Thrombotic Thrombocytopenic Purpura

What is Thrombotic Thrombocytopenic Purpura?

Thrombotic Thrombocytopenic Purpura (TTP) is a specific kind of anemia— a condition that involves the destruction of your red blood cells. It usually comes with five symptoms, including fever, low platelet count (a condition called thrombocytopenia), anemia, kidney dysfunction, and problems with the nervous system. You could be born with this condition (congenital) or you could develop it (acquired).

This condition happens because of a decrease or absence of a substance in your blood called ADAMTS13, which is responsible for breaking down another substance, the von Willebrand factor. Without enough ADAMTS13, your body can’t regulate the von Willebrand factor, causing it to form tiny blood clots (microthrombi) that can block blood flow to organs and damage them.

The most commonly affected organs are the brain (central nervous system) and kidneys. It’s very important that this condition is diagnosed quickly, because if left untreated, it can be life-threatening, with a mortality rate of about 90%. Thankfully, about 80% of people respond well to initial treatment, and after that the mortality rate falls to around 10-15%.

What Causes Thrombotic Thrombocytopenic Purpura?

TTP, or thrombotic thrombocytopenic purpura, is a condition that occurs due to a decrease or absence of a specific enzyme called ADAMTS13. This can be either present from birth (congenital) or develop later in life (acquired). Acquired TTP is more common and happens when the body mistakenly makes autoantibodies, which are substances that target and attack our own ADAMTS13 enzyme.

There are many things that can trigger the formation of these autoantibodies, such as the use of antiplatelet drugs (medicine that helps prevent blood clots), immunosuppressive agents (drugs that reduce the body’s immune response), HIV, estrogen-containing birth control, and pregnancy. These factors can lead to acquired TTP.

On the other hand, congenital TTP is less common and it occurs due to genetic mutations in ADAMTS13. But it’s important to note that just having a deficiency of the ADAMTS13 enzyme doesn’t always lead to TTP. Individuals with this hereditary deficiency might not show any symptoms until they experience a trigger event, like an infection or pregnancy.

It’s not exactly clear which factors increase the risk of developing these autoantibodies that can inhibit the ADAMTS13 enzyme, which is key in managing TTP.

Risk Factors and Frequency for Thrombotic Thrombocytopenic Purpura

TTP, or Thrombotic Thrombocytopenic Purpura, is a rare disease with the number of cases varying from one to 13 cases per million people, depending on where you are in the world. Although TTP can happen at any age, it is typically seen in people over 40; however, there are some instances where it can occur in children. You’ll find that TTP is more common in women, with twice as many cases as men. If left untreated, TTP can be extremely serious with a death rate of 90%. However, with proper treatment, this rate drops significantly to between 10% and 15%. It is rarely seen in kids. Some factors increasing the likelihood of TTP include being female, of African American descent, or pregnant.

• TTP is a rare disease, with cases varying from 1 to 13 per million people depending on location.
• It typically occurs in those over 40, but can also be present in children.
• Women are more likely to have TTP, with twice as many cases compared to men.
• Without treatment, the death rate from TTP is 90%. With proper treatment, this drops to 10% to 15%.
• TTP is very rare in children.
• Being female, of African American descent, or being pregnant increases the risk of TTP.

Signs and Symptoms of Thrombotic Thrombocytopenic Purpura

TTP, or Thrombotic Thrombocytopenic Purpura, is a medical condition that typically affects the nervous system more than the kidneys. This could cause symptoms like headaches, seizures, confusion, and dizziness. Some people may initially feel fatigued, have trouble breathing, develop small red or purple spots on the skin (petechiae), or experience some bleeding. Interestingly, neurological issues are most frequently reported by those with TTP, and abdominal pain is also a common symptom. It’s less common for patients to report bleeding as a symptom due to low platelet count. Although rare, TTP can affect the kidneys and the lungs, but this is usually only identified through biopsy. There are some cases where TTP affects the heart, indicated by high serum troponin levels, which can suggest a poor outcome. This diverse range of signs and symptoms often vary in severity, making TTP hard to diagnose without a high degree of clinical suspicion. Let’s consider findings from the Oklahoma Registry, a highly referred study which defines symptoms of TTP:

• Gastrointestinal symptoms (69% of cases)
• Weakness (63% of cases)
• Bleeding or purple spots (purpura) (54% of cases)
• Major neurological problems like coma, stroke, seizure, temporary focal abnormalities (41% of cases)
• Minor neurological problems like headache, confusion (26% of cases)
• Fever and chills (10% of cases)
• Classical pentad, a combination of hemolytic anemia, low platelet count, fever, acute kidney injury, and severe neurological signs (less than 5% of cases)

