Giving Venice a whirl again, and things are going great, the Ottomans are being smashed, non-HRE Italy is almost entirely mine, France and Austria are appeased, Austria proving a firm ally, and the Venetian Navy/Merchant Marine rules the Mediterranean.
Then disaster, as Circassia declares war on my holdings in the Crimea. No worries, I think, I can easily beat them. Except as I'm shipping troops over, Aragon declares war again to reconquer an Italian province. Which drags France in, as they're allied with Aragon for some ungodly reason. I sigh and send my troops back, but reassured that I've got Captain Habsburg on my side, I figure I'll be able to beat them away. Except, Austria decide to turn tail and break the alliance with me instead. Austria, who I've been allies with for almost 50 years, and great relations throughout. Yay. Well, that'll be fun.
At which point, all hell breaks loose. Ferrera, allied with Milan, the Papal States and Austria declares war.. and drags all of them in. Sensing weakness, the Ottomans declare too, swiftly followed by the Mamluks. So I'm now at war with France, Austria, the Ottomans and the Mamluks, as well as a host of minor/mid tier powers. Fantastic stuff, really fantastic.