key: cord-0965658-iimn4mjc authors: Avila, Jacob; Long, Brit; Holladay, Dallas; Gottlieb, Michael title: Thrombotic complications of COVID-19 date: 2020-10-01 journal: Am J Emerg Med DOI: 10.1016/j.ajem.2020.09.065 sha: e744d5aec128caebb50d58c5ab6618e37db10e37 doc_id: 965658 cord_uid: iimn4mjc INTRODUCTION: The novel coronavirus disease of 2019 (COVID-19) is associated with significant morbidity and mortality. The impact of thrombotic complications has been increasingly recognized as an important component of this disease. OBJECTIVE: This narrative review summarizes the thrombotic complications associated with COVID-19 with an emphasis on information for Emergency Medicine clinicians. DISCUSSION: Thrombotic complications from COVID-19 are believed to be due to a hyperinflammatory response caused by the virus. Several complications have been described in the literature. These include acute limb ischemia, abdominal and thoracic aortic thrombosis, mesenteric ischemia, myocardial infarction, venous thromboembolism, acute cerebrovascular accident, and disseminated intravascular coagulation. CONCLUSION: It is important for Emergency Medicine clinicians to be aware of the thrombotic complications of COVID-19. Knowledge of these components are essential to rapidly recognize and treat to reduce morbidity and mortality in these patients. level, with a greater than 16-fold increase in one study [29, 37, 43, 45, 46 ]. An elevated CRP has also been reported [29] . Treatment involves systemic anticoagulation and consultation with vascular surgery or interventional radiology [42] . Mesenteric ischemia is a less common occurrence with significant morbidity and mortality. This has been described in three case reports of patients with COVID-19 [46, 48, 49] . Symptoms can include abdominal pain [48, 49] , vomiting [48] , or diarrhea [49] . Labs may demonstrate an elevated D-Dimer [46] or an elevated CRP [48, 49] . Imaging should include a CTA of the mesenteric vessels, as a regular CT of the abdomen and pelvis with contrast may not identify this, particularly early in the course of symptoms [48] . Treatment should include systemic anticoagulation and consultation with general surgery, as well as either interventional gastroenterology or interventional radiology [42, 48] . An increased risk of acute coronary syndrome (ACS), including myocardial infarction (MI), is found in viral illnesses, with the greatest risk within the first week of illness due to systemic inflammation resulting in atherosclerotic plaque disruption [50] [51] [52] . Literature suggests acute MI ACS in the setting of COVID-19 can present with symptoms other than chest pain, such as respiratory distress or shortness of breath alone [53] . A case series of 18 patients with ST elevation MI on ECG and COVID-19 found 83% were male, with most over the age 60; however, only six patients (33%) had chest pain at the time of ST elevation on ECG [53] . In patients with STEMI, the American College of Cardiology states percutaneous coronary intervention (PCI) is the preferred therapy within 90 minutes from first medical contact, though fibrinolysis may be considered in patients who are "relatively stable" [57, 58] . Patients with equivocal symptoms, atypical electrocardiogram, or delayed presentation and possible but unconfirmed STEMI should undergo further evaluation including echocardiogram and serial ECGs. If the patient has non-STEMI with suspected COVID-19, further testing is recommended prior to catheterization, and in properly selected patients conservative therapy can be sufficient. Patients who are hemodynamically unstable with NSTEMI should be treated similarly as those with STEMI [57, 58] . Other medications used in the setting of ACS (e.g., aspirin) are unchanged in COVID-19. As the clinical picture of COVID- 19 In hospitalized patients not receiving prophylaxis, rates are approximately 0.9% for general admission and 15% to 32% among ICU patients [60, 61] . A German study performed consecutive autopsies of 12 deceased patients with COVID-19, finding bilateral DVTs in 7 (58%) cases, none of which were suspected before death [62] . Another study prospectively analyzed venous ultrasound exams on 34 consecutive patients admitted to the ICU with COVID-19 finding DVTs in 22 patients (65%), with 18 patients having bilateral DVTs [63] . On systematic evaluation 48 hours after admission, the authors also found that an additional five developed DVTs despite adequate prophylactic anticoagulation [63] . Another retrospective review of 26 consecutive ICU patients in France found DVTs in 18 patients (69%) receiving anticoagulation [64] . Patients hospitalized on the general medical floors also demonstrate an increased risk of DVT. A retrospective review of 71 non-ICU patients in France who