Only severe thrombocytopenia results in bleeding and defective thrombus formation in mice

Platelets are essential mediators of hemostasis and thrombosis. Platelet counts (PCs) in humans average 250 platelets/nL, but it is not entirely clear how platelet numbers affect hemostasis and occurrence of thrombotic events. Mice, displaying PCs of ~1000 platelets/nL, are widely used to assess platelet function in (patho-)physiology, but also in this species, the significance of PC for hemostasis and thrombotic disease is not established. We reduced PCs in mice to defined ranges between 0 and 1000 platelets/nL by platelet-depleting antibodies and challenged them in different arterial thrombosis models: the transient middle cerebral artery occlusion (tMCAO) stroke model and tail bleeding experiments. We show that thrombotic occlusion of the injured aorta and the carotid artery were partially impaired when PCs were reduced by 70% or 80%, respectively. In contrast, tail bleeding times and thrombus formation in small arterioles were largely unaffected by reductions of PC up to 97.5%. Similarly, infarct growth and neurological deficits after tMCAO were unaffected by reductions of PCs up to 90%, whereas a further reduction was protective. These results reveal that arterial thrombosis, cerebral infarction, and hemostasis in mice efficiently occur at unexpectedly low PCs, which may have implications for humans at risk of thrombotic or hemorrhagic disease.