Where does von Willebrand factor go?

VWF is removed from the blood by macrophages rather than scavenger receptors, suggesting a possible strategy for improving treatment of VWD and hemophilia.

In clinical hematology, von Willebrand factor (VWF) is a bit like the actor Jake Gyllenhaal: we care about him because of who clings to his arm rather than for any inherent quality. VWF is the consort for factor VIII, and many hematologists care more that VWF brings factor VIII to the party than getting to chat with VWF. This is unfair to VWF, of course. VWF is also essential for normal hemostasis and mild von Willebrand disease(VWD), due to partial deficiency of VWF, is more common than hemophilia A. However, we all know how bad bleeding can be when factor VIII is absent, so we care whether VWF is able to protect factor VIII. Thus, we also care whether factor VIII stays with VWF, even when it is removed from the blood by a clearance pathway.

VWF is an unusually large protein. It differs from most plasma proteins in that it is synthesized and secreted primarily by endothelial cells rather than hepatocytes. Rolled up like a spool of yarn, the secreted VWF travels in the blood until it unravels under vascular sheer stress or after engagement of the vascular wall. The unrolled VWF is a sticky, very long molecule. A single VWF multimer, attached to a vessel wall, can be a good deal longer than the width of an endothelial cell. As blood rushes by, the unrolled VWF thread is soon decorated by platelets that cling tightly enough to resist sheer force and the bumping of red cells. Thus, deficiency of VWF leads to bleeding problems caused by failure of platelet deposition. In a pathologic situation, excessive function of VWF is a dramatic feature of thrombotic thrombocytopenic purpura. In that disease, abnormally large VWF multimers in blood causes deposition of platelet-rich thrombi that fragment red blood cells and occlude blood flow to essential organs.

Each of the 20 to 50 subunits that make up a VWF multimer has a high affinity niche for a factor VIII molecule. When bound to VWF, factor VIII is prevented from binding to platelets and participating in the coagulation cascade. Factor VIII is also protected from spontaneous dissociation, from proteolytic degradation, and from clearance by scavenger receptors that line blood vessels. Thus, VWF substantially prolongs the plasma half-life of factor VIII. VWF has a longer plasma half-life than factor VIII and, until now, it hasn't been clear how VWF molecules are removed from the circulation or whether they take bound factor VIII molecules when they go.

In this issue of Blood, van Schooten and colleagues identify a cellular clearance pathway for VWF and, apparently, for VWF-bound factor VIII. The surprise is that VWF is cleared via a macrophage pathway rather than via the usual scavenger receptors that are localized primarily on hepatocytes, renal cells, and endothelial cells. It is fitting that VWF, the giant molecule, is cleared by a cellular pathway that is better known for removing unwanted cells than the lipoprotein receptor class of scavenger receptors that remove deteriorating coagulation proteins.

One important aspect of the newly demonstrated VWF clearance pathway is that it may be susceptible to pharmacologic interruption. Interference with the clearance pathway may be a strategy to improve the half-life of VWF or infused factor VIII. This approach might be considered for patients with mild VWD or for patients with mild hemophilia. Alternatively, it might be a strategy to increase the interval between infusions of factor VIII in patients with severe hemophilia. Knowledge of the clearance pathway may also provide mechanistic insights that are useful in trying to explain why plasma VWF is low in some cases of mild VWD or why it increases during pregnancy. It may also prove useful to know the normal clearance pathway for VWF when thinking about the mechanisms of disease conditions, such as thrombotic thrombocytopenic purpura. Thus, discovery of an unexpected clearance pathway provides insight into how VWF leaves the party and suggests tricks that we might play to keep factor VIII and her consort, VWF, around longer.