Manish Saha, MD
Manish Saha, MD

Dr. Manish Saha talks with Dr. Ron Falk about thrombotic microangiopathy, or TMA. They discuss two types of TMA, thrombotic thrombocytopenic purpura and hemolytic syndrome, and the symptoms associated with each. They also talk about the testing and treatment for TMA. Dr. Saha is an Assistant Professor of Medicine in the Division of Nephrology and Hypertension.

“The early symptoms are very vague. They may have malaise, weakness, and headache. Most of the time they get hospitalized because when the bloodwork is done, the platelet count is severely low in these patients, and sometimes so dangerously low they get admitted to the hospital. That’s when additional blood tests are done and ADAMTS13 and other evaluations are done, and when they are picked up.”

– Dr. Manish Saha on when TMA is often diagnosed

 

Ron Falk, MD: Hello, and welcome to the Chair’s Corner from the Department of Medicine at the University of North Carolina.

This is our series where we discuss different genetic diseases with physicians who treat patients with these conditions. Today, we will talk about thrombotic microangiopathy, or TMA.

We welcome Dr. Manish Saha, who is an Assistant Professor of Medicine in our Division of Nephrology and Hypertension. Welcome, Dr. Saha.

Manish Saha, MD: Thank you.

Types of TMA

Falk: What is thrombotic microangiopathy? What is TMA?

Saha: TMA, as the name suggests, is thrombosis or blood clots in small blood vessels of our body. These blood vessels are called arterioles or capillaries. Clinically, it is manifested as low platelet counts, also known as thrombocytopenia, because the platelet gets consumed in the clots. Then something called non-immune-mediated, or mechanical destruction of your red blood cells, giving rise to a low hemoglobin and making you anemic. If these blood clots form in any organ, you have organ-specific dysfunction. If it happens in the kidney, you have kidney injury. If it happens in the brain, you have neurological symptoms.

Falk: There are many types of thrombotic microangiopathies, many types of TMA. There are two of them that we should spend a little more time on. One of them is known as thrombotic thrombocytopenic purpura—can’t say that fast three times! It has an abbreviation known as TTP. What is TTP?

Saha: The clinical syndrome of TMA is shared by many disease entities, including what you said, TTP—as the name suggests, thrombotic thrombocytopenic purpura. It was originally described over sixty years ago, the patient had features of small blood clots in the blood vessels. They also had low platelet count—hence the name thrombocytopenia, and they had a purpuric rash. That’s how the name was initially coined. Now, TTP manifests as TMA with neurological syndrome—neurological symptoms of headache, confusion, signs and symptoms of stroke, and other features. It is one of the causes of TMA.

Falk: There used to be described what is known as a pentad, or five different features of TTP. What were those?

Saha: The pentad that was described, many years ago, included fever, low platelet count—also known as thrombocytopenia, neurological symptoms, kidney injury and low hemoglobin or anemia. This pentad was described years ago, but recent studies show that less than five percent of patients with TTP had the pentad of symptoms. TTP does not need to present with all of these features—they can just have one marker and still have TTP.

The role of enzyme ADAMTS13

Falk: One of the causes of TTP is an absence, or an inhibition of an enzyme known as ADAMTS13. There are various ways of pronouncing that acronym of a metalloproteinase. What is it?

Saha: ADAMTS13 is an enzyme that is made by the liver. It is called metalloprotease because it requires a metal like calcium or zinc for this action. So, if somebody has a vessel injury, the body makes another protein known as ultra large von Willebrand factor, which is a clotting factor. It helps in forming a clot at the site of injury of the blood vessel.

Falk: Which is normal—that’s what it’s supposed to do.

Saha: This is normal. This is regulated, because you don’t want this process to continue. Once the platelet plug is formed and the blood vessel is repaired, you want the process to stop there. That is where ADAMTS13 comes into play. What this enzyme does, it controls the process. The platelet plug is limited to the site of injury and it doesn’t get unregulated.

Falk: Really, what ADAMTS13 does, is to chop up high molecular weight, or ultra-high molecular weight von Willebrand’s factor, which comes out of cells known as endothelial cells. That’s how you stop the process you described. How does one as an individual, then, not have enough of this enzyme?

