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Arterial thrombotic complications in COVID-19 patients

Open AccessPublished:July 16, 2020DOI:https://doi.org/10.1016/j.jvscit.2020.06.012

      Abstract

      The coronavirus disease 2019 (COVID-19), a viral respiratory illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been described to predispose to thrombotic disease in both the venous and arterial circulations. We report four cases of an acute arterial occlusion in COVID-19 patients and literature review on the occurrence of arterial thrombosis in patients with COVID-19. Our findings demonstrate that physicians should be vigilant for signs of thrombotic complications in both hospitalized and new COVID-19 patients.

      Keywords

      Case report

      We report four cases of acute arterial occlusive disease or ischemia in patients with the coronavirus disease 2019 (COVID-19) that is caused by the virus designated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The patients presented at two Dutch hospitals (one university hospital and one large teaching hospital). Since the first presentation of a COVID-19 patient in The Netherlands on February 27 to May 1, there have been 378 reverse transcriptase-polymerase chain reaction-confirmed patients admitted to our two hospitals. Four cases involved an acute arterial occlusion. Medical history, smoking status, laboratory results, and anticoagulation therapy are detailed in Table I.
      Table IIdentified cases of acute arterial occlusive disease or ischemia in patients with COVID-19
      Case 1Case 2Case 3Case 4
      Medical historyNoneDiabetes mellitusGoutObstructive sleep apnea, obesity
      SmokingNonsmokerNonsmokerSmoking cessation 3 years priorNonsmoker
      Laboratory results
       CRP, mg/L2341004.7339
       Leukocytes, 109/L8.2137.223.6
       Thrombocytes, 109/L262458185237
       LDH, U/L868294186421
       aPTT, secondsN/A343534
       PT, secondsN/A14N/A14.7
       INRN/AN/A1.1N/A
       D-dimer, μg/LN/AN/AN/A28,186
      Anticoagulation therapy
       At admission
       Post-therapyApixaban, 5 mg twice dailyHeparin IVClopidogrel, 75 mg once daily

