Monocentric case-series of mesenteric vascular disease occurred in the first month of the COVID-19 pandemic

Objectives we describe Coronavirus Disease (COVID-19) patients also manifesting gastro-intestinal symptoms. Methods five women, between the ages of 32 and 82 years old, were admitted for acute abdomen, and received a nasopharyngeal swab for COVID-19 screening, lab test analysis, and contrast thoraco-abdominal CT-scan. All presented leukocytosis, different localizations of visceral vessels thrombosis and ischemia, and COVID-19. Results emergency laparotomy was accepted by all but 1, who died after 5 days. Postoperatively, 1 died of multi-organ failure, 3 were discharged home after 14, 8 and 10 days respectively, under anti-platelet and anticoagulation treatment. Conclusions in COVID-19 patients with acute abdomen, abdominal contrast CT-scans should be systematically extended to the thorax to detect visceral COVID-19 initial pulmonary signs. Emergency laparotomy and visceral arteries thrombectomy could be necessary.


Introduction
Gastrointestinal involvement in COVID-19 occurs in up to 39% of patients. 1 The positive staining of angiotensin I converting enzyme 2 (ACE2, the viral host receptor) is expressed in gastrointestinal epithelial cells present in the stool of patients tested positive for the RNA of SARS-COV-2 (Severe Acute Respiratory Syndrome-Coronavirus-2, the virus responsible for COVID-19). Evidence suggests SARS-COV-2 fecal-oral transmission. In patients with pulmonary symptoms, the beta-coronavirus responsible for COVID-19 disease can cause gastrointestinal infection possibly evolving in hemorrhagic colitis or bowel ischemia. 2 , 3 Moreover, four recent studies have highlighted a coexisting hypercoagulable state that can lead to mesenteric arterial thromboses. 4-7 ✩ Note: this research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. *

Material and methods
The expected medium number of patients presenting with mesenteric ischemia to our institution before COVID-19 pandemic was 2-3 patients per year. We describe our experience with patients manifesting bowel ischemia, and found affected by COVID-19: being positive for the reverse transcription polymerase chain reaction from nasopharyngeal swab. All patients were admitted to the ER, received airway and breathing support along the recommended therapeutic long-term subcutaneous enoxaparin sodium and life-long 100 mg/daily aspirin, underwent a thoraco-abdominal contrast CT-scan, and agreed to allow the authors to publish their case details and images.

Theory
In the current pandemic era, patients presenting acute abdominal pain should be suspected as COVID-19 positive.

Calculation
The abdominal contrast CT-scan, usually performed in patients with acute abdomen, should be extended to the thorax to promptly identify an eventual pulmonary involvement.

Results
Five women, between the ages of 32 and 82 years old, were admitted in the ER on March 2020, the 1st month of the pandemic. We experienced no other patients with mesenteric arterial/venous thrombosis associated with COVID-19 in the rest of 2020 and in the following year, at least until now.

Case series
The first patient, 82 years old, presented abdominal pain, mild respiratory symptoms, leukocytosis (23 x 10 9 /L), lymphopenia (2 x 10 9 /L), mild thrombocytosis (497 x 10 9 /L), elevated D-dimer level (7.8 mg/L), and normal activated partial thromboplastin time (aPTT). Images demonstrated bilateral pulmonary lung fields with a ground glass appearance, superior mesenteric artery acute thrombotic occlusion, and segmental small bowel ischemia ( Fig. 1 A-D). In a previous CT-scan, the SMA presented wall calcification and segmental atherosclerotic stenosis. The patient underwent successful emergency superior mesenteric artery embolectomy, and a 90 cm small bowel resection. ICU course was uneventful: the patient was discharged home on post-operative day 14.
The third patient, a 32 years old diabetic, presented vomiting, diarrhea, cough, cardiac arrest (the patient underwent prompt cardiopulmonary resuscitation and was intubated), leukocytosis (29,9x10 9 /L), lymphopenia (2,2 x 10 9 /L), elevated D-dimer level (6,79 mg/L), and prolonged aPTT (55''). Images showed subtotal bowel ischemia, mesenteric veins thrombosis, and signs of portal hypertension ( Fig. 3 ). Emergency bowel resection with laparostomy was undertaken for a small intestine transmural necrosis extended to the ileocecal valve. We assume this was a case of intestinal gangrene caused by splanchnic venous thrombosis. In the postoperative, subcutaneous enoxaparin sodium at the dosage of 6000 IU twice daily was given, but ICU course was unfavorable: the patient died of multi-organ failure on post-operative day 3.
The fifth patient, 68 years old, presented abdominal pain, fever, cough over the previous 5 days, guarding in the left upper quadrant, with worsening of pain upon deep inspiration, leukocytosis (21.3 x 10 9 /L), fibrin degradation product = 7.1 mcg/mL, elevated lactate dehydrogenase and C-reactive protein levels (480 U/L and 49 mg/L, respectively), and prolonged aPTT (74''). Images showed splenic artery thrombosis ( Fig. 5 A and B), and partial spleen infarction: a splenectomy was not necessary since, progressively, abdominal pain disappeared, and leukocytosis and lactate dehydrogenase levels normalized. ICU course was uneventful, and the patient was home discharged on post-operative day 10.
Patients 1, 4, and 5 did not experience any recurrent thrombotic events at the 6-month follow-up.

