PB0807 - The small, dense fraction of low-density lipoprotein (LDL) is the only plasma lipoprotein capable of enhancing von Willebrand factor (VWF) self-association

Background: In regions of elevated fluid shear stress, VWF multimers unfold and associate to produce larger and thicker strands and bundles of VWF that are very efficient at capturing platelets. Such strands can form on the surface of activated endothelium such as during thrombotic microangiopathies, or on biomaterials in contact with blood, particularly in regions of deranged flow and elevated shear stress. We showed that high-density lipoprotein is able to attenuate VWF self-association and reduce the formation of VWF/platelet thrombi, both in vitro and in a mouse model of thrombotic microangiopathy (PMID:26552698). We have also demonstrated that LDL has the opposite, prothrombotic effect: it enhances VWF self-association and promotes the formation of VWF/platelet thrombi.

Aims: All the low-density lipoproteins carry apolipoprotein B100 (apoB100) and are made up of several species, very low density (VLDL), intermediate density (IDL), and low density (LDL). The LDL fraction comprises two subfractions: small-dense (sd) LDL and large-buoyant (lb) LDL. In addition, another atherogenic lipoprotein also carries apoB-100, LP(a), in which the apoB-100 is complexed with apo(a). We sought to determine which fraction(s) was able to promote VWF self-association.

Methods: We separated the fractions by sequential KBr density centrifugation, first to separate HDL from the low-density lipoproteins, then to separate VLDL, IDL, and LDL, and finally to separate lb-LDL from sd-LDL. We purified LP(a) by a separate protocol.

Results: Of all the purified lipoprotein fractions, only sd-LDL accelerated VWF self-association and strand accumulation in a post-in-channel microfluidic device (see Figure). The effect of lipoproteins in this device correlated with their impact on in vivo microvascular thrombosis.

Conclusion(s): Sd-LDL is an independent risk factor for cardiovascular diseases; our results suggest that one reason may be through its ability to promote VWF self-association, thereby compromising microvascular blood flow and increasing the area at risk for infarction after coronary occlusion.