Thrombotic Thrombocytopenic Purpura (TTP)

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TTP stands for Thrombotic Thrombocytopenic Purpura. This is a life-threatening disorder affecting red blood cells, platelets (also known as thrombocytes), and the endothelial cells lining blood vessels. The key pathogenic feature of TTP is the formation of platelet aggregates within the microcirculation. The main clinical signs are thrombocytopenia, haemolytic anaemia, renal dysfunction, neurological signs, and fever. Modern treatments such as the infusion of freshly-frozen plasma can greatly reduce the risk of mortality from this disease. The underlying cause has been shown to be mutations in a gene that normally codes for an enzyme that acts on protein aggregates in the blood known as the von Willebrand factor.

Questions Received:

  1. Family member diagnosed with blood disease TTP. Can you give me any information on this? Currrently undergoing plasma exchange over a period of several days.

  2. My sister was diagnosed with TTP in May 1999. She responded quite well to the plasma pheresis. Unfortunately, she again became symptomatic this past month, in January. Again, she went through the same process. It had to be done at a different hospital. Her platelet count is back up to 241 now and things seem to be going well again. She had some questions that she wanted answered. Unfortunately, we cannot seem to find much information on this disease at all. Here are some questions for you. Please answer what you can - I appreciate it so very much.

Responses:

Family member diagnosed with blood disease TTP. Can you give me any information on this? Currrently undergoing plasma exchange over a period of several days.

15th May 1999; updated 4/10/2001

Thrombotic thrombocytopenic purpura (TTP) is quite rare. It affects many systems of the body. The main feature of TTP is the formation of clumps of platelets (also known as thrombocytes) within the smaller blood vessels. (Platelets are formed in the bone marrow as tiny fragments of large cells called megakaryocytes, and play an important role in normal blood clotting.) In TTP there seems to be an abnormal interaction between the lining of blood vessels and the platelets which leads to the formation of tiny blood clots (thrombosis) and proliferation of the cells forming the blood vessel walls. Patches of purplish discolouration appear because of damage to the vessels and the blood within them, hence the inclusion of ‘purpura’ in the name. These changes occur with only minimal inflammation but they are serious because they result in hemolytic anaemia (the red blood cells disintegrate), neurological symptoms, renal disease, and fever. TTP can occur in any age group but is most often seen in patients 30 to 50 years of age. Several factors seem to predispose towards the development of TTP, including infections, drugs, menses, pregnancy, autoimmune diseases, cancer, and bone marrow transplantation.

Until recently, the primary cause of TTP was unknown. Research suggested that the damage to the lining of blood vessels was triggered by plasma factor(s) that lead to the release of an abnormal von Willebrand factor which then causes platelet aggregation (Eldor, 1998). There was evidence that the condition was an autoimmune disease in which the immune system turned against normal cells and molecules within the body. However, it was considered to be premature to classify TTP as an autoimmune disease (Porta, Caporali, and Montecucco, 1999). The most recent research has shown that mutations in a member of the ADAMTS gene family on chromosome 9 is probably the underlying genetic cause of TTP (Levy et al, 2001). The gene ADAMTS13 codes for an enzyme that has the normal function of cleaving the aggregates of von Willebrand factor proteins, and in this way modulating the delicate interrelationships between platelets and blood vessel linings.

TTP has been treated with plasma exchange since the 1960s, and the outlook now is much improved. A variety of supportive treatments have been tried in combination with plasma exchange, for example: corticosteroids, vincristine, aspirin, and dipyridamole (Brailey, Brecher, and Bandarenko, 1999; Creager, Brecher, and Bandarenko, 1998). Cure is possible, although approximately half the patients will relapse after a disease-free period. Removal of the spleen seems to be helpful for people with relapsing TTP (Veltman et al, 1995). The recent identification of the genetic cause of TTP by Levy et al (2001) has opened the possibilities of specific enzyme replacement therapy and gene therapy in the future.

References

My sister was diagnosed with TTP in May 1999. She responded quite well to the plasma pheresis. Unfortunately, she again became symptomatic this past month, in January. Again, she went through the same process. It had to be done at a different hospital. Her platelet count is back up to 241 now and things seem to be going well again. She had some questions that she wanted answered. Unfortunately, we cannot seem to find much information on this disease at all. Here are some questions for you. Please answer what you can - I appreciate it so very much.

17th February 2000; updated 4th October 2001

Has there ever been any books published on this disease?

