Platelets and Thrombotic Antiphospholipid Syndrome

Abstract

Antiphospholipid antibody syndrome (APS) is an autoimmune disorder characterised by thrombosis and the presence of antiphospholipid antibodies (aPL): lupus anticoagulant and/or IgG/IgM anti-β2-glycoprotein I and anticardiolipin antibodies. APS carries significant morbidity for a relatively young patient population from recurrent thrombosis in any vascular bed (arterial, venous, or microvascular), often despite current standard of care, which is anticoagulation with vitamin K antagonists (VKA). Platelets have established roles in thrombosis at any site, and platelet hyperreactivity is clearly demonstrated in the pathophysiology of APS. Together with excess thrombin generation, platelet activation and aggregation are the common end result of all the pathophysiological pathways leading to thrombosis in APS. However, antiplatelet therapies play little role in APS, reserved as a possible option of low dose aspirin in addition to VKA in arterial or refractory thrombosis. This review outlines the current evidence and mechanisms for excessive platelet activation in APS, how it plays a central role in APS-related thrombosis, what evidence for antiplatelets is available in clinical outcomes studies, and potential future avenues to define how to target platelet hyperreactivity better with minimal impact on haemostasis.

Keywords: antiphospholipid antibodies; antiphospholipid syndrome; antiplatelets; platelets; thrombosis.

Figure 1

The central role of excess thrombin generation and platelet activation in pathophysiological mechanisms contributing to thrombosis in antiphospholipid syndrome (APS). Antiphospholipid antibodies (aPL) have impact on many different cells and pathways leading to thrombosis. (A) Endothelial cells are directly impacted by aPL causing increased tissue factor (TF) expression, as well as indirectly with aPL-related platelet microparticle-induced endothelial pyroptosis, resulting in thrombin generation. (B) aPL induce neutrophils to release extracellular traps (NETs), as well as reduce NETs clearance and activate platelets which also lead to NET formation, which in turn activates platelets. Neutrophils also expose phosphatidylserine (PS) to increase thrombin generation. (C) aPL lead to increased tissue factor expression by monocytes, causing increased thrombin generation. (D) aPL induce platelet activation, aggregation, and PS exposure, releasing platelet microparticles, generating bursts of thrombin for fibrin clot stabilisation. (E) aPL-related platelet and leukocyte activation leads to platelet-leukocyte aggregate formation, which potentiates further platelet activation and thrombin generation. (F) The classical and alternative pathways of complement activation are upregulated in APS, with some evidence of lectin pathway also being involved. Complement activation contributes to platelet activation and thrombin generation. (G) Protein C cleaves and inactivates coagulation factors V and VIII, necessary for thrombin generation. Protein C resistance is evident in APS, with anti-Protein C antibodies in APS observed in some studies. (H) The quantity and activity of von Willebrand Factor (vWF) is increased in APS, resulting in increased platelet adhesion, activation, and aggregation. Created with Biorender.com.

Figure 2

Platelets exhibit hyperreactivity through many pathways in antiphospholipid syndrome (APS). A large number of platelet receptor agonist stimulation pathways result in greater platelet activation in APS with lower concentrations of agonist. This is due to the “priming” by antiphospholipid antibodies (aPL) complexed to dimerised open-conformation β2 glycoprotein binding to Apolipoprotein E receptor 2 (ApoER2), glycoprotein (GP)Ib-IX-V receptor, and toll-like receptor 2 (TLR2). There is evidence that the Fc portion of some aPL can also prime platelets to hyperreactivity through the FcɣRIIa receptor and mTOR cluster 1 (mTORC1) signalling. The activity of AKT appears central to many of the priming pathways, most critically with the mTORC2-SIN1-AKT axis, although the upstream receptor for this pathway (shown as “?”) has not yet been identified. Hyperreactivity has been identified with ADP agonist stimulation through the P2Y₁₂ receptor, which is overexpressed in APS patient platelets. Protease-Activated Receptor (PAR) 1 and 4 signalling triggered by thrombin, α2-adrenoreceptor (AR) stimulated by adrenaline, and collagen signalling (presumably through GPVI receptor and α2β1 integrin) have all been shown to be hyperreactive. The platelet activation resulting from these pathways are illustrated. TXA—thromboxane, P-sel—P-selectin, TF—tissue factor, PS—phosphatidylserine. Created with Biorender.com.