Thrombotic thrombocytopenic purpura (TTP)

Thrombotic thrombocytopenia purpura (TTP) is a rare, serious blood disease. Major symptoms may include a severe decrease in the number of blood platelets (thrombocytopenia), abnormal destruction of red blood cells (hemolytic anemia), and disturbances in the nervous system and other organs occur as a result of small clots that form in the smallest arteries. The exact cause of thrombotic thrombocytopenic purpura is unknown.

The thrombocytopenia and hemolytic anemia are a result of these small clots in the blood vessels of many organs, potentially blocking the normal flow of blood through the vessels. Disturbances affecting the nervous system may include headaches, mental changes, confusion, speech abnormalities, slight or partial paralysis (paresis), seizures, or coma.

Fever, blood plasma proteins in the urine (proteinuria), and a very small number of red blood cells in the urine (hematuria) may also occur. Affected individuals also exhibit red rash-like areas of skin or patches of purplish discoloration (purpura) resulting from abnormal bleeding into the mucous membranes (the thin, moist layer lining the body’s cavities) and into the skin. Additional features of TTP can include abnormally heavy bleeding (hemorrhaging), weakness, fatigue, lack of color (pallor), and abdominal pain with nausea and vomiting. In half of individuals with TTP, increased levels of a chemical compound known as creatinine is found in the blood serum.

Acute renal failure requiring kidney dialysis occurs in only about 10 percent of individuals with TTP. Urine flow is often lower than normal. Within days, swelling of the feet, shortness of breath, headache, and fever may occur. Retention of water and salt in the blood may lead to high blood pressure, changes in brain metabolism, and congestion in the heart and lungs. Acute renal failure may lead to a buildup (accumulation) of potassium in the blood (hyperkalemia), which may cause irregular heartbeat.

TTP can develop during pregnancy and there may be serious complications during pregnancy in females with TTP. In general, TTP often occurs suddenly with great severity and may recur or persist.

The exact cause of TTP is not known. However, the disease is associated with a deficiency of an enzyme involved in blood clotting called the von Willebrand factor cleaving protease (also called ADAMTS13). The deficiency of this enzyme allows large complexes of the clotting protein known as von Willebrand factor to circulate in the blood, resulting in platelet clotting and the destruction of red blood cells.

It is believed that there is an acquired (non-inherited) form of TTP and a familial form. The acquired form may appear later in life, in late childhood or adulthood, and affected individuals may have a single episode or recurring episodes. This is referred to as immune mediated TTP.

If the disorder is present at birth (familial form), signs and symptoms may typically appear earlier, in infancy or early childhood. This is referred to as congenital TTP.

The acquired form may involve an autoimmune reaction. Autoimmune disorders are caused when the body’s natural defenses against “foreign” or invading organisms (e.g., antibodies) begin to attack healthy tissue for unknown reasons.

TTP can occur as a consequence of AIDS, the AIDS-related complex, or the human immunodeficiency virus (HIV) infection.

The current rate of occurrence for TTP is about 3.7 cases per million people each year. One estimate places the overall incidence rate at four of 100,000 individuals. Two-thirds of individuals with TTP are women. It usually affects people between 20 to 50 years old.

TTP is occasionally associated with pregnancy and collagen-vascular diseases (a group of diseases affecting connective tissue).

TTP appears to occur more frequently than usual in those who have human immunodeficiency virus (HIV) infection.

Rapid diagnosis and immediate treatment is very important in TTP. A diagnosis may be made based upon a thorough clinical evaluation, a detailed patient history, and identification of characteristic findings.

In many cases, plasmapheresis, or plasma exchange, is used to remove the antibodies that inhibit the ADAMTS13 protease and also add back the functional ADAMTS13 protein. In this process, blood is removed by a machine from the affected individual, blood cells are separated from plasma, the patient’s plasma is replaced with healthy plasma, and the blood is then returned to the patient by the machine. Patients are also routinely given steroids to inhibit the production of the anti-ADAMTS13 antibodies.

The blood product SD plasma (VIPLAS/SD) has been approved by the Food and Drug Administration (FDA) for the treatment of TTP.

In 2019, the FDA approved Cablivi (caplacizumab-yhdp) as the first therapy specifically indicated, in combination with plasma exchange and immunosuppressive therapy, for the treatment of adult patients with acquired TTP. Cablivi is the first targeted treatment that inhibits the formation of blood clots.

Genetic counseling may be of benefit for affected individuals and their families when congenital TTP has affected other family members. Other treatment is symptomatic and supportive.

When the standard treatment approach (in this case, plasma exchange) is not effective (refractory cases), treatment may involve chemotherapy or immune suppressive therapy-type treatments.

For cases when other treatments have been tried and not been effective, removing the spleen (splenectomy) may be considered. The safety and effectiveness of this treatment approach for individuals with TTP continues to be evaluated.