ADAMTS13 deficiency is a rare yet serious medical condition linked to blood clotting. It involves an enzyme, ADAMTS13, which regulates how blood clots form and dissolve. When this enzyme is insufficient or dysfunctional, it disrupts the body’s delicate balance of clot formation, leading to uncontrolled clotting and various health issues.
Understanding ADAMTS13 and its Role
ADAMTS13, formally known as “A Disintegrin And Metalloproteinase with a ThromboSpondin Type 1 Motif, 13,” is an enzyme primarily produced in the liver. It circulates in the plasma and regulates von Willebrand factor (vWF), a large protein that helps platelets adhere to damaged blood vessel walls during the initial steps of blood clotting.
vWF is secreted as very long, “ultra-large” multimers, which actively promote platelet adhesion and aggregation. ADAMTS13 acts as a molecular scissor, cleaving these ultra-large vWF multimers into smaller, less active pieces, particularly under high shear stress in small blood vessels.
This breakdown of vWF by ADAMTS13 prevents excessive platelet clumping. This function maintains normal hemostasis, the process that stops bleeding. Without adequate ADAMTS13 activity, large vWF multimers accumulate, leading to uncontrolled platelet aggregation and clot formation.
How Deficiency Manifests in the Body
When ADAMTS13 is severely deficient, large von Willebrand factor (vWF) multimers remain uncleaved and accumulate. These unusually large vWF multimers bind to platelets, forming microscopic blood clots (microthrombi) throughout small blood vessels. This widespread microthrombi formation is the underlying cause of thrombotic thrombocytopenic purpura (TTP).
Two primary types of ADAMTS13 deficiency lead to TTP. Hereditary TTP, also known as Upshaw-Schulman syndrome, occurs due to genetic mutations in the ADAMTS13 gene, leading to a lifelong low level of enzyme activity. Acquired TTP, which is more common, develops when the body’s immune system mistakenly produces autoantibodies that attack and inhibit the activity of ADAMTS13.
The microclots in TTP block blood flow to various organs, leading to a range of symptoms. Neurological problems can include headaches, confusion, seizures, and stroke. Kidney problems, such as kidney failure, can also occur. The passage of red blood cells through these narrowed, clot-filled vessels causes them to break apart, leading to microangiopathic hemolytic anemia, characterized by fragmented red blood cells called schistocytes.
The consumption of platelets in these microclots results in a low platelet count, a condition known as thrombocytopenia. Despite the excessive clotting, this low platelet count can paradoxically lead to bleeding issues, such as purpura or prolonged bleeding from minor injuries. Other general symptoms that may accompany ADAMTS13 deficiency include fatigue, fever, and abdominal pain.
Diagnosing ADAMTS13 Deficiency
Diagnosing ADAMTS13 deficiency relies on specific laboratory tests that measure the enzyme’s activity. The primary diagnostic test involves assessing the level of ADAMTS13 activity in a blood sample. A severe deficiency is typically indicated by an ADAMTS13 activity level of less than 10% of normal, which is strongly associated with a diagnosis of TTP. This low activity suggests that the enzyme is either absent, mutated, or inhibited.
In addition to measuring ADAMTS13 activity, other supportive laboratory findings help confirm a diagnosis of TTP. A low platelet count, or thrombocytopenia, is a consistent finding, as platelets are consumed in the formation of microthrombi. Signs of red blood cell destruction, characteristic of microangiopathic hemolytic anemia, are also observed. These include the presence of fragmented red blood cells, known as schistocytes, on a blood smear, elevated levels of lactate dehydrogenase (LDH), and decreased haptoglobin levels. Kidney function tests, such as serum creatinine levels, may also be monitored, as kidney involvement can occur due to microclot formation.
Managing the Condition
Managing ADAMTS13 deficiency, particularly in the context of acute TTP, requires urgent and targeted treatment due to the condition’s life-threatening nature. The main treatment strategies aim to address the underlying cause of the deficiency and mitigate the effects of microclot formation.
For acquired TTP, which is often immune-mediated, plasma exchange (plasmapheresis) is a cornerstone of treatment. During this procedure, the patient’s plasma, containing the harmful autoantibodies that inhibit ADAMTS13 and the accumulated large vWF multimers, is removed. It is then replaced with donor plasma, which provides functional ADAMTS13 enzyme and helps restore the balance of vWF cleavage. This process is typically initiated quickly and performed daily until platelet counts normalize.
Immunosuppressive therapy is also a component of treatment for acquired TTP, as it aims to suppress the immune system’s production of ADAMTS13-inhibiting antibodies. Medications such as corticosteroids are commonly used to reduce inflammation and immune activity. Rituximab, a monoclonal antibody that targets B lymphocytes (cells responsible for antibody production), may also be administered to further suppress the immune response and prevent relapses.
Newer therapies, such as caplacizumab, have also been introduced for acquired TTP. Caplacizumab is an antibody fragment that blocks the interaction between vWF and platelets, thereby reducing the formation of microthrombi and platelet consumption. This medication is typically used in combination with plasma exchange and immunosuppressive therapy. For hereditary TTP, the primary treatment involves regular plasma infusions, or infusions of fresh frozen plasma, to directly replace the missing ADAMTS13 enzyme. Long-term management and monitoring are often necessary for both forms of the condition to prevent relapses and manage potential ongoing complications.