Testing for Thrombotic Thrombocytopenic Purpura

To diagnose a condition called TTP (Thrombotic thrombocytopenic purpura), doctors rely heavily on laboratory tests since symptoms can vary greatly and damage to organs can sometimes be delayed. For a diagnosis, lab results must show low red blood cells (anemia) and low platelets (thrombocytopenia), signs of high-rate red blood cell breakdown (known as hemolysis), which include the presence of misshapen/red blood cells (schistocytes), increased unconjugated bilirubin (a waste product from red blood cell breakdown), increased reticulocyte (new red blood cell) count and increased lactate dehydrogenase (an enzyme found in red blood cells). Additionally, a protein in blood called haptoglobin (which binds free hemoglobin released from destroying red blood cells) may be decreased.

The doctor uses a scoring system called the PLASMIC score to predict the likelihood of TTP. This score is based on several factors present at examination time including platelet count, signs of hemolysis, size of red blood cells (MCV), the extent of blood clotting (INR), kidney function (creatinine), cancer status, and history of organ transplant or stem cell transplant. Each feature contributes one point to the score. The higher the score, the greater the chance of having TTP. If the score is over 5, there is a high likelihood of TTP and a low likelihood of TTP if the score is less than 5.

Additionally, doctors use a test called the ADAMTS13 activity assay, which measures a protein that helps regulate clotting in your blood. A level of less than 10% on this test confirms TTP diagnosis in patients who have signs of hemolysis and reduced platelet count. But this test is not just limited to TTP, as levels less than 10% have also been found in severe sepsis and systemic cancer conditions. A decrease in the ADAMTS13 activity to less than 20% after initial recovery from an acute episode is seen as a relapse, even if there is normal platelet count and no signs of hemolysis.

To assess the damage to organs, doctors check the levels of a protein called troponin in the blood (high levels usually indicate heart damage) and conduct a brain MRI (Magnetic Resonance Imaging) scan. MRI uses magnetic field and radio waves to create detailed images of the body.

Treatment Options for Thrombotic Thrombocytopenic Purpura

The main treatment for a condition known as thrombotic thrombocytopenic purpura (TTP) involves a process called plasma exchange, which basically swaps out the patient’s blood plasma with healthy plasma, and strong anti-inflammatory medications known as corticosteroids. Corticosteroids help suppress the immune system and reduce inflammation, which benefits patients with TTP by decreasing the overactivity of the body’s natural defense system and reducing the production of harmful antibodies. If a patient has symptoms of unexplained anemia (low blood count) and low platelets along with normal clotting function, doctors usually begin this treatment as quickly as possible.

The plasma exchange therapy works by effectively removing harmful substances from the bloodstream like ultra-large versions of a blood-clotting protein called von Willebrand factor (VWF) and autoantibodies against ADAMTS13, a protein that’s supposed to chop up VWF. When corticosteroids and plasma exchange treatment don’t seem to be working well enough, doctors may consider other treatments like surgically removing the spleen, or using certain drugs like cyclosporine, cyclophosphamide, vincristine, and rituximab which work in different ways to suppress the immune system.

Rituximab, a type of drug known as a monoclonal antibody, has shown promise in treating TTP that doesn’t respond to plasma exchange. It specifically targets B cells, a type of immune cell, and has a good response rate for stubborn and recurring TTP. Other mentioned drugs are less effective and are typically employed as a last resort when primary treatments have failed or in combination with secondary therapeutic strategies in challenging cases.

A newer drug, named caplacizumab, also a monoclonal antibody, suppresses the abnormal activity of the VWF protein and has shown promise in the treatment of TTP. Not only does it work more quickly than other drugs, but it has also been associated with a significant decrease in deaths. However, caplacizumab alone does not suppress the overactive immune response that produces harmful ADAMTS13 antibodies. This drug is given as an initial dose via a vein and then under the skin for about a month after stopping plasma exchange. Despite its benefits, caplacizumab can increase the risk of bleeding, which may need a halt or adjustment in therapy.

Administering plasma without exchange is not an effective treatment for TTP but can be used as a temporary measure if plasma exchange isn’t immediately available. If the patient’s red blood cell count is low, a blood transfusion can be given if necessary. The use of platelet transfusion is controversial and is usually avoided unless severe, life-threatening bleeding is present. Close monitoring of response to treatment is crucial in managing TTP, typically achieved by checking markers of red blood cell destruction daily. Plasma exchange is usually stopped once the number of platelets in the blood remain stable for more than two days.