Saha: In two ways. One is known as congenital TTP, where people have a defect in the genetic material that makes this enzyme. So, if you have a genetic mutation, you do not make enough of this enzyme. These patients present early in life, also known as congenital TTP. Adults can also have TTP, but usually they make enough of that ADAMTS13 enzyme, but there’s an autoantibody that inhibits the action of ADAMTS13.

Hemolytic uremic syndrome, HUS

Falk: There’s another leading cause of TMA, which is known as the hemolytic syndrome, or HUS. What is that?

Saha: HUS is hemolytic uremic syndrome. When it was initially described, they found that patients with TMA, instead of having neurological symptoms like in TTP, they have kidney failure. That’s where the term “uremia” was coined. Patients with TMA who primarily have kidney involvement have something called hemolytic syndrome. It can be caused mainly by two different entities. The first, and common one, is infections, and these infections are mainly from E. coli, shigella, pneumococcus, among other infections.

Falk: The most common one in the state of North Carolina, was at one point, a petting zoo at the North Carolina state fair. Petting goats that carried, on their fur, those bugs. You can also get those microorganisms or bacteria from food.

Saha: Yes, uncooked meat, including hamburgers , beef and other produces may be a source of this E.coli

Falk: It’s the reason to cook hamburgers all the way through, it’s the reason to wash things even like alfalfa sprouts really well, because otherwise those bacteria just aren’t washed away.

Saha: Correct.

Falk: In addition to the infectious causes of hemolytic uremic syndrome, there is something else called the “atypical” form, which is a genetic abnormality as well.

Saha: Correct. Atypical HUS is when you have the same features, but it’s not caused by an infection, but due to an unregulated activation of something called an alternate complement pathway. Complement pathway is one of our defense mechanisms that fights infections. A genetic defect or an antibody in one of these regulators lets this alternate complement pathway get activated uncontrollably and result in thrombotic microangiopathy.

Falk: In terms of the genetic causes of these thrombotic microangiopathies, there is the absence or deficiency of an enzyme that cleaves the protein that stops you from bleeding, and another genetic cause of the same kind of thrombotic microangiopathy is a defect in the way we control infection. So, both of these are genetic abnormalities that pertain to regulation of bleeding or regulation of infection—handling infections.

Saha: Correct.

Falk: What is the most common place for a patient to discover that they have thrombotic microangiopathy? Is it because they are hospitalized for clotting and bleeding and having neurological dysfunction, or are patients picked up in the outpatient setting?

Saha: It’s rarely picked up in the outpatient setting, because the early symptoms are very vague. They may have a malaise, weakness, and headache. Most of the time they get hospitalized because when the bloodwork is done, the platelet count is severely low in these patients, and sometimes so dangerously low they get admitted to the hospital. That’s when additional blood tests are done and ADAMTS13 and other evaluations are done, and when they are picked up.

Testing for TMA

Falk: How do you test for these TMA’s, and how accurate are those tests?

Saha: The initial part when you’re diagnosing someone with TMA, you just need routine bloodwork, to make sure you have evidence of low platelet counts, called thrombocytopenia, and have mechanical destruction of RBC’s, evident on peripheral smear as schistocytes, and you may have evidence of an organ dysfunction, like elevated creatinine because the kidneys are involved, or any other organ involvement.

Once you know you have evidence of thrombotic microangiopathy, then the question is, is it TTP or HUS, or any other secondary cause? For TTP, you need to measure the ADAMTS13 activity level, and for HUS, you need to make sure there is no infection. If there is not, and you are looking for atypical HUS (complement mediated), then you need to study the genetic defects that exist in the regulators of alternate complement pathway.

Falk: How accurate are those tests?

Saha: For atypical HUS (complement mediated), you can only expect to get about fifty percent positivity in patients who clinically present with atypical HUS. In the other fifty percent of patients, it can be normal, but they can still have atypical HUS.

Falk: Not because there’s not enough of it, but because it doesn’t function well.

Saha: It doesn’t function well, and maybe the testing we have now as of 2018 is not sensitive enough to pick up every mutation. Hopefully, with time it will improve. Also, we will find other causes.

Treating TTP & HUS

Falk: How do you treat somebody with TTP?

Saha: Congenital TTP is usually treated by plasma infusion, meaning you’re giving back to them normal ADAMTS13 that exists in blood. Patients who are adults and have adult-onset TTP, because it’s caused by an autoantibody, need to do something called a plasma exchange.

Falk: You get rid of it.

