By Heesun J. Rogers, MD, PhD, and Alan E. Lichtin, MD
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A breakthrough in understanding the pathogenesis of thrombotic thrombocytopenic purpura (TTP) came with the discovery of ADAMTS13 (A Disintegrin and Metalloproteinase with Thrombospondin type 1 motif, member 13), a plasma protein that cleaves von Willebrand factor, which interacts with platelets to promote blood clotting. If ADAMTS13 is lacking, unusually large multimers of von Willebrand factor can accumulate and trigger intravascular platelet aggregation and microthrombosis, causing the signs and symptoms of TTP.
This knowledge has practical applications: we can now measure ADAMTS13 activity, ADAMTS13 inhibitor, and antibodies against ADAMTS13 to help us diagnose TTP and distinguish it from other forms of thrombotic microangiopathy, such as hemolytic-uremic syndrome, that have similar symptoms but require different treatment.
This article describes typical presentations of acute and relapsing TTP; the role of laboratory testing, including the ADAMTS13 assay; and how to manage this condition.
A high risk of death without plasma exchange
TTP is characterized by disseminated microthrombi composed of agglutinated platelets and von Willebrand factor in small vessels. Tissue damage by microthrombi can cause thrombocytopenia, microangiopathic hemolytic anemia and multiorgan failure.
Untreated TTP has a mortality rate of about 90 percent. Rapid diagnosis and prompt initiation of daily therapeutic plasma exchange can improve this grave outlook.
ADAMTS13 deficiency can be acquired or congenital
Two major forms of TTP with ADAMTS13 deficiency and microvascular thrombosis are recognized:
Acquired TTP, the more common form, peaks in incidence between ages 30 and 50. It more often affects women, particularly during and after pregnancy (its estimated prevalence is 1 in 25,000 pregnancies), and African Americans. Acquired TTP may be:
- Primary (idiopathic or autoantibody-mediated), associated with severely decreased ADAMTS13 and the presence of ultra-large von Willebrand factor multimers
- Secondary (23 to 67 percent of cases), arising from a variety of conditions, including autoimmune disorders, solid organ or hematopoietic cell transplant, malignancy, drugs and pregnancy. Secondary TTP has a worse prognosis than idiopathic TTP.
Congenital TTP (Upshaw-Shulman syndrome) is a rare autosomal-recessive disease caused by compound heterozygous or homozygous mutations of the ADAMTS13 gene, producing nonfunctional ADAMTS13 protein. Patients have severely deficient ADAMTS13 activity but usually do not develop autoantibodies.
The clinical picture of TTP is not always classic
TTP is primarily diagnosed clinically, but diagnosis is often difficult because of various nonspecific symptoms. Typical TTP presents with the “classic pentad”:
- Severe thrombocytopenia (70 to 100 percent of patients)
- Microangiopathic hemolytic anemia with multiple schistocytes (70 to 100 percent) (Featured image)
- Neurologic involvement (50 to 90 percent)
- Renal abnormalities (about 50 percent)
- Fever (25 percent)
However, the entire picture often does not emerge in a single patient. Waiting for the entire pentad to develop before diagnosing TTP can have grave clinical consequences, and the presence of thrombocytopenia and unexplained microangiopathic hemolytic anemia are considered clinically sufficient to suspect TTP.
ADAMTS13 assay is key to diagnosis
Laboratory evidence typically includes hemolytic anemia and thrombocytopenia. 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. 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.
Plasma exchange is the mainstay of therapy
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. This procedure is the mainstay of therapy and brings 70 to 90 percent of patients with idiopathic TTP to remission. 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.
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. 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.
Relapse is common
About 20 to 50 percent of patients with idiopathic TTP experience a relapse. Most relapses occur within the first two years after the initial episode, with an estimated risk of 43 percent for relapse at 7.5 years.
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.
Patients who have a relapse and whose disease is refractory to therapeutic plasma exchange (10 to 20 percent of cases) have been treated with corticosteroids, splenectomy or immunosuppressive agents (cyclosporine, azathioprine or cyclophosphamide) with varying rates of success. Rituximab 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. Other potential therapies, including recombinant active ADAMTS13, are under investigation.
Dr. Rogers is Medical Director of Hemostasis and Thrombosis and a hematopathologist in the Department of Laboratory Medicine. Dr. Lichtin is staff in the Department of Hematologic Oncology and Blood Disorders.
This abridged article originally appeared in its full version in Cleveland Clinic Journal of Medicine. The full article includes case studies and a CME component as well as a full list of references.