received systematic lower extremity doppler exams prior to discharge found 16 patients (22%) developed DVT despite thromboprophylaxis with weight-based enoxaparin [65] . Similar to DVT, studies have also demonstrated a high rate of PE occurrence in patients with COVID-19. Post-mortem examination of 21 consecutive patients in Switzerland found PEs in four (19%) of the patients [66] . A similar autopsy study in Germany found PE was present in 42% of deceased patients, with PE being the cause of death in one-third of patients [62] . Multiple studies have also demonstrated a high prevalence of PE in ICU patients hospitalized with COVID-19. A study of 184 consecutive ICU patients with COVID-19 demonstrated confirmed VTE in 27% of patients by CTPA or compression duplex ultrasonography [67] . The majority J o u r n a l P r e -p r o o f Journal Pre-proof (81%) of VTE were PE despite standard pharmacological thromboprophylaxis [67] . Another review of 150 ICU patients found the most significant thromboembolic complication among patients was PE (16.7%) [8] . This same study compared a subgroup of patients with COVID-19 acute respiratory distress syndrome (ARDS) to non-COVID-19 ARDS and found PE rates were significantly higher in the COVID-19 ARDS group, 12% and 2%, respectively [8] . A case series of 107 consecutive patients admitted to the ICU in France demonstrated a PE rate of 20.6% [9] . The authors retrospectively reviewed ICU patients during the same period from the previous year and found a PE rate of 6.1% suggesting patients with severe COVID-19 infections are at higher risk than other non-COVID-19 critically ill patients [9] . Outside of the ICU, studies have demonstrated PE rates of 10% to 22% [11, 65] . A retrospective chart review of 327 general floor patients noted 44 patients were tested for VTE with an overall positive rate of 6.4% [4] . A retrospective review of 71 non-ICU COVID-19 patients in France revealed a PE rate of 10% despite receiving adequate thromboprophylaxis. The authors noted a d-dimer threshold of 10000 μg/L was only moderately predictive of VTE (negative predictive value 90%, positive predictive value 44%) [65] . Another retrospective chart review found ddimer levels of greater than 2660 μg/L had a 100% sensitivity and 67% specificity for PE [10] . A retrospective chart review of 100 patients hospitalized for COVID-19 who received CTPA found a PE rate of 23%, with a higher prevalence in ICU patients (74% vs 29%) [11] . It is unclear if these patients were receiving anticoagulation. Pre-existing cardiovascular disease was associated with higher incidence of PE [11] . More studies are needed to determine the utility of d-dimer levels for risk stratification of VTE in COVID-19 patients. There is limited data regarding PE prevalence among COVID-19 patients treated in the outpatient setting. However, one recent J o u r n a l P r e -p r o o f study in the ED found that among patients receiving a CTPA to evaluate for PE, the positivity rate was similar between COVID-19 patients and those without COVID-19 [68] . When testing for PE in COVID-19 patients, CTPA is the test of choice. If CTPA is contraindicated (e.g., renal failure, severe contrast dye reaction), only the perfusion scintigraphy of the ventilation-perfusion scan should be performed to minimize aerosolization of secretions [69, 70] . unless there are pre-existing contraindications [71, 72] . Low molecular weight heparin is preferred over unfractionated heparin to reduce healthcare worker exposure to infected patients [71] . If heparin-induced thrombocytopenia develops, fondaparinux should be used. Although some authors have advocated for intermediate or therapeutic dosing, both societies endorse standard prophylaxis dosing until more data is available [71, 72] . A review of 150 ICU COVID-19 patients demonstrated a low rate (2.7%) of bleeding complications among patients receiving prophylactic or treatment-based pharmacologic antithrombotic therapy [8] . Although limited, this suggests anticoagulation is relatively safe in COVID-19 patients who do not meet exclusion criteria. A retrospective study of 449 patients with severe COVID-19 infection found an improved 28-day mortality in patients receiving enoxaparin (40-60 mg daily) than those not receiving enoxaparin [73] . Some authors also advocate for the anti-inflammatory role of heparin in severe COVID-19 infection [74] . Heparin is known to decrease inflammation by inhibiting neutrophil activity, expression of inflammatory mediators, and the proliferation of vascular J o u r n a l P r e -p r o o f smooth muscle cells [75] . Admitted patients boarding in the emergency department should at minimum receive pharmacologic antithrombotic therapy with a low threshold for additional VTE testing if new symptoms