      Nadroparin (Fraxiparine), 2850 IU once daily
      Heparin IV
      In case 4, the patient was treated with heparin intravenously after therapy because of concomitant acute kidney failure, for which continuous venovenous hemofiltration was indicated. Acute atrial fibrillation and subsegmental pulmonary embolisms developed during recovery, for which acenocoumarol was started before discharge to a referral hospital.
       At dischargeApixaban, 5 mg twice dailyRivaroxaban, 10 mg once dailyAcenocoumarol
      In case 4, the patient was treated with heparin intravenously after therapy because of concomitant acute kidney failure, for which continuous venovenous hemofiltration was indicated. Acute atrial fibrillation and subsegmental pulmonary embolisms developed during recovery, for which acenocoumarol was started before discharge to a referral hospital.
      aPTT, Activated partial thromboplastin time; CRP, C-reactive protein; INR, international normalized ratio; IV, intravenous; LDH, lactate dehydrogenase; N/A, not available; PT, prothrombin time.
      a In case 4, the patient was treated with heparin intravenously after therapy because of concomitant acute kidney failure, for which continuous venovenous hemofiltration was indicated. Acute atrial fibrillation and subsegmental pulmonary embolisms developed during recovery, for which acenocoumarol was started before discharge to a referral hospital.
      The first patient, a 50-year-old healthy man, was admitted because of pneumonia, for which he received supplemental oxygen and chloroquine. Three days after admission, the patient developed acute claudication of the right limb without neurologic deficits. Computed tomography angiography (CTA) showed a short occlusion (3.5 cm) of the right common iliac artery (Fig 1). Surgical embolectomy was not possible because of a high risk for general anesthesia in relation to COVID-19, and thrombolytic therapy was not available because of capacity issues. After 3 days of systemic therapeutic heparin treatment, the patient was discharged home with mild claudication. However, 20 days later, the patient was readmitted with acute ischemia of both legs. CTA showed persistent occlusion of the right common iliac artery. A new thrombus was present at the left tibial-fibular trunk (TTF). The patient subsequently received alteplase for the right common iliac artery and left TTF. Owing to the dislodgment of thrombus to the right TTF and persistent ischemia, infragenual exploration and open thrombectomy were performed, with good clinical outcome.
      Figure thumbnail gr1
      Fig 1A 50-year-old COVID-19-positive man with no medical history developed acute claudication of the right limb without neurologic deficits 3 days after admission. Computed tomography angiography (CTA) showed short occlusion of the right common iliac artery.
      The second patient, a nonsmoking 55-year-old man, was referred with a pale pulseless left hand. There was no muscle weakness, with minimal sensory loss of the fingers. CTA was performed and showed a subclavian artery occlusion (Fig 2). One week before, the patient had had a fever without other symptoms. At presentation, the patient had no pulmonary symptoms, fever, or dyspnea. The saturation was 95%. The patient was treated with therapeutic heparin systemically. Because of the absence of fever and hypoxia, no treatment was started for the COVID-19 infection. After 1 day of heparin treatment, distal pulses were still absent, but refill was normalized, and the function of the hand was completely normalized, with no sensory loss. After 2 days, rivaroxaban was started, and the patient was discharged home.
      Figure thumbnail gr2
      Fig 2A 55-year-old COVID-19-positive man with a medical history of diabetes with oral metformin use presented with a pale, pulseless left hand without muscle weakness and minimal sensory loss of the fingers. Acquired computed tomography angiography (CTA) imaging showed subclavian artery occlusion. A, Sagittal view. B, Coronal view. C, Axial view.
      The third patient, a 62-year-old man, presented with right-sided hemiparesis. Computed tomography imaging showed dense media with a corresponding perfusion defect as well as M1 occlusion on CTA with subtotal stenosis of the internal carotid artery origin (Fig 3). There was no known history of internal carotid artery stenosis, and CTA showed minimal calcified atherosclerosis. The patient underwent intra-arterial thrombectomy with nearly complete reperfusion, except for some distal cortical emboli. On the second day of admission, the patient developed fever and cough due to COVID-19. Laboratory results were normal. Further symptoms were mild, without the need for supplemental oxygen or other treatment for COVID-19. As of June 9, 2020, the patient is still admitted for neurologic rehabilitation.
      Figure thumbnail gr3
      Fig 3A 62-year-old COVID-19-positive man presented with right-sided hemiparesis. A-C, Cerebral computed tomography showed (A) a left dense media sign, (B) occlusion on computed tomography angiography (CTA), and (C) corresponding perfusion defect. D, Digital subtraction angiography confirmed an M1 occlusion. E, After intra-arterial thrombectomy, cerebral blood flow was restored (Thrombolysis in Cerebral Infarction grade 2C).
      The fourth patient, a 58-year-old man, who presented with dyspnea and abdominal pain that had gradually developed within the past 2 weeks. The patient was admitted to the intensive care unit (ICU) for respiratory distress the same day. Gastric retention and abdominal distention were noted during the admission; abdominal portal-venous computed tomography imaging was performed, showing dilated small bowel loops, signs of bowel wall ischemia, an adjacent fluid collection, and splenic and renal infarctions without macrovascular arterial occlusion. Nonsignificant stenosing soft plaque was present in the proximal superior mesenteric artery. Subsequent laparotomy was performed, and a partial small bowel resection was performed for low-flow-associated bowel ischemia. Bowel function recovered. Three weeks after surgery, digital necrosis of both feet was observed clinically. Arterial duplex ultrasound was performed and showed no common femoral artery, profunda femoris artery, superficial femoral artery, or popliteal artery stenosis or occlusion. During recovery, the patient was transferred to a referral hospital. As of June 5, 2020, the patient has not yet been discharged.
      Consent has been given by all patients for the publication of the case details and images.

