Kagawa was reportedly suffering from back spasms before Japan's Asian section clash with Iraq.
Van Persie actually started for the Dutch against Hungary, but was forced off just after the break with a thigh injury (thank God it wasn't that ankle again).
These seem like preventive substitutions to the Japanese and Dutch sides rather than replacements for serious injuries, but we have little to go on for either player right now.
The absence of Kagawa, RVP and Rooney, as well as the series of injuries that has plagued the United defence, could seriously harm the team's chances of success, even at this very early stage of the season.
If all three of those players are missing, one struggles to see where the goals will come from for Fergie's men (with it being glaringly apparent in tonight's England game that both Tom Cleverley and, more worryingly, striker Danny Welbeck are prone to miss easy chances).
As an England fan I'm extremely disappointed by tonight's result. But the real worry right now is United's seeming inability to prevent their players from picking up knocks.
Of course, it's nobody's fault, just pure unluckiness. But if this jinx doesn't lift soon, this could be a nightmare campaign for the men in tablecloth red.
...fingers crossed it isn't.