The complement alternative pathway and hemostasis

Abstract

The complement and hemostatic systems are complex systems, and both involve enzymatic cascades, regulators, and cell components-platelets, endothelial cells, and immune cells. The two systems are ancestrally related and are defense mechanisms that limit infection by pathogens and halt bleeding at the site of vascular injury.Recent research has uncovered multiple functional interactions between complement and hemostasis. On one side, there are proteins considered as complement factors that activate hemostasis, and on the other side, there are coagulation proteins that modulate complement. In addition, complement and coagulation and their regulatory proteins strongly interact each other to modulate endothelial, platelet and leukocyte function and phenotype, creating a potentially devastating amplifying system that must be closely regulated to avoid unwanted damage and\or disseminated thrombosis.In view of its ability to amplify all complement activity through the C3b-dependent amplification loop, the alternative pathway of complement may play a crucial role in this context. In this review, we will focus on available and emerging evidence on the role of the alternative pathway of complement in regulating hemostasis and vice-versa, and on how dysregulation of either system can lead to severe thromboinflammatory events.

Transfusion medicine approaches for spontaneous intracerebral hemorrhage patients

“…Additionally, anticoagulant and fibrinolytic (and antifibrinolytic) proteins produced by nearby intact endothelium are critical for clot stability and limiting pathologic clot propagation and thrombotic complications. Finally, inflammation also regulates and activates coagulation [26]. And, while these systems are often described/assessed separately, it is important to highlight the complex interactions of all these components, and particularly the cellular drivers (e.g., platelets, red blood cells [RBCs]) [27] responsible for initiating and stabilizing clot formation.…”

Revisiting the relationship between complement and ulcerative colitis

“…By binding covalently to properdin (P), C3bBb convertase can become stabilized, providing a molecular basis for subsequent C5 cleavage. C3b deposition on the cell surface induces the formation of the C5 convertase, C3bBbC3b, in the AP 33,34,36,37 …”

“…C3b deposition on the cell surface induces the formation of the C5 convertase, C3bBbC3b, in the AP. 33,34,36,37 All three complement pathways converge at the production of the C5 convertase. The C5 convertase, C4bC2bC3b, in the CP and LP, and C3bBbC3b in the AP then process C5 into C5a and C5b.…”

The complement alternative pathway in health and disease—activation or amplification?

“…While this occurs at many different points in both proteolytic activation cascades, it is particularly apparent at the level of C3 activation. Beginning with an overview of both hemostasis and amplified C3 activation, Noris and Galbusera drive home the inter‐relationship of the two systems, and its malfunction in thrombotic conditions 24 . One interesting aspect of their discussion is that thrombotic thrombocytopenic purpura (TTP), a disease not commonly regarded as a disease of dysregulated complement activation, has an AP/AL activation component.…”

“…Beginning with an overview of both hemostasis and amplified C3 activation, Noris and Galbusera drive home the inter-relationship of the two systems, and its malfunction in thrombotic conditions. 24 One interesting aspect of their discussion is that thrombotic thrombocytopenic purpura (TTP), a disease not commonly regarded as a disease of dysregulated complement activation, has an AP/AL activation component. This again has implications relevant to AP/AL-directed therapeutics.…”