ADAMTS13 Activity Reflex Profile

CPT: 85397
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Test Details

Test Includes

ADAMTS13 activity with reflex to ADAMTS13 antibody when activity is less than 30%

Use

Differentiating thrombotic thrombocytopenic purpura (TTP) from a number of clinically similar conditions. Reflex to antibody assay is used to differentiate congenital from autoimmune ADAMTS13 deficiency.

Limitations

This test was developed, and its performance characteristics determined, by LabCorp. It has not been cleared or approved by the US Food and Drug Administration.

Methodology

In LabCorp’s liquid chromatography‐tandem mass spectrometry (LC/MS-MS) assay, ADAMTS13 activity is determined by measuring the cleavage of a synthetic polypeptide substrate (referred to as vWF73) added to plasma samples.23 The amino acid sequence of vWF73 corresponds to amino acid residues 1596 through 1668 of mature von Willebrand Factor (vWF) and, thereby, possesses the tyrosine‐methionine cleavage site and exosite necessary to undergo specific cleavage by plasma ADAMTS13.24 Using LC/MS-MS, cleavage of vWF73 is determined directly by measuring a specific proteolytic product of vWF73 whose quantity is directly proportional to the activity of ADAMTS13 in plasma. The LC/MS-MS activity assay is traceable to the WHO 1st International Standard for ADAMTS1325 to ensure accurate measurements and offers several advantages relative to comparable fluorescence‐based assays.

Additional Information

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 hemolytic 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 [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 with 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 it 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 TTP7,10-20; however, aHUS is not associated with severe reduction (ie, <10%) of ADAMTS13 activity.19 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

Specimen Requirements

Specimen

Plasma, frozen

Volume

1 mL

Minimum Volume

0.3 mL (Note: This volume does not allow for repeat testing.)

Container

Blue-top (sodium citrate) tube

Collection

Blood should be collected in a blue-top tube containing 3.2% buffered sodium citrate.1 Evacuated collection tubes must be filled to completion to ensure a proper blood-to-anticoagulant ratio.2,3 The sample should be mixed immediately by gentle inversion at least six times to ensure adequate mixing of the anticoagulant with the blood. A discard tube is not required prior to collection of coagulation samples.4,5 When noncitrate tubes are collected for other tests, collect sterile and nonadditive (red-top) tubes prior to citrate (blue-top) tubes. Any tube containing an alternate anticoagulant should be collected after the blue-top tubes. Serum gel-barrier tubes and serum tubes with clot initiators should also be collected after the citrate tubes. Centrifuge for 10 minutes and (using a transfer pipette) carefully remove two-thirds of the plasma without disturbing the cells. Deliver to a plastic transport tube, cap, and recentrifuge for 10 minutes. Use a second plastic pipette to remove the plasma, staying clear of the platelets at the bottom of the tube. Transfer the plasma into a LabCorp PP transpak frozen purple tube with screw cap (LabCorp N° 49482). The specimen should be frozen immediately and maintained frozen until tested. To avoid delays in turnaround time when requesting multiple tests on frozen samples, please submit separate frozen specimens for each test requested.

Storage Instructions

Freeze

Causes for Rejection

Severe hemolysis; improper labeling; clotted specimen; specimen diluted with IV fluids; samples thawed in transit; improper sample type; sample out of stability

