hmmm- if it's a zero client though, you won't be installing any software on the local client device. Nor will the USB device be being "interpreted" locally. ie, the usb device should be forwarded as is to the guest VM.
on the guest VM, i presume you have;
1. installed the device driver
2. installed your printer software
when the device is redirected to the guest machine, is it at that point that the printer software reports the com port is in use?
does your guest vm have any "virtual" com ports created in its hw spec? (if so, can you remove them from the virtual machine spec).
It is probably worth noting at this time though, that Serial Ports do not remote particularly well via USB. Their performance is dependent on the network quality between your client and agent. If you are running on a reliable LAN network, then it should be OK. But, if the clients are remote connected via an unreliable network (eg wifi across a WAN) then you may find the printer has communication issues.
Are we sure that it's not communication issues that are being reported (incorrectly) as "com2 in use" ? If possible, please test initially on a fast, low latency reliable network.
cheers
peterB