Abstract / Summary
Objective: Rare STAB2 loss-of-function variants emerged in population studies as being associated with elevated venous thromboembolism (VTE) risk. STAB2 encodes the cell-surface scavenger receptor stabilin-2, and reduced stabilin-2 function might increase VTE risk via elevated plasma levels of its ligands, including von Willebrand factor (VWF) and coagulation factor VIII (FVIII). Approach and Results: A 13-year-old patient with dependency on parenteral nutrition had experienced episodes of central venous catheter-related thrombosis, including the complete thrombotic occlusion of the deep pelvic veins, and pulmonary embolism. Exome sequencing for increased VTE risk identified a homozygous STAB2 splice-site variant and its effect on splicing was characterized in fibroblast-derived RNA and in a minigene splicing system. Plasma VWF, FVIII, and fibrinogen and serum hyaluronic acid (HA) levels were determined. Immunohistochemistry was performed on liver biopsy tissue. The STAB2 splice-site variant caused aberrant STAB2 mRNA splicing. The patient's healthy mother and one healthy sibling were also homozygous for the STAB2 splice-site variant but had no history of VTE. Plasma FVIII levels and VWF activity were elevated in all three, and VWF antigen was elevated in two homozygous individuals. Strikingly, approximately 1000-fold elevated HA levels were observed in all three homozygous individuals. Stabilin-2 immunohistochemistry on a liver biopsy from the proband's mother revealed no detectable signal, whereas control human liver showed strong labelling of liver sinusoidal endothelial cells. The STAB2 splice-site variant thus results in loss of detectable stabilin-2 protein. Conclusion: To current knowledge, this is the first family-based report of stabilin-2 deficiency with markedly elevated circulating HA, VWF, and FVIII levels in humans. These findings support impaired stabilin-2-dependent ligand clearance as a thrombosis susceptibility state with incomplete penetrance. The data are consistent with a significant role for stabilin-2 in circulating HA clearance in humans, but do not establish elevated HA itself as a cause of VTE.