The enzyme ADAMTS13 is a protein in the blood that plays a regulatory role in blood clotting. Its function is to prevent excessive or inappropriate clot formation throughout the body’s microcirculation. A severe deficiency in the activity of this enzyme leads to a life-threatening condition called Thrombotic Thrombocytopenic Purpura (TTP). This deficiency disrupts the delicate balance between stopping bleeding and maintaining free blood flow.
The enzyme is unable to cleave a large clotting protein, which allows excessive platelet aggregation and causes widespread blockages in the small blood vessels.
The Essential Function of ADAMTS13
The primary substrate of the ADAMTS13 enzyme is Von Willebrand Factor (vWF), a large, sticky protein essential for the initial steps of blood clotting. When a blood vessel is injured, vWF acts as a bridge, recruiting platelets to the site of damage to form a plug. This protein is initially produced as very long, highly adhesive strands called ultra-large multimers.
These ultra-large vWF multimers are too sticky and can cause spontaneous, uncontrolled clotting if left unchecked. ADAMTS13, a type of metalloprotease, acts as “molecular scissors,” cutting these long vWF chains into smaller, less adhesive functional units. This cleavage ensures that clotting only happens where necessary and not randomly throughout the circulation.
Without sufficient ADAMTS13 activity, the ultra-large vWF multimers accumulate in the bloodstream. These hyper-adhesive strands spontaneously capture and bind platelets, especially under the high-shear stress conditions found in small blood vessels. This uncontrolled platelet aggregation forms microthrombi, or tiny clots, that obstruct blood flow and lead to TTP.
The Resulting Health Crisis: Thrombotic Thrombocytopenic Purpura (TTP)
TTP is the severe clinical consequence that occurs when ADAMTS13 activity falls below a functional threshold, typically less than 10% of normal levels. The widespread formation of platelet-rich microthrombi causes mechanical damage to passing red blood cells and consumes platelets, leading to two defining features. The destruction of red blood cells as they are forced through partially blocked vessels is termed microangiopathic hemolytic anemia.
The consumption of platelets in forming these numerous clots results in a low platelet count, a condition called thrombocytopenia. This low count paradoxically increases the risk of bleeding even while the patient experiences inappropriate clotting. The microvascular blockages also deprive organs of oxygen, leading to a variety of symptoms.
These symptoms often include fever, neurological changes such as confusion or seizures, and kidney impairment, alongside the low platelet count and red blood cell destruction. TTP is a medical emergency because the microclots can rapidly cause severe damage to the brain, heart, and kidneys, demanding immediate intervention to prevent organ failure or death.
Distinguishing Inherited and Acquired Deficiency
ADAMTS13 deficiency can manifest in two primary forms: acquired or inherited, which differ significantly in cause. The most common form is acquired TTP, an autoimmune disorder where the body’s immune system mistakenly produces autoantibodies that target and neutralize the ADAMTS13 enzyme.
These autoantibodies act as inhibitors, blocking the enzyme’s ability to cleave vWF or increasing its clearance from the bloodstream. Acquired TTP can sometimes be triggered by external factors, including certain infections, specific medications, or pregnancy. Treatment for the acquired form must focus on replacing the missing enzyme and suppressing the immune response.
The second type is inherited TTP, also known as Upshaw-Schulman Syndrome, which is far rarer. This form is caused by a genetic mutation in the ADAMTS13 gene, resulting in the body producing a non-functional or severely insufficient amount of the enzyme. Since this is a genetic defect, patients with inherited TTP do not produce the inhibitory autoantibodies seen in the acquired form. Although the deficiency is present from birth, symptoms often first appear later in life, sometimes triggered by infection or physical stress.
Diagnostic Testing and Monitoring
Diagnosing TTP and distinguishing its type relies on specific laboratory tests, particularly the ADAMTS13 activity assay. This test measures the amount of functional enzyme present in the patient’s blood plasma. A definitive diagnosis of TTP is established when the measured ADAMTS13 activity is severely deficient, consistently falling below the 10% threshold of normal activity.
Because TTP symptoms overlap with other thrombotic microangiopathies, the ADAMTS13 activity level is crucial for differentiation. Once severe deficiency is confirmed, a second test measures the presence of an ADAMTS13 inhibitor (an autoantibody). The presence of this inhibitor strongly indicates acquired TTP, while its absence suggests the inherited form.
Monitoring treatment response and tracking progression involves routine blood work, such as daily platelet counts. Doctors also monitor signs of ongoing red blood cell destruction by measuring levels of lactate dehydrogenase (LDH) and haptoglobin. Consistent monitoring of these markers guides treatment duration and helps anticipate potential relapses.
Management and Therapeutic Approaches
The treatment of acute TTP is a medical emergency requiring immediate initiation of therapy before laboratory confirmation of ADAMTS13 activity is complete. The mainstay of treatment for acquired TTP is Plasma Exchange (PLEX), a procedure often performed daily. PLEX involves removing the patient’s plasma, which contains the autoantibodies and ultra-large vWF multimers, and replacing it with healthy donor plasma that provides functional ADAMTS13 enzyme.
Acquired TTP is also treated with immunosuppressive therapies to halt autoantibody production. Corticosteroids are administered alongside PLEX to dampen the immune response. A monoclonal antibody, such as rituximab, is often used to target the B-cells responsible for producing the autoantibodies, promoting sustained remission. Newer targeted therapies, like caplacizumab, are also used to block the interaction between vWF and platelets, providing an immediate anti-clotting effect.
The treatment strategy for inherited TTP differs significantly because there are no antibodies to remove. Patients with the inherited form are typically managed with Plasma Infusion, which involves simply infusing fresh frozen plasma to replace the missing enzyme, without the need for the exchange process or immunosuppression.