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Splenic Artery Infarct Requiring Surgery: A Rare Complication of COVID-19 Infection

Introduction. Coronavirus disease (COVID-19) from SARS-CoV-2 infection is linked to a hypercoagulable state, leading to arterial and venous thrombotic events, of which pulmonary embolism is the most frequent. However, arterial thromboembolisms may also occur as visceral infracts in unusual sites, such as the renal, splenic, and intestinal arteries. Case Report. A 46-year-old unvaccinated male with a COVID-19 infection was admitted to the COVID-19 isolation ward with symptoms of respiratory infection. He complained of epigastric pain and fever for several days; radiological imaging of the abdomen revealed complete splenic arterial occlusion due to a large infarct. He was treated with low molecular weight heparin (enoxaparin) in therapeutic doses, resulting in minimal improvement. However, the pain worsened, and eventually, a laparotomy and splenectomy were performed. He was hospitalized for another 36 days before he was discharged in good condition. A second surgery was performed to remove a noninfected encapsulated hematoma from the subdiaphragmatic space. The patient remained healthy afterward, with no relapses. Discussion. Although rare, the number of cases of visceral infarcts in COVID-19 patients has increased. Splenic artery infarct is an exceptional case of acute abdominal pain that can be treated successfully with anticoagulant medication. Splenectomy may be required to manage refractory pain after failure of conservative management.


Introduction
Coronavirus disease-2019 (COVID-19) is a viral infection caused by a member of the coronavirus family, the severe acute respiratory syndrome coronavirous-2 (SARS-CoV-2) [1,2]. The disease was first reported in China in December 2019; since then, it has spread all over the world, turning into a pandemic, causing millions of deaths and infecting more than five hundreds of millions of people [3][4][5]. The clinical presentation of COVID-19 may range from asymptomatic disease to severe illness, but the virus predominantly attacks the pulmonary system, leading to acute lung injury and diffuse alveolar damage [3]. However, it has been well established that the effects of COVID-19 are not restricted to the lungs and can involve multiple organs, progressing into a systemic disease [1,3].
SARS-CoV-2 infection has been linked to a hypercoagulable state, leading to diverse arterial and venous thrombotic events [6][7][8]. The latter has been recorded in several organs, such as venous thromboembolism and disseminated intravascular coagulation (DIC) [6,9,10]. Of these events, pulmonary embolism is the most prevalent and may be present, even in the absence of classic respiratory symptoms and fever [8,11,12]. On the other hand, arterial thrombotic events are less commonly described [6,9,10]. Arterial thromboembolism encompasses a variety of conditions,   Case Reports in Surgery including myocardial infarction, stroke, and visceral infarcts, such as renal, splenic, and intestinal infarcts [2,13,14]. Despite their rarity, abdominal visceral infarcts are increasingly being detected and documented as the disease is spreading. Herein, we present the case of a middle-aged man with COVID-19 disease and severe acute splenic artery occlusion warranting surgery despite receiving therapeutic anticoagulants.

Case Presentation
A 46-year-old Caucasian male presented to the emergency department of a secondary care hospital complaining of a gradually progressing shortness of breath, fever, dry cough, and dyspnea. He did not receive any vaccination against SARS-COV-2 and had tested positive for COVID-19 one week before his presentation, but he did not seek any medical attention since the appearance of symptoms. On clinical examination, the patient appeared tachypneic, stressed, and had severe hypoxia when breathing air (oxygen saturation ðSpO 2 Þ = 80%, partial pressure of oxygen ðpO 2 Þ = 52:6 mmHg), and febrile (body temperature > 37:5°C). The initial X-ray of the chest revealed bilateral diffuse infiltrations in the middle and lower pneumonic fields, more so on the right lung ( Figure 1).
Other laboratory tests were unremarkable (D-dimer and coagulation times were normal), and so were the rest of his vital signs. Although he had a history of chronic asthma, he was not taking any medication and remained free from asthmatic crisis for years. Additionally, he reported a history of chronic hepatitis B (HBV) without having any symptom relevant to this chronic infection. Also, he mentioned having depression-like symptoms without treatment.
