Hemolytic-uremic syndrome

Definitions & Key takeaways

Hemolytic-uremic syndrome (HUS) is a serious condition that's characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. It is usually caused by E. coli O157:H7 infection and presents with fever, jaundice, stomach cramps, vomiting, and diarrhea. A person with HUS may also have a rash, red or purple dots on the skin, and tiredness.

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Introduction0:00–0:26

‘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.

Typical hemolytic uremic syndrome0:26–4:54

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.
Escherichia coli or E. coli is usually the culprit, and children often pick it up through contaminated food or drink, like contaminated beef or unpasteurised milk from an infected cow.
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.
So that toxin gets absorbed by intestinal blood vessels and is then picked up by immune cells like eosinophils, basophils and neutrophils.
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.
Normally, any disruption to the endothelial cell lining of a blood vessel is immediately repaired by primary hemostasis which is where a platelet plug forms to prevent more bleeding.
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.
Now, there are other relatively rare ways for abnormal clots to start forming and these are lumped together and called atypical hemolytic uremic syndrome.

Atypical hemolytic uremic syndrome4:54–5:46

In atypical hemolytic uremic syndrome, there is no preceding diarrhea so it’s also known as D- hemolytic uremic syndrome.
In this type, there is often damage to the endothelial cells lining these glomerular capillaries, and that damage can come from infectious causes that are not associated with diarrhea, as well as certain medications, or autoimmune causes.
There are also familial forms of atypical hemolytic uremic syndrome, where genetic mutations seem to relate to a predisposition for damage to these endothelial cells.
Regardless of the cause, the end result follows a pattern similar to typical hemolytic uremic syndrome, where the glomerular endothelium gets damaged and in response blood clots start to form in the kidneys.
Now, the classic of findings in hemolytic uremic syndrome is microangiopathic hemolytic anemia or MAHA, thrombocytopenia, and acute renal failure.

Signs and symptoms5:46–7:38

Microangiopathy refers to the endothelial damage that occurs in the small blood vessels, and the hemolytic anemia refers to the fact that the clots that form within these small blood vessels act like boulders in a river, making it difficult for red blood cells to flow through without getting damaged and destroyed.
Unlucky red blood cells can get smacked up against a blood clot and break forming schistocytes which are cell fragments or ‘helmet’ cells which look like little red helmets with pointed ends after a bit of the cell broke off.
Ultimately this destruction of red blood cells leads to a decreased number of normal functioning red blood cells in the blood, also known as hemolytic anemia.
This results in the usual symptoms of anemia like weakness, fatigue, and lethargy, but can also cause jaundice as well because of the red blood cell destruction.
The thrombocytopenia or low number of platelets results from them getting used up in clot formation, and it means that clots can’t form when they need to - which causes easy bruising and purpura which is bleeding into the skin.
Finally, severe ongoing damage to the capillary endothelium of the glomeruli in the kidney can result in renal failure and that can lead to uremia or excess urea in the blood.
In addition to the classic symptoms of hemolytic uremic syndrome, individuals with thrombotic thrombocytopenic purpura typically have neurologic findings because blood clots can affect the blood supply to the brain.
This might result in visual disturbances, altered mental status and even seizures and stroke, which can lead to death. People suffering from TTP usually also have fever.

Diagnosis7:38–8:15

Hemolytic uremic syndrome is diagnosed by evaluating the urine for signs of kidney damage - like proteinuria - excess protein in the urine and hematuria - which is the presence of blood in the urine.
There may also be elevated waste products like urea and creatinine in the urine. On a blood smear, there may be evidence of schistocytes or helmet cells, and in cases where there is a history of bloody diarrhea, the stool can be cultured to look for the culprit bacteria.
Finally, in suspected TTP-HUS, ADAMTS13 activity in plasma can be measured. Treatment of typical or D+ hemolytic uremic syndrome is mainly supportive as the Shiga-like toxin gradually clears out of the body over a matter of days to weeks.

Treatment8:15–9:03

It’s thought that killing bacteria with antibiotics can potentially result in increased release of toxin from dead bacteria which can worsen the problem, so it’s not typically recommended.
In TTP-HUS, a key treatment option is plasmapheresis where the patient’s plasma is exchanged with plasma that has a normal amount of ADAMTS13 and lacks the antibodies that might be destroying it.
Of the various types, atypical hemolytic-uremic syndrome usually has the worst prognosis and treatment usually involves identifying and addressing the underlying cause.
Alright, as a quick recap - hemolytic uremic syndrome is a disease characterised by microangiopathic hemolytic anemia, thrombocytopenia, and renal failure.

Review9:03–10:30

Typical hemolytic uremic syndrome is caused by bacteria like E. coli O157:H7, but it is also associated with thrombotic thrombocytopenic purpura, as well as atypical causes.
The diagnosis is made by analyzing the blood or urine, and the treatment for typical hemolytic uremic syndrome is supportive.