TTP: Deadly but Difficult to Diagnose. Part I

She visited her primary care provider (PCP) because of bruises on her arms and legs. She felt well; but she figured she should get the bruising checked out. She had no idea that she had spontaneously developed a disorder that kills 90% of people without treatment. And surprisingly, neither did her PCP.

TTP is a deadly blood disorder that is difficult to diagnose

TTP (thrombotic thrombocytopenic purpura) is a rare autoimmune blood disorder that kills 90% of patients who get it and don't receive the right treatment. However, TTP is also difficult to diagnose because it occurs spontaneously in people who were previously well. When people become unwell with TTP, at first they don't think it is a serious problem because the symptoms are non-specific, including fatigue, bruising, abdominal pain, diarrhea and/or nausea. These symptoms are hardly symptoms that cause people to go in to get checked out. When they do go in to get checked out, sometimes, these symptoms are not big enough to worry their providers. However, these symptoms indicate that blood vessels are getting "clogged" up with blockages that could seriously damage the brain, heart, and kidneys, and ultimately, kill the person with the disorder. Therefore, TTP needs to be recognized and treated early.

TTP is like an evolving drama with four key players

At a microscopic level, there are four key players in the TTP drama: 1) ADAMTS13 (A disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13), 2) VWF (Von Wilebrand factor), 3) platelets, 4) red blood cells, and 5) white blood cells. We'll introduce this cast of characters as follows:

1. ADAMTS13 is like a school teacher with a pair of scissors. ADAMTS13 is a blood protein that acts like a pair of scissors to regulate the action of VWF. When VWF grows too long, ADAMTS13 reacts by cutting it down to size. ADAMTS13, therefore, helps regulate the action of VWF by cutting it down to size.

2. VWF is like a carefree, sometimes out of control, glue. VWF is the glue that helps platelets sticks to damaged surfaces and to each other. One VWF monomer sticks to another VWF monomer to make a longer VWF strand. VWF monomers continue to stick to each other until they make very long multimers (ultralarge VWF). The longer VWF gets, the stickier it gets. That's why ADAMTS13 is needed to keep VWF in check by cutting it down to size.

3. Platelets are like the secret service who act cool until they get activated. Platelets are the chief players in fixing blood vessel injury. When a blood vessel is injured, platelets get activated to form a temporary platelet plug. This platelet plug provides the surface for blood clotting factors to reinforce the platelets by creating a strong fibrin clot, thereby helping the injured site heal. Under normal circumstances, platelets don't get activated unless there is an injured blood vessel. However, when VWF grows very long and becomes sticky, platelets stop following normal protocols and stick to vessel surfaces and to each other.

4. Red blood cells are like workers maintaining a supply chain. Red blood cells transport oxygen throughout the body. Red blood cells go to great lengths to deliver their supply of oxygen to all cells, even cells in hard to reach locations. Red blood cells are flexible and reach tough spots by squeezing through tiny blood vessels (capillaries). Under normal circumstances, they squeeze through capillaries without any problems.

5. White blood cells are like soldiers who protect the body from invasion. White blood cells protect the body from infection. Certain white blood cells are trained to produce antibodies. These antibodies recognize foreign elements, tag them, and alert the body's defense mechanisms to destroy them. These white blood cells are trained to recognize the body so that they never attack the body's citizens, only foreign elements.

Like all good dramas, these five characters live in harmony until a villain enters the picture. Let's introduce the TTP drama in seven acts as follows:

ACT ONE: A Villain is born

ADAMTS13 inhibitor was once an antibody whose job it was to protect the body from foreigners. However, one day, ADAMTS13 inhibitor wakes up with a programming flaw. This programming flaw tells ADAMTS13 inhibitor that ADAMTS13 is a foreign object that needs to be caught and destroyed. Now, ADAMTS13 inhibitor has only one mission in life - to capture and destroy ADAMTS13.

ACT TWO: ADAMTS13 is captured

ADAMTS13 goes to work one day and runs into ADAMTS13 inhibitor, whom ADAMTS13 mistakes for a soldier on duty. But, unbeknownst to ADAMTS13, ADAMTS13 inhibitor has become a sworn enemy. Therefore, ADAMTS13 inhibitor captures ADAMTS13 and hauls ADAMTS13 away to be destroyed. With ADAMTS13 out of the picture, there is no one left to cut VWF down to size. This gap creates the perfect scenario in which VWF spirals out of control.

ACT THREE: With no ADAMTS13, VWF spirals out of control

Without ADAMTS13 to cut VWF down to size, VWF grows unchecked into ultralarge VWF. Ultralarge VWF begins to accumulate, unchecked, in blood vessels all over the body. Ultralarge VWF accumulates in the brain, the kidneys, the heart . . . Ultralarge VWF accumulates everywhere. Without ADAMTS13 around, ultralarge VWF is completely out of control, which becomes a serious problem for platelets.

