What is Thrombotic Thrombocytopenic Purpura Evaluation and Management?
Thrombotic thrombocytopenic purpura (TTP) is a rare condition that causes blood clots to form in small blood vessels due to a specific type of anemia known as microangiopathic hemolytic anemia. Symptoms of TTP include fever, anemia (a deficiency in red blood cells), low platelet count, and problems with kidney function and the nervous system. TTP happens when there are inadequate levels of a protein called von Willebrand factor-cleaving protease ADAMTS13, which may be due to either a birth defect or an acquired condition. When there’s not enough ADAMTS13, tiny blood clots form which can block blood flow and cause harm to the organs.
There are two main types of TTP – immune-mediated and congenital (present at birth). The most common type is immune-mediated, often resulting from a severe deficiency of ADAMTS-13 primarily due to autoantibodies – harmful antibodies that the body mistakenly produces to attack its own proteins. The lack of ADAMTS-13 causes large clusters of a certain protein to form, resulting in platelet (types of blood cells) sticking together and forming microthrombi, small clots that can harm organs. Immune-mediated TTP can also be categorized as primary or secondary, the latter being due to other diseases, like HIV, systemic lupus (a type of autoimmune disease), antiphospholipid syndrome, or severe inflammation of the pancreas.
While TTP is a rare disease, it can cause severe complications even if treated. Therefore, early identification and treatment are key to better outcomes. However, diagnosing TTP can be challenging because its symptoms are similar to many other conditions. Regular follow-up care is crucial for managing potential consequences, other autoimmune disorders, and to avoid potential relapses.
TTP was first identified in 1924 in a case involving a 16-year-old girl who came in with fever, weakness, temporary focal neurological deficits (issues with brain, spinal cord or nerves functions), a dangerously low platelet count, and microangiopathic hemolytic anemia. The term TTP was used first in 1947, based on autopsy results from another fatal case. Until the 1990s, TTP had a very low survival rate. The introduction of a treatment called therapeutic plasma exchange (a process of removing the plasma and replacing it with a healthy substance) in the 1990s increased the survival rate drastically from 10-20% to 80%.
What Causes Thrombotic Thrombocytopenic Purpura Evaluation and Management?
The progression of our knowledge on TTP, a blood disorder, is fascinating. It shifted from being understood as a clinical issue to having a specific biological cause: a significant shortage of an enzyme called ADAMTS-13. This enzyme, produced in the liver, plays a crucial role in breaking down large protein structures known as vWF multimers into smaller pieces.
Normally, cells lining our blood vessels release these large vWF multimers. ADAMTS-13, working like a pair of molecular scissors, recognizes a specific site on these large proteins and cuts them into smaller pieces. These smaller proteins are less likely to stick to platelets, the tiny blood cells that help our body form clots to stop bleeding.
Most cases of TTP are due to the body producing antibodies that attack ADAMTS-13. This is known as immune TTP or iTTP. In essence, the body mistakenly targets its own enzyme, preventing it from efficiently cutting the vWF proteins, which in turn can lead to excessive blood clotting. Though these antibodies are usually found during TTP attacks, up to 25% of cases might not show any, possibly due to various factors such as enhanced removal of ADAMTS-13, the reduced sensitivity of tests, or other associated effects, like infections.
TTP can also be triggered by drugs, and it’s often regarded as a different type because it doesn’t usually involve a lack of ADAMTS-13. There is an exception, though, with a drug called ticlopidine that is linked to reduced ADAMTS-13 levels in most cases.
The rare causes of ADAMTS-13 deficiency include inherited gene mutations, which lead to a type of TTP called Upshaw-Schulman syndrome or congenital TTP. This only accounts for a small portion of TTP cases and occurs more in children than adults. There are about 150 different mutations identified worldwide. People with this inherited form often show no symptoms until a triggering event (like an infection) sparks an acute attack.
Risk Factors and Frequency for Thrombotic Thrombocytopenic Purpura Evaluation and Management
TTP, or Thrombotic Thrombocytopenic Purpura, is a rare condition that affects a small number of adults each year. While anyone can get it, it is more common in adults than children, with 90% of cases occurring in adults and just 10% in children. It tends to affect women more than men, and African Americans are 8 times more likely to have it than White Americans. In the United States, people in their 50s are most likely to develop TTP, but in Europe, it’s most common in people in their 30s. Pregnant women and children are more likely to have a genetic cause for their TTP.
- TTP is a rare condition, affecting 1.5 to 6 people per million adults each year.
- Most cases, about 90%, are in adults, and about 10% in children.
