(A) Common clinical signs and symptoms as well as comorbidities and other cofactors for disease progression distinguish long COVID, also known as PASC, from acute COVID-19. In particular, female sex at birth is linked to a higher incidence of PASC, while male sex at birth is a risk factor for acute COVID-19 progression. Multiple metabolic and cardiovascular risk factors exacerbate acute COVID-19. Overall, age, BMI, and prior respiratory or cardiovascular history do not affect the incidence of PASC but may influence its clinical phenotype. (B) An acute thromboinflammatory process characterizes acute COVID-19. Clinical progression parallels biomarkers of EC injury and a hyperinflammatory state, including enhanced release of proinflammatory cytokines and chemokines, activation of complement and coagulation cascades, platelet activation, NETosis, and, ultimately, hypoxia. IFN-I signals can promote an antiviral response via MxA and exacerbate inflammation. AKI, acute kidney injury; AMI, acute myocardial infarction; ANC, absolute neutrophil count; ATN, acute tubular necrosis; CRP, C-reactive protein; CVD, cardiovascular disease; DM-1, DM-2, diabetes mellitus types 1 and 2; DVT, deep vein thrombosis; eGFR, estimated glomerular filtration rate; ENT, ear, nose, and throat; ESRD, end-stage renal disease; LFTs, liver function tests; NET, neutrophil extracellular trap; PASC, post-acute sequelae of SARS-CoV-2 infection; PE, pulmonary embolism; POTS, postural orthostatic tachycardia syndrome; TF, tissue factor; vWF, von Willebrand factor.