ADAMTS13 Antibody

ADAMTS13 (a disintegrin and metalloprotease with thrombospondin 1 repeats) cleaves von Willebrand factor (vWF) between a tyrosine-1605 and methionine-1606 under circulatory conditions of high-shear stress.^6-14 ADAMTS13 has also been referred to as von Willebrand factor-cleaving protease. Congenital or acquired deficiency of ADAMTS13 is characterized by the presence in plasma of unusually large vWF factor multimers which are more platelet-adhesive than the smaller multimers found in normal plasma. Congenital ADAMTS13 deficiency, also referred to as Upshaw-Schulman syndrome, is an autosomal recessive disorder that is associated with ADAMTS13 activity levels below the level of detection of activity assays (ie, >10% for the assay used by LabCorp.^6-9 ADAMTS13 deficiency (both congenital and autoimmune) is associated with the formation of platelet-rich thrombi in the microcirculation in a clinical condition referred to as thrombotic thrombocytopenic purpura (TTP). Diagnosis of TTP involves documentation of thrombocytopenia and microangiopathic haemolytic anemia, evident on a blood smear. TTP is a life-threatening disease characterized by moderate to severe consumptive thrombocytopenia, red cell fragmentation, and elevated LDH levels (due to red cell destruction) and, ultimately, end-organ ischemia.^8-10 Renal insufficiency and neurologic damage are end stage manifestations of TTP that are rarely seen in countries with advanced medical care.^6-9 TTP is more common in women than men and can be present at any age, but the peak is between 30 and 40 years.¹⁴ Most patients with TTP present with nonspecific constitutional symptoms, such as weakness, abdominal pain, nausea, and vomiting. When these symptoms are associated with laboratory evidence of disseminated microvascular thrombi (also referred to as thrombomicroangiopathy or TMA) with thrombocytopenia and/or hemolytic anemia, schistocytes and elevated LDH, TTP should be considered in the differential diagnosis.⁹

Antibody to ADAMTS13 is not usually detected in patients with congenital deficiency. Most TTP cases are idiopathic and are associated antibodies to ADAMTS13 that reduce circulating functional enzyme levels. Acquired TTP is caused by autoantibodies that inhibit the proteolytic activity of ADAMTS13 and/or bind to ADAMTS13 and accelerate its clearance from plasma.^11,13-18 Studies have shown that quantitative immunoassays for IgG-specific autoantibodies to ADAMTS13 are more sensitive than the functional (ie, inhibition) assays for detecting antibodies against ADAMTS13.^16-18

Measurement of ADAMTS13 can play a role in differentiating TTP from a number of clinically similar conditions that have different underlying causes.^7-9 These syndromes, which can be associated with pregnancy, organ transplantation, and certain medications, generally do not exhibit significantly reduced ADAMTS13 activity levels.⁸ Hemolytic uremic syndrome (HUS) is clinically similar to TTP, but is associated with acute renal failure.⁷ Diarrhea-associated HUS accounts for most cases and is usually by infection with Shiga-toxin-producing Escherichia coli (O157:H7). Diarrhea-negative or atypical HUS (aHUS) is thought to be caused by uncontrolled complement activation occurring in both children and adults and shares many of the clinical features of TTP.^7,10-20; however, aHUS is not associated with severe reduction (ie, <10%) of ADAMTS13 activity.¹⁰ Disease classification based on clinical features alone can be unreliable and can result in inappropriate treatment or delay in the initiation of effective treatment.⁷ In patients exhibiting laboratory evidence of thrombocytopenia and microangiopathic hemolysis, therefore, the measurement of ADAMTS13 activity can be invaluable in differentiating TTP from other clinically similar conditions.⁷

Severe deficiency of ADAMTS13 (<10% activity for the LabCorp assay) is a relatively specific finding in patients with a clinical diagnosis of either hereditary or acquired TTP.^11,21 An ADAMTS13 activity level greater than 10% (the diagnosis threshold for severe deficiency) does not completely exclude clinical diagnosis of TTP. As many as 40% of patients with clinically diagnosed TTP have ADAMTS13 levels greater than 10%.^11,21 Other conditions that could have normal or mild-to-moderate deficiency of ADAMTS13 activity include hemolytic uremic syndrome (HUS), atypical hemolytic uremic syndrome (aHUS), and other thrombotic microangiopathies associated with hematopoietic stem cell and solid organ transplantation, liver disease, DIC, sepsis, pregnancy, or effects of certain medications (eg, ticlopidine, clopidogrel, cyclosporine, mitomycin C, quinine, etc).²²