Thrombotic thrombocytopenic purpura diagnostic study of choice
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Saeedeh Kowsarnia M.D.[2],Sogand Goudarzi, MD [3], Anum Ijaz M.B.B.S., M.D.[4]
Overview
Immune thrombotic thrombocytopenic purpura (iTTP) is a thrombotic microangiopathy characterized by microangiopathic hemolytic anemia and thrombocytopenia due to severe ADAMTS13 deficiency (<10%). Diagnosis is based on recognizing these laboratory features and confirming markedly reduced ADAMTS13 activity, while the classic clinical pentad is present in fewer than 10% of patients. ADAMTS13 activity testing is the diagnostic study of choice, and clinical prediction scores (e.g., PLASMIC or FRENCH) are used to guide empiric treatment while awaiting results. Prompt recognition and differentiation from other thrombotic microangiopathies is essential because early treatment markedly improves survival.
Diagnosis of TTP
Diagnostic evaluation of TTP begins with confirming thrombocytopenia and MAHA, calculating a clinical risk score, and ordering ADAMTS13 testing. Empiric therapy should not be delayed while awaiting ADAMTS13 results when suspicion is moderate or high.[1]
Diagnostic Study of Choice
- Patients with thrombocytopenia and MAHA without another clear cause of thrombotic microangiopathy should undergo ADAMTS13 activity testing.[2]
- TTP is diagnosed when MAHA and thrombocytopenia are present with ADAMTS13 activity <10%. [3],[4]
- ADAMTS13 activity should ideally be measured before plasma exchange because donor plasma may falsely elevate levels.[5]
- ADAMTS13 activity is commonly measured using fluorescence resonance energy transfer or chromogenic ELISA assays.[4]
- Testing is frequently performed at reference laboratories and results may take more than 72 hours.[5]
- Empiric treatment should be initiated in patients with high clinical suspicion while awaiting ADAMTS13 results, including those with ADAMTS13 activity of 10–20% pending repeat testing.[1]
Laboratory Diagnostic Tests
- Key laboratory findings include thrombocytopenia, typically with platelet count <30 × 10⁹/L.[1],[8].
- Microangiopathic hemolytic anemia is diagnosed by elevated LDH, indirect bilirubin, reticulocytosis, low haptoglobin, and a negative direct Coombs test.[9]
- Peripheral blood smear demonstrates schistocytes comprising ≥1% of red blood cells.[9]
- Daily smear examination may be necessary because schistocytes may initially be absent.[9]
- Coagulation studies (PT, APTT) are usually normal or only mildly prolonged in iTTP.
Anti-ADAMTS13 Testing
- Confirmation of iTTP requires testing for anti-ADAMTS13 antibodies using a functional inhibitor assay and/or IgG ELISA.[5]
- Detectable antibodies are present in approximately 67%–97.8% of patients.[1]
- Absence of detectable antibodies does not exclude iTTP.[4], [10]
- Persistently severe deficiency without antibody detection suggests congenital TTP and should prompt genetic sequencing of the ADAMTS13 gene.[1], [11]
Clinical Prediction Scores
- Clinical prediction scores such as the PLASMIC or French Thrombotic Microangiopathy Reference Center score estimate the probability of severe ADAMTS13 deficiency.[1]
- A PLASMIC score ≥5 has sensitivity approximately 99% for iTTP.[12]. PLASMIC score is the most commonly used predicition score.
- A FRENCH score ≥1 has sensitivity approximately 98.8% for iTTP.[13]
- Empiric treatment should be started in patients with high clinical probability while awaiting ADAMTS13 results.[1]
PLASMIC score
Risk of ADAMTS13 deficiency in adults with suspected TTP :
- Low-risk = 0 to 4 points
- Intermediate risk = 5 points
- High-risk = 6 to 7 points
FRENCH Score (modified)
- Platelet count < 30 x 109/L (+1)
- Creatinine < 2.26 mg/dL (+1)
Score ≥ 1= Probability of severe ADAMTS13 deficiency.
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Chiasakul T, Cuker A (November 2018). "Clinical and laboratory diagnosis of TTP: an integrated approach". Hematology Am Soc Hematol Educ Program. 2018 (1): 530–538. doi:10.1182/asheducation-2018.1.530. PMC 6246034. PMID 30504354.
- ↑ Zheng XL, Vesely SK, Cataland SR, Coppo P, Geldziler B, Iorio A, Matsumoto M, Mustafa RA, Pai M, Rock G, Russell L, Tarawneh R, Valdes J, Peyvandi F (October 2020). "ISTH guidelines for the diagnosis of thrombotic thrombocytopenic purpura". J Thromb Haemost. 18 (10): 2486–2495. doi:10.1111/jth.15006. PMC 8146131 Check
|pmc=value (help). PMID 32914582 Check|pmid=value (help). - ↑ Hassan S, Westwood JP, Ellis D, Laing C, Mc Guckin S, Benjamin S, Scully M (December 2015). "The utility of ADAMTS13 in differentiating TTP from other acute thrombotic microangiopathies: results from the UK TTP Registry". Br J Haematol. 171 (5): 830–5. doi:10.1111/bjh.13654. PMID 26359646.
