I used to leave the red wire disconnected because of the voltage difference issue. Then one day I realised that when the Pi is powered off, the PL2303 continues to supply 3.3V on its RX pin. Also, if the PC is powered off, the Pi's TX supplies 3.3V to the unpowered PL2303. Holding logic pins high when a chip is unpowered is not considered good, so I took to connecting the red wire.
(We now believe that the Pi's GPIO will not draw significant current at 3.3V and try to power the whole chip, but I have not checked the PL2303.)
USB ports are required to have resettable current trips of less than 5A, so there is a polyfuse in the PC as well. Between the two power supplies there are two polyfuses, the tiny red and black wires with total resistance over 2Ω, plus the power supply's cable. I would be surprised if there is enough current to trip either fuse, let alone produce smoke. I measure about 60mA.
The manufacturer's
literature I have found says that resistance jumps are
not cumulative after the first trip or soldering event. The only things that should cause permanent damage are overvoltage (~13.2V) and overcurrent (~100A).