Renal microvascular thrombiThe incidence of acute kidney injury (AKI) in patients with COVID-19 is high, from 9% to 27% in retrospective studies, and similar to patients who have other pneumonias.11Diao B. Wang C. Wang R. et al.Human kidney is a target for novel severe acute respiratory syndrome coronavirus 2 infection., 12Sise M.E. Baggett M.V. JO Shepard et al.Case 17-2020: a 68-year-Old man with Covid-19 and acute kidney injury., 13Chen Y.T. Shao S.C. Hsu C.K. et al.Incidence of acute kidney injury in COVID-19 infection: a systematic review and meta-analysis. Many factors contribute to AKI, but findings from biopsy studies suggest that it is compounded by microvascular thrombosis. Autopsies from 6 patients showed widespread acute tubular necrosis and glomerular capillary damage from complement activity.11Diao B. Wang C. Wang R. et al.Human kidney is a target for novel severe acute respiratory syndrome coronavirus 2 infection. Viral inclusions were found in kidney cells supporting direct infection as a mechanism of localized cell death and inflammatory response. Renal perfusion deficits have been observed on imaging, as well.10Idilman I.S. Telli Dizman G. Ardali Duzgun S. et al.Lung and kidney perfusion deficits diagnosed by dual-energy computed tomography in patients with COVID-19-related systemic microangiopathy. Renal biopsy studies, though limited, demonstrate thrombotic microangiopathy, complement deposition in the mesangial space, fibrin thrombi in the glomeruli, and cortical necrosis in patients with severe AKI.14Boudhabhay I. Rabant M. Roumenina L.T. et al.Case report: Adult post-COVID-19 Multisystem inflammatory syndrome and thrombotic microangiopathy.,15Jhaveri K.D. Meir L.R. Flores Chang B.S. et al.Thrombotic microangiopathy in a patient with COVID-19. Hypercoagulability, defined as a low ADMATS13/VWF antigen ratio, was strongly associated with worsened AKI and severe illness, further supporting renal microthrombosis as a contributory factor to the high incidence of AKI in patients with COVID-19.16Henry B.M. Benoit S.W. de Oliveira M.H.S. et al.ADAMTS13 activity to von Willebrand factor antigen ratio predicts acute kidney injury in patients with COVID-19: evidence of SARS-CoV-2 induced secondary thrombotic microangiopathy.Hepatic microvascular thrombiCOVID-19 illness is associated with acute liver injury. Proposed mechanisms of injury are systemic inflammation, hepatic ischemia, drug toxicity, and hepatic microthrombi, which have been seen on autopsy.9Rapkiewicz A.V. Mai X. Carsons S.E. et al.Megakaryocytes and platelet-fibrin thrombi characterize multi-organ thrombosis at autopsy in COVID-19: a case series.,24Hundt M.A. Deng Y. Ciarleglio M.M. et al.Abnormal liver Tests in COVID-19: a retrospective observational cohort study of 1,827 patients in a major U.S. Hospital Network. A series of postmortem liver biopsies in patients with COVID-19, without preexisting liver disease or clinical signs of hepatic failure, found that greater than 50% had sinusoidal microthrombi and those individuals had 10-fold higher liver enzyme levels than those who did not have microthrombi.25Kondo R. Kawaguchi N. McConnell M.J. et al.Pathological characteristics of liver sinusoidal thrombosis in COVID-19 patients: a series of 43 cases. Liver involvement in severe COVID-19 infection was confirmed in a second autopsy series demonstrating hepatic steatosis and elevated megakaryocytes in hepatic sinusoids, which were associated with systemically elevated D-dimer and liver enzyme levels in those individuals.26Zhao C.L. Rapkiewicz A. Maghsoodi-Deerwester M. et al.Pathological findings in the postmortem liver of patients with coronavirus disease 2019 (COVID-19).Importantly, 2 types of microthrombi have been described in hepatic sinusoids: sinusoidal erythrocyte aggregation (SEA) and PMT. PMT thrombosis was associated with significant steatosis as compared with patients with COVID-19 without sinusoidal microthrombosis (79% vs 35%, P = .02).25Kondo R. Kawaguchi N. McConnell M.J. et al.Pathological characteristics of liver sinusoidal thrombosis in COVID-19 patients: a series of 43 cases. Both PMT and SEA thrombosis were associated with significant neutrophil accumulation in the hepatic sinusoids, illustrating the inflammatory component of microthrombotic injury. Compared with SEA, patients with PMT thrombosis were found to have increased incidence of liver injury.25Kondo R. Kawaguchi N. McConnell M.J. et al.Pathological characteristics of liver sinusoidal thrombosis in COVID-19 patients: