Reviews
Thrombotic thrombocytopenic purpura: The role of ADAMTS13
ADAMTS13 testing is useful in diagnosing this disease, guiding therapy, and predicting relapse.
Our knowledge of the pathogenesis of thrombotic microangiopathies has greatly advanced in the last decade, improving the diagnosis and treatment of these diseases.
Many conditions involve thrombotic microangiopathies (Table 1). This article reviews the most common ones, ie, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, atypical hemolytic uremic syndrome, and antiphospholipid syndrome—their clinical features (focusing on the kidney), course, and management. Of note, although the diseases are similar, their pathogeneses and treatments differ.
DIFFERENT PATHWAYS TO MULTIORGAN THROMBOSIS
The thrombotic microangiopathies are multisystem disorders that can affect children and adults and often present with prominent renal and neurologic involvement. Endothelial injury is likely the inciting factor leading to thrombosis in the kidney and in many other organs. The causes variously include:
- Toxins from bacteria or drugs
- Abnormal complement activation, genetic or autoantibody-induced
- Procoagulant factors, eg, antiphospholipid antibodies
- Loss of anticoagulants, eg, from a defect of ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13); ADAMTS13 is also known as von Willebrand factor-cleaving protease
- Severe hypertension.
The histopathologic features are similar in all the thrombotic microangiopathies. Laboratory findings include thrombocytopenia, microangiopathic hemolytic anemia (with schistocytes on the peripheral blood smear), and high serum lactate dehydrogenase (LDH) levels; these are also markers of treatment progress. Bilirubin may be elevated and haptoglobin absent. Renal biopsy reveals thrombi in the glomeruli and arterioles.
THROMBOTIC THROMBOCYTOPENIC PURPURA
A young woman with fever, bruising, and renal failure, then blindness
A 36-year-old black woman who had been previously healthy presents to her doctor with fever and bruising.
Her hematocrit is 28% (reference range 38%–46%), platelet count 15 x 109/L (150–450), and prothrombin and partial thromboplastin times are normal. Her peripheral blood smear shows microangiopathic hemolytic anemia with schistocytes.
Over the next few days, her urine output declines and she develops sudden blindness followed by decreased mental acuity. Blood is drawn and sent for ADAMTS13 assay. Treatment is started at once with daily therapeutic plasma exchange. The assay results, when they arrive, show marked ADAMTS13 reduction (< 5%). Over the ensuing weeks, her mental acuity improves, her vision returns, and her renal function improves.
ADAMTS13 deficiency is definitive
Thrombotic thrombocytopenic purpura is characterized by:
- Neurologic abnormalities and acute renal failure
- Thrombocytopenia and microangiopathic hemolytic anemia
- Histologic evidence of thrombotic microangiopathy
- Deficiency of von Willebrand factor-cleaving protease (ADAMTS13 < 10%).
von Willebrand factor forms ultralarge multimers in the circulation that interact with platelets; these are normally cleaved by ADAMTS13. With ADAMTS13 deficiency (from either a genetic mutation or autoantibodies), the ultralarge multimers lead to coagulation as blood flows through small vessels.1
In 2003, Tsai2 evaluated 127 patients over age 10 who had thrombocytopenia and microangiopathic hemolysis with no plausible cause or features suggestive of hemolytic uremic syndrome. All were severely deficient in ADAMTS13. Subsequently, thrombotic thrombocytopenic purpura has been defined by a severe actual or effective deficiency of ADAMTS13.
Prompt plasma exchange is critical
Although the ADAMTS13 assay is important for diagnosing thrombotic thrombocytopenic purpura, in suspected cases daily plasma exchange should be started promptly, before test results return. Plasma exchange removes autoantibodies to ADAMTS13 from the blood, removes circulating ultralarge von Willebrand factor multimers, and replaces the missing ADAMTS13. Untreated, the disease is progressive, with irreversible renal failure, neurologic deterioration, and a 90% mortality rate. Plasma exchange reduces the mortality rate to less than 15%. If another diagnosis is confirmed, plasma exchange can be stopped.
Plasma exchange has been shown in clinical trials to be superior to plasma infusion in normalizing platelet counts and reducing mortality.3,4 Mortality rates were comparable with different replacement fluids vs fresh-frozen plasma, including solvent or detergent-treated plasma, and cryo-poor (cryosupernatant) plasma.4 Antiplatelet therapy, platelet transfusions, and splenectomy are ineffective.
Glucocorticoids for early treatment
An appropriate strategy is to add a glucocorticoid to plasma-exchange therapy at once (oral prednisone 1 mg/kg per day or intravenous methylprednisolone 125 mg twice daily) and withdraw it after several days if it is determined that it is not needed. Steroids for suspected thrombotic thrombocytopenic purpura can be justified for several reasons:
- The results of the ADAMTS13 assay are usually delayed, so steroids provide coverage for other diagnoses.
- They are helpful if thrombotic thrombocytopenic purpura is idiopathic (which is true for most cases) and if the patient has a poor response to initial therapy with plasma exchange.
- They are indicated for patients whose platelet counts do not increase with several days of plasma exchange or whose thrombocytopenia recurs as plasma exchange is decreased.
Rituximab improves survival
Rituximab, a chimeric (half murine) monoclonal antibody against CD19 and CD20 B cells, suppresses antibody production by knocking out the precursors of antibody-producing cells.
Anecdotal reports and small studies involving a total of 42 patients have been published on the use of rituximab for thrombotic thrombocytopenic purpura. Courses of rituximab varied greatly, from 1 to 13 weekly doses at 375 mg/m2, with 4 doses being the most common. Complete remission occurred in 90% of cases.5,6 A typical study from 2014 involved 48 patients (30 of whom received rituximab) followed by severe ADAMTS13 deficiency during remission.7 Despite the small study size, the investigators found significantly improved relapse-free survival rates with rituximab treatment.
But rituximab can cost $25,000 for 2 doses of 1,000 mg, and this will most likely prohibit its routine use. The cost and insurance coverage vary with location and policies.
Based on such studies, a reasonable strategy is to treat thrombotic thrombocytopenic purpura with:
- Daily plasma exchange
- Steroids, at least until the diagnosis is certain
- Rituximab if warranted.
New targeted therapies
Caplacizumab, a humanized immunoglobulin that inhibits the interaction between ultralarge von Willebrand factor multimers and platelets, has the potential to change this strategy when it receives US Food and Drug Administration approval, which is expected soon.
Peyvandi et al8 randomized 75 patients with acquired thrombotic thrombocytopenic purpura to either subcutaneous caplacizumab 10 mg daily for 30 days or placebo. Both groups had daily plasma exchange. The treatment group had a 39% reduction in median time to normalization of platelets vs the placebo group, and 3 of 36 patients had exacerbations, compared with 11 of 39 patients in the placebo group. Although 8 patients relapsed within the first month after stopping caplacizumab, their cases were brought under control. There were also more bleeding episodes with caplacizumab (54% vs 38%), most being mild to moderate. Two patients in the placebo group died, but none in the treatment group.
The fact that platelet normalization occurred significantly faster with caplacizumab, even in some patients who had not yet had plasma exchange therapy initiated, has enormous clinical significance. The low platelet count in thrombotic thrombocytopenic purpura is a marker of susceptibility to rapid damage to the brain and kidneys, so correcting it quickly is critical.
Other strategies for new drug development include replacing the deficient ADAMTS13 with a recombinant molecule and blocking antibody production (the same mode of action as rituximab and glucocorticoids).9 Using all 3 strategies to treat thrombotic thrombocytopenic purpura may be the future standard of care.
