Most of this seems to center around Settlement/1812/Mexican War/ACW strife. Those PODs are too distant to keep the USA together as we know it.
I would suggest, for maintaining the 50 states, something simpler. Like screwing up America's handling of the Great Depression and pretty much everything that happened after that. 1929 to modern day dystopia.
Well, this is the Before-1900 forum; the presumption may well be that the POD must therefore conform to the terms of the forum.
By that token, let me suggest: Bryan beats McKinley in 1896. Free Silver and economic turmoil following that cause significant disruption, and the Panic of 1907 becomes even worse, leading to a significant US economic collapse that is never quite recovered from; ultimately the United States spends much of the 20th Century as a second-rate power, dominated by European financial interests.
I can't say that Free Silver actually would do this, but it's certainly how the Republicans advertised Bryan's candidacy...