What is Thrombotic Thrombocytopenic Purpura?
Thrombotic thrombocytopenic purpura is a rare blood disorder that leads to unusual blood clotting in the small blood vessels. It can come in two forms: idiopathic also called primary and on the other hand secondary thrombotic thrombocytopenic purpura. In the secondary form of the disease there is a primary condition that can lead to thrombotic thrombocytopenic purpura as a complication of the primary disease. Conditions that can lead to secondary thrombotic thrombocytopenic purpura are certain cancers, pregnancy, HIV-infection, bone marrow transplantation, and certain medications like e.g. the malaria medication quinine or immunosuppressants like Cyclosporine A and tacrolimus (FK506).
If no such condition exists in the patient, the condition is called idiopathic thrombotic thrombocytopenic purpura. In either case overactive large fragments of a protein called von Willebrand factor that is involved in blood clotting causes blood clots in the microvasculature that can inhibit blood flow in certain organs mainly the brain and the kidney, but also other organs like the heart, and can cause multi-organ failure and death, if left untreated. Von Willebrand factor fragments are usually inhibited and degraded by an enzyme called ADAMST13. This enzyme does not work well in thrombotic thrombocytopenic purpura, which leads to the over-activity of von Willebrand factor, the accumulation of large fragments of it, and the formation of blood clots mainly in the small blood vessels (called microvasculature).
Inhibition of the ADAMST13 enzyme can happen through certain medications like in some cases of secondary thrombotic thrombocytopenic purpura, or by a genetic defect in the enzyme itself. The condition in which a genetic defect of the ADAMST13 enzyme exists is called Upshaw-Schulman syndrome and is an inherited form of primary thrombotic thrombocytopenic purpura. If factors produced by the immune system (the system that protects us form pathogens like viruses and bacteria, but sometimes harms the body by mistake) inhibit the ADAMST13 enzyme, this form of thrombotic thrombocytopenic purpura is called autoimmune thrombotic thrombocytopenic purpura, and is a special form of the idiopathic kind of the disease. The inhibition of the ADAMST13 enzyme is a necessary component of the process that leads to thrombotic thrombocytopenic purpura, but there must be other factors that lead to the diseases, as many people with a genetic defect in the enzyme have surprisingly few symptoms. Scientists believe that activation of von Willebrand factor in certain situations like e.g. during an infections plays a major role in precipitating an episode, but the exact mechanism is still unknown.
The formation of so many blood clots at once leads to excessive use of platelets, the cell fragments that build parts of the clots. This causes a deficiency of platelets in the blood which medically is called thrombocytopenia. It can lead to bleeding, mostly from the nose and gums, and increased, even spontaneous, bruising, medically called purpura.
Symptoms and Diagnosis of Thrombotic Thrombocytopenic
The symptoms of thrombotic thrombocytopenic purpura have all to do with the formation of blood flow restricting blood clots in the microvasculature mainly of the brain and kidney, and with the excessive use of platelets leading to thrombocytopenia. Classic thrombotic thrombocytopenic purpura presents with five distinctive symptoms called a pentad of symptoms, but sometimes patients don’t display all five. These five symptoms are neurologic problems like hallucinations, bizarre behavior, altered mental state, headaches, and stroke; kidney failure; fever; thrombocytopenia (low platelet counts) with bruising, bleeding, and purpura, and blood clots in the small blood vessels leading to hemolytic anemia and jaundice.
How is Thrombotic Thrombocytopenic Purpura diagnosed?
The definitive diagnosis is made when the above mentioned five symptoms occur together in a patient. However, mortality in untreated thrombotic thrombocytopenic purpura is so high that an assumption of thrombotic thrombocytopenic purpura is usually made even if a patient shows only blood clots in small blood vessels with hemolytic anemia and thrombocytopenia, so treatment can be started early.
What are the treatment options for Thrombotic Thrombocytopenic Purpura?
Thrombotic thrombocytopenic purpura used to be treated by transfusion of donor blood plasma. This treatment adds fresh active ADAMST13 enzyme to the blood of the patient and can relief the symptoms of the disease. However, the amount of donor plasma that can be added to the blood stream of a patient is limited, as too much can be harmful due to fluid overload. In the early 1990, it was noted that a procedure called plasmapheresis is more efficient in relieving symptoms of thrombotic thrombocytopenic purpura compared to just plasma transfusions. In plasmapheresis, the plasma of the patient is collected and replaced with donor plasma, so instead of just adding some active ADMAST13 enzyme and leaving the faulty enzyme (in the case of the inherited form of thrombotic thrombocytopenic purpura), or diluting inhibiting factors (as in the case of autoimmune thrombotic thrombocytopenic purpura), plasmapheresis removes inhibiting factors or faulty enzyme and replaces it with fresh functioning enzyme and plasma without inhibiting factors. In an acute episode of thrombotic thrombocytopenic purpura the plasmapheresis treatment has to be repeated daily and has to continue for 1-8 weeks to fully resolve the symptoms. It is not completely clear what laboratory parameters reliably indicate that the treatment can be stopped, but usually the blood levels of an enzyme called lactate dehydrogenase is used to assess the success of the treatment together with other blood tests.
In patients with the inherited form of thrombotic thrombocytopenic purpura, Upshaw-Schulman syndrome, plasma transfusions every few weeks can prevent the appearance of life-threatening symptoms.
Patients with idiopathic thrombotic thrombocytopenic purpura usually present in critical condition and the mortality of the disease is around 90%, if left untreated. Surprisingly, many patients make a full recovery with treatment and the long-term survival of treated idiopathic thrombotic thrombocytopenic purpura is quite good with 80-90%. Unfortunately, this is not true for the secondary form of thrombotic thrombocytopenic purpura that can have a high mortality despite treatment. The reasons for this difference are still unknown, but might have something to due with the underlying condition.