Last updated:
2/20/2025
Years published: 1989, 1991, 1996, 1998, 1999, 2000, 2006, 2007, 2017, 2021, 2025
NORD gratefully acknowledges Answering T.T.P. (Thrombotic Thrombocytopenic Purpura) Foundation and Spero Cataland, MD, Professor-Clinical, Hematology, Physician, FGP-Hematology, 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. There is an acquired/autoimmune form of the disease referred to as immune mediated TTP (iTTP) and a congenital form of the disease (cTTP). 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, heart and other organs occur because of small clots that form in the smallest arteries. The exact cause of TTP is unknown.
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 have 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. Even though the platelets are typically very low in people with TTP, the real danger of the disease results from the widespread clotting seen throughout the body and less commonly from bleeding.
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.
iTTP and cTTP 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.
iTTP may appear later in life, in late childhood or adulthood, and affected individuals are at risk for 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 (congenital form), signs and symptoms will commonly occur in infancy (less than 2 years of age) but can also occur later in life. This is referred to as cTTP. It is not uncommon for females who are born without the ADAMTS13 protease to not have symptoms until their first pregnancy. A congenital deficiency of the ADAMTS13 protease places individuals at risk for an acute TTP episode, but typically a “second hit” or factor is required to trigger an acute episode. This may occur in pregnancy, acute infections, alcohol overuse, or any other clinical events that may increase inflammation or stress on the body.
iTTP can occur because of AIDS, the AIDS-related complex, or the human immunodeficiency virus (HIV) infection or other autoimmune diseases. People 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 are females. This condition usually affects people between 20 to 50 years of age, but people of any age may be affected.
As stated previously, TTP (iTTP and cTTP) 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 untreated human immunodeficiency virus (HIV) infection.
Rapid diagnosis and immediate treatment are 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 clinical diagnosis is confirmed by the finding of severely deficient (<10%) ADAMTS13 activity and the presence of an anti-ADAMTS13 antibody in patients with iTTP. People with cTTP will present similarly with very low ADAMTS13 activity, but without evidence of an ADAMTS13 antibody inhibitor.
The diagnosis of cTTP is confirmed by genetic testing for variants in the ADAMTS13 gene.
Treatment
In many affected people, 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 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 caplacizumab-yhdp (Cablivi) as the first therapy specifically indicated, in combination with plasma exchange and immunosuppressive therapy, for the treatment of adults with acquired TTP. Cablivi is the first targeted treatment that inhibits the formation of blood clots.
In 2023, the FDA approved an enzyme replacement therapy called Adzynma to prevent and treat episodes of cTTP.
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 (plasma exchange) is not effective, treatment may involve additional immune suppressive therapy-type treatments. Caplacizumab has been shown to decrease the early recurrences of iTTP after stopping plasma exchange (exacerbations of iTTP) and decrease the risk for refractory iTTP. Ongoing studies are presently underway to study the safety of treating iTTP with either caplacizumab or recombinant ADAMTS13 alone without plasma exchange. While splenectomy may have a role in the prevention of future TTP episodes it is generally not thought to be effective or safe in people with 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:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Völker LA, Kaufeld J, Balduin G, et al. Impact of first-line use of caplacizumab on treatment outcomes in immune thrombotic thrombocytopenic purpura. J Thromb Haemost. 2023;21(3):559-572. doi:10.1016/j.jtha.2022.11.010
Izquierdo CP, Mingot-Castellano ME, Fuentes AEK, et al. Real-world effectiveness of caplacizumab vs the standard of care in immune thrombotic thrombocytopenic purpura. Blood Adv. 2022;6(24):6219-6227. doi:10.1182/bloodadvances.2022008028
Coppo P, Bubenheim M, Azoulay E, et al. A regimen with caplacizumab, immunosuppression, and plasma exchange prevents unfavorable outcomes in immune-mediated TTP. Blood. 2021;137(6):733-742. doi:10.1182/blood.2020008021
Dutt T, Shaw RJ, Stubbs M, et al. Real-world experience with caplacizumab in the management of acute TTP. Blood. 2021;137(13):1731-1740. doi:10.1182/blood.2020007599
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.
Kappers-Klunne MC, Wijermans P, Fijnheer R, Croockewit AJ, van der Holt B, de Wolf JT, Löwenberg B, Brand A. Splenectomy for the treatment of thrombotic thrombocytopenic purpura. Br J Haematol.. 2005 Sep;130(5):768-76. doi: 10.1111/j.1365-2141.2005.05681.x.
Bennett CL, et al. Thrombotic thrombocytopenia purpura associated with clopidogrel. N Engl J Med. 2000;342:1773-77.
Pogliani EM, et al. Defibrotide in recurrent thrombotic thrombocytopenia purpura. Clin Appl Thromb Hemost. 2000;6:69-70.
Rock G, et al. Thrombotic thrombocytopenia purpura treatment in year 2000. Haematolgica. 2000;85:410-19.
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.
INTERNET
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No: 274150. Last update: 05/20/2024. Available at: https://www.omim.org/entry/274150?search=274150&highlight=274150 Accessed Feb 5, 2025.
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