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

Abstract

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 multiorgan failure, termed catastrophic APS (CAPS). CAPS affects only about ∼1% of APS patients, often presents as a thrombotic microangiopathy and has a fulminant course with >40% mortality, despite the best available therapy. Animal models have 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 because of the presence of germline variants in genes crucial for complement regulation. Together, these data make complement inhibition an attractive and potentially lifesaving therapy to mitigate morbidity and mortality in severe thrombotic APS and CAPS.

Keywords: antiphospholipid syndrome; complement; eculizumab; genetics; thrombosis.

FIGURE 1

Complement regulation and dysregulation. Complement is activated by three pathways: (1) the lectin pathway, (2) the classical pathway, and (3) the alternative pathway. Importantly, the alternative pathway of complement (APC) also serves as an amplification loop for the lectin and classical pathways, accounting for the majority of complement activation products. The magnitude of APC activation depends on the amplification (green) and the degradation pathways (red). C3 tickover allows C3b to covalently bind to nearby cell surfaces. Once factor B binds to C3b, it is cleaved by factor D to generate the APC C3 convertase (C3bBb). C3bBb cleaves C3 to generate even more C3b setting off the amplification loop. Factor H (H) inhibits C3 amplification; it competes with B for binding to C3b, is a cofactor for factor I-catalyzed cleavage of C3b to iC3b (an opsonin), and accelerates decay of the C3 convertase (C3bBb). In the normal state, these pathways are in homeostasis. Dysregulation, for example from a loss of function mutation in CFH that reduces degradation (red loop), leads to an increase in the amplification loop because degradation of the C3 convertase (C3b.Bb) is blocked, resulting in increased production of complement effectors C3a, C5a and C5b-9 (the membrane attack complex). Additionally, complement amplifying triggers such as infection, surgery, or pregnancy can enhance the activation loop (green) and increase complement activation over the threshold required for clinical disease. (Figure was created using biorender.com.)

FIGURE 2

Multiple “hits” contributing to complementopathy. Complement-mediated disorders such as aHUS, HELLP syndrome, and catastrophic APS share clinical features including thrombocytopenia, widespread small vessel thrombosis, and ischemic end-organ injury. These disorders are associated with inherited mutations in complement regulation genes, which confer a predisposition to disease. These mutations have incomplete penetrance and a complement amplifying ‘trigger’ is often required for the disorder to manifest. In addition to tissue injury from direct effects of complement, thrombosis is a hallmark of complementopathies, and the thrombotic risk is mitigated on treatment with terminal complement inhibitors. (Figure was created using biorender.com.)