- Women are 2 to 3 times more likely to develop it than men.
- African Americans are 8 times more likely to have it than White Americans.
- In the United States, people in their 50s are most likely to get it, but in Europe, it’s most common in people in their 30s.
- Pregnant women and children are more likely to have a genetic reason for their TTP.
Signs and Symptoms of Thrombotic Thrombocytopenic Purpura Evaluation and Management
Thrombotic thrombocytopenic purpura (TTP) is a medical condition that may initially present with nonspecific symptoms, making it challenging to diagnose without a high degree of suspicion. Often, these symptoms include weakness, headaches, confusion, nausea, vomiting, and diarrhea. Some patients may recall having a recent infection before the occurrence of these symptoms. Surprisingly, the set of symptoms known as the classic five, which includes fever, mental confusion, anemia, low platelet count, and kidney failure, are seen in fewer than 10% of patients.
- Weakness
- Headache
- Confusion
- Nausea
- Vomiting
- Diarrhea
More commonly seen are severe reductions in platelet count and a type of anemia characterized by the presence of broken red blood cells on a blood smear. These can lead to bleeding, general weakness, and difficulty catching one’s breath. However, less than 10% of patients may show external bleeding due to a severe reduction in their platelet count.
The brain may also become involved in up to 60% of cases, with a wide range of symptoms, from headaches and mental confusion to stroke-like episodes, seizures, and even unconsciousness. Symptoms related to the heart like chest pains and elevated heart proteins are common. This may sometimes develop into irregular heart rhythms and heart failure. An extremely rare but serious complication is a heart attack. Digestive tract symptoms can include abdominal pain, nausea, vomiting, and diarrhea. A substantial proportion of patients, up to 35%, can also experience blood clot-related gut damage. Kidney failure is uncommon and is more suggestive of a similar condition known as hemolytic uremic syndrome, although it doesn’t rule out TTP.
Finally, some patients may show symptoms linked to a previous or co-existing health condition (secondary TTP), such as bacterial infection, Lupus, antiphospholipid syndrome, HIV, pregnancy, certain medications, cancer and organ transplantation.
Testing for Thrombotic Thrombocytopenic Purpura Evaluation and Management
To determine the activity of ADAMTS-13, a vital protein that helps control blood clotting, complex testing methods are required. However, these aren’t always readily available in urgent situations. Therefore, initial treatment often begins based on the symptoms a patient has. Blood tests can reveal low platelet counts (thrombocytopenia), presence of ‘schistocytes’ or broken red blood cells (indicating microangiopathic hemolysis), presence of autoantibodies to ADAMTS-13, and decreased ADAMTS-13 activity. Also, the direct Coombs test (a test for autoimmune diseases) should mostly come out negative, and the coagulation test (the time it takes blood to clot) should not be unusually prolonged. Other unusual lab results might include lower than normal haptoglobin (a protein that binds to the hemoglobin), higher than normal number of immature red blood cells (reticulocytes), elevated levels of the enzyme LDH, and increased amount of indirect bilirubin.
In patients who present with both low platelet counts and hemolytic anemia (where red blood cells are destroyed faster than they can be replaced), the critical indicator for a condition called acquired thrombotic TTP is ADAMTS-13 activity level below 10%, regardless if inhibitory autoantibodies are detectable or not. This finding is specific for TTP and indicates there’s no other likely cause for these symptoms.
Doctors consider the treatment a success, or ‘clinical response,’ if platelet count is above 150×109/L and LDH levels are less than 1.5 times the upper limit of normal. ‘Clinical remission’ refers to this improved condition lasting for more than 30 days after the final plasma exchange treatment. If, despite five essential treatments called plasma exchanges and appropriate steroid use, the patient still has severe low platelet counts and high LDH levels, the TTP is considered to be ‘refractory’ or persistently resistant to treatments.
Treatment Options for Thrombotic Thrombocytopenic Purpura Evaluation and Management
Thrombotic thrombocytopenic purpura (TTP), a blood disorder, is usually treated first with a procedure called therapeutic plasma exchange (TPE) which involves swapping the patient’s plasma with healthy plasma. The idea is to start TPE as soon as possible and continue daily until the patient’s platelet count stabilizes and there are no new signs of organ damage. If TPE doesn’t show the expected improvement, the doctor might consider removing certain harmful substances like autoantibodies, immune complexes, large proteins called vWF multimers, and pro-inflammatory cytokines from the patient’s blood. In some stubborn cases, TPE may even be performed twice daily.
