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Mice Expressing Low Levels of CalDAG-GEFI Exhibit Markedly Impaired Platelet Activation With Minor Impact on Hemostasis

Objective—The tight regulation of platelet adhesiveness, mediated by the &agr;IIb&bgr;3 integrin, is critical for hemostasis and prevention of thrombosis. We recently demonstrated that integrin affinity in platelets is controlled by the guanine nucleotide exchange factor, CalDAG-GEFI (CD-GEFI), and its target, RAP1. In this study, we investigated whether low-level expression of CD-GEFI leads to protection from thrombosis without pathological bleeding in mice. Approach and Results—Cdg1low mice were generated by knockin of human CD-GEFI cDNA into the mouse Cdg1 locus. CD-GEFI expression in platelets from Cdg1low mice was reduced by ≈90% when compared with controls. Activation of RAP1 and &agr;IIb&bgr;3 was abolished at low agonist concentrations and partially inhibited at high agonist concentrations in Cdg1low platelets. Consistently, the aggregation response of Cdg1low platelets was weaker than that of wild-type platelets, but more efficient than that observed in Cdg1−/− platelets. Importantly, Cdg1low mice were strongly protected from arterial and immune complex–mediated thrombosis, with only minimal impact on primary hemostasis. Conclusions—Together, our studies suggest the partial inhibition of CD-GEFI function as a powerful new approach to safely prevent thrombotic complications.