Updates in the Management of Warm Autoimmune Hemolytic Anemia.

Warm autoimmune hemolytic anemia (wAIHA) is an uncommon and heterogeneous disorder caused by autoantibodies to RBC antigens. Initial evaluation should involve the DAT, with wAIHA typically IgG positive with or without C3 positivity, and a search for underlying conditions associated with secondary wAIHA, which comprise 50% of cases. First-line therapy involves glucocorticoids, increasingly with rituximab, though a chronic relapsing course is typical. While splenectomy and a number of immunosuppressive therapies have been used in the setting of relapsed and refractory disease, the optimal choice and sequence of therapies is unknown, and clinical trials should be offered when available. Newer investigational targets include spleen tyrosine kinase inhibitors, monoclonal antibodies targeting CD38, Bruton's tyrosine kinase inhibitors, complement inhibitors, and antibodies against neonatal Fc receptors.

Complement dysregulation is associated with severe COVID-19 illness.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) may manifest as thrombosis, stroke, renal failure, myocardial infarction, and thrombocytopenia, reminiscent of other complement- mediated diseases. Multiple clinical and preclinical studies have implicated complement in the pathogenesis of COVID-19 illness. We previously found that the SARS-CoV-2 spike protein activates the alternative pathway of complement (APC) in vitro through interfering with the function of complement factor H, a key negative regulator of APC. Here, we demonstrated that serum from 58 COVID-19 patients (32 patients with minimal oxygen requirement, 7 on high flow oxygen, 17 requiring mechanical ventilation and 2 deaths) can induce complementmediated cell death in a functional assay (the modified Ham test) and increase membrane attack complex (C5b-9) deposition on the cell surface. A positive modified Ham assay (>20% cell-killing) was present in 41.2% COVID-19 patients requiring intubation (n=7/17) and only 6.3% in COVID-19 patients requiring minimal oxygen support (n=2/32). C5 and factor D inhibition effectively mitigated the complement amplification induced by COVID-19 patient serum. Increased serum factor Bb level was associated with disease severity in COVID-19 patients, suggesting that APC dysregulation plays an important role. Moreover, SARS-CoV-2 spike proteins directly block complement factor H from binding to heparin, which may lead to complement dysregulation on the cell surface. Taken together, our data suggest that complement dysregulation contributes to the pathogenesis of COVID-19 and may be a marker of disease severity.

Antiphospholipid syndrome: complement activation, complement gene mutations and therapeutic implications

Antiphospholipid syndrome (APS) is an acquired thromboinflammatory disorder characterized by the presence of antiphospholipid antibodies as well as an increased frequency of venous or arterial thrombosis and/or obstetrical morbidity. The spectrum of disease varies from asymptomatic to a severe form characterized by widespread thrombosis and multi-organ failure, termed catastrophic APS (CAPS). CAPS affects only about ∼1% of APS patients and often presents as a thrombotic microangiopathy and has a fulminant course with >40% mortality, despite the best available therapy. Animal models have previously implicated complement in the pathophysiology of thrombosis in APS, with more recent data from human studies confirming the interaction between the coagulation and complement pathways. Activation of the complement cascade via antiphospholipid antibodies can cause cellular injury and promote coagulation via multiple mechanisms. Finally, analogous to classic complement-mediated diseases such as atypical hemolytic uremic syndrome, a subset of patients with APS may be at increased risk for development of CAPS due the presence of germline variants in genes crucial for complement regulation. Together, these data make complement inhibition an attractive and potentially life-saving therapy to mitigate morbidity and mortality in severe thrombotic APS and CAPS.

Direct activation of the alternative complement pathway by SARS-CoV-2 spike proteins is blocked by factor D inhibition.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly contagious respiratory virus that can lead to venous/arterial thrombosis, stroke, renal failure, myocardial infarction, thrombocytopenia, and other end-organ damage. Animal models demonstrating end-organ protection in C3-deficient mice and evidence of complement activation in humans have led to the hypothesis that SARS-CoV-2 triggers complement-mediated endothelial damage, but the mechanism is unclear. Here, we demonstrate that the SARS-CoV-2 spike protein (subunit 1 and 2), but not the N protein, directly activates the alternative pathway of complement (APC). Complement-dependent killing using the modified Ham test is blocked by either C5 or factor D inhibition. C3 fragments and C5b-9 are deposited on TF1PIGAnull target cells, and complement factor Bb is increased in the supernatant from spike protein-treated cells. C5 inhibition prevents the accumulation of C5b-9 on cells, but not C3c; however, factor D inhibition prevents both C3c and C5b-9 accumulation. Addition of factor H mitigates the complement attack. In conclusion, SARS-CoV-2 spike proteins convert nonactivator surfaces to activator surfaces by preventing the inactivation of the cell-surface APC convertase. APC activation may explain many of the clinical manifestations (microangiopathy, thrombocytopenia, renal injury, and thrombophilia) of COVID-19 that are also observed in other complement-driven diseases such as atypical hemolytic uremic syndrome and catastrophic antiphospholipid antibody syndrome. C5 inhibition prevents accumulation of C5b-9 in vitro but does not prevent upstream complement activation in response to SARS-CoV-2 spike proteins.