Centre-back Smalling returned to action following a month out with a groin injury on Sunday, replacing Jonny Evans after just 30 minutes of the humiliating 5-3 loss against Leicester City.
With Evans - who suffered ankle bruising during that thrilling contest at the King Power Stadium - now joining Phil Jones on the injury list at Old Trafford, Smalling was expected to partner summer signing Marcos Rojo at the heart of Manchester United's defence against face a dangerous West Ham outfit who toppled Liverpool in hugely impressive fashion last week.
The chances of Smalling featuring against Sam Allardyce's side were called into question this morning, however, with reports suggesting that the 24-year-old had supposedly suffered a thigh injury in training on Wednesday.
Tentative claims that Smalling could sit out for the visit of West Ham have been confirmed by Van Gaal this afternoon in his traditional pre-match press conference, leaving Manchester United with somewhat of a conundrum moving forward.
"Evans' bone is bruised. Smalling left yesterday's session because he had stiff legs. I won't take risks with player," the Dutchman was quoted by the club's official Twitter account.
Who will fill in?
Smalling's absence will lead to all manner of debate over who Van Gaal should choose to play at the back on Saturday.
Despite Rojo looking somewhat shaky against Leicester, he surely must be guaranteed a starting berth as the only fit and available senior player in Manchester United's current first-team squad with any real experience of playing in central defence.
But who will feature alongside the Argentine? With Michael Keane out on loan at Burnley and presumably unable to be recalled, speculation that began circulating earlier on Thursday hinted that 19-year-old Paddy McNair could be drafted in from the U21 squad.
Whether Van Gaal would be willing to turn to a younger player to fill the void remains to be seen. If he is, then it could be that Tom Thorpe - the England U21 international who has slightly more experience than McNair - is the man to get the nod.
Alternatively, Van Gaal could decide to drop a midfielder back to fill the role. With Michael Carrick still not thought to be quite yet ready to return following surgery to repair an ankle ligament injury in July, Dutch utility man Daley Blind could be asked to take on a slightly unfamiliar role.