ACT FOUR: Ultralarge VWF depletes the platelet workforce

Ultralarge VWF is a big draw for platelets, who leave their regular duties to stick to vessel surfaces and each other. Instead of doing their usual job of finding and fixing injured vessels, they are induced by ultralarge VWF to stick in places where they otherwise have no business sticking to. Although there is no injury to be fixed, these platelets become activated, form platelet plugs, and provide a surface for blood clotting factors to form fibrin clits. Thus platelets form small blood clots, or microthrombi, throughout the body, especially in critical organs like the brain, heart, and kidneys. More and more platelets are recruited by ultralarge VWF until much of the platelet work force is depleted in a condition called thrombocytopenia (low platelets).

ACT FIVE: Red blood cells are caught in the crossfire

The microscopic blood clots (or microthrombi) formed by platelets block the smallest blood vessels (capillaries), thus impairing the passage of the red blood cells. The red blood cells come to work and find their usual passages blocked; however, like good employees, they don't turn back. Rather, they attempt to force their way through the blockages. Some red blood cells are lucky enough to make it through. Most, however, are unlucky. In the process of trying to squeeze through the blockade, these red blood cells get torn apart and destroyed. This destruction leads to a decrease in the number of red blood cells, a condition known as anemia. The resulting fragments of destroyed red blood cells are seen in the blood when viewed under the microscope as (broken red blood cells) schistocytes.

ACT SIX: Widespread chaos ensues

When red blood cells are torn apart, it leads to widespread inflammation. Broken red blood cells spill their contents into the blood, causing elevated blood levels of a red blood cell enzyme, lactate dehydrogenase (LDH). The broken red blood cells also spill hemoglobin, which gets mopped up by a protein called haptoglobin. As haptoglobin sticks to the spilled hemoglobin, it gets used up in the process, leading to low blood haptoglobin levels. Finally, the body's factory ramps up red blood cell production to make up the numbers. However, because red blood cells are being broken up at an alarming rate, the red blood cells being sent out into the circulation are younger and younger. These young red blood cells are called reticulocytes. So, the reticulocyte numbers also accumulate in the blood. The result of this chaos is called hemolysis, marked by increased LDH levels, low haptoglobin levels, and increased reticulocytes.

ACT SEVEN: The perfect storm

While this drama is unfolding at a microscopic level, the person experiencing all these problems has no idea what is going on but their body. However, their body feels the effects of the raging chaos as follows:

1. The low red blood cell counts (anemia) cause fatigue or malaise. The person experiencing anemia feels tired and weak. At first, this fatigue is not enough to make them panic. They just wonder if they have been working too hard. They may feel unwell enough to know something is wrong; but they may just dismiss these symptoms. As time goes on though, they will start to feel the damaging effects of limited oxygen and they will start to experience lightheadedness or dizziness.

2. The low platelet counts (thrombocytopenia) can cause bruising or bleeding. Platelets typically decrease to levels below 50 (normal range 150-450 X 10^9/L) before it becomes obvious that the platelet count is dangerously low. These low counts may present as bruising on the arms and legs, which people may not take seriously. Low platelet counts may also present as bleeding into the skin (petechiae), urine (hematuria), excessive bleeding with periods (menorrhagia), or nosebleeds (epistaxis). If left long enough, life-threatening bleeding could occur.

3. The red blood cell breakage (hemolysis) causes an inflammatory response. The release of substances into the blood that are not supposed to be there can cause an inflammatory response. This inflammatory response leads to body to act as if it is fighting a major infection. Thus, the person may feel sick (malaise) or have a fever. However, the fevers and symptoms of feeling unwell can come and go and people don't always take fevers seriously. Eventually, however, the inflammation can lead to a serious condition in which the blood pressure gives out (hypotension) and the person ends up fighting for their life in the intensive care unit.

4. The microthrombi damage important organs. The platelets form microthrombi that block blood flow to critical organs like the brain, heart, and kidneys.

The brain: Microthrombi blocking blood flow to the brain can cause a major stroke. However brain microthrombi can also present with non-specific symptoms like brain fog, confusion, and forgetfulness. Serious symptoms like stroke get people's attention; however, the other "less serious" symptoms like the confusion sometimes keep people from being taken seriously. Left untreated, the brain microthrombi can cause a devastating brain injury, leaving permanent damage.

The heart: Microthrombi blocking blood flow to the heart can cause chest pain. But they can also cause serious heart damage such as a fatal heart attack.

The kidneys: Microthrombi in the kidney can cause kidney damage, which is usually mild; but can be severe enough to need serious intervention.

From the above, you can see that TTP can be hard to diagnose because people typically have no idea that there is major chaos happening in their bodies. Therefore, early recognition and diagnosis is key so that TTP can be successfully treated. In my next blog post on TTP, I will write about how TTP can be diagnosed and managed.