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Thrombotic thrombocytopenic purpura: The role of ADAMTS13

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ADAMTS13 ASSAY IS KEY TO DIAGNOSIS

Laboratory evidence typically includes hemolytic anemia (reticulocytosis, schistocytes, elevated indirect bilirubin, reduced haptoglobin, elevated lactate dehydrogenase) and thrombocytopenia.3 There are no significant abnormalities in prothrombin time, international normalized ratio, activated partial thromboplastin time, fibrinogen, or D-dimer level.

Measuring the levels of ADAMTS13 activity, ADAMTS13 inhibitor, and ADAMTS13 antibody is becoming standard to confirm the diagnosis of TTP, to determine if it is congenital or acquired, and to distinguish it from thrombocytopenic conditions such as hemolytic-uremic syndrome, idiopathic thrombocytopenic purpura, and heparin-induced thrombocytopenia.4,5 A newer ADAMTS13 assay based on fluorescence energy transfer (FRET) technology with a synthetic amino acid-von Willebrand factor peptide substrate has a faster turnaround time and less test variability.6,16,17 This FRET assay can give the result of ADAMTS13 activity within 2 hours. In comparison, the assay based on multimeric von Willebrand factor takes 2 to 3 days, and mass spectrometry to measure the cleavage products of a synthetic von Willebrand factor molecule takes about 4 hours.3,10,16

About two-thirds of patients with the clinical diagnosis of idiopathic TTP have ADAMTS13 activity levels lower than 10%.5,14,18 In the appropriate clinical setting, this threshold level is highly sensitive (89%–100%) and specific (99%–100%) in differentiating TTP from other thrombotic angiopathies.2,3,18

Note: The ADAMTS13 assay was needed for early correct diagnosis in Case 1 and Case 2.

Inhibitors provide more clues

Autoantibodies can be classified according to whether they inhibit ADAMTS13 activity.

Neutralizing inhibitors. Most cases of acquired, idiopathic TTP with severe ADAMTS13 deficiency are related to circulating autoantibodies that neutralize ADAMTS13 activity. This ADAMTS13 inhibitor level is obtained by measuring residual ADAMTS13 activity after mixing equal amounts of patient plasma with normal pooled plasma. ADAMTS13 inhibitor is detectable in 44% to 93% of patients with severely deficient ADAMTS13 activity.3,6,19

Nonneutralizing inhibitors. From 10% to 15% of patients with TTP with severe ADAMTS13 deficiency lack ADAMTS13 autoantibodies measured by enzyme immunoassay but have nonneutralizing immunoglobulin G (IgG) or IgM autoantibodies. In such cases, ADAMTS13 deficiency may be related to increased antibody-mediated clearance or other unknown mechanisms.

Neutralizing inhibitors and nonneutralizing inhibitors may be present simultaneously in some patients.3,10,19,20

Blood factors affect ADAMTS13 activity

Specimen factors can affect ADAMTS13 activity and antibody levels.

Hemoglobin is a potent inhibitor of ADAMTS13, so an elevated plasma level of free hemoglobin (> 2 g/dL) can reduce ADAMTS13 activity, as can hyperbilirubinemia (> 15 mg/dL).

High levels of endogenous von Willebrand factor, lipids, thrombin, or other proteases that may cleave ADAMTS13 can also reduce ADAMTS13 activity.3 Conversely, recent plasma exchange or transfusion can mask the diagnosis of TTP because of false normalization of ADAMTS13 activity. In addition, ADAMTS13 autoantibody can be detected in other immune-mediated disorders (eg, systemic lupus erythematosus, antiphospholipid syndrome), and hypergammaglobulinemia, as well as in 10% to 15% of healthy individuals.19

CONSIDER OTHER CONDITIONS

Before diagnosing TTP, other conditions causing thrombocytopenia and hemolytic anemia should be excluded by taking a careful clinical, laboratory, and medication history (Table 2). Of these conditions, the most challenging to differentiate from TTP—and often indistinguishable from it at presentation—is hemolytic-uremic syndrome (Table 3).