      Discussion

      The current outbreak of the SARS-CoV-2 is spreading throughout the globe, causing high morbidity and mortality. Preliminary data have reported an increased risk of venous thromboembolism and acute myocardial infarctions, most likely caused by excessive inflammation, platelet activation, endothelial dysfunction, and stasis.
      • Chen S.
      • Huang B.
      • Luo D.J.
      • Li X.
      • Yang F.
      • Zhao Y.
      • et al.
      [Pregnancy with new coronavirus infection: clinical characteristics and placental pathological analysis of three cases].
      However, there have also been reports of arterial thrombosis. To investigate the prevalence and incidence of arterial occlusions, we performed a review of the current literature. MEDLINE was searched for peer-reviewed publications on COVID-19 and arterial thromboembolic complications. Four retrospective cohort studies, consisting of a total of 738 patients, and eight case report studies have reported the occurrence of arterial thrombotic events (Table II). In a series of 150 ICU patients referred to four French ICUs reported by Helms et al,
      • Helms J.
      • Tacquard C.
      • Severac F.
      • Leonard-Lorant I.
      • Ohana M.
      • Delabranche X.
      • et al.
      High risk of thrombosis in patients in severe SARS-CoV-2 infection: a multicenter prospective cohort study.
      four arterial occlusions were observed, of which one caused mesenteric ischemia, one limb ischemia, and two cerebral ischemia. von Willebrand factor activity, von Willebrand factor antigen, and factor VIII were considerably increased in all patients, and 50 of 57 tested patients (87.7%) had positive lupus anticoagulant.
      Table IIStudies found in literature review
      StudyStudy designNo.Arterial thrombotic eventsType
      Helms et al
      • Helms J.
      • Tacquard C.
      • Severac F.
      • Leonard-Lorant I.
      • Ohana M.
      • Delabranche X.
      • et al.
      High risk of thrombosis in patients in severe SARS-CoV-2 infection: a multicenter prospective cohort study.
      Multicenter retrospective cohort150 ICU patients2 (1.3%)

      1 (0.7%)

      1 (0.7%)
      Ischemic stroke

      Mesenteric ischemia

      Limb ischemia
      Klok et al
      • Klok F.A.
      • Kruip M.
      • van der Meer N.J.
      • Arbous M.S.
      • Gommers D.
      • Kant K.M.
      • et al.
      Incidence of thrombotic complications in critically ill ICU patients with COVID-19.
      Multicenter retrospective cohort180 ICU patients3 (3.7% cumulative incidence)Ischemic stroke
      Lodigiani et al
      • Lodigiani C.
      • Iapichino G.
      • Carenzo L.
      • Cecconi M.
      • Ferrazzi P.
      • Sebastian T.
      • et al.
      Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy.
      Single-center retrospective cohort388 patients9 (2.5%)

