The overall goal of this competitive renewal is to define the biology of antiphospholipid antibody syndrome, catastrophic antiphospholipid antibody syndrome and severe forms of COVID-19, and to discover novel biomarkers and therapeutic targets. Complementopathies are diseases where end-organ damage is driven by failure to regulate complement on host cells and complement inhibition mitigates cellular and end-organ damage. Classic examples include paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (ahUS), and cold agglutinin disease (CAD). Complementopathies are frequently triggered by inflammation and are often associated with a severe thrombotic phenotype, often in the microcirculation. A hallmark is the presence of microthrombi in venules and arterioles due to endothelial injury (thrombotic microangiopathy). Our previously funded submission entitled, Complementopathies: genotype and phenotype, led to a number of seminal discoveries. We validated and refined a cell-based assay (modified Ham test, mHam) that measures complement regulation on human cells, and established the HELLP (hemolysis elevated liver function tests and low platelets) syndrome, antiphospholipid antibody syndrome (APS), catastrophic antiphospholipid antibody syndrome (CAPS), and most recently, severe COVID-19 as complementopathies. The mHam was validated because diseases with a positive mHam were found to have and increase in germline mutations in complement regulatory genes (aHUS, HELLP), an antibody or protein that activates complement (anti-?2-GPI antibodies, COVID-19) or both a germline mutation and an antibody (CAPS). Furthermore, we were able to change standard of care for aHUS by demonstrating that terminal inhibition can be discontinued in most aHUS patients. This proposal is a natural extension of our previously funded work and seeks to extend this work by addressing many unresolved questions in the field. Specifically, we will: 1) develop more reliable biomarkers for APS/CAPS by defining which APS autoantibodies activate complement; 2) identify APS patients who may not require lifelong anticoagulation; 3) prove that germline mutations in complement regulatory genes are common in CAPS; 4) prove that end-organ damage/microvascular thrombosis/endothelial damage from SARS-CoV-2 infection is due to unregulated activity of complement; and 5) demonstrate that germline mutations in complement regulatory genes are more common in patients with more severe forms of COVID19. If funded, we expect to translate our findings into clinical trials that lead to approved drugs for the treatment of severe APS/CAPS, and COVID19.