The patient was transferred immediately to the special isolation ward made for the coronavirus-infected patients, where he was put on a high flow nasal cannula (HFNC) for high flow oxygenation. He remained on HFNC for 14 days and was then switched to 50% oxygenation with a venturi mask. During the first week, he was febrile, which resolved in the second week. During the hospital stay, he complained of mild epigastric pain, which was initially related to the cough; when the symptoms worsened, he was scheduled for computed tomography (CT) of the abdomen and the thorax (on day 2 of hospital admission). The first CT scan did not show any abdominal pathology, but the pulmonary findings of infiltrations, pyknosis, diffuse ground-glass opacities, and diffuse alveolar damage were typical of a SARS-COV-2 infection (Figure 2).
The patient's epigastric pain was constant and could not be relieved with any drug; eventually, the pain intensity  3 Case Reports in Surgery increased so much as to hamper the patient's resting phase. A second CT scan of the abdomen was done on day 14 which revealed a complete obstruction of the splenic artery from a large splenic infract and complete absence of blood circulation in the spleen ( Figure 3).
It was decided that the patient be managed conservatively with low molecular weight heparin (LMWH)-enoxaparin 6000 units: 0:6 mL × 2 subcutaneously (SC). He had minimal relief from pain and was admitted for portosplenic triplex and abdominal ultrasonography (US), which revealed that the splenic artery obstruction was complete and there was normal flow of blood inside the splenic and portal vein; the rest of the findings were unremarkable. Treatment with enoxaparin was continued for six days; however, on the seventh day (day 21 of hospital admission), the patient's health deteriorated clinically. Epigastric pain increased, and pulmo-nary function declined, accompanied by high fever and unilateral pleuritis. A surgical consultation was sought, and emergency surgery was scheduled the same day.
The patient underwent laparotomy and splenectomy, which went well; his postoperative course was uneventful. All postoperative laboratory parameters were within normal ranges besides an isolated elevation in C-reactive protein (CRP) levels (32 mg/dL at the 5 th postoperative day (day 26 of admission)). The patient also had a mild fever for a week postoperatively. Eventually, he was fully mobilized without the need for any supplementary oxygen. However, despite the improvement in his clinical condition, the patient continued to be febrile. On the 11 th postoperative day (day 32 of admission), he again complained of abdominal pain and was scheduled for a CT scan of the lungs and abdomen, which revealed a large fluid collection in the left subdiaphragmatic space that contained a solid encapsulated lesion with peripheral enhancement using intravenous contrast material and left pleural effusion accompanied by atelectasis of the left lung ( Figure 4).
Initially, the symptoms were believed to be due to the contamination of a hematoma in the splenic bed. Blood cultures were taken, and newer antibiotics were prescribed. The patient was followed-up for another 12 days until another surgical consultation was sought. Throughout this period, he experienced waves of febrile and afebrile episodes; abdominal pain, especially in the left subcostal area, was steady but well tolerated. All blood cultures tested negative for any possible microorganisms. All vaccines recommended after splenectomy against pneumococcus, Haemophilus influenzae, and meningococcus B and C were administered on the appropriate postoperative day according to the national vaccination policy of our country [15]. The attending consultant from the infection pathology unit, in coordination with the surgical team, decided to proceed with a second operation to evacuate the collection, which seemed to be the underlying cause of fever and pain.
The second operation was undertaken 24 days after the first surgery (i.e., on day 45 of admission). The incision scar from the previous surgery was used to approach the peritoneal cavity; a well-encapsulated hematoma was evacuated and copiously washed out until clean water could be suctioned from the suction device. There was no pus or dead tissues in any of the peritoneal spaces. Culture samples were taken from the extracted specimen, and a silicone drain was placed at the site of the splenectomy.
The postoperative course was uneventful, and the patient remained afebrile for 10 days before being discharged from the hospital on the 56 th day of his admission. Three days before his discharge, another CT scan of the chest was done, which confirmed permanent damage to his lungs caused by the coronavirus, a small residual hematoma in the left upper abdomen, and two small encapsulated collections at the base of the left lung ( Figure 5).
