304
W. Li et al.
in thrombosis and inflammation. Prekallikrein-deficient mice survive thrombotic
events but retain normal hemostatic capacity. Therefore, aptamers targeting kallikrein
may be safer alternative anticoagulants with anti-inflammatory benefits [110].
10.9 Aptamers Against P-Selectin
The current standard anticoagulation is effective for the prevention and recurrence
of venous thrombosis and thrombus progression. However, thrombolysis is very
difficult and extension of a primary DVT and post-thrombotic syndrome is common
[113].
The selectins family is composed of three homologous cell adhesion molecules, Pselectin, L-selectin, and E-selectin. P-selectin is expressed on the surface of platelets
and vascular endothelial cells after stimulating by cytokine or thrombin [114]. In the
early stage of tissue injury or infection, p-selectin binds to ligands on the surface of
neutrophils and initiates rolling on activated vascular endothelium [115]. P-selectin
is known as a mediator of platelet/leukocyte involved in TF-mediated thrombosis
and prothrombotic cell accumulation on the vascular injury surface [115]. The
selectins mediate cell adhesion through calcium-dependent binding of the sialylated,
fucosylated carbohydrate Sialyl Lewis X presented by mucin-like glycoproteins
[116].
Parma and his colleagues screened out an anti-P-selectin aptamer with a high
binding affinity in the sub-nanomolar range(16-710 pM) that bounds 10
5 –10
6 -fold
more tightly than the native minimal carbohydrate ligand Sialyl Lewis X. Binding
selectivity of aptamers to P-selectin was 10
4 –10
5 -fold higher than human E-selectin
or L-selectin. Since p-selectin is expressed on the surface of thrombin-activated
platelets, these aptamers can be applied to block the binding between activated
platelets and neutrophils. Preclinical and clinical trials are being awaited [117].
10.9.1 Aptamers Against vWF
There are two categories of antiplatelet drugs to reduce the risk of thrombosis-related
clinical events. The first category is surface receptors and pathways inhibitor that
partly inhibits platelet function for chronic therapy, and the second category is surface
receptors for global platelet function. Antiplatelet drugs of the first category usually
include clopidogrel (Plavix) and aspirin, which inhibit pathways of platelet activation
and/or aggregation with a modest antithrombotic effect. However, clopidogrel and
aspirin contribute to an increased surgical bleeding risk and should be contraindicated up to 7 days before an operation. The second catogory of the antiplatelet
drug is platelet GP IIb/IIIa inhibitors, for example, abciximab and eptifibatide,
which can effectively reduce thrombotic cardiovascular events in ACS patients but
increase periprocedural hemorrhagic risk. A desirable antiplatelet agent should not
W. Li et al.
in thrombosis and inflammation. Prekallikrein-deficient mice survive thrombotic
events but retain normal hemostatic capacity. Therefore, aptamers targeting kallikrein
may be safer alternative anticoagulants with anti-inflammatory benefits [110].
10.9 Aptamers Against P-Selectin
The current standard anticoagulation is effective for the prevention and recurrence
of venous thrombosis and thrombus progression. However, thrombolysis is very
difficult and extension of a primary DVT and post-thrombotic syndrome is common
[113].
The selectins family is composed of three homologous cell adhesion molecules, Pselectin, L-selectin, and E-selectin. P-selectin is expressed on the surface of platelets
and vascular endothelial cells after stimulating by cytokine or thrombin [114]. In the
early stage of tissue injury or infection, p-selectin binds to ligands on the surface of
neutrophils and initiates rolling on activated vascular endothelium [115]. P-selectin
is known as a mediator of platelet/leukocyte involved in TF-mediated thrombosis
and prothrombotic cell accumulation on the vascular injury surface [115]. The
selectins mediate cell adhesion through calcium-dependent binding of the sialylated,
fucosylated carbohydrate Sialyl Lewis X presented by mucin-like glycoproteins
[116].
Parma and his colleagues screened out an anti-P-selectin aptamer with a high
binding affinity in the sub-nanomolar range(16-710 pM) that bounds 10
5 –10
6 -fold
more tightly than the native minimal carbohydrate ligand Sialyl Lewis X. Binding
selectivity of aptamers to P-selectin was 10
4 –10
5 -fold higher than human E-selectin
or L-selectin. Since p-selectin is expressed on the surface of thrombin-activated
platelets, these aptamers can be applied to block the binding between activated
platelets and neutrophils. Preclinical and clinical trials are being awaited [117].
10.9.1 Aptamers Against vWF
There are two categories of antiplatelet drugs to reduce the risk of thrombosis-related
clinical events. The first category is surface receptors and pathways inhibitor that
partly inhibits platelet function for chronic therapy, and the second category is surface
receptors for global platelet function. Antiplatelet drugs of the first category usually
include clopidogrel (Plavix) and aspirin, which inhibit pathways of platelet activation
and/or aggregation with a modest antithrombotic effect. However, clopidogrel and
aspirin contribute to an increased surgical bleeding risk and should be contraindicated up to 7 days before an operation. The second catogory of the antiplatelet
drug is platelet GP IIb/IIIa inhibitors, for example, abciximab and eptifibatide,
which can effectively reduce thrombotic cardiovascular events in ACS patients but
increase periprocedural hemorrhagic risk. A desirable antiplatelet agent should not