Patients with
sickle cell disease exhibit both acute and chronic activation of the coagulation and fibrinolytic systems. To test the relationship between sickle cell pathology and activation of the
hemostatic system, mice with targeted deletions of
plasminogen (Plg) or
fibrinogen (Fib) were crossed with transgenic mice expressing
Hb SAD [beta(6Glu-Val) (HbS), beta(23Val-Ile) (HbAntilles), and beta(121Glu-Gln) (
HbD-Punjab)].
Fibrinogen deficiency dramatically reduced the survival of mice with
Hb SAD to a much greater degree than mice with normal
hemoglobin. The combination of
Hb SAD and
fibrinogen deficiency had a greater effect on mortality than that obtained by adding the mortality risks of each defect alone. The deleterious effect of the combination of
Hb SAD and
fibrinogen deficiency on mortality was accelerated by
hypoxia. The excess mortality associated with
plasminogen deficiency was identical in SAD and control mice. The adverse effect of
fibrinogen deficiency on mortality in SAD mice is not consistent with the simple hypothesis that
fibrin deposition is uniformly deleterious in the context of vaso-occlusive
sickle cell disease. Rather, our findings suggest that the contribution of
fibrinogen to tissue repair may in some contexts limit
sickle cell disease pathophysiology.