      3 ICU, 6 general ward
      Ischemic stroke
      Bellosta et al
      • Bellosta R.
      • Luzzani L.
      • Natalini G.
      • Pegorer M.A.
      • Attisani L.
      • Cossu L.G.
      • et al.
      Acute limb ischemia in patients with COVID-19 pneumonia.
      Single-center retrospective cohort20 patients20Acute limb ischemia
      Le Berre et al
      • Le Berre A.
      • Marteau V.
      • Emmerich J.
      • Zins M.
      Concomitant acute aortic thrombosis and pulmonary embolism complicating COVID-19 pneumonia.
      Case report1Intra-aortic thrombus
      de Barry et al
      • de Barry O.
      • Mekki A.
      • Diffre C.
      • Seror M.
      • Hajjam M.E.
      • Carlier R.Y.
      Arterial and venous abdominal thrombosis in a 79-year-old woman with COVID-19 pneumonia.
      Case report1Mesenteric thrombosis
      Oxley et al
      • Oxley T.J.
      • Mocco J.
      • Majidi S.
      • Kellner C.P.
      • Shoirah H.
      • Singh I.P.
      • et al.
      Large-vessel stroke as a presenting feature of Covid-19 in the young.
      Case report5Large-vessel stroke
      Vulliamy et al
      • Vulliamy P.
      • Jacob S.
      • Davenport R.A.
      Acute aorto-iliac and mesenteric arterial thromboses as presenting features of COVID-19.
      Case report1Aorta-iliac and mesenteric
      Avula et al
      • Avula A.
      • Nalleballe K.
      • Narula N.
      • Sapozhnikov S.
      • Dandu V.
      • Toom S.
      • et al.
      COVID-19 presenting as stroke.
      Case report4Ischemic stroke
      Giacomelli et al
      • Giacomelli E.
      • Dorigo W.
      • Fargion A.
      • Calugi G.
      • Cianchi G.
      • Pratesi C.
      Acute thrombosis of an aortic prosthetic graft in a patient with severe COVID-19 related pneumonia.
      Case report1Aortic prosthetic graft occlusion
      González-Pinto et al
      • Gonzalez-Pinto T.
      • Luna-Rodriguez A.
      • Moreno-Estebanez A.
      • Agirre-Beitia G.
      • Rodriguez-Antiguedad A.
      • Ruiz-Lopez M.
      Emergency room neurology in times of COVID-19: malignant ischemic stroke and SARS-CoV-2 infection.
      Case report1Large-vessel stroke
      Beyrouti et al
      • Beyrouti R.
      • Adams M.E.
      • Benjamin L.
      • Cohen H.
      • Farmer S.F.
      • Goh Y.Y.
      • et al.
      Characteristics of ischaemic stroke associated with COVID-19.
      Case report6Ischemic stroke
      ICU, Intensive care unit.
      Furthermore, a single-center cohort study from Bellosta et al
      • Bellosta R.
      • Luzzani L.
      • Natalini G.
      • Pegorer M.A.
      • Attisani L.
      • Cossu L.G.
      • et al.
      Acute limb ischemia in patients with COVID-19 pneumonia.
      reported increased incidence of patients presenting with acute limb ischemia in 2020, 16% vs 2% throughout the same calendar period in 2019. Klok et al
      • Klok F.A.
      • Kruip M.
      • van der Meer N.J.
      • Arbous M.S.
      • Gommers D.
      • Kant K.M.
      • et al.
      Incidence of thrombotic complications in critically ill ICU patients with COVID-19.
      reported that thrombotic complications were observed in 31% of ICU patients in a multicenter cohort of 180 patients admitted to the ICU of three Dutch hospitals. Arterial complications were relatively rare, however, with a cumulative incidence of 3.7%, all of which consisted of ischemic stroke. Similar findings of ischemic stroke occurrence were reported by Lodigiani et al
      • Lodigiani C.
      • Iapichino G.
      • Carenzo L.
      • Cecconi M.
      • Ferrazzi P.
      • Sebastian T.
      • et al.
      Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy.
      in a cohort of 388 patients admitted to an academic hospital in Milan, Italy. Nine patients (2.5%) developed ischemic stroke, of whom three patients were at the moment admitted to the ICU and six were on a general ward.
      The eight case reports describe the occurrence of acute arterial occlusions in the aorta and mesenteric and cerebral arteries.
      • Le Berre A.
      • Marteau V.
      • Emmerich J.
      • Zins M.
      Concomitant acute aortic thrombosis and pulmonary embolism complicating COVID-19 pneumonia.
      • de Barry O.
      • Mekki A.
      • Diffre C.
      • Seror M.
      • Hajjam M.E.
      • Carlier R.Y.
      Arterial and venous abdominal thrombosis in a 79-year-old woman with COVID-19 pneumonia.
      • Oxley T.J.
      • Mocco J.
      • Majidi S.
      • Kellner C.P.
      • Shoirah H.
      • Singh I.P.
      • et al.
      Large-vessel stroke as a presenting feature of Covid-19 in the young.
      • Vulliamy P.
      • Jacob S.
      • Davenport R.A.
      Acute aorto-iliac and mesenteric arterial thromboses as presenting features of COVID-19.
      • Avula A.
      • Nalleballe K.
      • Narula N.
      • Sapozhnikov S.
      • Dandu V.
      • Toom S.
      • et al.
      COVID-19 presenting as stroke.
      • Giacomelli E.
      • Dorigo W.
      • Fargion A.
      • Calugi G.
      • Cianchi G.
      • Pratesi C.
      Acute thrombosis of an aortic prosthetic graft in a patient with severe COVID-19 related pneumonia.
      • Gonzalez-Pinto T.
      • Luna-Rodriguez A.
      • Moreno-Estebanez A.
      • Agirre-Beitia G.
      • Rodriguez-Antiguedad A.
      • Ruiz-Lopez M.
      Emergency room neurology in times of COVID-19: malignant ischemic stroke and SARS-CoV-2 infection.
