I had read about KNOTS before I watched it, so like others have said, the cast departures weren't necessarily "shocks" for me.
However, there are some that effected me during my journey through the series.
The departures of Don Murray and Constance McCashin were definitely the most heart-wrenching, but I can't say that their exits necessarily messed up the show for me. Sid's death provided significant storyline and growth for Karen and their kids, as did Laura's death for Greg. Karen walking down the hall in silence to hear the news from the surgeon is flawless, just like the highly improvised two-parter that dealt with Laura's passing. There are so many classic KNOTS moments inside those episodes. When I talk about the show to people that have never seen it, I generally bring up these two storylines as examples of the series' quality storytelling.
In saying that, I'd have to say Donna Mills' exit at the end of Season 10 had to be the biggest shake-up to the flow of the show. Abby had been fundamental to KNOTS during its heyday, and her departure left a vacancy in the ensemble that was never properly filled. Sure, there were "vixens" in Anne and Claudia, but they didn't have the same effect as Abby had.
Douglas Sheehan's departure after Season 8 was handled the most shabbily. I honestly think the producers missed a golden opportunity to bring Ben back a some point in the later seasons. They could've kept the arc of Jill using Ben's memory to bother Val, but maybe brought Ben back as surprising Jill in the process.
The other exits didn't really bother me either way.