Hemolytic-uremic syndrome

Hemolytic-uremic syndrome presents with a triad of thrombocytopenia, acute renal failure, and microangiopathic hemolytic anemia, with increased lactate dehydrogenase levels. Renal dysfunction from ischemia or tissue injury by microvascular thrombi predominates. Hemolytic-uremic syndrome most often occurs in children and is often related to hemorrhagic enterocolitis caused by infection with Escherichia coli O157:H7 or Shigella species (90%–95% of cases).1,2,5

From 5% to 10% of cases of hemolytic- uremic syndrome are atypical. These cases are not associated with diarrhea, and many are caused by genetic mutations that result in chronic excessive complement activation. Implicated genes regulate complement regulator factor H (20%–30% of cases) or CD46 (10%) and other cofactors, or autoantibodies against factor H (10%), which affect the alternate complement pathway.6,21–23

Initial therapeutic plasma exchange is commonly undertaken for atypical hemolytic- uremic syndrome, particularly for patients at risk of rapid progression to end-stage renal failure. But despite such treatment, about 60% of these patients die or develop permanent renal damage within 1 year.2,3,24

Eculizumab, a monoclonal antibody against complement component C5, has been approved by the US Food and Drug Administration for atypical hemolytic-uremic syndrome and may improve quality of life.25–27

PLASMA EXCHANGE IS THE MAINSTAY OF THERAPY

In 2012, the British Society for Haematology published revised guidelines for managing TTP and other thrombotic microangiopathies.28

Acquired idiopathic TTP with reduced ADAMTS13 activity requires immediate therapeutic plasma exchange. Daily plasma exchange combines plasmapheresis to remove circulating ultralarge von Willebrand factor-platelet strings and autoantibodies against ADAMTS13, and infusion of fresh-frozen plasma to replace ADAMTS13.18 This procedure is the mainstay of therapy and brings 70% to 90% of patients with idiopathic TTP to remission.1,2,5,6 However, the optimal duration of daily plasma exchange and the number of procedures required is highly variable according to clinical condition. Therapeutic plasma exchange can also cause plasma-related adverse reactions.9,28 Congenital TTP requires plasma infusion or exchange depending on the patient’s severity of ADAMTS13 deficiency.

Corticosteroids are used in combination with daily therapeutic plasma exchange, although evidence from controlled trials of their efficacy in this setting is lacking. Patients with severely decreased ADAMTS13 activity or low titers of ADAMTS13 autoantibodies tend to respond to the therapy.5,8,29

An ADAMTS13 assay with a short turn-around time can help guide the decision to initiate therapeutic plasma exchange. However, if there is a strong clinical suspicion of TTP, plasma exchange should be initiated immediately without waiting for test results.5,30 Monitoring ADAMTS13 activity or inhibitor during initial plasma exchange therapy has had conflicting results in several studies and is generally not recommended for patients with acquired TTP.8,30,31

RELAPSE IS COMMON

About 20% to 50% of patients with idiopathic TTP experience a relapse (Case 2). Most relapses occur within the first 2 years after the initial episode, with an estimated risk of 43% for relapse at 7.5 years.5,9

Factors that predict a higher risk of relapse include persistently severely decreased ADAMTS13 activity, positive inhibitor, and high titers of autoantibodies to ADAMTS13 during symptomatic TTP. During clinical remission, persistence of autoantibodies also indicates increased risk.1,3,5,6,9

Patients who have a relapse and whose disease is refractory to therapeutic plasma exchange (10%–20% of cases) have been treated with corticosteroids, splenectomy, or immunosuppressive agents (cyclosporine, azathioprine, or cyclophosphamide) with varying rates of success. Rituximab (monoclonal anti-CD20) has recently been used as second-line therapy in refractory or relapsing immune-mediated TTP or idiopathic TTP with neurologic or cardiac symptoms associated with a poor prognosis. Therapy including rituximab results in improved response and progression-free survival.32 Other potential therapies, including recombinant active ADAMTS13, are under investigation.9,23,28,30,33,34

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