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Diagnosis and Management of aTTP: An Expert’s Review of Current Clinical Practice

Paul Coppo, MD, PhD

Professor of Hematology
Sorbonne University
Doctor of Hematology, AP-HP
Paris, France

Paul Coppo, MD, has disclosed that he has received consulting fees from Alexion Pharmaceuticals, Octapharma AG, Roche, Sanofi Aventis , Sanofi, and Takeda and fees for non-CME/CE services from Alexion Pharmaceuticals, Roche, Sandoz, Sanofi Aventis, and Takeda.

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Released: October 21, 2021

Acquired/autoimmune thrombotic thrombocytopenic purpura (aTTP) is an immune-mediated and potentially life-threatening syndrome of thrombotic microangiopathy manifested by excessive platelet aggregation and endothelial cell destruction, with subsequent thrombocytopenia, microangiopathic hemolytic anemia, and multiorgan failure (heart, kidneys, and central nervous system) leading to substantial morbidity and mortality. The cause of aTTP is deficiency in a plasma metalloprotease known as ADAMTS13, which mitigates the propensity of von Willebrand factor and platelets to form microvascular thrombosis when exposed to high shear stress in the microcirculation. In this commentary, I provide an overview of aTTP diagnosis and management using current International Society on Thrombosis and Haemostasis guidelines, ADAMTS13 biomarker testing, and novel targeted therapies.

Initial Patient Presentation
Most patients presenting with aTTP—approximately 70% of cases—are women. These women are typically of childbearing age and are often overweight or obese. These patient characteristics are suggestive of estrogen’s role in the pathophysiology of the disease. Clinically, patients can present with associated organ damage including cerebral involvement such as headache, confusion, fatigue, focal deficiency, or even seizures or coma. In other instances, they can present with abdominal pain because of digestive tract or pancreatic involvement and—in most severe cases—can have heart involvement with cardiac rhythm disturbances. Even directly, they can have a fatal case of aTTP if they have significant cardiac involvement.  

Initial Workup, Biomarker Characterization, and Treatment of aTTP
When we look at laboratory tests, patients can present with microangiopathic hemolytic anemia characterized by the presence of schistocytes on blood smear. Cytopenias can be profound, with hemoglobin levels of approximately 8 g/dL and platelet counts typically below 30 x 109/L. Patients also have features of hemolysis and mild renal involvement. In addition, it is crucial to assess cardiac troponin to address whether these patients have cardiac involvement, as this feature is of prognostic value. Taken together, these features are very important because the association of profound thrombocytopenia with mild renal involvement can be predictive of a severe ADAMTS13 deficiency, and ADAMTS13 activity is the best biomarker to differentiate aTTP from the other forms of thrombotic microangiopathy. However, ADAMTS13 activity testing is not usually available in real time during an emergency. In most countries and centers around the world, ADAMTS13 activity results are available, at best, within 3‑7 days. Thus, given the need to start these patients on adaptive therapy during an emergency, practitioners have developed surrogate indicators for ADAMTS13 with the French score and the PLASMIC score for adult patients with no comorbid conditions (eg, pregnancy, cancer, sepsis, organ/tissue transplantation). It also is worth noting that the French and PLASMIC scores may not be reliable for assessing aTTP in children. However, both scores tell the same story, which is that in a patient with features of thrombotic microangiopathy and no associated disease or condition, severe thrombocytopenia and mild renal involvement are strongly associated with a severe ADAMTS13 deficiency. French and PLASMIC scores can help inform whether we should immediately start an adaptive treatment in those patients. Acute treatment for aTTP may include targeted therapies such as rituximab and the anti–von Willebrand factor nanobody caplacizumab, along with plasma exchange and steroids—provided that severe ADAMTS13 deficiency will be ascertained in the following days. In addition, associated comorbidities in these patients also should be evaluated for an optimal management.

Current Challenges in aTTP: Delay in Diagnosis Can Lead to Death
Diagnosing aTTP can be challenging because presentation of this rare disease is sudden. The incidence of aTTP is only 2-6 cases per million individuals, and it can be challenging to reach an accurate diagnosis in a timely manner. Moreover, a delay in diagnosis can lead to more complications or even death. For these reasons, it is imperative for practitioners (eg, urgent care providers, hematologists, internal medicine specialists, and nephrologists) to become familiar with the presentation and clinical features suggestive of an aTTP diagnosis based on the International Society on Thrombosis and Haemostasis guidelines: bicytopenia, which are microangiopathic hemolytic anemia (eg, hemoglobin and hematocrit below the lower limit of the reference range, low haptoglobin, elevated lactate dehydrogenase, the presence of schistocytes in peripheral blood smear) with thrombocytopenia (platelets <100 x 109/L); organ failure; and bicytopenia with schistocytes, and the sudden and acute nature of the disease—usually within very few prodromes. Most patients who still die from aTTP do so because there is a delay in diagnosis and treatment. Current treatments for aTTP are very effective, and most patients can be cured—at least for the acute phase. In our collective experience, those patients who still die from aTTP died simply because we did not have enough time to start the treatment for a very aggressive disease that was not diagnosed in a timely fashion.

American Society of Hematology (ASH) Satellite Symposia on aTTP
Want to learn how to save the lives of patients with aTTP with accurate and timely diagnosis? Join me, Ara Metjian, MD, and Marshall Mazepa, MD, at the upcoming ASH 2021 satellite symposium titled “aTTP: Clinical Application of Precision Medicine and New Guidelines.” We will discuss the diagnosis and initial management of aTTP, how to manage relapsed or refractory aTTP, and ongoing clinical trials for aTTP, including key abstracts from ASH 2021. We also will cover exciting new plasma exchange–free regimens for aTTP and new perspectives on how to alleviate management and the burden of care.

Your Thoughts?
What challenges do you experience in the diagnosis and management of aTTP? I encourage you to answer the polling question and join the conversation in the discussion box below.

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