33.
Intravitreal TPA: a Precursor of Anti-VEGF Therapy?
Lutz Hesse (Heilbronn)
Today intravitreal application of recombinant tissue plasminogen activator (rTPA) followed by
gas injection is a sufficient, convenient and worldwide used technique for effective removal of
freshly formed submacular hemorrhage caused by various diseases.
This technique was first introduced in 1996 by Wilson Herriot. Tissue-type plasminogen activator
and its substrate plasminogen are key components in the fibrinolytic system. rTPA is a
proteolytic enzyme that mediates the cleavage of plasminogen into plasmin. The serine protease
plasmin subsequently dissolves fibrin clots. When this technique was introduced most
ophthalmologists believed that rTPA is not really necessary to dislodge the blood from the
macula and/or the large enzyme can not cross the retina. However, a few years later the therapeutic
principle of this procedure was accepted: enzym induced lysis of the clot and subsequent
mechanical displacement through the gas bubble. Crossing of intravitreal rTPA through the retina is possible and may
be facilitated by mechanically induced microlesions of the retina. After enzymatic treatment of subretinal hemorrhage
further growth of the underlying choroidal membran was rare indicating an unknown effect of the therapy.
Recent laboratory angiogenesis research demonstrated further biological effects of plasmin activation. Fibrin is a temporary
matrix which not only covers a wound, but also provides a structure for invading endothelial cells in angiogenesis like a subretinal
choroidal neovascular membran. Destroying the fibrin matrix inhibits the tubular formation of endothelial cells.
A second anti-angiogentic effect is a plasmin-catalyzed cleavage of the vascular endothelial growth factor (VEGF). A loss of
its carboxyl-terminal heparin-binding domain causes a significant loss in its bioactivity (100 fold).
Conclusion: Intravitreally injected rTPA + gas is not only a mechanical therapy but reduces the risk of further growth of the
underlying neovascular membran. Consequently intravitreal injected rTPA in submacular hemorrhage was the first antiangiogentic
agent used in ophthalmology.