The Good Old TCP/IP Stack
The next limitation to consider is the TCP/IP Stack. How many simultaneous open TCP connections can your front end servers handle, and what do these correspond to the backward (or downward if you like) TCP connections in your stack (application servers, DB, FS).
The TCP connections are not end to end, they are node to node specific. Hence connection handle wise, all layers of LB -> cache server -> app server -> DB/FS need to be in sync. For instance, there must be a sane relation between the number of connections made to the application server and from the application server to the database.