At the one-month follow-up visit, the patient was healthy, with no pulmonary difficulties or any other symptoms. He complied with all postoperative instructions regarding the postsplenectomy vaccination program, as well as the antithrombotic (enoxaparin 0, 6 IU for 6 months) and  Case Reports in Surgery antibiotic (amoxicillin 500 mg for 2 years) treatments; he was eventually vaccinated for coronavirus. It was also suggested to him to have blood tests for platelets, liver function, and clotting times every 3 months for the first year postoperatively and then consult a hematologist for further instructions. Seven months after his discharge, he is doing well, with no further complications (Table 1).

Discussion
Splenic infarction occurs as a result of obstruction of the splenic artery or its branches due to thrombosis or embolism [7,8]. The most common causes of arterial obstruction are neoplasms, cardioembolic events, and hematological diseases; however, this event has also been linked to acute viral infections, which often trigger states of hypercoagulability [16][17][18][19]. SARS-CoV-2 infection is also associated with a prothrombotic state and an increased risk of venous and arterial thromboembolism [8,11,20].
In the case of a SARS-CoV-2 infection, endothelial integrity and normal venous blood flow may be dysregulated due to endothelial or vascular injury, resulting in venous stasis [8,[21][22][23]. Additionally, the cytokine storm that accompanies the response to coronavirus infection may activate the coagulation system, causing systemic inflammation, endothelial cell activation, and the release of tissue factors, predisposing the tissue to thrombosis [2,6,17,20,22]. Also, there is an abnormal increase in the levels of coagulation parameters, such as D-dimers, fibrin degradation products (FDP), thromboelastographic (TEG) values, and prolonged coagulation times (like activated partial-thromboplastin time, aPTT), which may be associated with coronavirus infection [11,16,[24][25][26][27]. Platelet function is also known to be affected by COVID-19 disease, i.e., abnormal platelet function may explain arterial thrombosis resulting from an increase in platelet activation at suboptimal thresholds and an increase in platelet aggregation in COVID-19 patients [20,25]. Despite these hypotheses, the exact mechanism underlying coronavirus-induced coagulopathy remains undetermined [16,28,29].
The most common thrombotic event reportedly associated with COVID-19 is pulmonary embolism [11,12,16], whereas splanchnic vein or artery thrombosis is less common, and splenic artery infarct and occlusion are rarely reported [7,13,16]. Splenic infarction is an unusual cause of abdominal pain and is mostly caused by an underlying hematological condition [8,16]. Other causes of splenic infarction are cardiovascular disorders, coagulation disorders, hypertension, diabetes mellitus, and viral infections [13,16]. Splenic artery infarct often manifests with medium to severe abdominal pain and tenderness in the left hypochondrium or left upper abdominal quadrant, fever, nausea, vomiting, besides occasional dyspnea, tachypnea, and tachycardia [2,13]. The imaging modality of choice for diagnosis is a contrast-enhanced abdominal CT scan [8,17,19,30].
LMWH is the first-line treatment for vesical artery thrombosis, and the same treatment has been followed in most cases of splenic artery thrombosis reported in the literature [31,32]. Other treatment therapies include the use of antiplatelet agents (acetylsalicylic acid, ASA, and clopidogrel) and recently invented anticoagulant agents that trigger thrombin (apixaban and dabigatran). All these medical agents can be used for both prophylaxis and treatment depending on the patient's features and medical condition. However, failure of medical treatment in splenic artery occlusion is a strong indication for surgery, besides other scenarios such as hemorrhage, aneurysm, or a splenic abscess due to COVID-19 infection [28,32,33]. In our patient, we administered LMWH therapy in therapeutic doses for seven days until the patient's clinical deterioration forced us to proceed to laparotomy and splenectomy. In situations where the spleen has to be removed abruptly, the risk of postsplenectomy infection and sepsis is higher [2,34].
