What does setting "Guarantee Unblocking serial communication" does and when to apply.

Some Win32 communication functions block while the driver confirms that the device has completed a task (e.g., EscapeCommFunction, SetCommState). This wait is normally on the order of milliseconds but may be delayed by seconds or minutes if TCP is retransmitting packets. I.e., every time a user application calls a Win32 communication function, that thread blocks until the driver completes the request. Check this box if you want the driver to guarantee that Win32 communication function calls will not block.
For instance, if an application calls EscapeCommFunction and specifies CLRDTR, EscapeCommFunction blocks until RealPort confirms that the remote device has lowered DTR. While in most circumstances the blocking only takes a matter of milliseconds, if the network connection were to be severed while this call was pending, an application might block for up to thirty seconds while the Windows network stack tries retransmitting the unacknowledged network packets. To avoid this situation, check this box; an application’s serial comm API calls will never block, but some calls may return to the application before the actual call is fully processed.

Note that this feature does not apply to WriteFile calls. To specify that WriteFile calls not block, enable the option, Complete Write Requests Immed., found on the Port TCP tab.