Platelet CD36 Links Not Only α-Granule–Derived Proteins to Thrombus Stability But Also Metabolic and Oxidant Stress to a Prothrombotic Phenotype
RL Silverstein - Arteriosclerosis, thrombosis, and vascular biology, 2014 - Am Heart Assoc
RL Silverstein
Arteriosclerosis, thrombosis, and vascular biology, 2014•Am Heart AssocS100A9) was elevated in platelets from patients presenting with acute myocardial infarction.
They followed up on this observation by reporting that MRP-8/MRP-14 heterodimers
(S100A8/A9) are expressed in and secreted by platelets in response to agonists, and that
deletion of the MRP-14 gene in mice markedly prolonged arterial thrombosis times in
multiple vascular injury models. Infusion of wild-type platelets or purified MRP-14 into the
MRP-14–deficient mice reversed the defect. Using mice deficient in CD36 showed that …
They followed up on this observation by reporting that MRP-8/MRP-14 heterodimers
(S100A8/A9) are expressed in and secreted by platelets in response to agonists, and that
deletion of the MRP-14 gene in mice markedly prolonged arterial thrombosis times in
multiple vascular injury models. Infusion of wild-type platelets or purified MRP-14 into the
MRP-14–deficient mice reversed the defect. Using mice deficient in CD36 showed that …
S100A9) was elevated in platelets from patients presenting with acute myocardial infarction. They followed up on this observation by reporting that MRP-8/MRP-14 heterodimers (S100A8/A9) are expressed in and secreted by platelets in response to agonists, and that deletion of the MRP-14 gene in mice markedly prolonged arterial thrombosis times in multiple vascular injury models. Infusion of wild-type platelets or purified MRP-14 into the MRP-14–deficient mice reversed the defect. Using mice deficient in CD36 showed that CD36 was required for MRP-14–dependent thrombosis. Thus, CD36 can promote platelet activation and thrombus formation and stability by interacting with at least two endogenous ligands released from activated platelets in the microenvironment of a forming thrombus, as well as several endogenous danger-associated molecular patterns that circulate in plasma under pathological conditions. Individuals with inherited or acquired conditions associated with higher levels of CD36 or its ligands may be predisposed to acute arterial thrombotic events, whereas CD36 deficiency in humans is surprisingly common, occurring in≤ 1% of individuals from Asian or African backgrounds; no reports have linked CD36 deficiency or genetic polymorphisms of thrombospondin-1 or MRP-14 with a bleeding diathesis. Perhaps the role of the platelet CD36 system in normal hemostasis is subtle enough to be compensated by other redundant system, or perhaps more likely the clinical phenotyping of subtle bleeding disorders was not robust enough to detect associations in published genome-wide studies. It is tempting to speculate that the hemostatic role of thrombospondin-1 and MRP-8/MRP-14 signaling via CD36 may have provided the evolutionary pressure that led to high levels of expression of this receptor on the platelet surface. In our modern world of diet-induced metabolic and inflammatory stress, this situation may not be advantageous, but targeting this prothrombotic pathway may have potential for treating or preventing atherothrombotic disorders.
Am Heart Assoc