Since Fernando displayed interest in marrying either, let's say Isabel dies before they're wed (maybe around the same time as her brother, maybe she's killed en route to wed Fernando, either way, she's making like a doornail - my reason for this is simple: no power on earth will make her wed against her wishes, and she's not marrying against her will once Alfonso dies). So, his backup is to marry La Beltraneja (Fernando apparently came into possession of Enrique IV's will after Isabel died, and therein Enrique swore that Juana "la Beltraneja" was his daughter) and promise to protect her rights a la Affonso V of Portugal.
How different is Spanish (is there even a Spain as we know it?) history?