The U.S.S. Defiant was destroyed. The next Defiant, a renamed Sao Paulo, should have taken the registry and advanced in the lettering like the Enterprise does but it doesn't. Why? Because the didn't have the budget to change the letter when they used old stock footage for other episodes.
Ron Moore himself says he considers the second defiant to have an A in there. Too bad it's not canon though and for stupid reasons. XP
Evidently they sometimes start anew. This has happened SEVERAL times like with the Defiant (Connie), Prometheus and more. I'm guessing it requires something of an epic ship to have a letter on the end.
I wouldn't think the Defiant could follow suit since it's directly connected to the Defiant that was destroyed. It's the same class and was literally named after the lost ship.
The requirements to be a Legacy ship and carry it's name and get a letter are unknown. But what I do know is that the Defiant HAD to have earned that right. Maybe the last one before that (apparently that connie) didn't.