In this issue of Blood, Fujioka and colleagues demonstrate that the von Willebrand factor–cleaving protease ADAMTS13 limits brain infarction in a murine model of ischemic stroke.1
Platelet aggregation at sites of vascular injury is essential for normal hemostasis but also causes myocardial infarction and is-chemic stroke, the latter representing the second leading cause of death and severe disability worldwide. Acute stroke treatment currently relies on thrombolysis, which is applicable to only a limited portion of patients, as the treatment is safe only when applied within the first 6 hours after the incident. However, it is also recognized that reflow does not guarantee salvage of brain tissue. An attempt to improve the outcome by application of abciximab antibodies directed against the platelet fibrinogen receptor GPIIb/IIIa recently failed due to excess brain hemorrhages and inefficacy.2 Thus, there is a strong need for novel treatment strategies.
The GPIb-VWF axis in experimental stroke development. In the postischemic cerebral microvasculature, UL-VWF released from activated or damaged endothelial cells and platelets promotes platelet recruitment and thrombus growth. In flowing blood, UL-VWF is cleaved by ADAMTS13 to smaller VWF multimers that are less adhesive and circulate in plasma. Absence of ADAMTS13 leads to increased thrombus formation and larger infarctions, whereas infusion of exogenous ADAMTS13 reduces thrombotic activity and infarct size. An even stronger inhibition of thrombotic activity and, consequently, markedly reduced infarct size is achieved by inhibition of GPIb or absence of VWF.
The GPIb-VWF axis in experimental stroke development. In the postischemic cerebral microvasculature, UL-VWF released from activated or damaged endothelial cells and platelets promotes platelet recruitment and thrombus growth. In flowing blood, UL-VWF is cleaved by ADAMTS13 to smaller VWF multimers that are less adhesive and circulate in plasma. Absence of ADAMTS13 leads to increased thrombus formation and larger infarctions, whereas infusion of exogenous ADAMTS13 reduces thrombotic activity and infarct size. An even stronger inhibition of thrombotic activity and, consequently, markedly reduced infarct size is achieved by inhibition of GPIb or absence of VWF.
The initial recruitment of platelets to the injured vessel wall is mediated by the reversible interaction between the platelet receptor glyco-protein (GP) Ib and the large multimeric glyco-protein von Willebrand factor (VWF) bound to subendothelial collagen or the surface of activated endothelial cells, followed by cellular activation and aggregation. Recent studies have revealed that inhibition of GPIb or absence of VWF strongly protects mice from ischemic brain infarction without causing intracerebral hemorrhage despite a significant prolongation of bleeding times.3,4 This indicates that the GPIb-VWF axis may represent a suitable target for stroke prevention and treatment.5
The most thrombogenic variant of VWF is ultra-large VWF (UL-VWF; > 20 million kDa), which is stored in platelet α-granules and Weibel-Palade bodies of endothelial cells from where it is released in response to injury and/or inflammation to facilitate the recruitment of platelets and immune cells. To limit the thrombotic activity to the site of injury, nonoccupied UL-VWF is rapidly cleaved by the metalloprotease ADAMTS13 to less-active VWF multimers that circulate in plasma.6 The important physiological function of ADAMTS13 becomes most evident in patients suffering from thrombotic thrombocytopenic purpura (TTP), which is in many cases caused by acquired ADAMTS13-inhibiting autoantibodies. In such patients, neurological deficits are frequently observed that are caused by thrombotic events in the cerebral microvasculature,6 indicating that ADAMTS13 activity might be a major determinant of cerebrovascular thrombosis.
Fujioka et al now provide direct evidence that ADAMTS13 indeed limits thrombotic events and, consequently, neurological damage in a murine stroke model.1 In this widely used model, transient cerebral ischemia is induced by advancing a thread through the carotid artery into the middle cerebral artery (MCA), thereby markedly reducing regional cerebral blood flow. It is known that in this model thrombus formation continues despite reperfusion after removal of the vessel-occluding thread and that final infarct size depends on the previous occlusion time.5 The authors demonstrate that the regional cerebral blood flow at early (0.5 hours) and late (24 hours) time points following a 30-minute transient MCA occlusion (tMCAO) was decreased in Adamts13−/− mice compared with wild-type controls. This was accompanied by increased accumulation of immune cells and thrombi in the brain tissue and finally resulted in significantly larger infarctions and stronger neurological deficits in the mutant animals 24 hours after ischemia. These results are in perfect agreement with those very recently reported in an independent study by Zhao and coworkers, who also found increased susceptibility of Adamts13−/− mice to focal cerebral ischemia.7 In addition, these authors demonstrated that the infusion of a high dose of recombinant human ADAMTS13 into a wild-type mouse immediately before reperfusion reduced infarct volume but did not cause intracerebral hemorrhage. These findings confirm and extend the concept that the GPIb-VWF axis is of paramount importance for (experimental) stroke development and that interference with this early step of platelet–vessel wall and platelet-platelet interaction represents an attractive therapeutic approach (see figure).
We hope that the compelling evidence provided by these independent investigations will encourage preclinical studies to translate this promising approach from animals to patients.
Conflict-of-interest disclosure: The authors declare no competing financial interests. ■
