February 24, 2021
Years published: 1989, 1991, 1996, 1998, 1999, 2000, 2006, 2007, 2017, 2021
NORD gratefully acknowledges Answering T.T.P. (Thrombotic Thrombocytopenic Purpura) Foundation and Spero Cataland, MD, Professor-Clinical, Hematology, Physician, FGP-Hematology, Associate Professor of Internal Medicine, The Ohio State University, for assistance in the preparation of this report.
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 TTP 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 that can be a sign of low platelets. 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 are found in the blood.
Acute renal failure requiring kidney dialysis occurs in only about 10 percent of individuals with TTP. 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 in future pregnancies.
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.
There is an acquired (non-inherited) form of TTP referred to as immune-mediated TTP (iTTP) and a familial form referred to as congenital TTP (cTTP). iTTP may appear later in life, in late childhood or adulthood, and affected individuals may have a single episode or recurring episodes. This form or TTP is considered to be an autoimmune disease and is caused when patients develop an antibody against the ADAMTS13 protease leading to low levels of the protease.
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 cTTP. Women with cTTP may also present with an acute TTP episode for the first time at the time of their first pregnancy.
iTTP can occur as a consequence of AIDS, the AIDS-related complex, or the human immunodeficiency virus (HIV) infection or other autoimmune diseases. Patients with iTTP may also be diagnosed in the future with other autoimmune diseases as well.
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 iTTP cases are women. It usually affects people between 20 to 50 years of age but people of any age may be affected.
TTP is occasionally associated with pregnancy and collagen-vascular diseases (a group of diseases affecting connective tissue).
TTP appears to occur more frequently in people who have human immunodeficiency virus (HIV) infection.
Childhood-onset or iTTP often occurs concurrently with systemic lupus erythematosus (SLE). A search of the literature by investigators at the University of Toronto demonstrated that approximately half of the cases of childhood-onset TTP met criteria for “incipient or definite SLE”. The best indicator for the presence or later development of SLE appeared to be excessive serum proteins in the urine (high-grade proteinuria) at the time of diagnosis of TTP. The researchers recommended that physicians rule out concomitant SLE in all children who present with TTP.
Symptoms of the following disorders can be similar to those of thrombotic thrombocytopenia purpura. Comparisons may be useful for a differential diagnosis:
Hemolytic uremic syndrome (STEC HUS) is an uncommon disease that occurs in 5 to 15 percent of individuals, especially children, who are infected by the Escherichia coli (E. coli) bacterium. This organism releases toxins into the gut that are absorbed into the bloodstream and may be transported by white blood cells (leukocytes) to the kidneys. This results in acute renal injury. There may also be damage to the brain with seizures and even coma, the pancreas with pancreatitis and occasionally diabetes mellitus, and other organs. STEC HUS mainly affects young children between one and 10 years. The onset of HUS is preceded by an illness characterized by vomiting, abdominal pain, fever, and, usually, bloody diarrhea. (For more information on this disorder, choose “STEC HUS” as your search term in the Rare Disease Database.)
Immune thrombocytopenic purpura (ITP) is a blood disease with no specific known cause (idiopathic). It is characterized by thrombocytopenia, abnormal bleeding into the skin and mucous membranes and anemia. ITP occurs most frequently in children and young adults, and more frequently in females than males. A viral infection may precede ITP especially in children. (For more information on this disorder, choose “ITP” as your search term in the Rare Disease Database.)
Henoch-Schönlein purpura (HSP) is a rare inflammatory disease of the small blood vessels (capillaries) and is usually a self-limited disease. It is the most common form of childhood vascular inflammation (vasculitis) and results in inflammatory changes in the small blood vessels. The symptoms of HSP usually begin suddenly and may include headache, fever, loss of appetite, cramping, abdominal pain, painful menstruation, hives, bloody diarrhea and joint pain. Red or purple spots typically appear on the skin (petechiae). Inflammatory changes associated with HSP can also develop in the joints, kidneys, digestive system, and, in rare cases, the brain and spinal cord (central nervous system). The exact cause of HSP is not fully understood, although research demonstrates that it is related to an abnormal response by the immune system or, in some rare cases, an extreme allergic reaction to certain substances (e.g., foods or drugs). (For more information on this disorder, choose “Henoch” as your search term in the Rare Disease Database.)
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. The diagnosis is confirmed by the finding of severely deficient (<10%) ADAMTS13 activity and the presence of an anti-ADAMTS13 antibody in patients with iTTP.
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 anti-CD20 antibody rituximab is also used commonly in the treatment of iTTP to also suppress the production of the anti-ADAMTS13 antibodies with an effect that lasts much longer than steroids.
The blood product SD plasma (VIPLAS/SD) has been approved by the U.S. 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 is recommended 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 additional immune suppressive therapy-type treatments. Initial data suggest that caplacizumab may prevent the development of refractory iTTP, but this still must be confirmed with future studies. While splenectomy may have a role in the prevention of future TTP episodes it is generally not thought to be effective or safe in cases of refractory iTTP.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov.
All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website. There are several exciting treatments presently under study to improve both the initial treatment of TTP as well as for patients.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
Scully M, Cataland SR, Peyvandi F, Coppo P, Knöbl P, Kremer Hovinga JA, Metjian A, de la Rubia J, Pavenski K, Callewaert F, Biswas D, De Winter H, Zeldin RK; HERCULES Investigators. Caplacizumab treatment for acquired thrombotic thrombocytopenic purpura. N Engl J Med.. 2019 Jan 24;380(4):335-346.. doi: 10.1056/NEJMoa1806311. Epub 2019 Jan 9.
Scully M, McDonald V, Cavenagh J, Hunt BJ, Longair I, Cohen H, Machin SJ. A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura. Blood. 2011 Aug 18;118(7):1746-53. doi: 10.1182/blood-2011-03-341131. Epub 2011 Jun 2.
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Chemnitz HM, et al. Thrombotic thrombocytopenia purpura (Moschkowitz syndrome) caused by ticlopidine. Med Klin. 2000;95:96-100.
Bruni R, et al. Cascade filtration for TTP: an effective alternative to plasma exchange with cryodepleted plasma. Transfus Sci. 1999;21:193-99.
Haberle J, et al. New strategies in diagnosis and treatment of thrombotic thrombocytopenia purpura: case report and review. Eur J Pediatr. 1999;158:883-87.
Lara PN Jr, et al. Improved survival with plasma exchange in patients with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Am J Med. 1999;107:573-79.
Kupper Y, et al. Tielopidine and thrombotic thrombocytopenic purpura. N Engl J Med. 1997;337:1245.
Fava S, et al. Thrombotic thrombocytopenic purpura-like syndrome in the absence of schistocytes. Br J Haematol. 1995;89:643-44.
Sierakow SJ, et al. Thrombotic thrombocytopenic purpura. A review. Cor Vasa. 1988:30:60-72.
Holdrinet RS, et al. Hormonal dependent thrombotic thrombocytopenic purpura (TTP). Scand J Haematol. 1983:30:250-56.
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No: 274150. Last update: 11/17/2020. Available at: https://www.omim.org/entry/274150?search=274150&highlight=274150 Accessed Feb 23, 2021
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