Page 16 - 2021_12-Haematologica-web

P. Gresele et al.
Figure 1. Hypothesized interactions between platelets and adenovirus- es. Adenoviruses (Ad) induce platelet activation either by binding to platelet coxsackie and adeno- virus receptor (CAR) or to platelet- surface integrins, such as αvb3 or α5b1. Moreover, circulating Ad-elicit- ed IgG or immune complexes may directly activate platelets through FcgRIIa. Gas6 exposed by cerebral vein endothelial cells may bind Ad and activate platelets acting on Tyro3, Axl and Mer (TAM) receptors. Ad may also bind CAR expressed by cerebral vein vessels in this way activating endothelial cells which in turn may elicit platelet activation.
regulatory protein of the complement system.31 C4BP binds to activated platelets through mechanisms involv- ing chondroitin sulfate expressed on activated platelets32 and to membrane-associated protein S on platelets.33 Interestingly, the protein C anticoagulant pathway plays a peculiar pathophysiological role in CVST.34
Small but measurable amounts of EPCR are also found in plasma. Soluble EPCR binds both protein C and acti- vated protein C with an affinity similar to that of mem- brane-bound EPCR35 but, in contrast to the latter, it inhibits activated protein C anticoagulant activity thus limiting its ability to inactivate activated factor V, and also binds protein C impeding its activation by thrombin- thrombomodulin complexes.32,36 An increase in soluble EPCR was observed in CVST, possibly leading to a proco- agulant condition and enhanced risk of thrombosis.37
Finally, Gas6 (encoded by the growth arrest-specific 6 gene), a vitamin K-dependent protein with 44% sequence homology with protein S but devoid of anticoagulant activity, is widely expressed in the cerebral nervous sys- tem where it is found on resting endothelial cells. Gas6 potentiates platelet activation acting on Tyro3, Axl and Mer (TAM) receptors leading to thrombus formation38 and in vitro studies have shown that Gas6 binds to Ad enhancing their gene expression.39
The affinity of different Ad for coagulation factors is variable, with a considerable number of Ad types unable to bind them. Ad-5, Ad-2 and Ad-16 bind strongly to fac- tor X.40 Moreover, the ability of Ad to bind coagulation factors is species-specific, e.g., Ad-5 binds human and mouse factor X with similar affinity, but Ad-2 binds human factor X with 10-fold lower affinity than mouse factor X.41
Vitamin K-dependent coagulation factors VII, IX, X, and protein C mediate the binding of Ad to hepato- cytes.42-44 For instance, for Ad-5 hepatotropism is critically dependent on the ability of the Ad-5 hexon to bind factor
X. In contrast, non-factor X-binding Ad, such as Ad-48 and Ad-26, do not show hepatocyte tropism.45 The pri- mary reason why factor X is required for Ad-5 transduc- tion to the liver is that it protects Ad-5 from attack by complement.46
It has been previously ascertained that components of intramuscularly-injected vaccines, including the Ad vec- tor, are disseminated in the circulation47 and it is thus con- ceivable that some of the above described activating interactions between Ad and platelets, endothelium and the blood clotting system can occur in recipients of Ad- vector-based vaccines. However, so far no experimental evidence that this may have a role in VITT is available and actually it seems unlikely that sufficiently high circu- lating levels of a non-replicating Ad vector may be reached to trigger platelet activation or blood coagulation changes. In fact, it should be considered that around 2,500 billion virions/kg are required to trigger this reac- tion in mice and non-human primates,29,48 and even if all the Vaxzevria viral content were to spill-over into the blood after intramuscular administration, a concentration of 0.7 billion/kg Ad viral vectors would be reached, which is probably insufficient to activate platelets/coagulation.49
Antibody-dependent enhancement
and vaccine-associated adverse events
Antibody-dependent enhancement (ADE) is an immunological form of a more general phenomenon called enhanced respiratory disease, leading to the clinical worsening of respiratory viral infections. ADE can occur either through an antibody-mediated increase of virus uptake by Fcg receptor IIa (FcgRIIa)-expressing phagocytic cells, thus facilitating viral infection and replication, or by boosting immune activation through excessive Fc-medi- ated immunological cell effector functions or immune
3036
haematologica | 2021; 106(12)