ADAMTS13 is an enzyme circulating in the blood plasma, produced primarily by specialized cells in the liver. It plays a highly specific role in the complex system that controls blood clotting. Its presence and proper function are integral to ensuring blood flows smoothly through the vascular network. A disruption in the availability of this enzyme can lead to significant health complications.
The Function of ADAMTS13
The primary function of ADAMTS13 is to regulate the size and activity of a large protein called von Willebrand Factor (vWF). Under normal conditions, vWF is released into the bloodstream, where it acts as a sticky adhesive, helping platelets adhere to a blood vessel injury to form a clot. However, when first released, vWF exists in a very large, “ultra-large” form that is hyperactive and can cause platelets to clump together without an injury.
To prevent this inappropriate clotting, ADAMTS13 acts as a pair of molecular scissors. It specifically targets and cleaves the ultra-large vWF multimers into smaller, less sticky versions. This cleavage is particularly effective under the high fluid shear stress found in small blood vessels, which unfolds the vWF protein and exposes the cleavage site for ADAMTS13. This ensures the most dangerous forms of vWF are managed where they could cause the most harm.
By moderating the size of vWF, ADAMTS13 ensures that this clotting factor is available when needed for injury but does not trigger spontaneous clot formation throughout the circulatory system. This regulatory action is a constant process that maintains hemostatic balance.
Thrombotic Thrombocytopenic Purpura (TTP)
Severe ADAMTS13 deficiency leads to a rare and life-threatening blood disorder known as Thrombotic Thrombocytopenic Purpura (TTP). Without sufficient ADAMTS13 activity, ultra-large vWF multimers accumulate in the circulation. These large vWF strands spontaneously bind to platelets, causing them to aggregate and form numerous small blood clots, or microthrombi, within small blood vessels.
These microthrombi can lodge in arterioles and capillaries throughout the body, obstructing blood flow and leading to organ damage. The organs most commonly affected are the brain, kidneys, and heart, resulting in a variety of severe symptoms. Neurological problems can range from headaches and confusion to seizures and coma. The formation of these clots also consumes a large number of platelets, leading to a sharp drop in their count, a condition called thrombocytopenia.
Simultaneously, as red blood cells try to squeeze past these micro-clots, they are subjected to high shear forces that cause them to fragment and rupture. This process, known as microangiopathic hemolytic anemia, leads to a low red blood cell count and the appearance of “schistocytes,” or fragmented red cells, on a blood smear. The combination of low platelets, anemia, and organ ischemia defines the clinical presentation of TTP.
Causes of ADAMTS13 Deficiency
A deficiency in ADAMTS13 can arise from two distinct origins: an acquired autoimmune condition or a congenital genetic disorder. The more common of the two is acquired TTP, also referred to as immune-mediated TTP (iTTP). In this form, the body’s immune system mistakenly identifies ADAMTS13 as a foreign substance and produces autoantibodies that attack and neutralize the enzyme or accelerate its clearance from the blood.
The less common cause is congenital TTP (cTTP), also known as Upshaw-Schulman syndrome. This is a rare, inherited disorder resulting from mutations in the ADAMTS13 gene. Individuals with cTTP are born with this genetic defect and are unable to produce sufficient quantities of functional ADAMTS13 enzyme. While people with cTTP have a chronic deficiency, they may not experience symptoms until they encounter a trigger, such as an infection or pregnancy, which increases vWF levels and overwhelms their limited enzyme capacity.
Diagnosis and Measurement
Confirming a diagnosis of TTP relies on specific laboratory tests that measure the amount and function of the ADAMTS13 enzyme in the blood. When a patient presents with suggestive symptoms, doctors will order these specialized assays. While treatment often begins based on strong clinical suspicion, these tests are important for confirming the diagnosis and guiding long-term management.
The primary diagnostic test is the ADAMTS13 activity assay. This test directly measures how well the enzyme is functioning by incubating a patient’s plasma with a vWF substrate and quantifying the cleavage product. A severely deficient level of activity, defined as less than 10%, is a hallmark finding that strongly supports a diagnosis of TTP.
To differentiate between the acquired and congenital forms of the disorder, an ADAMTS13 inhibitor assay is performed. This test detects the presence of autoantibodies that are blocking the enzyme’s function. A positive inhibitor test indicates the presence of these neutralizing antibodies and confirms a diagnosis of acquired TTP. Conversely, a negative inhibitor test in a patient with severely low ADAMTS13 activity points towards a diagnosis of congenital TTP, which can be confirmed with genetic testing.
Therapeutic Interventions
Treatment for TTP is a medical emergency aimed at restoring ADAMTS13 levels, removing harmful autoantibodies, and preventing further clot formation. A primary therapy for acquired TTP is plasma exchange (plasmapheresis). This procedure involves removing the patient’s plasma, containing the autoantibodies and excess vWF, and replacing it with donor plasma rich in the functional ADAMTS13 enzyme. Daily plasma exchange continues until the platelet count returns to a safe level and signs of organ damage resolve.
Alongside plasma exchange, patients with acquired TTP are treated with immunosuppressive therapy. High-dose corticosteroids are used to dampen the immune system’s production of autoantibodies. For more severe cases, a monoclonal antibody called rituximab may be administered. Rituximab targets and destroys the B-cells responsible for producing the autoantibodies, providing lasting suppression of the autoimmune attack.
For individuals with congenital TTP, treatment involves regular infusions of fresh frozen plasma to supply the missing ADAMTS13 enzyme, particularly during high-risk periods like pregnancy or infection. A newer class of targeted therapies has also emerged, such as caplacizumab. This antibody fragment blocks the initial binding of vWF to platelets, and while it does not address the enzyme deficiency, it directly inhibits the clot-forming process to manage the acute phase of the disease.