Thrombotic microangiopathy (TMA) is an all-encompassing term that is used to describe an occlusive microvascular disease, manifested by microangiopathic hemolytic anemia (MAHA) and thrombocytopenia (Figure 1). Thrombotic thrombocytopenic purpura (TTP) is a rare TMA that typically presents in adulthood and has a worldwide incidence of 1.5-6 cases per million per year. In the United States, the incidence is 2.99 cases per million per year (1). Although TTP is uncommon, it is a devastating disease with high mortality if left untreated and should be considered a clinical emergency. The classical pentad of clinical manifestations (fever, thrombocytopenia, MAHA, acute kidney injury [AKI], and neurological manifestations) is not present in a majority of the patients, and presence of thrombocytopenia and MAHA alone should be sufficient to consider a diagnosis of TTP. Early diagnosis and treatment are crucial, as untreated TTP has a mortality of >90%. It is important that nephrologists be aware of the manifestations and management of the disease, as kidney complications are common and may lead to chronic kidney disease (2).
The International Society on Thrombosis and Haemostasis (ISTH) has published new clinical practice guidelines for the diagnosis and treatment of TTP. Developed in partnership with McMaster University, the ISTH TTP guidelines are the product of a rigorous, systematic review of evidence by a guideline panel comprised of clinical experts, methodologists, and patient representatives (3, 4). The guidelines can be reviewed in detail on the ISTH website (https://www.isth.org/page/TTPGuidelines).
TTP is caused by severe inherited deficiency of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13; hereditary or congenital TTP) or due to the presence of antibodies against ADAMTS13 (immune-mediated TTP). ADAMTS13 is responsible for cleaving von Willebrand factor (VWF) multimers, thereby regulating unchecked platelet adhesion and thrombosis in the microvasculature. ADAMTS13 activity of <10% denotes severe disease and confirms the diagnosis of TTP. The PLASMIC clinical score was developed and validated to predict which patients might have an ADAMTS13 activity less than 10% and is now recommended to help with pretest probability and support the diagnosis of TTP (5, 6). The score includes platelet count, hemolysis, presence or absence of malignancy, solid organ or bone marrow transplant, mean corpuscular volume (MCV), international normalized ratio (INR), and serum creatinine (Figure 2). ISTH recommends testing for ADAMTS13 activity for all cases of suspected TTP, but its suggestions for further management are stratified on whether the test is readily available (within 72 h) or available after delay (3-7 days) or whether it is not available at all (3).
The management of TTP involves use of corticosteroids, therapeutic plasma exchange (TPE), rituximab, and/or caplacizumab. Table 1 gives an overview of the ISTH treatment recommendations. Caplacizumab (Cablivi) is an anti-VWF monoclonal antibody, and the US Food and Drug Administration (FDA) approved its use in the United States in February 2019 for treatment of adult patients with acquired TTP. It was approved for use in the European Union (EU) in 2018. In a double-blind randomized controlled trial (RCT), 145 patients were randomized to receive either caplacizumab or placebo, along with TPE. The percentage of patients with a composite outcome of TTP-related death, recurrence of TTP, or thromboembolic event was 74% lower in the treatment group compared to placebo (12% vs. 49%) (7).
It should be noted that a Patient Advisory Panel provided guidance to the committee on its recommendations. Conflicts of interest (COIs) among the committee members for 12 months prior to the initiation date were gathered, and individuals with major COIs were required to abstain from formulating and voting on specific recommendations. The COIs of committee members are noted on the last page of each paper. A majority of recommendations are based on very low certainty evidence, as this is a rare disease with few RCTs. Caplacizumab is extremely expensive ($270,000 per TTP episode) and may not be widely available (8). In cost-effectiveness models, caplacizumab was deemed not cost effective when compared to standard of care (corticosteroids and TPE with or without rituximab) (8). Therefore, recommendations for its use are not generalizable among US medical centers and even less so across the world. The American Society of Nephrology is not providing an endorsement of these guidelines but merely sharing the recommendations for informational and educational purposes. A high index of suspicion, timely and accurate diagnosis, and early treatment with TPE or plasma exchange are crucial in reducing morbidity and mortality from this life-threatening disease.
Sukumar S, et al. Thrombotic thrombocytopenic purpura: Pathophysiology, diagnosis, and management. J Clin Med 2021; 10:536. doi: 10.3390/jcm10030536
Little DJ, et al. Long-term kidney outcomes in patients with acquired thrombotic thrombocytopenic purpura. Kidney Int Rep 2017; 2:1088–1095. doi: 10.1016/j.ekir.2017.06.007
Zheng XL, et al. ISTH guidelines for the diagnosis of thrombotic thrombocytopenic purpura. J Thromb Haemost 2020; 18:2486–2495. doi: 10.1111/jth.15006
Zheng XL, et al. ISTH guidelines for treatment of thrombotic thrombocytopenic purpura. J Thromb Haemost 2020; 18:2496–2502. doi: 10.1111/jth.15010
Bendapudi PK, et al. Derivation and external validation of the PLASMIC score for rapid assessment of adults with thrombotic microangiopathies: A cohort study. Lancet Haematol 2017; 4:e157-e164. doi: 10.1016/S2352-3026(17)30026-1
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, Bendapudi PK Derivation and external validation of the PLASMIC score for rapid assessment of adults with thrombotic microangiopathies: A cohort study. Lancet Haematol 2017; 4: e157-e164. doi: 10.1016/S2352-3026(17)30026-1 10.1016/S2352-3026(17)30026-1
Wynick C, et al. Validation of the PLASMIC score for predicting ADAMTS13 activity <10% in patients with suspected thrombotic thrombocytopenic purpura in Alberta, Canada. Thromb Res 2020; 196:335–339. doi: 10.1016/j.thromres.2020.09.012
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, Wynick C Validation of the PLASMIC score for predicting ADAMTS13 activity <10% in patients with suspected thrombotic thrombocytopenic purpura in Alberta, Canada. Thromb Res 2020; 196: 335– 339. doi: 10.1016/j.thromres.2020.09.012 10.1016/j.thromres.2020.09.012
Scully M, et al. Caplacizumab treatment for acquired thrombotic thrombocytopenic purpura. N Engl J Med 2019; 380:335–346. doi: 10.1056/NEJMoa1806311
Goshua G, et al. Cost effectiveness of caplacizumab in acquired thrombotic thrombocytopenic purpura. Blood 2021; 137:969–976. doi: 10.1182/blood.2020006052