Meanwhile, for cases of chronic TTP, plasma infusions can maintain sufficient levels of the ADAMTS-13 enzyme. Nonetheless, this method alone isn’t usually sufficient to treat TTP and is often seen as a short-term solution until plasma exchange can be performed. Also, platelets (blood clotting cells) are generally not recommended due to research indicating they might worsen TTP symptoms — they are only considered if the patient is actively bleeding or if a surgical procedure is planned.
Corticosteroids, a type of medication that reduces inflammation, is also usually given alongside TPE unless there are medical reasons not to use them. These medications work because TTP often has an autoimmune component, meaning the body’s immune system mistakenly attacks its own cells. Corticosteroid use can help reduce the number of TPE sessions needed, lower the risk of treatment-related complications, and improve treatment success rates.
Some patients might not respond to the initial treatment plan, which typically involves TPE and corticosteroids. In those cases, a medication called rituximab can inhibit the formation of harmful autoantibodies. This medication is usually given once a week for four weeks. Although rituximab can have side effects, they are typically mild. However, it may take up to two weeks for patients to notice an improvement after starting rituximab. Other drugs such as vincristine, cyclosporine A, cyclophosphamide, and bortezomib could be used to suppress the production of autoantibodies.
For patients who do not respond to TPE and rituximab, or for the ones who experience repeated episodes of TTP, a surgical procedure called splenectomy, the removal of the spleen, might be recommended. This is based on the understanding that the spleen is often the site where harmful autoantibodies are produced.
Another treatment option is a drug called caplacizumab, which was specifically created to treat TTP. It works by preventing platelets from sticking to vWF multimers (large proteins that help in blood clotting). However, it doesn’t fix the underlying issue of an ADAMTS-13 enzyme deficiency, so it’s typically used in combination with TPE and corticosteroids.
In situations where TTP is triggered by another disease (secondary immune-mediated TTP), that underlying condition also needs to be treated. Pregnant patients are usually treated with TPE and steroids, as the safety of other treatments during pregnancy has not been studied.
One of the biggest challenges in managing TTP is the unpredictable risk of the condition coming back, which could happen anywhere from one to twenty years after the first episode. While rituximab can help some patients by reducing the chance of relapse, it is also important to weigh the risks of this treatment, such as infusion reactions, reactivation of hepatitis B, lung fibrosis, and a rare brain disease called progressive multifocal leukoencephalopathy. There is limited information on this topic, but some data suggest that the benefits of rituximab therapy outweigh the potential risks.
What else can Thrombotic Thrombocytopenic Purpura Evaluation and Management be?
Diagnosing certain medical conditions can be tricky and involves exploring several possibilities. In this case, there are several conditions a doctor might think about, like:
- Evans syndrome
- Antiphospholipid syndrome
- Disseminated intravascular coagulation (also known as DIC)
- Hemolytic uremic syndrome (HUS), especially if the patient is showing signs of significant kidney failure
- Other reasons for thrombotic microangiopathy (TMA), such as certain drugs, high blood pressure, or cancer.
In pregnant patients, it becomes vital to take into consideration HELLP syndrome, which is characterized by the breakdown of red blood cells, elevated liver enzymes, and a low platelet count, or Upshaw-Schulman syndrome – a type of hereditary thrombotic thrombocytopenic purpura (cTTP). Both these conditions can appear for the first time during pregnancy.
Possible Complications When Diagnosed with Thrombotic Thrombocytopenic Purpura Evaluation and Management
Even with treatment, complications can still be severe, with individuals enduring these complications representing 10% to 20% of all patients. Common complications include brain impairments, sudden kidney damage, and bleeding issues. Tiny clots can also impact other body systems, such as the heart, lungs, and digestive tract. Negative reactions to treatments, especially TPE, might involve low blood pressure, severe allergic reactions, fluid overload, and a decrease in blood calcium due to citrate being given.
Long-term issues are believed to be prevalent, likely due to the ongoing nature of the disease. People often experience long-term brain-related issues like reduced focusing ability, slower information processing, diminished rapid language generation, and memory problems which could stem from tiny vessels in the brain being damaged over several acute episodes. Moreover, in prolonged monitoring, patients exhibited higher instances of high blood pressure, depression, and death. However, the precise cause of these conditions is not yet known, and they could be linked to other concurrent health issues.
Simplified Complications:
- Brain impairments
- Kidney damage
- Bleeding issues
- Heart, lung, and digestive issues due to tiny clots
- Low blood pressure
- Severe allergic reactions
- Fluid overload
- Decrease in blood calcium
- Reduced focusing ability
- Slower information processing
- Diminished rapid language generation
- Memory problems
- High blood pressure
- Depression
- Possible death