Saha: You get rid of the antibody against ADAMTS13 , and you treat them with immunosuppression like steroids and other medications to stop antibody production.

Falk: How about HUS? How do you treat that?

Saha: HUS, if it’s caused by an infection, you treat the infection and supportive therapy. If it is atypical HUS(complement mediated), then there is a specific drug , anti-complement 5 medication, also known as Eculizumab, that you may consider

Falk: That has really revolutionized the treatment, especially children with atypical HUS. It has made it so that their life expectancy is pretty good.

Saha: Correct. Since the FDA approved it a couple of years ago, this is probably the only drug that is available that has revolutionized the treatment and the prognosis or outcome of atypical HUS.

Falk: Unfortunately, it is an extremely expensive drug.

Saha: It is very expensive, yes.

Falk: One that should really only be used if you know for sure that the person has an inherited complement deficiency.

Saha: Yes, only when the suspicion is very high, or you have evidence should you consider it.

Falk: Tell us a little bit more about this drug Eculizumab, which is an infusion given once a month that inhibits what is known as C5, or the fifth component of complement.

Saha: This drug is an infusion. There is no pill or subcutaneous version yet. There is induction phase, and there’s a maintenance phase, and the dose vary according to your weight. This is a drug that inhibits complement factor 5. Patients is at risk for something known as Neisseria meningitis. They need to be vaccinated for all the serogroups that are recommended by the CDC, as well as antibiotic prophylaxis for the first few weeks at least, if not longer, when you’re starting to be on Eculizumab infusion.

Falk: Then there’s the maintenance phase.

Saha: Then there’s the maintenance phase that is a little bit more complicated to see how long you should use it. It depends on, how is the patient responding to it? What is the recovery of the organ involvement? And what kind of mutation does the patient have?

Falk: In atypical HUS at this point, the question is not if the drug is useful, it’s very, very useful and lifesaving, but when can one stop it? There is tremendous controversy about when you can stop that drug.

Saha: Yes, it is a wonderful drug for the right diagnosis, but there is no consensus on when you should stop it.

Falk: Or if you can.

Saha: Right, but even if you stop it for one reason or another, you should see your patients regularly with a very close follow-up.

Falk: The side effects of this drug are inhibiting part of the normal process of getting rid of infections, so the side effects, as you described, are lots of infectious diseases, but most commonly, bacteria that causes meningitis.

Saha: Correct, because it affects the complement pathway which is part of our defense mechanism against infection, the greatest worry is the bacteria known as Neisseria meningitis, causing infection in the brain known as meningitis.

Prognosis, inheritance & more information

Falk: What is the overall quality of life then of somebody who has thrombotic microangiopathy?

Saha: If the disease is diagnosed early, and the treatment is appropriate, they should have a good life expectancy. At the same time, they are at risk for certain long-term chronic diseases. Patients, if they have kidney involvement, they are at risk for chronic kidney disease. If they had brain involvement, they’re at risk for cognitive dysfunction and depression. If their heart was involved, they are at risk for cardiomyopathy, or heart problem, or hypertension. As you follow these patients regularly they should be screened for all these chronic disorders that they may develop over time.

Falk: Hopefully with good therapy, though, and routine follow-up, the life expectancy should be really pretty good.

Saha: Yes, it should be pretty good, if diagnosed and treated early.

Falk: What are the chances, then, if somebody has a genetic form of TTP, or atypical HUS, will pass that condition on to their children?

Saha: Congenital TTP is usually transmitted as autosomal recessive disease. That means you need to get one copy of genetic defect from each parent, while atypical HUS can present in both autosomal dominant or autosomal recessive. If someone is affected by atypical HUS in autosomal dominant fashion, meaning there’s a fifty percent chance that their offspring will have or will carry that mutation. This increases the risk of the disease but just carrying the mutation may not be enough to cause symptoms as a additional trigger may be required.

Falk: A secondary stimulus. Where can somebody find more information about TMA if they’re looking on the web?

Saha: One of the websites is unckidneycenter.org. Another one is Atypical HUS Foundation. A third one is Genetics Home Reference.

Falk: Thank you so much, Dr. Saha.

Saha: Thank you.

Falk: Thanks so much to our listeners for tuning in. Next time, we will be talking with Dr. Nigel Key on hemophilia. You can subscribe to the Chair’s Corner on iTunes, SoundCloud, or like us on FaceBook.