"The United States condemns in the strongest possible terms today’s terrorist attack in Istanbul, Turkey. Two American citizens were among those killed in this heinous attack," National Security Council spokesman Ned Price said in a statement.
"Our thoughts and prayers go out to the families and loved ones of those killed, and we wish a speedy recovery to those injured."
Five people were killed in the attack --the sixth suicide bombing in Turkey in the past year, the Associated Press reported.
Israeli Prime Minister Benjamin Netanyahu confirmed that at least two of the victims were Israelis. An Israeli diplomat in Istanbul said the two also held American citizenship.
"We can sadly confirm that two Israeli civilians were killed and we might have a third fatality," he said.
Israel was cooperating with other intelligence agencies to determine whether the attack was directed at Israelis specifically. Two planes were being sent to Istanbul to evacuate others wounded in the blast.
The majority of the Israelis caught up in the attack were on a culinary tour of the city, officials said. The group had just eaten breakfast nearby when the blast ripped through the street. Israeli media named one of the victims as 60-year-old Simha Damari, a mother of four and said her husband was also wounded in the attack.
Several foreigners were among 36 people wounded, according to the health ministry.
The attacker was deterred from an initial target by police and detonated the bomb "out of fear", an official said, according to Sky News.
Istanbul Governor Vasip Sahin said the explosion occurred outside a local government office on Istiklal Street, which is also home to cafes, restaurants and foreign consulates.
"This is a suicide attack, a terrorist attack," Sahin said at the scene, according to Sky News. The governor said the bomber was also killed.
Police swiftly sealed off the area as ambulances and a forensic team rushed to the scene after the bombing about 11 a.m. Normally packed cafes were either closed or virtually empty, with business owners making frantic calls to loved ones to assure them of their safety. Rattled tourists wondered where to go.
"It was one loud explosion," said Muhammed Fatur, a Syrian who works at a butcher shop near the scene of the explosion. "Police came to the scene and sealed off the area."
Eli Bin, the head of Israel's rescue service MDA, told Channel 2 TV "there is one Israeli killed whose family has been notified" and said 10 Israelis were wounded in the attack. Turkey's private Dogan news agency said the Israeli killed in the attack was a woman. Israel was investigating to see if its nationals were purposely targeted.
Turkey's health minister, Mehmet Muezzinoglu, said the 36 people wounded included six Israelis, two Irish citizens and one person each from Iceland, Germany, Dubai and Iran.
Turkey was already on edge following two recent suicide car bomb attacks in the capital, Ankara, which were claimed by a Kurdish militant group that is an off-shoot of the outlawed Kurdistan Workers' Party, or PKK. The most recent bombing attack, on March 13, targeted bus stops on Ankara's busiest street, killing 37 people including two bombers.
Prime Minister Ahmet Davutoglu convened a security meeting in Istanbul following the attack. His deputy, Numan Kurtulmus said in televised remarks "it is clear that some people are giving logistic support (to terrorists), that some are giving political support and that they are even providing financial support as well as arms."
"Turkey has always said that terrorism has no religion, no language and no race and that terrorism has to be condemned no matter who the perpetrators are," he said. "This sad event has shown once again how right our position is," Davutoglu said in a statement.
There was no immediate claim of responsibility but suspicion fell on the Islamic State group and on Kurdish militants who have claimed two recent attacks in the capital, Ankara. DNA samples were taken from family members of two possible Islamic State militants who could be the bomber, the private Turkish Dogan news agency reported.
British singer Skin wrote on Facebook that the blast went off near her Istanbul hotel and that buildings "shook like paper." She also expressed solidarity with the "innocent people and their families caught in this evil situation."
Turkey has had heightened security in Ankara and Istanbul in the run-up to a Kurdish spring festival of Newroz on March 21, which Kurds in Turkey traditionally use to assert their ethnic identity and demand greater rights.
Cengiz Fidaner, who owns a cafe near the explosion site, told the AP "the explosion was not so big but I felt it in my heart because our people died. They want a war but our people want peace. This is because of Newroz."
NATO's Secretary General Jens Stoltenberg condemned the attack in Istanbul, describing it as "yet another terrorist outrage targeting innocent civilians and our ally Turkey." And the U.S. embassy in Turkey expressed shock over the attack on its Twitter account. "We mourn with the families of the lost, and we wish the injured a speedy recovery."
Iranian Foreign Minister Javar Zarif, who was in Istanbul to meet with his Turkish counterpart Mevlut Cavusoglu, also condemned the "inhumane" attack and offered his condolences.
The Irish foreign and trade minister, Charlie Flanagan, expressed "horror and sadness" at the attack and confirmed that a number of Irish citizens were among the injured.
Video posted on social media apparently capturing the aftermath of the blast showed several motionless bodies lined up at the foot of shuttered shops as a second ambulance arrives at the scene.
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