The storm "is going to be a real mess," said Bruce Sullivan, a senior meteorologist with the National Weather Service in Silver Spring, Maryland.
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"The main system is injecting a lot of moisture and cold air out over the Southern Plains," he said. "It's going to bring quite a bit of precipitation."
Rainfall and snow associated with the system stretched over 1,500 miles (2,400 km), from southeastern Colorado to southern Massachusetts, meteorologists said.
About 2,000 flights were canceled and 5,600 were delayed as of early evening on Sunday due to the storm, according to the airline tracking site FlightAware.com.
"Ripple-effect flight delays and cancellations are likely to reach nationwide," said AccuWeather meteorologist Alex Sosnowski.
Boston and New York City should see only light snowfall, but lingering freezing rain could complicate Monday morning's rush hour for commuters.
By Sunday afternoon, up to nine inches of snow had already fallen on parts of Indiana.
More than 40,000 homes in northeast Ohio were without power due to downed transmission lines, according to Chad Self, a spokesman for utility provider First Energy. Most customers should have power restored by late Monday, the utility said.
Margie Gibson, 60, of Perry, 40 miles (65 km) northeast of Cleveland, said the storm disrupted power at her home.
"The power keeps popping on and off every half-hour. It goes off and comes right back on," she said.
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Central Arkansas, Tennessee and Kentucky were also at risk for heavy ice conditions and power outages, according to AccuWeather.
Though temperatures will not be as frigid as during some other storm systems this winter, when the so-called polar vortex pushed Arctic air across large swaths of the county, the cold air will blanket areas as far south as Texas and North Carolina.
Temperatures in Lubbock, Texas, in the northwestern part of the state, were around 80 degrees Fahrenheit (27 Celsius) on Saturday but by Sunday morning were a bone-chilling 18 degrees (minus 8 degrees Celsius), Sullivan of the National Weather Service said.
Amanda Dyer watched a vehicle slide off the road as she dropped her husband off at the Dallas/Fort Worth International Airport on Sunday.
"There was slush kicking up from the cars and the road," she said. "When we got home our car doors were frozen shut."
Forecasters urged motorists to use caution because slick roads and fast-moving bands of snow could cause traffic accidents.
In southwest Missouri, slick conditions were blamed in the death early Sunday of a 13-year-old girl when the driver of the Ford Explorer she was riding in went off the highway and overturned.
The Missouri State Highway Patrol reported two adults and another child in the vehicle suffered serious injuries, and nobody in the car was wearing a seatbelt.
On Saturday in Colorado, a heavy midday dump of snow led to a 104-vehicle pileup in Denver. One woman was killed and 30 people were hospitalized, police and local media said.
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