Thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) is a blood disorder that results in blood clots forming in small blood vessels throughout the body. This results in a low platelet count, low red blood cells due to their breakdown, and often kidney, heart, and brain dysfunction. Symptoms may include large bruises, fever, weakness, shortness of breath, confusion, and headache. Repeated episodes may occur. In about half of cases a trigger is identified, while in the remainder the cause remains unknown. Known triggers include bacterial infections, certain medications, autoimmune diseases such as lupus, and pregnancy. The underlying mechanism typically involves antibodies inhibiting the enzyme ADAMTS13. This results in decreased break down of large multimers of von Willebrand factor (vWF) into smaller units. Less commonly TTP is inherited, known as Upshaw–Schulman syndrome, such that ADAMTS13 dysfunction is present from birth. Diagnosis is typically based on symptoms and blood tests. It may be supported by measuring activity of or antibodies against ADAMTS13. With plasma exchange the risk of death has decreased from more than 90% to less than 20%. Immunosuppressants, such as glucocorticoids, and rituximab may also be used. Platelet transfusions are generally not recommended. About 1 per 1,000,000 new people are affected annually. Onset is typically in adulthood and women are more often affected. About 10% of cases begin in childhood. The condition was first described by Eli Moschcowitz in 1924. The underlying mechanism was determined in the 1980s and 1990s.

Signs and symptoms The signs and symptoms of TTP may at first be subtle and nonspecific. Many people experience an influenza-like or diarrheal illness before developing TTP. Neurological symptoms are very common and vary greatly in severity. Frequently reported symptoms include feeling very tired, confusion, and headaches. Seizures and symptoms similar to those of a stroke can also be seen. Other symptoms include, but are not limited to jaundice or paleness of the skin, a fast heart rate or shortness of breath, or dots on the skin known as petechiae. High blood pressure has also been observed as a symptom. As TTP progresses, blood clots form within small blood vessels (microvasculature), and platelets (clotting cells) are consumed. As a result, bruising, and rarely bleeding can occur. The bruising often takes the form of purpura, while the most common site of bleeding, if it occurs, is from the nose or gums. Larger bruises (ecchymoses) may also develop. The classic presentation of TTP, which occurs in less than 10% of people, includes five medical signs. These are:

Fever Changes in mental status Thrombocytopenia Reduced kidney function Hemolytic anemia (microangiopathic hemolytic anemia).

Causes TTP, as with other microangiopathic hemolytic anemias (MAHAs), is caused by spontaneous aggregation of platelets and activation of coagulation in the small blood vessels. Platelets are consumed in the aggregation process and bind vWF. These platelet-vWF complexes form small blood clots which circulate in the blood vessels and cause shearing of red blood cells, resulting in their rupture and formation of schistocytes. The two best understood causes of TTP are due to autoimmunity (acquired TTP), caused by autoantibodies targeting ADAMTS13, or congenital TTP: an inherited deficiency of ADAMTS13 (known as the Upshaw–Schulman syndrome).

Autoimmune In 1998, the majority of cases were shown to be caused by the inhibition of the enzyme ADAMTS13 by antibodies. Knowledge of this relationship between reduced ADAMTS13 and the pathogenesis of TTP is credited to two independent groups of researchers (Furlan and Tsai) who published their research in the same issue of the New England Journal of Medicine. ADAMTS13 is a metalloproteinase responsible for the breakdown of von Willebrand factor (vWF), a protein that links platelets, blood clots, and the blood vessel wall in the process of blood coagulation. Very large vWF multimers are more prone to lead to coagulation. Hence, without proper cleavage of vWF by ADAMTS13, coagulation occurs at a higher rate, especially in the microvasculature, part of the blood vessel system where vWF is most active due to high shear stress.

Genetic

TTP may also be congenital. Such cases may be caused by mutations in the ADAMTS13 gene. This hereditary form of TTP is called Upshaw–Schulman syndrome (also spelled Upshaw–Schülman). People with this inherited ADAMTS13 deficiency have a surprisingly mild phenotype, but develop TTP in clinical situations with increased von Willebrand factor levels (e.g. infection). Reportedly, less than 5% of all TTP cases are due to Upshaw–Schulman syndrome. People with this syndrome generally have 5–10% of normal ADAMTS-13 activity. A 2024 study suggested that hereditary TTP is underdiagnosed and should be considered in cases of unexplained stroke, neonatal jaundice, and severe pre-eclampsia. The study estimated the global prevalence of hereditary TTP at 40 per million, in contrast to previously reported estimates of 0.5 to 2.0 per million.

Secondary Secondary TTP is diagnosed when the person's history mentions one of the known features associated with TTP. It comprises about 40% of all cases of TTP. Predisposing factors are:

Cancer Bone marrow transplantation Pregnancy Medication use: Antiviral drugs (acyclovir) Certain chemotherapy medications such as gemcitabine and mitomycin C Quinine Oxymorphone Quetiapine Bevacizumab Sunitinib Platelet aggregation inhibitors (ticlopidine, clopidogrel, and prasugrel) Immunosuppressants (ciclosporin, mitomycin, tacrolimus/FK506, interferon-α) Hormone altering drugs (estrogens, contraceptives, hormone replacement therapy) HIV-1 infection The mechanism of secondary TTP is poorly understood, as ADAMTS13 activity is generally not as depressed as in idiopathic TTP, and inhibitors cannot be detected. Probable etiology may involve, at least in some cases, endothelial damage, although the formation of thrombi resulting in vessel occlusion may not be essential in the pathogenesis of secondary TTP. These factors may also be considered a form of secondary aHUS; people presenting with these features are, therefore, potential candidates for anticomplement therapy.

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