Quebec platelet disorder (QPD) is an autosomal dominant, bleeding disorder with a unique, platelet-dependent gain-of-function defect in fibrinolysis, without systemic fibrinolysis. This is caused by a duplication mutation on chromosome 10 that selectively increases the levels of urokinase-type plasminogen activator (uPA) transcripts and protein in megakaryocytes/platelets >100-fold, with minimal effects on uPA in other cells, plasma, and urine. Increased megakaryocyte/platelet uPA is stored in α-granules and depletes platelet stores of active plasminogen activator inhibitor 1, triggering intra-platelet plasmin generation and degradation of diverse α-granule proteins, including factor V. Plasma coagulation and fibrinolytic proteins are unaffected. The molecular mechanism involves repositioning of a megakaryocyte-specific gene enhancer element, which normally upregulates VCL during megakaryopoiesis, which “rewires” PLAU on the disease chromosome to selectively upregulate PLAU expression in megakaryocytes, mirroring the increased VCL expression. QPD symptoms include the following: delayed-onset, prolonged bleeding with hemostatic challenges unless treated with a fibrinolytic inhibitor; impaired wound healing; soft tissue hematomas; large bruises; epistaxis; joint bleeds; spontaneous hematuria; and prolonged menstrual bleeding. Fibrinolytic inhibitor drugs (e.g., tranexamic acid (TXA)) are the only effective treatment. Laboratory findings include the following: an approximate 50% reduction in platelet counts that improves during fibrinolytic inhibitor therapy, impaired platelet aggregation with epinephrine, diverse α-granule protein degradation, a platelet-dependent gain-of-function-defect in fibrinolysis, and impaired platelet-rich plasma thrombin generation proportionate to the platelet factor V deficiency. The simplest, most specific approach to diagnosis is molecular testing for the causative duplication mutation and unique breakpoint. Cord-blood testing of QPD offspring is recommended for early molecular diagnosis and treatment to reduce morbidity from bleeding.