Blood carries oxygen, immune cells, nutrients such as sugar, amino acids, vitamins to living cells and takes away carbon-dioxide, urea and other waste products. To facilitate the transport of nutrient rich blood, larger organisms have evolved a closed circulatory system where blood is retained within the blood vessels. Injury caused within the blood vessel hinders the normal blood flow, leading to life threatening conditions. Hence it is necessary to regulate blood flow and terminate blood loss by formation of clot at the site of injury. Clotting is assisted by platelets (blood cells) which bind together with Von willebrand factor (VWF, protein present in blood). Blood clot is retained at the site of injury until blood vessel is repaired.
The main enzyme regulating the formation of blood clot is ADAMTS13 (a protein present in blood). ADAMTS13 cleaves VWF, which then binds with platelets to form blood clot. In absence of ADAMTS13 and additional triggers, VWF is left uncleaved and it binds together with platelets forming unnecessary blood clots. In a rare disease called Thrombotic thrombocytopenia purpura (TTP), a lack in activity of ADAMTS3 enzyme is observed, forming unnecessary clots in blood vessels and blocking the flow of blood to various tissues and organs.
Thrombotic Thrombocytopenic Purpura (TTP)
TTP is a rare blood disorder caused due to deficiency in enzyme ADAMTS13. Thrombotic refers to blood clots, Thrombocytopenic refers low platelet count and Purpura refers to purple spots on skin caused due to internal bleeding from blood vessels (figure 1).
Figure 1: Internal bleeding (purpura) observed under the skin of TTP patient.
The population affected with TTP, has been reported to be four cases per million people per year, with women being more affected than men. The main symptoms of TTP are reduced platelet count (thrombocytopenia), microangiopathic hemolytic anemia, renal dysfunction, heart attack, abdominal pain, nausea and vomiting.
Types of TTP
TTP is classified into two general types Congenital and acquired. Congenital TTP is a hereditary disease caused due to mutation in ADAMTS13 gene, characterised by absence of ADAMTS13 in circulation. Treatment includes plasma infusion therapy, where donor ADAMTS13 is supplied, by administration of fresh frozen plasma.
Acquired TTP is a autoimmune disorder where anti antibodies are developed against ADAMTS13, which then bind to active ADAMTS13 and block the activity of the enzyme. Patients are treated with plasma exchange therapy, where autoantibodies of ADAMTS13 are removed from plasma and replaced with donor fresh plasma. This process is continued until the patient has normal platelet count. It is difficult to suppress the autoantibody formation against ADAMTS13, hence the treatment is combined with an immunosuppressant such as Rituximab which assists in programmed cell death of B-cells.
Animal models of TTP
Animal models are useful tools for understanding the mechanism of TTP and for testing new strategies for prevention and treatment of TTP. In order to understand the disease mechanism, TTP is induced in animals (preferably mice) either by genetic modification or administration of auto antibodies. Different therapies are being tested on these ADAMTS13 deficient mice. Research has shown that additional environmental factors such as infection, pregnancy, heavy alcohol intake, trauma, myocardial infection and surgical procedures are required to trigger TTP. Hence, absence of ADAMTS13 alone does not cause TTP, a secondary trigger is needed for generating this rare disease.
Last modified: December 17, 2018