The ADAMTS13 activity and inhibitor assays are useful for the diagnosis of congenital or acquired form of TTP.
ADAMTS13 is a plasma protein responsible for regulating the interaction of platelets with von Willebrand factor (VWF) and physiologic proteolytic cleavage of ultra large (UL) VWF multimers at the Tyr(1605)- Met(1606) bond in the A2 domain of VWF. Reduced or absent ADAMTS13 activity can retain UL VWF that can trigger intravascular platelet aggregation and microthrombi causing clinical symptoms or signs of thrombotic thrombocytopenic purpura (TTP).
Measurement of ADAMTS13 activity and its inhibitor is crucial in the diagnosis of TTP, potentially fatal thrombotic microangiopathy (TMA) syndrome and further differentiation of congenital (Upshaw-Schulman syndrome) versus acquired (e.g. autoimmune-related disorder) etiology.
TTP is a rare life-threatening disease with an estimated incidence of four to six cases per million, and affects more often women, particularly pregnant or postpartum women (estimated incidence of one per 25,000 pregnancies), and African-Americans. TTP is primarily diagnosed clinically, and its correct diagnosis is often very difficult.
TTP is characterized by microangiopathic hemolytic anemia including numerous schistocytes in the peripheral blood smear, thrombocytopenia, neurologic symptoms, fever, renal dysfunction, variable organ damage and ischemia, and deficient ADAMTS13 activity, usually less than 30%.
Approximately two-thirds of patients with a clinical diagnosis of idiopathic TTP will have less than 10% ADAMTS13 activity. Decreased ADAMTS13 activity in TTP is often related to autoantibodies that inhibit or clear ADAMTS13. ADAMTS13 inhibitor is observed in 44-93% of patients with severely deficient ADAMTS13 activity. Relapse occurs in 20-25% of TTP patients. Persistence of severe deficiency of ADAMTS13 activity or an inhibitor suggests high risk of relapse in symptomatic TTP.
Congenital TTP (Upshaw-Shulman syndrome) is a rare inheritable disease with an autosomal recessive pattern, and caused by genetic mutations within the ADAMTS13 gene producing non-functional ADAMTS13 protein. These patients will have severely deficient ADAMTS13 activity with high risk for recurrent episodes of TTP, and usually do not develop autoantibodies to ADAMTS13.
Acquired TTP is more common than congenital forms, and may be considered to be primary or idiopathic (the most frequent type) or associated with distinctive clinical conditions (secondary TTP). Early detection and initiation of plasma exchange is critical for better survival of patients. Quantitative measurement of ADAMTS13 activity by fluorescence energy transfer (FRET) technology will assist in the correct diagnosis of TTP.
Quantitation of the ADAMTS13 activity level will be also useful to distinguish patients with TTP from other thrombocytopenic conditions such as hemolytic uremic syndrome (HUS), immune thrombocytopenic purpura (ITP) or heparininduced thrombocytopenia (HIT).
Activity levels below 0.10 IU/mL are seen in acquired and hereditary thrombotic thrombocytopenic purpura (TTP). Not all patients with TTP will exhibit low levels of ADAMTS13 activity with this assay, i.e., post bone marrow transplantation, drug-induced TTP, and mutations of ADAMTS13 at the CUB domain.
Mild decreases in ADAMTS13 activity are seen in a wide variety of conditions including metastatic cancer, neonates, serious infections and cirrhosis of the liver.
Decreased ADAMTS13 activity (equal to or less than 68%) can be observed in idiopathic (autoimmune-related) TTP, TMA syndrome, congenital ADAMTS13 deficiency (UpshawSchulman syndrome) and secondary to other clinical conditions such as HUS, ITP, solid organ or bone marrow transplantation, sepsis, DIC, HIV infection, inflammation, bloody diarrhea, liver disease, pregnancy, malignancy, or certain drug effects (e.g., clopidogrel, cyclosporin, mitomycin C, ticlopidine, tacrolimus, etc).
1. If ADAMTS13 activity is decreased (less than 30%), ADAMTS13 inhibitor assay is further evaluated for titration of inhibitor unit. a) Greater than 0.4 Inhibitor Unit is diagnostic of idiopathic TTP. b) Less than 0.4 Inhibitor Unit suggests autoantibody assay (send-out test) for further differentiation of congenital or acquired TTP. Autoantibody, usually IgG by ELISA method, is elevated in idiopathic TTP. However, it can be detected in other immune-mediated disorders, and some healthy individuals (10-15%). If autoantibody is low, ADAMTS13 sequencing for genetic mutation is suggested to rule out congenital TTP.
2. Severely decreased ADAMTS13 activity (less than 5-10%) is considered as a relatively specific laboratory finding for the clinical diagnosis of congenital and acquired idiopathic TTP.
3. Mildly decreased ADAMTS13 activity (30-67%) is often observed in TTP patients secondary to other clinical conditions, and unlikely related to idiopathic (autoimmunerelated) TTP. However, if there is a strong clinical suspicion of TTP, inhibitor assay can be performed.
Recent plasma exchange or immunosuppressive therapy may raise the observed activity levels.
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