There is a medical textbook published in 1992 called "Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura" edited by B.S. Kaplan, R.S. Trompeter, and J.L. Moake. It is published by Marcel Dekker (ISBN: 0824786637). It is expensive, so it might be best to borrow it from a library. Alternatively, consult an up-to-date review published in a medical journal rather than a book - books tend to be somewhat out-of-date by the time they are published. For example, see the review by Eldor, A. (1998) Thrombotic thrombocytopenic purpura: diagnosis, pathogenesis and modern therapy. It is in the journal Baillières Clinical Haematology, volume 11(part 2), pages 475-495 (published in June 1998). Another good review can be found in Brailey, L.L., Brecher, M.E., and Bandarenko, N. (1999) Apheresis and the thrombotic thrombocytopenic purpura syndrome: current advances in diagnosis, pathophysiology, and management. Therapeutic Apheresis, 3(1), 20-24 (Feb). You will find medical journals like these at a medical or university library, or they might be obtainable on loan or as a photocopy via your normal library. Everyone is looking forward to the day - apparently not too far away now - when full-text journal publications are readily available online.

Where can I get more info?

If you have access to the Internet, try searching with the various search engines such as AltaVista, Yahoo, or Infoseek - there is a lot of useful information out there. When you type in the keywords thrombotic thrombocytopenic purpura, enclose them in quotation marks like this "thrombotic thrombocytopenic purpura" so that they are searched for as a unit and not individually. If you would like to join an online discussion group about blood disorders, you might find the bulletin board at www.bloodnet.org useful.

To access a vast (free!) collection of research abstracts on TTP and other medical topics, visit PubMed at www.ncbi.nlm.nih.gov/PubMed/ and carry out searches there. Experiment with the keywords you put in and the order in which you put them until you begin to find what you want, and add the word ‘review’ at the end of them in order to select the more comprehensive publications. When you find a publication that matches what you want, click on the ‘Related publications’ option to display a list of other papers on the same topic. You can then download the abstracts, save them as a text file to disc, and study them offline in a word-processing program.

When and where was the TTP disease actually researched and treatments tested?

Thrombotic thrombocytopenic purpura (TTP) was originally described in 1924 (Elkins et al, 1996). Research has been ongoing in many centres and in many countries and a great advance in treatment was made about 30 years ago with the introduction of plasma therapy - infusions or exchange transfusions of plasma or plasma-cryosupernatant have become the main treatments for TTP along with corticosteroids, platelet inhibitor drugs, vincristine and splenectomy (Eldor, 1998; Brailey, Brecher, and Bandarenko, 1999). In most cases remissions can be attained, and cures are now common - although approximately one-half of the patients will relapse. Mortality from this disease has fallen sharply in recent years.

First treatment was strictly fresh frozen plasma; second round involved the plasma in addition to albumin. Why use the albumin?

We are not familiar with the addition of albumin, although the difference here may be in the use of whole plasma rather than plasma-cryosupernatant. Another form of blood protein called immunoglobulin is sometimes administered during plasma exchange (eg: Debourdeau et al, 1999).

How rare is TTP?

Thrombotic thrombocytopenic purpura occurs in approximately one person in a million (Elkins et al, 1996).

Is it more prevalent in certain environmental areas?

Being so rare, it will be extremely difficult to detect regional patterns in the occurrence of TTP. Several environmental factors are known to increase the risk of TTP, however. For example, food contaminated with the micro-organism Escherichia coli O157 is linked with TTP (Koutkia, Mylonakis, and Flanigan, 1997; Dundas et al, 1999; Vernozy-Rozand, 1999), and people infected with HIV are also at greater risk (de Man et al, 1997; Sutor, Schmidt, and Albrecht, 1999). Other predisposing conditions include pregnancy, cancer, bone marrow transplantation, connective tissue disease, and certain drugs such as mitomycin, metronidazole, oral contraceptives, cyclosporine, and ticlopidine - a platelet anti-aggregation factor (Muszkat et al, 1998; Chen, Kim, and Sutton, 1999).

Any clues as to what activates it?

The most likely explanation is mutations in the ADAMTS13 gene (Levy et al, 2001). This gene codes for an enzyme that normally splits aggregated von Willebrand factor in the blood. If the enzyme is not available or is in an inactive form, the delicate interactions between platelets, and between platelets and the endothelial cells lining the walls of blood vessels are disturbed. This alters the balance between clotting and bleeding, and results in the formation of small clots in a variety of body organs (Furlan, 1996; Moake, 1998). Another possibility is an autoimmune response against the enzyme, although currently the evidence for this is limited (Moake and Chow, 1998; Musio et al, 1998; Porta, Caporali, and Montecucco, 1999). (An autoimmune disease is one in which the immune system turns against normal substances and tissues in the body, rather than responding only to abnormal materials.)

Spleen removal - is this inevitable if it keeps reoccurring? How risky is this surgery? Will this completely take care of the TTP?

Splenectomy is effective for some people in whom TTP relapses. It is not clear how the treatment works, although of course the spleen is intimately linked with the immune system and monitors the quality of circulating red blood cells. Use of the procedure is still under discussion (Debourdeau et al, 1999). As with any major surgery there will be risks - discuss these carefully with the medical team looking after your sister.

Is there ever any permanent damage done to your body? (Heart valves, etc.)

Yes, there is the potential for permanent tissue damage, although this is usually at a low level and does not express itself in clinical signs and symptoms (Podolsky et al, 1999).

References

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