Deficiency of Plasma Plasminogen Activator Inhibitor 1 Results in Hyperfibrinolytic Bleeding

Deficiency of Plasma Plasminogen Activator Inhibitor 1 Results in Hyperfibrinolytic Bleeding,Myoung H. Lee,Evan Vosburgh,Kristen Anderson,Jan McDonagh

Deficiency of Plasma Plasminogen Activator Inhibitor 1 Results in Hyperfibrinolytic Bleeding   (Citations: 31)
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A 63-year-old man was evaluated for a lifelong history of bleeding commencing with frequent epistaxis as a child; all previous routine coagulation parameters were within the normal range. The patient's hemorrhagic disorder is char- acterized predominantly by delayed bleeding at surgical sites. In the resting state, there was no clinical or laboratory evidence of excessive fibrin(0gen)olysis. Bleeding was not caused by disseminated intravascular coagulation, factor Xlll deficiency, a2-antiplasmin deficiency, or dysfibrinogen- emia. It was found that the patient was deficient in plasma PAI-1 antigen and activity but with approximately half nor- mal antigen and normal activity of platelet PAI-1. The low ASCULAR FIBRINOLYSIS is a complex and critical V process for controlling hemostasis and thrombosis. It is precisely regulated and is initiated by the release of active tissue plasminogen activator (t-PA) from endothelial cells. t- PA activity is very low in normal and the majority of t-PA is complexed with type 1 plasminogen activator in- hibitor (PAI-l).3 PAI- 1 is a relatively unstable molecule with two different conformational forms-active and latent!.5 Binding of PAL I to vitronectin stabilizes the active confor- mation?,' PAL1 is in human plasma, platelets, and basement At present, the origin of plasma PAI- 1 is not known, but it is most likely that endothelial cells and/or liver are responsible for plasma PAI- 1 prod~ction.~ Platelet PAI- 1 is present in a granules.' Recently, much attention has been given to the role of PAI-1 in the fibrinolytic system, suggesting that it is the pri- mary regulatory element in this system!,' It inhibits both t- PA and urokinase activity by forming a stoichiometric com- plex with either activator. Computer-simulated kinetic models for the active t-PA levels in plasma predicted that the level of active PAI- 1 in the blood is an important regulator of the concentration, half-life, and circadian variation of active t- PA." Several pathophysiologic problems are reported in relation to abnormal concentrations of plasma PAI-1. Increased PAI- 1 activity in blood appears to be associated with certain thromboembolic diseases, such as myocardial infarction,'l,12 deep vein thrombo~is,'~*'~ and postoperative thrombosis in patients undergoing elective hip surgery.15 However, direct evidence to support the conclusion that elevated PAI-I ac- tivity in blood is a major cause of thrombosis remains to be verified because a IO-fold increase in plasma PAL1 occurs during pregnancy and is not strongly associated with throm- boembolic diseases.16 There may be a convincing, if limited, correlation between decreased PAI- I activity and a hyperfibrinolytic bleeding tendency. Hyperfibrinolytic bleeding is characterized by nor- mal platelet and coagulation activities. Delayed bleeding oc- curs because a normal hemostatic plug is formed, but it is later more susceptible to breakdown owing to increased fi- brinolytic activity. Presently, there are five dissimilar cases reported relating decreased PAI- 1 activity to hyperfibrinolytic bleeding. DiCval et a1 reported a case of a lifelong delayed bleeding disorder associated with a quantitative deficiency of concentration of plasma PAL1 was insufficient to neutralize circulating t-PA, resulting in high t-PA activity with normal antigen and causing the hyperfibrinolytic activity observed. Studies on seven family members of the proband indicated autosomal inheritance of plasma PAL1 deficiency. Studies on this patient emphasize a clear correlation between de- creased plasma PAL1 activity and hyperfibrinolytic bleeding and also emphasize the unique role of plasma PAL1 in the balance between the coagulation and fibrinolytic mecha- nisms. 0 1993 by The American Society of Hematology. PAI-I in their patient's plasma but with a normal level of PAL1 in platelets"; Francis et all8 described a patient with amyloidosis who had severe bleeding and produced auto- antibodies against PAI- 1. A patient with low PAL 1 activity and normal PAI-1 antigen was reported by Schleef et all9; and a postoperative bleeding case associated with an excess of t-PA activity and low PAI-1 activity was reported by Stan- kiewicz et aLZ0 Fay et alZ1 recently reported a case of deficient PAL1 in plasma and platelets that was explained by a mo- lecular defect in the PAI-l gene. In this report, we present a patient with low plasma levels of PAL1 antigen and activity but with functional platelet PAL 1, which was associated with a lifelong delayed bleeding disorder. We also report plasma PAI-1, t-PA activity, and antigen levels in the patient's family members.
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