      • Beyrouti R.
      • Adams M.E.
      • Benjamin L.
      • Cohen H.
      • Farmer S.F.
      • Goh Y.Y.
      • et al.
      Characteristics of ischaemic stroke associated with COVID-19.
      Complications of COVID-19, including coagulopathy,
      • Zhou F.
      • Yu T.
      • Du R.
      • Fan G.
      • Liu Y.
      • Liu Z.
      • et al.
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      ,
      • Zhang Y.
      • Cao W.
      • Xiao M.
      • Li Y.J.
      • Yang Y.
      • Zhao J.
      • et al.
      [Clinical and coagulation characteristics of 7 patients with critical COVID-2019 pneumonia and acro-ischemia].
      may contribute to the development of arterial ischemic events. Elevated D-dimer levels in the setting of COVID-19 have been described in three of the previously described cohort studies.
      • Helms J.
      • Tacquard C.
      • Severac F.
      • Leonard-Lorant I.
      • Ohana M.
      • Delabranche X.
      • et al.
      High risk of thrombosis in patients in severe SARS-CoV-2 infection: a multicenter prospective cohort study.
      ,
      • Lodigiani C.
      • Iapichino G.
      • Carenzo L.
      • Cecconi M.
      • Ferrazzi P.
      • Sebastian T.
      • et al.
      Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy.
      ,
      • Bellosta R.
      • Luzzani L.
      • Natalini G.
      • Pegorer M.A.
      • Attisani L.
      • Cossu L.G.
      • et al.
      Acute limb ischemia in patients with COVID-19 pneumonia.
      Furthermore, D-dimer levels were elevated in 15 of 17 patients tested in six identified case reports.
      • Oxley T.J.
      • Mocco J.
      • Majidi S.
      • Kellner C.P.
      • Shoirah H.
      • Singh I.P.
      • et al.
      Large-vessel stroke as a presenting feature of Covid-19 in the young.
      • Vulliamy P.
      • Jacob S.
      • Davenport R.A.
      Acute aorto-iliac and mesenteric arterial thromboses as presenting features of COVID-19.
      • Avula A.
      • Nalleballe K.
      • Narula N.
      • Sapozhnikov S.
      • Dandu V.
      • Toom S.
      • et al.
      COVID-19 presenting as stroke.
      • Giacomelli E.
      • Dorigo W.
      • Fargion A.
      • Calugi G.
      • Cianchi G.
      • Pratesi C.
      Acute thrombosis of an aortic prosthetic graft in a patient with severe COVID-19 related pneumonia.
      • Gonzalez-Pinto T.
      • Luna-Rodriguez A.
      • Moreno-Estebanez A.
      • Agirre-Beitia G.
      • Rodriguez-Antiguedad A.
      • Ruiz-Lopez M.
      Emergency room neurology in times of COVID-19: malignant ischemic stroke and SARS-CoV-2 infection.
      • Beyrouti R.
      • Adams M.E.
      • Benjamin L.
      • Cohen H.
      • Farmer S.F.
      • Goh Y.Y.
      • et al.
      Characteristics of ischaemic stroke associated with COVID-19.
      In our centers, D-dimer levels were determined in one patient and found to be significantly elevated. Although an apparent correlation is suggested, possible causality needs to be investigated. Moreover, COVID-19 causes elevated cytokine levels, including but not limited to tumor necrosis factor α, interleukin (IL) 1β, IL-6, and interferon γ.
      • Liu B.
      • Li M.
      • Zhou Z.
      • Guan X.
      • Xiang Y.
      Can we use interleukin-6 (IL-6) blockade for coronavirus disease 2019 (COVID-19)-induced cytokine release syndrome (CRS)?.
      Previous research has shown that elevated levels of exogenous tumor necrosis factor α may exacerbate focal ischemic injury in stroke as well as intestinal ischemia in an experimental setting.
      • Barone F.C.
      • Arvin B.
      • White R.F.
      • Miller A.
      • Webb C.L.
      • Willette R.N.
      • et al.
      Tumor necrosis factor-alpha. A mediator of focal ischemic brain injury.
      • Souza D.G.
      • Soares A.C.
      • Pinho V.
      • Torloni H.
      • Reis L.F.
      • Teixeira M.M.
      • et al.
      Increased mortality and inflammation in tumor necrosis factor-stimulated gene-14 transgenic mice after ischemia and reperfusion injury.
      • Souza D.G.
      • Teixeira M.M.
      The balance between the production of tumor necrosis factor-alpha and interleukin-10 determines tissue injury and lethality during intestinal ischemia and reperfusion.
      Likewise, IL-1β administration leads to increased infarct size, whereas lack of IL-1β reduces infarct size in experimental focal cerebral ischemia models.
      • Kawabori M.
      • Yenari M.A.
      Inflammatory responses in brain ischemia.
      Guidance for considerations in the preventive and therapeutic use of antithrombotic agents as well as potential drug interactions between antiplatelet agents and investigational therapies for COVID-19 has recently been published.
      • Bikdeli B.
      • Madhavan M.V.
      • Jimenez D.
      • Chuich T.
      • Dreyfus I.
      • Driggin E.
      • et al.
      COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up.
      Further research is warranted to elucidate this suggested association between COVID-19 and ischemic complications, its possible underlying pathogenesis, and prevention.

      Conclusions

      Our findings demonstrate that physicians should be vigilant for signs of arterial thrombotic complications in COVID-19 patients.

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