This review summarizes our current knowledge of
plasminogen activator inhibitor (PAI-1) deficiency and proposes some novel treatments for this condition.
PAI-1 is a fast acting inhibitor of tissue and
urokinase plasminogen activators (tPA and uPA).
PAI-1 controls/slows clot lysis triggered by tPA activated
plasminogen.
PAI-1 deficiency was once considered to be an extremely rare disorder characterized by frequent and prolonged
bleeding episodes.
PAI-1 deficiency is now thought to be more frequent than initially reported and is known to be caused by mutations in the
PAI-1 gene that produce a dysfunctional
PAI-1 protein or slow the secretion of
PAI-1 into the circulation.
PAI-1 deficiency is characterized by hyperfibrinolysis that results in frequent
bleeding episodes. Patients with this condition form normal
blood clots that are quickly lysed by unopposed tPA-activated
plasmin. Spontaneous
bleeding is rare in
PAI-1 deficient patients, but moderate hemorrhaging of the knees, elbows, nose, and gums can be triggered by mild
trauma. Additionally, prolonged
bleeding after surgery is common and menstrual
bleeding may be severe. Moderate
PAI-1 deficiency is associated with a lifelong
bleeding tendency, but severe deficiencies can be life-threatening. The diagnosis of this disorder remains challenging due to the lack of a clear definition of
PAI-1 deficiency as well as a lack of standardized tests. Patients with mild
PAI-1 deficiency may be treated with
antifibrinolytic agents (ε-
aminocaproic acid or
tranexamic acid); however, not all patients respond well to these treatments. These patients may be treated with wild-type PAI-1; however, this molecule quickly converts into its inactive form. We propose to use
PAI-1 with an extended half-life to treat these patients.