conservative	Yes	Yes	NA	NA	Good
10)	F	65	159.5	39.2	Unruptured aneurysm	SA CE	ASA CPG	NA	NA	EP	NA	NA	Conservative	No (Continued at a reduced dose)	–	NA	NA	Good
11)	F	75	134	37	Unruptured aneurysm	FD	ASA CPG	159–254	Yes	H	2 hrs after surgery	CT: hematoma in middle ES UGE: submucosal hematoma in upper to middle ES	Conservative, transfusoin	Yes	Yes 3rd day	NA	11th day	Good
12)	F	68	NA	NA	Ruptured aneurysm	BA CE	None	NA	Yes	H	PO 2nd day	UGE: submucosal hematoma in middle to lower ES	Conservative, transfusion	–	–	NA	NA	Deceased
13)	F	73	155	53	Unruptured aneurysm	SA CE	ASA CPG	NA	Yes	H, S, chest discomfort	3.5 hrs after surgery	CT: hematoma in middle to lower ES UGE: submucosal hematoma in middle to lower ES, laceration and bleeding in esophagogastric junction	Conservative, Transfusion, SB tube, endoscopic clipping	Yes	Yes 1st day	10th day	10th day	Good
This case	F	80	159	49	Unruptured aneurysm	FD, CE	ASA CPG	185–351	Yes	CP	Immediately after surgery	CT: hematoma in middle to lower ES	Conservative	Yes	Yes 3rd day	15th day	10th day	Good

ACT, activated clotting time; AP, antiplatelets; ASA, acetylsalicylic acid; BA, balloon-assisted; BP, back pain; BW, body weight; CE, coil embolization; CP, chest pain; CPG, clopidogrel; DC, double catheter; ED, elemental diet; EP, epigastric pain; ES, esophagus; EVT, endovascular therapy; F, female; FD, flow diverter; H, hematemesis; NA, not available; PO, postoperative; Ref. no, reference number; S, shock; s, seconds; SA, stent-assisted; SB, Sengstaken–Blakemore; UGE, upper gastrointestinal examination; V, vomiting

An interesting characteristic of cases with SEH is that, in addition to being older women, they tend to have low body weight. Including this case, the average weight of patients in SEH cases, excluding the 2 cases without weight records, was 46.7 kg, which is lower than the average for Japanese women (in their 60 s, 54.7 kg; 70 or older, 51.1 kg).¹⁵⁾ The relationship between body weight and bleeding risk during antiplatelet therapy is not fully understood, but some reports have suggested that low body weight increases the bleeding risk in association with P2Y12 inhibitors during antiplatelet therapy.^16,17) In addition, several studies have reported low body weight as a risk factor for hemorrhagic complications among patients with venous thrombosis¹⁸⁾ or atrial fibrillation¹⁹⁾ receiving anticoagulation therapy. Based on these findings, since perioperative antiplatelet and anticoagulant therapy is essential in neuroendovascular procedures, and neuroendovascular therapy additionally involves endotracheal intubation and nasogastric tube insertion under general anesthesia, it can be considered a treatment procedure that may pose a potential risk of SEH in patients with low body weight. Further investigation is required to explore the relationship between low body weight and SEH associated with neuroendovascular therapy in a larger case series. In addition, further investigation through subsequent studies is needed to determine the optimal perioperative antithrombotic therapy for patients at risk of hemorrhagic complications associated with neuroendovascular therapy, particularly by evaluating the effectiveness of tailored antiplatelet therapy based on platelet aggregation tests.

Conclusion

We have reported a rare case of SEH following flow diverter stenting with adjunctive coil embolization for an unruptured cerebral aneurysm. When symptoms such as chest pain or hematemesis are identified after neuroendovascular therapy, SEH should be included among the differential diagnoses. The present case and previously reported cases suggest that conservative management with temporary interruption of antiplatelet therapy and early resumption after confirming hemostasis can lead to favorable outcomes in SEH cases associated with neuroendovascular therapy requiring antiplatelet therapy.

Disclosure Statement

The authors declare that they have no conflicts of interest.

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