There will still be the problem of the papal states, the pope would raise hell like OTL for any Italian nation. Also there would be the Hasburgs pushing from west and north, they need to be weakened but they can also play the role of an unifying threat. Furthermore you have the rival trading Genovians and Barbary pirates which threaten Venice's most important source of income: trade with the East.
The Hasburg marriages can be easily taken away, you can create a stronger Islamic presence in the western Mediterranean to delay colonization and Spanish formation (with the side effect of more Barbary pirates hurting Venetian trade) , Venice needs to defeat and diplomatically isolate Genoa resolutely (which has the unfortunate side-effect of a power vacuum for Milan) and prevent other major trading cities from popping up, to reduce Barbary piracy Venice needs to hold the Dalmatian coast earlier, and there needs to be a greater Christian presence along the Mediterranean to reduce Islamic pirates (which runs counter to weakening Spain with a greater Islamic presence). The more fragmentation in the middle east the better, so no single unified nation can hinder Venetian trade. Venice can turn Cyprus into a sugar plantation earlier, more profits.