In 2020, the International Society on Thrombosis and Hemostasis issued several guidelines for the treatment of TTP. Strongly recommending corticosteroids and plasma exchange as primary treatment, adding rituximab for patients experiencing their first acute episode of TTP. For those with recurring TTP, the guidelines suggest using rituximab as a preventative measure, especially when other autoimmune disorders are present. For patients in remission but with still low levels of the ADAMTS13 protein, trusted interventions include corticosteroids, plasma exchange, rituximab, and caplacizumab. The guidelines also suggest using plasma infusion products to prevent disease in pregnant patients with low ADAMTS13 but no active symptoms of TTP.

What else can Thrombotic Thrombocytopenic Purpura be?

The various possible triggers for a specific blood disorder called Thrombotic Thrombocytopenic Purpura (TTP) include:

• Cancer-related TTP, frequently seen with stomach, breast, and prostate cancers
• Disseminated intravascular coagulation, another blood clotting condition, which differs from TTP in lab tests
• TTP triggered by a bone marrow transplant, resulting from the transplant process itself or complications like organ rejection and infections
• Ordinary conditions like severe high blood pressure, pregnancy-related complications, autoimmune diseases like Lupus, and blood vessel diseases like scleroderma which can sometimes lead to TTP
• An immune system issue that results in low platelet counts
• TTP that is linked to infections like CMV, Streptococcus pneumonia, and HIV
• TTP caused by medications, which can include chemotherapy drugs, antibiotics, and heart medications, particularly clopidogrel

How clopidogrel leads to TTP is not fully understood. But, patient data indicates the drug seems to injure blood vessel linings, which then leads to TTP. While it is rare, occurring in about one in 20,000 patients taking this medication, it tends to happen within the first two weeks of starting the drug. Skin reactions may be the first sign of this serious side effect. Stopping the medication alone doesn’t stop TTP and patients usually require a blood treatment called plasma exchange along with steroids. Additional treatment with a drug named rituximab is considered if needed. With prompt plasma exchange treatment, nearly all patients survive. But, if the diagnosis and treatment are delayed, survival rates drop to about 27%.

What to expect with Thrombotic Thrombocytopenic Purpura

If left untreated, thrombotic thrombocytopenic purpura, a rare blood condition, can be fatal in 90% of cases. But if treated early on, specifically with methods like plasma exchange and corticosteroids, the death rate can decrease to 15%. The longer a person waits to get treatment, the higher the chance they may experience serious health complications.

Quickly recognizing the symptoms of the disease and starting treatment with plasma exchange and corticosteroids can greatly decrease the chance of death. The main reason people may die from this condition involves the formation of blood clots in the coronary arteries, which can lead to a heart attack, heart failure, and even sudden death.

Possible Complications When Diagnosed with Thrombotic Thrombocytopenic Purpura

If plasma exchange is not immediately possible, plasma infusion can be used as an alternative. Plasma infusion, while effective, might lead to issues like congestive heart failure. However, once a plasma exchange is established, such problems can be managed and often reversed.

There are certain risks associated with plasma exchange (PEX). These are primarily connected to the positioning of the central venous catheter and exposure to donor plasma. Transfusion-related acute lung injury (TRALI) is one such risk that can arise. Another study found that about 4.4% of patients with a condition known as TTP died due to complications arising from PEX. These complications included serious conditions like lung bleeding and infections related to the central venous catheter.

Some other potential complications that were less severe, but still significant, included bloodstream infections, blood clot formation related to the catheter that necessitated systemic anticoagulation (blood-thinning) treatment, and severe allergic reactions. However, the study went on to state that incidences of complications associated with plasma exchange have noticeably reduced over a period of 15 years. This decrease has been attributed to the use of combined treatment methods that reduce the necessary frequency and duration of plasma exchange treatments.

Common Side Effects:

• Congestive heart failure with rigorous plasma infusion
• Risks associated with venous catheter placement
• Exposure to donor plasma
• Transfusion-related acute lung injury (TRALI)
• Death due to complications in about 4.4% of the patients
• Severe conditions like lung bleeding and cord-related infections
• Bloodstream infections
• Blood clot formation related to the catheter
• Severe allergic reactions.

Preventing Thrombotic Thrombocytopenic Purpura

The amount of time that a patient may need to spend in rehabilitation is often determined by the severity of their organ damage and any lasting symptoms. It’s crucial for patients to be aware and check if the signs and symptoms of their condition called thrombotic thrombocytopenic purpura, a rare blood disorder, return. Once the treatment involving plasma exchange (a process where plasma in the patient’s blood is replaced with new plasma or a plasma substitute) and corticosteroids (drugs that reduce inflammation) is reduced, it’s important to regularly monitor their laboratory tests.

It’s possible for the condition to come back quickly, if it does at all. In such a situation, there are preventative treatments available. Drugs such as rituximab can be used in certain patients (as outlined above), and caplacizumab, another drug, can be used as a preventative measure.