Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening blood disorder in which the blood cells that play a key role in blood clotting (platelets) are rapidly consumed by excessive clotting. In medical terms, "thrombotic" means the tendency to form blood clots, "thrombobytopenic" means a low count of platelets, and "purpura" describes skin discolorations caused by a bleeding condition. Thus, TTP is a state of reduced platelets caused by the formation of blood clots that can result in skin discoloration.
At one time, TTP was almost always fatal. More than 90 percent of patients who suffered from the condition died. However, due to new treatment techniques, more than 90 percent of people who suffer from TPP now survive. The standard treatment for TTP is called plasma exchange. In this procedure, plasma transfusions are coupled with removal of the platelets from the blood. After several days of this treatment, signs and symptoms should improve.
About TTP
Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening blood disorder in which the blood cells that play a key role in blood clotting (platelets) are rapidly consumed by excessive clotting. These blood clots can form throughout the body, resulting in the symptoms associated with TPP. They are most common, however, in the kidney and brain. The condition got its name from the following:
Thrombotic refers to blood clots (thrombi). The formation of many blood clots throughout the body consumes the body’s supply of platelets and can cause widespread damage to many organs.
Thrombocytopenic refers to a reduced number of platelets, otherwise known as thrombocytes.
Purpura refers to the typical bleeding that occurs with this condition, especially in the mucous membranes or beneath the skin, often producing bruises or a rash-like appearance. A similar disorder that affects children is called hemolytic-uremic syndrome.
People may become very ill with this disease and kidney abnormalities may develop. If left untreated, the disorder is almost always fatal. With treatment, up to 90 percent of TTP patients survive. Symptoms associated with TPP may occur suddenly (e.g., acute onset), but the disease course is generally weeks or months.
Only about four out of every 100,000 people develop TTP. It is seen most often in adults from 20 to 50 years old. The condition is slightly more common in women. A related condition called hemolytic uremic syndrome (HUS) is so similar in its symptoms and treatment that many researchers treat TTP as a single condition. HUS is generally more common in children.
Signs and symptoms of TTP
TTP was first recognized as a new condition in 1925. Although there are many symptoms that are associated with TTP, the diseases are generally characterized by a "classic pentad" of five symptoms, including:
Thrombocytopenia
Hemolytic anemia, which is defined as an anemia caused by destruction of red blood cells
Neurological symptoms, including seizures, visual disturbances, confusion and others
Decreased kidney function
Fever, which is not always present
In addition, the following signs may be present:
Bleeding into the skin or mucous membranes (purpura)
Bruising
Petechiae (small purplish hemorrhagic spots on the skin or mucous membrane)
Widespread ecchymoses (skin discolorations due to large irregularly formed areas of bleeding into the skin)
Pallor
Yellowing of the skin (jaundice)
Enlargement of the spleen (splenomegaly)
Abnormal heart rhythm (arrhythmia), such as tachycardia (heart rate over 100 beats per minute) or heart failure
Causes and diagnosis for TTP
The exact cause of TTP is unknown, but a number of underlying factors have been identified. Under normal circumstances, a blood protein known as Von Willebrand factor (VWf) is produced by endothelial cells, which line the insides of arteries. VWf is an important part of the blood-clotting cascade and helps platelets gather at the site of a wound. Typically, VWf is released into the blood stream in large structures known as "unusually large von Willebrand factor." Once in the blood, these large structures are reduced in size by a substance known as ADAMTS13. Among people with TTP, however, there is a deficiency in ADAMTS13, meaning that these large VWf structures stay intact. This is thought to encourage inappropriate blood clotting when these structures attach to blood platelets.
While this appears to be a leading factor in TTP, there are several other mechanisms that have been identified. Many patients with TPP have high levels of an autoantibody to ADAMTS13. This means that the immune system has identified ADAMTS13 as a foreign invader and is attacking and destroying it. This finding is especially common among people with TTP due to unknown causes, or idiopathic TTP. In these cases, TTP may be an autoimmune disease in which the body mistakenly identifies normal cells (e.g., ADAMTS13) as invaders and attacks and destroys them.
Additional theories that may explain TTP include endothelial injury, possibly caused by a drug, which causes platelet aggregation, and the shiga toxin, which is released during infection with the E. coli and other bacteria.
Whatever the underlying cause, there are certain populations that seem more vulnerable to TTP. Among women, it may be triggered by pregnancy or by the use of estrogen (e.g., birth control pills). TTP has also been associated with HIV (the virus that causes AIDS), as well as toxins associated with spider and bee venoms (in rare cases). In rare cases, TPP occurs after cardiovascular surgery, especially coronary artery surgery.