a series of 43 cases.Conversely, a third large autopsy series found minimal microthrombi, with 50% having mild hepatitis and 75% with macrovesicular steatosis. Hepatic vascular findings were limited to scarce nondiffuse vascular abnormalities with 6 patients showing signs of veno-occlusive disease and 5 patients showing signs of arteriolar muscular hyperplasia.27Lagana S.M. Kudose S. Iuga A.C. et al.Hepatic pathology in patients dying of COVID-19: a series of 40 cases including clinical, histologic, and virologic data. Of note, in all 3 autopsy studies, steatosis was not associated with obesity or diabetes, suggesting that hepatic steatosis in these decedents of COVID-19 was not secondary to nonalcoholic fatty liver disease, but more likely a consequence of inflammation.25Kondo R. Kawaguchi N. McConnell M.J. et al.Pathological characteristics of liver sinusoidal thrombosis in COVID-19 patients: a series of 43 cases.Pulmonary embolismCOVID-19 has been associated with an increased incidence of PE ranging from 8.3% to 23%, depending on the severity of illness, based on retrospective studies.29Poyiadji N. Cormier P. Patel P.Y. et al.Acute pulmonary embolism and COVID-19., 30Fauvel C. Weizman O. Trimaille A. et al.Pulmonary embolism in COVID-19 patients: a French multicentre cohort study., 31Faggiano P. Bonelli A. Paris S. et al.Acute pulmonary embolism in COVID-19 disease: Preliminary report on seven patients. In comparison, the incidence of any venous thrombosis in the general population is 0.1%.32The epidemiology of venous thromboembolism. There is conflicting evidence that obesity predisposes to developing PE in the context of COVID-19 and it may depend on the severity of illness. Male sex and concomitant cardiovascular disease (CVD) are potentially predisposing factors, as well.31Faggiano P. Bonelli A. Paris S. et al.Acute pulmonary embolism in COVID-19 disease: Preliminary report on seven patients. Multiple studies indicate that patients with PE have higher D-dimer levels when compared with patients with COVID-19 without PE, suggesting that D-dimer levels can be used for diagnostics, prognostic purposes, and risk stratification.29Poyiadji N. Cormier P. Patel P.Y. et al.Acute pulmonary embolism and COVID-19., 30Fauvel C. Weizman O. Trimaille A. et al.Pulmonary embolism in COVID-19 patients: a French multicentre cohort study., 31Faggiano P. Bonelli A. Paris S. et al.Acute pulmonary embolism in COVID-19 disease: Preliminary report on seven patients.In a study of moderate COVID-19, there was a lower incidence of PE (8.3%) and neither obesity nor diabetes was predisposing factors.30Fauvel C. Weizman O. Trimaille A. et al.Pulmonary embolism in COVID-19 patients: a French multicentre cohort study. Patients who were treated with anticoagulation, either prophylactic or therapeutic dose, low-molecular-weight heparin (LMWH) or subcutaneous unfractionated heparin (UFH) before or during hospitalization, had a significantly lower odds for developing PE.30Fauvel C. Weizman O. Trimaille A. et al.Pulmonary embolism in COVID-19 patients: a French multicentre cohort study. Importantly, PE was more likely to develop in patients with delayed hospitalization.30Fauvel C. Weizman O. Trimaille A. et al.Pulmonary embolism in COVID-19 patients: a French multicentre cohort study. Interestingly, in a study of all-comers on statins predating mild, moderate or severe COVID-19 illness, treatment resulted in a significantly lower odds ratio (OR) of PE; OR: 0.4 [95%, confidence interval (CI): 0.23–0.75].29Poyiadji N. Cormier P. Patel P.Y. et al.Acute pulmonary embolism and COVID-19. Thus, anticoagulation, statins, and modulating the intensity of the inflammatory response to COVID-19 may be helpful in avoiding PE in hospitalized individuals.Venous thromboembolism and arterial thromboembolic complicationsMulti-center inpatient studies show a 10% to 14.7% incidence of venous thromboembolism in COVID-19 illness compared with 0.1% of the general population, but up to as high as 45.4% in ICU-level patients.32The epidemiology of venous thromboembolism., 33Boonyawat K. Chantrathammachart P. Numthavaj P. et al.Incidence of thromboembolism in patients with COVID-19: a systematic review and meta-analysis., 34Chen S. Zhang D. Zheng T. et al.DVT incidence and risk factors in critically ill patients with COVID-19., 35Demelo-Rodriguez P. Cervilla-Munoz E. Ordieres-Ortega L. et al.Incidence of asymptomatic deep vein thrombosis in patients with COVID-19 pneumonia and elevated D-dimer levels. Many develop asymptomatic DVT. Some centers only screened symptomatic patients; thus, the incidence is likely underreported in those studies. Like PE, patients with COVID-19 with DVT had higher D-dimer levels.34Chen S. Zhang D. Zheng T. et al.DVT incidence and risk factors in critically ill patients with COVID-19., 35Demelo-Rodriguez P. Cervilla-Munoz E. Ordieres-Ortega L. et al.Incidence of asymptomatic deep vein thrombosis in patients with COVID-19 pneumonia and elevated D-dimer levels., 36Lodigiani C. Iapichino G. Carenzo L. et al.Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy. There were no differences in baseline sex, age, or BMI of patients with COVID-19 who developed DVT as compared with those who did not, in limited studies.34Chen S. Zhang D. Zheng T. et al.DVT incidence and risk factors in critically ill patients with COVID-19., 35Demelo-Rodriguez P. Cervilla-Munoz E. Ordieres-Ortega L. et al.Incidence of asymptomatic deep vein thrombosis in patients with COVID-19 pneumonia and elevated D-dimer levels., 36Lodigiani C. Iapichino G. Carenzo L. et al.Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy. Additionally, DVT was linked to worse multi-system organ function and breakthrough from prophylactic anticoagulation.A large, single-center, retrospective study of 362 patients found an incidence of total venous and arterial thromboembolic events of 7.7%, but this number may be underestimated as there was no surveillance of asymptomatic patients.36Lodigiani C. Iapichino G. Carenzo L. et al.Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy. Most of those diagnosed with DVT also had concomitant PE; nonsurvivors had higher D-dimer levels.36Lodigiani C. Iapichino G. Carenzo L. et al.Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy.A prospective study of 156 COVID-19 positive inpatients evaluated the incidence of asymptomatic DVT. Patients received standard DVT prophylaxis of enoxaparin 40 mg per day or bemiparin 3500 IU per day. Of the 156 surveilled, 23 patients (14.7%) developed DVT with the majority (22/23) developing distal DVT. Patients who developed DVT had higher average D-dimer levels than those without (4527 vs 2050 ng/mL, P 35Demelo-Rodriguez P. Cervilla-Munoz E. Ordieres-Ortega L. et al.Incidence of asymptomatic deep vein thrombosis in patients with COVID-19 pneumonia and elevated D-dimer levels. There was no significant difference in obesity, sex, or age in patients who developed DVT versus those who did not.35Demelo-Rodriguez P. Cervilla-Munoz E. Ordieres-Ortega L. et al.Incidence of asymptomatic deep vein thrombosis in patients with COVID-19 pneumonia and elevated D-dimer levels.The incidence of DVT seems higher in critically ill patients with COVID-19.34Chen S. Zhang D. Zheng T. et al.DVT incidence and risk factors in critically ill patients with COVID-19. In a retrospective, single-center analysis of 88 ICU patients receiving thromboprophylaxis with LMWH, 40 developed DVT (45.4%).34Chen S. Zhang D. Zheng T. et al.DVT incidence and risk factors in critically ill patients with COVID-19. In this study, DVT was not associated with BMI, age, sex, and platelet counts, but was associated with elevated sequential organ failure assessment (SOFA) scores (6 vs 4, P P P P = .007). Anatomically, most DVTs were distal and bilateral.34Chen S. Zhang D. Zheng T. et al.DVT incidence and risk factors in critically ill patients with COVID-19. Thus, prophylactic LMWH may be insufficient for the prevention of DVT in the ICU population.StrokeThe incidence of stroke in COVID-19 infection is approximately 1.7%.37Siow I. Lee K.S. Zhang J.J.Y. et al.Stroke as a neurological complication of COVID-19: a systematic review and meta-analysis of incidence, outcomes and Predictors. By comparison, the risk of stroke in the general population is 0.2%.38Rosamond W.D. Folsom A.R. Chambless L.E. et al.Stroke incidence and survival among middle-aged adults: 9-year follow-up of the Atherosclerosis Risk in Communities (ARIC) cohort. Studies point to severe COVID-19 infection or underlying cardiovascular risk factors as highly contributory to stroke.39Qureshi A.I. Baskett W.I. Huang W. et al.Acute ischemic stroke and COVID-19: an analysis of 27 676 patients.,40Li Y. Li M. Wang M. et al.Acute cerebrovascular disease following COVID-19: a single center, retrospective, observational study. In comparison to incident DVT and PE, there seems to be a stronger association of underlying CVD risk factors with COVID-19-associated stroke.Retrospective case-control studies have documented increased