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A 40-year male comes to the office because of low urine output for the past 48 hours. He also says that his feet and ankles appear swollen. He has had kidney stones in the past, which have reduced his urine output, but he states that this does not feel the same. Examination shows pitting edema to the ankles. The differential diagnosis includes thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome. Which of the following findings is most helpful in differentiating thrombotic thrombocytopenic purpura from hemolytic-uremic syndrome?
Content Reviewers:Rishi Desai, MD, MPH
‘Hemo’ refers to the blood, ‘lytic’ refers to breaking down, and ‘uremic’ refers to increased urea levels in the blood.
And this helps explain hemolytic uremic syndrome because the two main effects are destruction of red blood cells and the declining function of the kidney causing uremia - both of which result from tiny blood clots that form in tiny blood vessels - predominantly in the kidneys.
Classically, especially in children, hemolytic uremic syndrome is triggered by a bout of bloody diarrhea.
When that happens, it’s called diarrhea-positive or D positive hemolytic syndrome, sometimes shortened to HUS or simply typical HUS.
The particular strain of E.coli responsible for hemolytic uremic syndrome is known as enterohemorrhagic E. coli or EHEC, serotype O157:H7.
These numbers and letters refer to the specific antigens on the surface of the bacteria.
‘157’ refers to the O-antigen present in the lipopolysaccharide cell wall and ‘7’ refers to the H-antigen located on the flagella of the bacteria.
Other strains of E. coli as well as other bacteria can also cause hemolytic uremic syndrome, but E. coli O157:H7 is the most common culprit.
After entering the digestive tract, E. coli O157:H7 attaches to the intestinal wall and secretes a toxin called Shiga-like toxin.
The toxin gets its name due to its structural similarity with shiga toxin produced by Shigella dysenteriae, another bacteria that causes bloody diarrhea and subsequent hemolytic uremic syndrome.
From there, the toxin is carried on the surface of these cells to the site of blood filtration - which is the glomerular capillaries of the kidney.
Endothelial cells lining these glomerular capillaries express a glycolipid receptor called globotriaosylceramide or Gb3-receptor that has an incredibly strong affinity for the shiga-like toxin - the receptor is like a little magnet that can simply snatch the toxin away from a white blood cell as it drifts by.
Once the toxin binds to the Gb3-receptor, it gets engulfed by the endothelial cell and once inside, it wreaks havoc on the cell.
The toxin prevents aminoacyl-tRNA, which is the little molecule that carries the amino acids to make proteins, from binding to the ribosome.
This stops all protein synthesis in the cell.
In addition to this it also leads to fragmentation of the DNA that activates apoptotic or cell-suicide pathways which causes the endothelial cell to die.
So when large numbers of kidney endothelial cells start undergoing apoptosis, lots of tiny blood clots start to form in the kidneys.
Another way that clots form is through a condition called thrombotic thrombocytopenic purpura or TTP.
In TTP, clots start to form inappropriately, and the underlying reason has to do with a molecule called von Willebrand factor or vWF - named for a Finnish doctor named Erik von Willebrand.
vWF is a huge protein made by the endothelial cells and platelets, and the protein gets released when it's time for platelets to stick together to form a clot.
Now, platelets have a glycoprotein receptor on their surfaces called the Gp-Ib receptor that binds with the vWF protein.
You can think of vWF as a very tiny piece of sticky tape that multiple platelets bind to and form a clot.
Under normal conditions, once time has passed and the clot has served its role, the von Willebrand factor protein gets chopped into small pieces by an enzyme that floats around in the blood called ADAMTS13.
In thrombotic thrombocytopenic purpura, the ADAMTS13 enzyme is not as active, which means that there is excess von Willebrand factor floating around in the blood, and that von Willebrand factor starts binding to platelets and forming clots willy-nilly throughout the body including the kidneys.
This inappropriate formation of clots also means that there are fewer platelets available when clots are actually needed.