The two-vehicle crash happened around 1:45 a.m. Wednesday.
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Police say an Audi sedan and an SUV were headed in opposite directions. Witnesses say the driver of the sedan veered into opposing traffic and crashed into the SUV.
Three of the four passengers inside the SUV were killed, including one who was ejected. They were all in their 30s.
A woman was the lone survivor inside the SUV. She is listed in critical condition in the hospital. Police say her brother was one of the victims killed in the crash.
Action Cam Video: Deadly head-on crash in South Philadelphia
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The driver of the Audi was also taken to the hospital. Once there, doctors discovered he had been stabbed multiple times.
"When he gets to the hospital, doctors tell the police that are on the scene that the male victim who is a John Doe has over ten stab wounds to his chest and stomach. Investigators did find a bloody knife in the sedan that the male was driving," Philadelphia Police Chief Inspector Scott Small said.
The knife had a 10-inch blade, police say.
Detectives are investigating the circumstances surrounding the stabbing.
Police say one of the men who died in the crash was wearing a sweater with a Mummers string band logo. The man's affiliation with the Mummers is not clear at this time.