We also conducted a literature search across the Medline, PubMed, and Google Scholar databases regarding splenic artery infarct or occlusion in COVID-19 patients and found that such an infarct due to thrombosis appears  We found that the treatment and prevention strategies for such thrombotic events in the presence of COVID-19 infection were debatable [11,31]. The standard of care is antithrombotic treatment using medicines such as heparin, LMWH, ASA, apixaban, rivaroxaban, and antiplatelet agents such as clopidogrel and ticagrelor [20,45]. However, contro-versy arises as to whether hospital patients with COVID-19 infection without signs of thromboembolism should receive prophylactic or therapeutic anticoagulation [11,24]. In our literature search, we found that 38 of the 45 cases received medical treatment-eight received heparin, 29 received LMWH (mainly enoxaparin), and in the remaining 16 cases, other anticoagulation medicines (ASA, clopidogrel, etc.) were used. Two of the patients underwent conservative treatment with no further details, while the treatment followed for another two patients was not reported. In only 3 cases,  [34], Besutti et al. [35], and Imam and Hammond [36] did the clinician proceed to splenectomy for treating a severe splenic infarct. Our patient is only the fourth case that required a splenectomy as an essential component of treatment. Furthermore, we discovered that in 28 of the 45 reported cases, there were simultaneous thrombosis and infarcts in other tissues, such as the kidneys, brain, aorta, lungs, bowel, and splenic vein. In 14 cases, the patients had isolated thrombosis in the splenic artery, and in 3 cases, there was no record of any simultaneous thrombosis. Fortunately, the clinical outcome of the splenic infarct was favorable in most cases, with 31 of 45 cases reporting improvement or full recovery of the splenic artery occlusion. Unfortunately, five patients were diseased due to sepsis or heavy medical comorbidities. In nine patients, the clinical outcomes were not reported.
To the best of our knowledge, this case report is only the second case in Greece of a patient developing a splenic artery infarct due to COVID-19 infection and only the 4 th case so far that warranted surgery despite conservative treatment with anticoagulant agents, such as LMWH. Based on the existing literature, we can conclude that thrombosis from COVID-19 infection is not unusual and can occur regardless of the use of antithrombotic agents [27,37,38]. Moreover, an increase in D-dimer levels is not sufficient to diagnose arterial or venous thrombosis owing to the considerable inflammatory reaction and significant rise in D-dimer levels following COVID-19 infection [2,16]. Nevertheless, the chances of hypercoagulability that accompanies this disease should raise suspicion of thrombotic events in unusual sites, and treatment with anticoagulants should start immediately after diagnosis [14,24]. A combination of more than two agents is sometimes necessary, and prolonged treatment, even after improvement, is, at times, inevitable [45]. Routine use of LMWH should be followed in patients with SARS-CoV-2 infection, although some authors consider this controversial [11,27,31,38,39]. There is no consensus regarding the best therapy for arterial occlusion, and different authors have used a variety of medications for treating arterial infarcts after coronavirus infection [21,28]. However, it is crucial to determine the best therapy for acute arterial thrombosis in which not only the appropriate anticoagulant treatment regimen but also the correct dose is essential to improve prognosis, relieve symptoms, and significantly reduce mortality and disability [21,40]. In addition, splenectomy is a risk factor for overwhelming bacterial sepsis. If this situation exposes patients with COVID-19 infection in greater risk than patients without COVID-19 infection is not known as data are absent in current literature. In advance there is no evidence that absence of spleen places patients in greater risk for COVID-19 infection [46]. Furthermore, from a brief review of the literature, we observed that antithrombotic treatment with LMWH, ASA, and other anticoagulants results in improvement in splenic artery infarcts, causes recanalization of the splenic artery, and that splenectomy is required only in the case of clinical deterioration of the patient [20,30,31,33,41,47]. While we await further data from clinical trials regarding treatment guidelines, a reasonable approach would be to continue with regular-dose thromboprophylaxis in all COVID-19 patients and to provide therapeutic anticoagulation in patients with confirmed thrombotic events [2,14,21,24,35,39].

Conclusion
Emergency physicians, clinicians, and general surgeons must be very cautious of the thrombotic events associated with SARS-CoV-2 occurring in unusual sites, such as the splenic artery. Splenic artery thrombosis or infarction may be suspected in COVID-19 patients who suffer from acute upper abdominal pain, especially in the epigastrium and the left hypochondrium, regardless of the absence of prothrombotic states or hematological abnormalities. Conservative treatment with LMWH is the first-line treatment followed by anticoagulants and antiplatelet agents. Splenectomy is the last strategy when conservative methods have failed. High index of suspicion is mandatory when COVID-19 infection is accompanied with acute abdominal pain.

Consent
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the editor-in-chief of this journal.