Table 1.

Potential therapeutic strategies against platelet hyperreactivity for further research in thrombotic antiphospholipid syndrome.

Therapeutic Strategy	Available Agents	Potential Benefits/Limitations
Inhibiting P2Y12 receptor	Clopidogrel, prasugrel, ticagrelor, etc.	Benefits:
		Overexpression of P2Y12 in APS and associated platelet hyperreactivity Pre-clinical studies demonstrate ticagrelor can reverse platelet hyperreactivity to ADP in APS Known safety profile and clinical use together with anticoagulation
		Limitations:
		Increased bleeding risk, especially in combination with current standard therapy
Increasing cyclic AMP	Cilastazol, dipyridamole	Benefits:
		Can reverse downregulation of cyclic AMP seen in APS platelets Known safety profile
		Limitations:
		Increased bleeding risk, especially in combination with current standard therapy
Reducing procoagulant platelet formation	Ciclosporin, acetazolamide	Benefits:
		Procoagulant platelets predominantly involved in thrombosis, less impact on haemostasis Procoagulant platelets are downstream of many of the pathological processes in APS Will block the platelet-derived thrombin generation induced by aPL
		Limitations:
		Current agents have many off-target adverse effects that limit use
mTOR inhibition	Everolimus, sirolimus	Benefits:
		Preclinical studies have demonstrated reduction in platelet hyperreactivity downstream of FcɣRIIa signalling induced by aPL Will inhibit mTOR-mediated endothelial activation in APS as well No impact on haemostasis
		Limitations:
		Current agents have many off-target adverse effects that limit use
Inhibition of mTORC2 (SIN1)-AKT axis	?	Benefits:
		Mouse models have demonstrated reversal of platelet hyperreactivity and thrombosis in any vascular bed induced by aPL No prolongation of tail bleeding time in mouse model with SIN1 deficiency, so appears to be thrombosis-specific Could potentially target AKT upstream with available PI3K inhibitors
		Limitations:
		No specific available agents with known safety profiles in humans. AKT inhibitors and any developed agents have many off-target adverse effects that limit use
Reducing Neutrophil Extracellular Traps (NETs)	Dipyridamole, ?	Benefits:
		Excess NETs formation and impaired clearance in APS with prothrombotic effect Dipyridamole has a known safety profile Potential for repurposing agents that could reduce NETs, e.g., crizanlizumab (blocks P-selectin-PSGL interaction required for platelet-neutrophil interaction, used in sickle cell disease)
		Limitations:
		Increased bleeding risk with dipyridamole Direct NETs inhibition will likely compromise normal response to pathogens
Inhibiting excessive complement activation	Eculizumab (C5), ravalizumab (C5), sutimlimab (C1s), pegcetacoplan (C3), etc.	Benefits:
		Complement activation plays a key role in APS thrombosis and can induce procoagulant platelets Known safety profiles and clinical experience Would not impact haemostasis
		Limitations:
		Current agents have many off-target adverse effects that limit use