Assad may find it difficult to replace the four security chiefs killed in an audacious bombing in the national security headquarters as they met to plot the regime's next moves to combat a 17-month-old uprising that has defied the military might of Assad's regime.
One of the key men to watch is Assad's maternal cousin and the regime's business manager, Rami Makhlouf. He has amassed great wealth for himself, and for other leading figures in the regime, over the years.
He may be the closest regime stalwart to Assad following the death Wednesday of the president's brother-in-law, Maj. Gen. Assef Shawkat.
Assad, a former eye doctor in London, is likely to lean heavily on someone so trusted as Makhlouf, particularly since the bombing in the very heart of the regime punctured the ruling elite's aura of ruthless and unassailable power -- a critical, possibly fatal, psychological blow.
"The intimate circle that stood with him in the past year and a half of rebellion has now vanished," observed Israeli analyst Noga Tarnopolsky.
"I think the worst thing for Assad is that ... until now most officers remain loyally at their posts but the dynamic may change now, with people saying 'let's abandon the sinking ship'."
Assad's whereabouts aren't known. He's been reported to be in the port city of Latakia on the Mediterranean, a major Syrian naval base where the Russians maintain a highly secure facility for their Black Sea Fleet.
At a time when Assad should have been highly visible, spitting defiance to reassure his loyalists, despite the pitched battles between his forces and the rebels who have advanced into the capital itself in their most brazen challenge yet, he's nowhere to be seen.
Neither was his brother Maher, who commands the Presidential Guard and the army's 4th Armored Division, both manned by fellow Alawites and considered diehard loyalists.
But Maher's reckless and hot-headed, not the kind of aide the president needs right now.
This absence from view, in itself, confirms that the regime is reeling and suggests that Assad may have lost confidence in those around him to strike back for Wednesday's assault on the seat of Syrian power.
"Bashar today can no longer trust almost anyone who's close to him, and that's going to send a shiver through his inner circle and their confidence," said Joshua Landis, associate professor of Middle Eastern Studies at the University of Oklahoma.
Landis lived in Damascus for several years and learned to read the ways of a regime whose inner workings have been opaque for decades and whose obsession with security verged on the paranoid.
All this will affect Assad's key backers, Iran, Russia and China, who may seek to cut their losses before the final collapse, and indeed may even hasten that eventuality.
"The probability of a coup is rapidly rising," global intelligence consultancy Stratfor observed.
"In light of the critical Tlass defection and Wednesday's attack, future defections will start to affect the regime's higher levels of leadership and will raise the potential for the Alawite core to begin to fragment."
Shawkat, who was married to Assad's older sister Bushra, was the president's chief enforcer and privy to the most intimate affairs of the ruling family.
A former chief of military intelligence and lately deputy defense minister, Shawkat, ruthless in the extreme, was Assad's indispensable ally, although he kept a low public profile.
Two more of Assad's closest aides were seriously wounded when a bomb, apparently planted by a well-placed mole in Assad's security apparatus, exploded in the room where they were meeting.
All of the officers who were killed or wounded Wednesday were longtime associates, some of whom served Hafez Assad, who founded the minority Alawite regime in a 1970 military coup.
The president may find others reluctant to step into dead men's shoes and face the threat of assassination by rebels who have been able to worm their way deep into the regime's security apparatus.
So he'll likely turn to Makhlouf, and his brother Hafez, a senior intelligence officer, for support and guidance. If they show signs of quitting, Assad's days as president may be numbered.
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