Identification of Coagulation Factor XI as a Ligand for Platelet Apolipoprotein E Receptor 2 (ApoER2)

Abstract

Objective-Factor XI (FXI) promotes hemostasis and thrombosis through enhancement of thrombin generation and has been shown to play a critical role in the formation of occlusive thrombi in arterial injury models. The aim of this study was to investigate the mechanisms governing interactions between FXI and platelets. 2 Inherited FXI deficiency causes a mild bleeding diathesis and is protective against ischemic stroke, 3,4 whereas an elevated FXI plasma level is an independent risk factor for thrombotic diseases such as deep vein thrombosis. 5 Consistent with these observations, FXI plays a critical role in experimental thrombus growth in rabbits, mice, and primates. 6 -10 See accompanying article on page 1409 FXI circulates as a disulfide-linked homodimer in complex with plasma high molecular weight kininogen (HK). FXI shares high sequence homology (58% amino acid identity) with the functionally-distinct plasma protein prekallikrein, which also circulates in complex with HK. 11,12 Although the serine protease domain of each FXI subunit is similar to catalytic domains for other coagulation proteases, the noncatalytic portion contains 4 apple domains (A1 to A4), a feature shared only with prekallikrein. 12,13 The FXI A3 domain has been shown to contain binding sites for FIX and for the platelet receptor glycoprotein Ib-IX-V (GPIb). 14,15 FXI binding has been localized to the leucine-rich repeat (LRR) sequences on the NH 2 -terminal globular domain of GPIb␣, at a site distinct from the anionic thrombin-binding domain of GPIb␣. 16,17 It is unknown whether FXI-platelet binding is solely mediated by GPIb␣ or whether other platelet receptor(s) exist that can support interactions with FXI.GPIb␣ has been shown to form a complex on the platelet surface with apolipoprotein E receptor 2 (ApoER2, LRP8), 18 -20 a member of the low-density lipoprotein (LDL) family of receptors. ApoER2 initiates intracellular signaling through the adaptor protein disabled-1 (Dab-1) in platelets. 21 The extracellular domain of ApoER2 consists of 3 regions: (1) the type A-binding repeats of LDL-binding domains displaying a negatively-charged surface, which are responsible for receptor-ligand interactions; (2) type B repeats, which are homologous to regions in the epidermal growth factor precursor; and (3) the protein stack of O-linked sugar domains that separate the LDL-binding domains from the cellular surface. We have recently shown that platelet and leukocyte ApoER2 mediate interactions with the anticoagulant serine protease, activated protein C. 22,23 Here, we present the first evidence that identifies FXI as a ligand for ApoER2.

Inhibition of factor XI activation attenuates inflammation and coagulopathy while improving the survival of mouse polymicrobial sepsis

“…At present, there is no known direct mechanistic link between FXI activation and these cytokines, although there is evidence that FXIa has direct cellular signaling functions through the receptor apoER2 and possibly others. 48,50 We speculate that the limited inflammatory response associated with 14E11 treatment may be linked with the suppression of pathologic intravascular thrombin generation, as evidenced by the attenuated TAT levels, platelet consumption, and microvascular thrombosis. Disseminated thrombosis causes a mechanical disruption of blood flow and organ perfusion deficits, leading to moderate to severe tissue ischemia that produces an acute inflammatory response.…”

New Fundamentals in Hemostasis

“…In addition, GPIb␣ has been reported to bind the coagulation factors FXI, FXII, and high-molecular-weight kininogen (7) and may also function as a coreceptor for FVIIa (314) and FXI(a) (17). On the other hand, recent findings suggest that FXI binds to platelets via the receptor LRP8 (ApoeER2) (317). LRP8 may also serve as a binding site for APC (326).…”

Structure and function of factor XI

“…35,70 When human blood lacking FXII activity is perfused over collagen at arterial shear rates, platelets deposit in aggregates and fibrin strands form. 70 Addition of an antibody that blocks FXIa activation of FIX prevents fibrin formation. Interestingly, adding inhibitors of FVIIa/TF does not affect fibrin formation, suggesting that platelets may play a role in FXI activation.…”

“…[67][68][69] However, FXI binding to platelets assayed under flow (discussed in "FXI interactions with platelet receptors") is not enhanced by HK. 70 The sites on FXI and PK that bind HK are probably similar. Studies using FXI/PK chimeras, individual apple domains, and short peptide sequences derived from apple domains indicate the A2 domain is required for HK binding, with additional contributions from A1 and A4.…”