Discussion
Gastrointestinal manifestations have been reported in 3-39% of patients with COVID-19, and in 3-10% of those initially presenting isolated mild gastrointestinal symptoms and later pulmonary infection. 6 , 8 SARS-COV-2 RNA has been found on fecal sample of patients with hemorrhagic colitis and bloody diarrhea. 2 Previous evidences have shown virus replication in the bowel, consequently causing pro-thrombotic sequelae not confined to the pulmonary circulation, with fatal complications like mesenteric ischemia or bowel wall necrosis. 4 The pro-thrombotic consequences of SARS-COV-2 may be directly due to its architecture. The membrane of the virus presents a Spike protein (S protein) which binds to the ACE2 receptor located on the membrane of host cells. ACE2 is hyper-expressed in the lungs, intestine, oral mucosa, liver, and endothelium. The binding of SARS-COV-2 to ACE2 reduces the degradation of angiotensin II, which in turn promotes the production of IL-6 and induces a cytokine storm. It has been demonstrated that angiotensin II promotes the expression of tissue factor and plasminogen activator inhibitor-1 by endothelial cells, leading to a hypercoagulable state. 9 In our series, the main symptom wasn't pulmonary distress, but acute abdomen together with female sex, diabetes, and radiologic signs of ground glass pulmonary opacity at CT-scan.
All of our patients received therapeutic doses of enoxaparin sodium. Treatment with low-molecular-weight heparin is necessary for all hospitalized patients with COVID-19. The recommended dosages are 40 mg/daily or 30 mg/daily, in patients with creatinine clearance of more than 30 mL/min or between 15 and 30 mL/min, respectively; unfractionated heparin is recommended when creatinine clearance is less than 15 mL/min. 10 , 11 COVID-19 patients requiring ICU are considered to be at highest risk of thrombotic complications and death, and necessitate higher doses of anticoagulants. It is recommended to increase the dose by 30% in patients with BMIs > 40 kg/m. 2 , 12 Patients with preexisting significant comorbidities should receive anticoagulants for at least three months after hospital discharge and undergo clotting time, platelet counts, and D-dimer level follow-ups. Macrovascular thrombosis can cause occlusion of visceral vessels determining visceral ischemia.
In our series, all patients were women; female gender has been found to be more frequently associated with known hypercoagulable disorders. Recently published papers have reported associated coagulopathy disorders in COVID-19 patients. These studies have highlighted the presence of a coexisting hypercoagulable state, which might be associated with higher mortality. 13 Hospitalized patients with moderate/severe COVID-19, and those with poorer outcomes, are noted to have prolonged aPTT and elevated D-dimer values. 14 Hypercoagulability, induced by a systemic inflammatory state and endothelial activation, may lead to mesen- teric vascular thrombosis. A recent evidence has shown small bowel vessel thrombosis involving the submucosal arterioles, thereby pointing to an in-situ thrombosis of small mesenteric vessels rather than an embolic event. 15 The histology pattern of the bowel, secondary to a mesenteric thrombosis, showed a prominent endotheliitis of the submucosa with a clear evidence of direct viral infection of the endothelial cells such as extended swelling with mononuclear cell infiltrate. 16 COVID-19 is associated with increased level of angiotensin and stimulates other prothrombotic proteins such as factor VIII, tissue factor, von Willebrand factor, and plasminogen activation inhibitor-1. 10 Macrovascular thrombi can be observed in both visceral venous and arterial circulation, even in the absence of severe respiratory symptoms.

Conclusions
Mesenteric and venous thrombosis should be considered in patients with acute abdomen and COVID-19 positive. Thoraco-abdominal CTA should be considered as a diagnostic test when indicated. A common CT finding in our patient series was thick-walled, edematous and dilated bowel, suspicious of acute mesenteric ischemia. Given our low numbers, a multicenter retrospective study would be helpful to conclude whether the achievement of a systemic thoracic scanner is mandatory.
In our series, acute abdomen with bowel ischemia in COVID-19 is associated with poor prognosis, and high rate of mortality. Emergency laparotomy and eventually visceral arterial thrombectomy should be considered in these patients, whenever possible.

Declaration of Competing Interest
No competing interests to declare.