There are also several drugs that have been linked to TTP. These include:
Certain anticoagulants, including ticlopidine and, to a lesser extent, clopidogrel. Ticlopidine was commonly prescribed for people who just had a heart attack, stroke, mini-stroke, balloon angioplasty or stenting procedure. Although designed to help prevent the formation of blood clots, ticlopidine was linked in a number of studies done on people who developed TTP within a month after beginning ticlopidine therapy. It is estimated that TTP developed in between one out of every 1,600 patients and one out of every 4,800 who took ticlopidine. In response to the higher risk of TTP, clopidogrel has been developed. Although it appears to be safer than ticlopidine, researchers have still found a link between taking clopidogrel and the development of TTP in a small number of people.
Quinine. This over-the-counter medication is used to treat muscle cramps and is the most common cause of drug-induced TTP.
Cancer-fighting chemotherapy drugs. TTP has been associated with four chemotherapy regimens: mitomycin C, cisplatin, gemcitabine, and the use of radiation and high-dose chemotherapy prior to bone marrow cell transplantation.
Cyclosporine. This medication is designed to suppress the immune system. It is throught to cause TPP through direct endothelial injury and enhanced platelet aggregation. In most cases, the TTP will resolve if the medication is discontinued.
The diagnosis begins with the physician taking the patient’s complete medical history and then giving the patient a physical examination. The physician will also run blood tests to determine if there has been a reduction of platelets in the blood. The majority of patients will show this reduction of platelets, neurological changes (e.g., confusion) and anemia (a low red blood cell count).
Treatment and prevention of TTP
The treatment of TTP depends on the possible causes. Among children who suffer from TTP after bloody diarrhea, the condition often resolves itself. Similarly, if the TTP was provoked by certain drugs, such as anti-cancer drugs, the first line of treatment is to discontinue the medication.
Among adults with idiopathic TTP, or TTP that cannot be linked to any single cause, the treatment consists of plasma exchange, which involves infusion of fresh plasma coupled with a procedure that removes platelets (plasmapheresis). Steroid drugs are often included in the treatment regimen. This treatment is extremely successful. Prior to the availability of plasma treatment, up to 90 percent of adult patients with TTP died. Today, this figure is reversed: 90 percent of adult TTP patients can be successfully treated with plasma exchange.
During plasma exchange, the patient’s blood is withdrawn in a process similar to a blood donation. The plasma (the fluid part of blood without the blood cells) is then passed through a cell separator to remove the large VWf structures and autoantibodies. The remaining portion of the concentrated plasma is saved, reconstituted to normal volume with a plasma substitute and returned to the patient as a blood transfusion. According to studies, side effects occur with this treatment in as many as 60 percent of patients. Of the major side effects, most are due to the use of a central venous catheter during the blood withdrawal. They include infections, hemorrhage and venous blood clots.
If no side effects are present, this treatment is repeated daily until blood tests show improvement, usually for 7 to 16 days. It is estimated, however, that between 10 and 20 percent of patients do not respond to this initial treatment. These patients are frequently recommended for more intensive plasma exchange therapy, sometimes undergoing two exchanges a day. If that doesn’t work, physicians may add certain medications to the plasma, which have been shown to aid therapy. Once a normal platelet count has been reached, treatment generally tapers off until a lasting remission is achieved.
As a final resort, removal of the spleen (splenectomy) may be recommended. Although there are some conflicting studies, removal of the spleen has been shown to improve the condition among some patients. With modern plasma exchange techniques, the improved outcomes for this disease have increased, so that 80 to 90 percent of patients now go on to complete recovery. Some fatalities still occur, however, and patients who have had the disorder should be monitored with blood tests and physical examinations for several years. Unfortunately, it is not uncommon for TTP patients to have sudden relapses that require another round of plasma exchange. In fact, some patients may need to deal with these recurrences throughout life.
Since the exact cause of TTP is unknown, there is no known way to prevent the disease. However, there are drugs and toxins (poisons) that are suspected in causing some cases of TTP. They include:
Specific anticoagulants (medications that inhibit blood clotting)
Specific chemotherapy drugs used in treating non–malignant tumors
Specific birth control pills
Quinine
At the present time, research is underway to study and define the connection between TTP and these substances.
Questions for your doctor
Preparing questions in advance can help patients to have more meaningful discussions with their physicians regarding their conditions. Patients may wish to ask their doctor the following questions related to thrombotic thrombocytopenic purpura:
A member of my family had thrombotic thrombocytopenic purpura, am I at increased risk?
Could this condition be caused by one of the medications I am taking?
What types of tests do you recommend I take to diagnose this condition?
How urgently do I need to undergo treatment for this condition?
Do I need to undergo a plasma exchange to treat this condition? What are the chances of successfully treating my condition with a plasma exchange?
If a plasma exchange fails to cure my condition, what additional treatment would you recommend?
If my condition is successfully treated with a plasma exchange, will I need any further treatment? Will I need to regularly visit a doctor? How often?
Could I have a relapse of this condition later on in life?
Do you expect this condition to damage my kidneys in any way?
Could thrombotic thrombocytopenic purpura complicate my existing heart condition in any way?