Clinical Information

Footnotes

1. Adcock DM, Kressin DC, Marlar RA. Effect of 3.2% vs 3.8% sodium citrate concentration on routine coagulation testing. Am J Clin Pathol. 1997 Jan; 107(1):105-110.8980376
2. Reneke J, Etzell J, Leslie S, Ng VL, Gottfried EL. Prolonged prothrombin time and activated partial thromboplastin time due to underfilled specimen tubes with 109 mmol/L (3.2%) citrate anticoagulant. Am J Clin Pathol. 1998 Jun; 109(6):754-757.9620035
3. National Committee for Clinical Laboratory Standardization. Collection, Transport, and Processing of Blood Specimens for Coagulation Testing and General Performance of Coagulation Assays; Approved Guideline. 5th ed. Villanova, Pa: NCCLS; 2008. Document H21-A5:28(5).
4. Gottfried EL, Adachi MM. Prothrombin time and activated partial thromboplastin time can be performed on the first tube. Am J Clin Pathol. 1997 Jun; 107(6):681-683.9169665
5. McGlasson DL, More L, Best HA, Norris WL, Doe RH, Ray H. Drawing specimens for coagulation testing: Is a second tube necessary? Clin Lab Sci. 1999 May-Jun; 12(3):137-139.10539100
6. Mannucci PM, Peyvandi F. TTP and ADAMTS13: When is testing appropriate? Hematology Am Soc Hematol Educ Program. 2007:121-126.18024619
7. Tsai HM. Pathophysiology of thrombotic thrombocytopenic purpura. Int J Hematol. 2010 Jan; 91(1):1-19.20058209
8. Kremer Hovinga JA, Vesely SK, Terrell DR, Lämmle B, George JN. Survival and relapse in patients with thrombotic thrombocytopenic purpura. Blood. 2010 Feb 25; 115(8):1500-1511.20032506
9. Peyvandi F, Lavoretano S, Palla R, et al. ADAMTS13 and anti-ADAMTS13 antibodies as markers for recurrence of acquired thrombotic thrombocytopenic purpura during remission. Haematologica. 2008 Feb; 93(2):232-239.18223285
10. Zheng XL, Sadler JE. Pathogenesis of thrombotic microangiopathies. Annu Rev Pathol. 2008; 3:249-277.18215115
11. Lämmle B, Kremer Hovinga JA, George JN. Acquired thrombotic thrombocytopenic purpura: ADAMTS13 activity, anti-ADAMTS13 autoantibodies and risk of recurrent disease. Haematologica. 2008 Feb; 93(2):172-177.18245649
12. Moake J. Thrombotic thrombocytopenia purpura (TTP) and other thrombotic microangiopathies. Best Pract Res Clin Haematol. 2009 Dec; 22(4):567-576.19959109
13. Sadler JE. von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura. Blood., 2008 Jul 1; 112(1):11-18.18574040
14. Scully M. Inhibitory anti-ADAMTS13 antibodies: Measurement and clinical application. Blood. 2010 Jan; 24(1):11-16.19963308
15. Zheng XL, Kaufman RM, Goodnough LT, Sadler JE. Effect of plasma exchange on plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in patients with idiopathic and nonidiopathic thrombotic thrombocytopenic purpura. Blood. 2004 Jun 1; 103(11):4043-4049.14982878
16. Scheiflinger F, Knöbl P, Trattner B, et al. Nonneutralizing IgM and IgG antibodies to von Willebrand factor-cleaving protease (ADAMTS13) in a patient with thrombotic thrombocytopenic purpura. Blood. 2003 Nov 1; 102(9):3241-3243.12855569
17. Shelat SG, Smith P, Ai J, Zheng XL. Inhibitory autoantibodies against ADAMTS13 in patients with thrombotic thrombocytopenic purpura bind ADAMTS13 protease and may accelerate its clearance in vivo. J Thromb Haemost. 2006 Aug; 4(8):1707-1717.16879212
18. Rieger M, Mannucci PM, Kremer Hovinga JA, et al. ADAMTS13 autoantibodies in patients with thrombotic microangiopathies and other immunomediated diseases. Blood. 2005 Aug 15; 106(4):1262-1267.15890682
19. Waters AM, Licht C. aHUS caused by complement dysregulation: New therapies on the horizon. Pediatr Nephrol. 2011 Jan; 26(1):41-57. Erratum: 2013 Jan; 28(1):165.20556434
20. Loirat C, Frémeaux-Bacchi V. Atypical hemolytic uremic syndrome. Orphanet J Rare Dis. 2011 Sep 8; 6(1):60.21902819
21. Froehlich-Zahnd R, George JN, Vesely SK, et al. Evidence for a role of anti-ADAMTS13 autoantibodies despite normal ADAMTS13 activity in recurrent thrombotic thrombocytopenic purpura. Haematologica. 2012 Feb; 97(2):297-303.21993669
22. Zhou Z, Nguyes TC, Guchhait P, Dong JF. Von Willebrand factor, ADAMTS-13, and thrombotic thrombocytopenic purpura. Semin Thromb Hemost. 2010 Feb; 36(1):71-81.20391298
23. Kokame K, Matsumoto M, Fujimura Y, Miyata T. VWF73, a region from D1596 to R1668 of von Willebrand factor, provides a minimal substrate for ADAMTS‐13. Blood. 2004 Jan 15;103(2):607‐612.14512308
24. Crawley JT, de Groot R, Xiang Y, Luken BM, Lane DA. Unraveling the scissile bond: how ADAMTS13 recognizes and cleaves von Willebrand factor. Blood. 2011 Sep 22;118(12):3212‐3221.21715306
25. Hubbard AR, Heath AB, Kremer Hovinga JA, Subcommittee on von Willebrand Factor. Establishment of the WHO 1st International Standard ADAMTS13, plasma (12/252): communication from the SSC of the ISTH. J Thromb Haemost. 2015 Jun;13(6):1151‐1153.25714758

LOINC® Map

Order Code Order Code Name Order Loinc Result Code Result Code Name UofM Result LOINC
117921 ADAMTS13 Activity Reflex Panel 53622-7 117928 ADAMTS13 Activity % 53622-7
Reflex Table for ADAMTS13 Activity
Order Code Order Name Result Code Result Name UofM Result LOINC
Reflex 1 117920 ADAMTS13 Antibody 117917 Comment: N/A
Reflex Table for ADAMTS13 Activity
Order Code Order Name Result Code Result Name UofM Result LOINC
Reflex 1 117920 ADAMTS13 Antibody 117916 ADAMTS13 Antibody u/mL 40824-5
Reflex Table for ADAMTS13 Activity
Order Code Order Name Result Code Result Name UofM Result LOINC
Reflex 1 117925 ADAMTS13 Antibody 117931 Comment N/A
Reflex Table for ADAMTS13 Activity
Order Code Order Name Result Code Result Name UofM Result LOINC
Reflex 1 117925 ADAMTS13 Antibody 117916 ADAMTS13 Antibody u/mL 40824-5
Reflex Table for ADAMTS13 Activity
Order Code Order Name Result Code Result Name UofM Result LOINC
Reflex 1 117931 Comment 117931 Comment N/A
Reflex Table for ADAMTS13 Activity
Order Code Order Name Result Code Result Name UofM Result LOINC
Reflex 1 117920 ADAMTS13 Antibody 117917 Comment: N/A
Reflex Table for ADAMTS13 Activity
Order Code Order Name Result Code Result Name UofM Result LOINC
Reflex 1 117920 ADAMTS13 Antibody 117916 ADAMTS13 Antibody u/mL 40824-5
Reflex Table for ADAMTS13 Activity
Order Code Order Name Result Code Result Name UofM Result LOINC
Reflex 1 117931 Comment 117931 Comment N/A

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