develop. Acute cerebrovascular disease, including ischemic stroke, is a severe neurologic complication of COVID-19 and can be a presenting symptom [76] [77] [78] [79] . Studies suggest a rate of ischemic stroke approaching up to 5% in patients with COVID-19, likely associated with the inflammatory and hypercoagulable state [77] [78] [79] [80] . This mirrors other respiratory infections in which the risk of stroke increases by 3.2-7.8 fold within the first several days of infection [81, 82] . The risk of mortality in patients with COVID-19 with acute ischemic stroke reaches 38% [83] . However, despite this increased risk of stroke, during the current COVID-19 pandemic, a decrease in the number of acute stroke investigations has been observed, likely due to patient fear of exposure in medical centers [76, [84] [85] [86] [87] . Patients infected by COVID-19 affected by stroke are usually older, typically over 70 years of age, with significant comorbidities such as liver and renal disease [76, 83] . Other factors associated with increased risk of stroke in the setting of COVID-19 include hypertension, diabetes, cancer, lung disease, and prior cerebrovascular disease [76, 77, 79, 80] . However, there are cases of ischemic stroke, even large vessel occlusion, affecting young patients with COVID-19 [88] . Literature suggests the median duration from onset of COVID-19 symptoms to stroke is approximately 10 days [76, 83] . Significant coagulation abnormalities in patients with COVID-19 include increased D-dimer, prolonged prothrombin time, and abnormal platelet levels [83, 89] . D-J o u r n a l P r e -p r o o f Journal Pre-proof dimer levels in patients with stroke and COVID-19 are significantly higher compared to other patients with COVID-19 infection, with one study demonstrating a 12-fold increase in those experiencing stroke [83] . In patients with suspected stroke, protection of healthcare providers is essential even if patients are asymptomatic, which may occur in 18% to 31% of patients ultimately diagnosed with COVID-19 [90, 91] . The American Heart Association recommends using appropriate screening guidelines, personal protective equipment, and crisis resource management for evaluating and managing patients with suspected cerebrovascular accidents [87, 92] . All patients with suspected stroke should be evaluated as suspected COVID-19 in the prehospital and ED settings [92] . Personal protection equipment including contact and droplet precautions are recommended when caring for non-ventilated patients and those not undergoing aerosol-generating procedures, known as a "protected code stroke" [87] . A face mask or surgical mask should also be placed on the patient. Evaluation includes noncontrast head computed tomography (CT) within 20 minutes of arrival in the ED. For those with suspected large vessel occlusion, further imaging including CT angiography, CT perfusion, or magnetic resonance imaging (MRI) is recommended. If further imaging will be needed during hospitalization or may impact management (i.e., CT perfusion), then this should be obtained at the time of head CT if able. Similarly, providers should consider using a single test modality (e.g., noncontrast head CT followed by CT angiography of the head and neck), rather than separate imaging modalities (e.g., CT of the head, followed by MRI and carotid ultrasound imaging) to reduce machine and technician utilization [92] . J o u r n a l P r e -p r o o f Management of ischemic stroke is unchanged whether COVID-19 is present, with IV alteplase recommended for eligible patients presenting within 3 hours (and for highly selected patients within 4.5 hours of therapy) [87, 92] . As discussed, patients with COVID-19 often demonstrate coagulation system abnormalities and also have risk of hepatic and renal dysfunction. However, the risk of hemorrhage in patients with COVID-19 receiving thrombolysis is unclear. Patients with COVID-19 are eligible for mechanical thrombectomy in the setting of internal carotid artery or middle cerebral artery occlusion if they can be treated within 6 hours of symptoms, do not demonstrate extensive ischemic tissue on imaging, and have a NIHSS score > 6 [87, 92] . Disseminated intravascular coagulation (DIC) is suggested when there is dysregulation of the coagulation pathways causing both systemic coagulation and hemorrhage associated with thrombocytopenia, and elevated fibrin-degradation products (FDP), prolonged PT, and an elevated fibrinogen level [93] [94] [95] . DIC commonly presents as thrombosis and hemorrhage in different locations [93] [94] [95] . DIC has multiple inciting causes and possesses a mortality rate ranging from 46-76% [94] . DIC in COVID-19 patients is also correlated with mortality. 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