Summary
In a 29 year old white male with osteonecrosis of both hips and a shoulder, and in
his family, we measured basal and stimulated (10 min cuff venous occlusion at 100
mgHg) fibrinolytic activity to determine whether low fibrinolytic activity might be
heritable and etiologically associated with osteonecrosis. The proband’s basal tPA-Fx
was low, 0.08 IU/ml (normal 0.11-1.94), tPA-Ag was normal (11.6 ng/ml), plasminogen
activator inhibitor activity (PAI-Fx) was very high, 119 U/ml (normal 3.5-27), as
was his plasminogen activator inhibitor antigen (PAI-Ag), 202 ng/ml (normal 3.2-37.1).
The proband’s basal PAI-Fx (119) and PAI-Ag (202) were respectively 6 and 13 standard
deviations greater than the mean PAI-Fx (17 ± 15 U/ml) and the mean PAI-Ag (25 ± 13
ng/ml) in 172 concomitantly studied hyperlipidemic men. Alpha-2 antiplasmin, fibrinogen,
plasminogen and Lp(a) were normal. Despite lowering TG to 301 mg/dl, basal tPA-Fx
remained low, 0.05; PAI-Fx and PAI-Ag remained very high (109 and 191). Following
venous occlusion, stimulated tPA-Fx remained very low, 0.1 (normal 2.3-11.3), but
tPA-Ag rose normally to 17 (normal 8.4-31.4); stimulated PAI-Fx and PAI-Ag were very
high, 134 and 223, (normal PAI-Fx 3.6-24, PAI-Ag 12-96). Stimulated D-dimer was <
the 10th percentile, 0.084 μg/ml. With such high PAI-Fx available to bind tPA, occlusionstimulated
tPA-Fx could not rise, and fibrinolysis could not be initiated. Neither diseases nor
drugs could explain the high PAI-Fx and PAI-Ag, low tPA-Fx, or osteonecrosis. The
proband’s father, mother, and sister had very high basal PAI-Ag (240, 69, 66 ng/ml),
high basal PAI-Fx (24, 24, 35 U/ml), and normal basal tPA-Fx (0.6, 1.0, and 0.2 IU/ml).
Basal PAI-Ag, PAI-Fx, and tPA-Fx were normal in the proband’s son (13, 12, 0.3). The
proband’s very high PAI-Fx and PAI-Ag appeared to be inherited, possibly as an autosomal
dominant trait, producing hypofibrinolysis. We speculate that his osteonecrosis was
caused by familial hypofibrinolysis mediated by high PAI, with subsequent inability
to activate fibrinolysis, resulting in inadequate lysis of venous thrombi in bone,
impaired bone venous circulation, and venous hypertension of bone characteristic of
osteonecrosis.