stroke in hospitalized COVID-19 patients, and conversely, more frequent COVID-19 infection in those hospitalized with stroke during the time frame of the pandemic. COVID-19 was more often associated with stroke in Black individuals in a larger, multicenter analysis.39Qureshi A.I. Baskett W.I. Huang W. et al.Acute ischemic stroke and COVID-19: an analysis of 27 676 patients. Black individuals with COVID-19 comprised a greater proportion of stroke cases compared with noninfected Black controls (44.7% vs 19.6%, P 39Qureshi A.I. Baskett W.I. Huang W. et al.Acute ischemic stroke and COVID-19: an analysis of 27 676 patients. Conversely, White individuals with COVID-19 accounted for a smaller proportion of stroke cases compared with White individuals without COVID-19 (35.9% vs 56.3, P 39Qureshi A.I. Baskett W.I. Huang W. et al.Acute ischemic stroke and COVID-19: an analysis of 27 676 patients. Patients with hypertension, type 2 diabetes mellitus (T2DM), atrial fibrillation, and congestive heart failure at baseline were more likely to develop stroke. Hospitalized patients with COVID-19-associated stroke had higher mortality rates (19.4% vs 6.2%, P P = .003).39Qureshi A.I. Baskett W.I. Huang W. et al.Acute ischemic stroke and COVID-19: an analysis of 27 676 patients.From March to April 2020, COVID-19 was more frequently diagnosed in those with stroke, after adjusting for age, sex, vascular risk factors, and underlying comorbidities.41Belani P. Schefflein J. Kihira S. et al.COVID-19 is an Independent risk factor for acute ischemic stroke. Patients presenting with stroke were infected with COVID-19 46.3% of the time as compared with 18.3% of the time for nonstroke patients (P = .001).41Belani P. Schefflein J. Kihira S. et al.COVID-19 is an Independent risk factor for acute ischemic stroke. Similar data from a single-center retrospective study support the observation that severe COVID-19, hypertension and T2DM are associated with increased incidence of stroke, but in this study, age was a significant factor as well, with all strokes occurring in patients greater than 60 years.40Li Y. Li M. Wang M. et al.Acute cerebrovascular disease following COVID-19: a single center, retrospective, observational study. Patients with COVID-19 infected stroke have poorer outcomes and prolonged neurologic deficits, with worse neurologic disabilities at discharge and a higher incidence of delirium than stroke patients without COVID-19.42Benussi A. Pilotto A. Premi E. et al.Clinical characteristics and outcomes of inpatients with neurologic disease and COVID-19 in Brescia, Lombardy, Italy.Prevention and treatment of thrombosis in COVID-19 infectionThere is varying evidence on indications, dose, and efficacy of medical therapy for thrombotic complications of COVID-19. Studies suggest the greatest effect in preventing thrombotic injury is with heparins rather than direct oral anticoagulants (DOAC).46Investigators A. Investigators AC-a Investigators R.-C. et al.Therapeutic anticoagulation with heparin in Noncritically ill patients with Covid-19., 47Investigators R.-C. Investigators AC-a Investigators A. et al.Therapeutic anticoagulation with heparin in critically ill patients with Covid-19., 48Lopes R.D. de Barros E.S.P.G.M. Furtado R.H.M. et al.Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial., 49Chocron R. Galand V. Cellier J. et al.Anticoagulation before hospitalization is a potential Protective factor for COVID-19: Insight from a French multicenter cohort study. It is important to note that many studies are nonrandomized and focus on macrovascular rather than microvascular thrombosis.Heparin has been studied in several randomized controlled clinical trials in noncritically and critically ill patients.46Investigators A. Investigators AC-a Investigators R.-C. et al.Therapeutic anticoagulation with heparin in Noncritically ill patients with Covid-19.,47Investigators R.-C. Investigators AC-a Investigators A. et al.Therapeutic anticoagulation with heparin in critically ill patients with Covid-19. Patients were randomized to either therapeutic doses of UFH or LMWH based on local dosing protocols or standard thromboprophylaxis. In noncritically ill patients, therapeutic heparin increased organ support-free days, defined as the total number of days without respiratory or cardiovascular support, OR: 1.27 (95% CI: 1.03–1.58). Patients on therapeutic heparin were less likely to die (OR: 0.72 95% CI: 0.53–0.98). There was a nonstatistically significant increase in bleeding (OR: 1.8, 95% CI: 0.9–3.74).