- ↑ 4.0 4.1 4.2 4.3 Mackie I, Mancini I, Muia J, Kremer Hovinga J, Nair S, Machin S, Baker R (December 2020). "International Council for Standardization in Haematology (ICSH) recommendations for laboratory measurement of ADAMTS13". Int J Lab Hematol. 42 (6): 685–696. doi:10.1111/ijlh.13295. PMID 32672897 Check
|pmid=value (help). - ↑ 5.0 5.1 5.2 Wu N, Liu J, Yang S, Kellett ET, Cataland SR, Li H, Wu HM (January 2015). "Diagnostic and prognostic values of ADAMTS13 activity measured during daily plasma exchange therapy in patients with acquired thrombotic thrombocytopenic purpura". Transfusion. 55 (1): 18–24. doi:10.1111/trf.12762. PMID 24953079.
- ↑ Moore GW, Meijer D, Griffiths M, Rushen L, Brown A, Budde U, Dittmer R, Schocke B, Leyte A, Geiter S, Moes A, Cutler JA, Binder NB (July 2020). "A multi-center evaluation of TECHNOSCREEN® ADAMTS-13 activity assay as a screening tool for detecting deficiency of ADAMTS-13". J Thromb Haemost. 18 (7): 1686–1694. doi:10.1111/jth.14815. PMID 32239643 Check
|pmid=value (help). - ↑ Pascual C, Nieto JM, Fidalgo T, Seguí IG, Díaz-Ricart M, Docampo MF, Del Rio J, Salinas R (June 2021). "Multicentric evaluation of the new HemosIL Acustar® chemiluminescence ADAMTS13 activity assay". Int J Lab Hematol. 43 (3): 485–493. doi:10.1111/ijlh.13414. PMID 33264480 Check
|pmid=value (help). - ↑ Page EE, Kremer Hovinga JA, Terrell DR, Vesely SK, George JN (April 2017). "Thrombotic thrombocytopenic purpura: diagnostic criteria, clinical features, and long-term outcomes from 1995 through 2015". Blood Adv. 1 (10): 590–600. doi:10.1182/bloodadvances.2017005124. PMC 5728353. PMID 29296701.
- ↑ 9.0 9.1 9.2 Zini G, d'Onofrio G, Erber WN, Lee SH, Nagai Y, Basak GW, Lesesve JF (December 2021). "2021 update of the 2012 ICSH Recommendations for identification, diagnostic value, and quantitation of schistocytes: Impact and revisions". Int J Lab Hematol. 43 (6): 1264–1271. doi:10.1111/ijlh.13682. PMID 34431220 Check
|pmid=value (help). - ↑ Simon D, Leclercq M, Joly B, Veyradier A, Coppo P, Benhamou Y (June 2025). "Acquired thrombotic thrombocytopenic purpura without detectable anti-ADAMTS13 antibodies: a possible underlying autoimmune mechanism". Haematologica. 110 (6): 1368–1372. doi:10.3324/haematol.2024.285391. PMC 12130786 Check
|pmc=value (help). PMID 39323409 Check|pmid=value (help). - ↑ Zhao T, Fan S, Sun L (November 2021). "The global carrier frequency and genetic prevalence of Upshaw-Schulman syndrome". BMC Genom Data. 22 (1): 50. doi:10.1186/s12863-021-01010-0. PMC 8600861 Check
|pmc=value (help). PMID 34789164 Check|pmid=value (help). - ↑ Paydary K, Banwell E, Tong J, Chen Y, Cuker A (September 2020). "Diagnostic accuracy of the PLASMIC score in patients with suspected thrombotic thrombocytopenic purpura: A systematic review and meta-analysis". Transfusion. 60 (9): 2047–2057. doi:10.1111/trf.15954. PMID 32757237 Check
|pmid=value (help). - ↑ Coppo P, Schwarzinger M, Buffet M, Wynckel A, Clabault K, Presne C, Poullin P, Malot S, Vanhille P, Azoulay E, Galicier L, Lemiale V, Mira JP, Ridel C, Rondeau E, Pourrat J, Girault S, Bordessoule D, Saheb S, Ramakers M, Hamidou M, Vernant JP, Guidet B, Wolf M, Veyradier A (April 2010). "Predictive features of severe acquired ADAMTS13 deficiency in idiopathic thrombotic microangiopathies: the French TMA reference center experience". PLoS One. 5 (4): e10208. doi:10.1371/journal.pone.0010208. PMC 2859048. PMID 20436664.