Public Comment: Treatment of Thrombotic Thrombocytopenic Purpura (TTP) Guideline Update

The International Society on Thrombosis and Haemostasis (ISTH) published the first clinical practice guidelines for diagnosis and treatment of thrombotic thrombocytopenic purpura (TTP) in 2020 (1–3). To assess the need for updates, a guideline panel convened between March and September in 2024 and agreed that sufficient evidence had emerged since 2020 to warrant review and update of the original recommendations. After a comprehensive literature search was conducted to identify relevant studies, the guideline panel met and systematically reviewed the new evidence. Data were extracted, and evidence profiles were prepared.  The guideline panel then categorized the previously issued recommendations into three groups: 

• Group A: Recommendations not requiring an update 
• Group B: Recommendations requiring an incorporation of new evidence, but with no anticipated change in direction or strength of previously issued recommendation 
• Group C: New recommendations or previous recommendations requiring assessment, vote, and update considering the new evidence

The ISTH welcomes the public to comment on the Group C recommendations. Clinicians, researchers, allied health professionals, policy makers, industry representatives, patients, caregivers, and other members of the public are welcome to contribute to this process. Comments will be reviewed by the guideline panel and relevant comments will be addressed. 

The guideline panel focused its discussions on new evidence from the Scully et al, 2024 NEJM paper (4), which provides direct evidence on the efficacy and safety of recombinant ADAMTS13 compared to those of fresh frozen plasma (FFP) and also provided non-comparative evidence on the efficacy and safety of FFP itself. The guideline panel also reviewed the registry data generated between 2019 and 2024, providing new insight into the severity and impact on patient lives of congenital TTP (cTTP). Previous reports from registries and literature have reported high incidence of major morbidities, including stroke, end-stage kidney disease (ESKD), and cardiac injury (5,6). A recent chart review reported organ damage occurred in 22/78 (28.2%) patients during acute episodes during the study period or during isolated TTP manifestations at index, of which neurological (n=15), renal (n=11), and cardiac (n=8) damage were most common (7). A large systematic review of 226 patients across 96 reports, reported that 14% experienced premature death, including nine neonatal deaths due to severe hemolysis(8). Among survivors older than 40 years, 51% experienced at least one major morbidity, such as stroke, ESKD, or severe cardiac dysfunction. Women with undiagnosed or poorly managed cTTP frequently experience miscarriages, fetal growth restriction, and preeclampsia-like complications with fetal mortality rates up to 50% (9). The guideline panel ultimately decided to add a new Population, Intervention, Comparison, and Outcome (PICO) to the guidelines, and to revise the old PICO about FFP vs watch-and-wait strategy. 


All comments are due by March 19, 2025.

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1.    Zheng XL, Vesely SK, Cataland SR, Coppo P, Geldziler B, Iorio A, et al. ISTH guidelines for the diagnosis of thrombotic thrombocytopenic purpura. J Thromb Haemost [Internet]. 2020 Oct 1 [cited 2025 Mar 3];18(10):2486–95. Available from: https://pubmed.ncbi.nlm.nih.gov/32914582/
2.    Zheng XL, Vesely SK, Cataland SR, Coppo P, Geldziler B, Iorio A, et al. ISTH guidelines for treatment of thrombotic thrombocytopenic purpura. J Thromb Haemost [Internet]. 2020 Oct 1 [cited 2025 Mar 3];18(10):2496–502. Available from: https://pubmed.ncbi.nlm.nih.gov/32914526/
3.    Zheng XL, Vesely SK, Cataland SR, Coppo P, Geldziler B, Iorio A, et al. Good practice statements (GPS) for the clinical care of patients with thrombotic thrombocytopenic purpura. Journal of Thrombosis and Haemostasis. 2020 Oct 1;18(10):2503–12. 
4.    Scully M, Antun A, Cataland SR, Coppo P, Dossier C, Biebuyck N, et al. Recombinant ADAMTS13 in Congenital Thrombotic Thrombocytopenic Purpura. N Engl J Med [Internet]. 2024 May 2 [cited 2025 Mar 3];390(17):1584–96. Available from: https://pubmed.ncbi.nlm.nih.gov/38692292/
5.    Van Dorland HA, Taleghani MM, Sakai K, Friedman KD, George JN, Hrachovinova I, et al. The International Hereditary Thrombotic Thrombocytopenic Purpura Registry: key findings at enrollment until 2017. Haematologica [Internet]. 2019 [cited 2025 Mar 3];104(10):2107–15. Available from: https://pubmed.ncbi.nlm.nih.gov/30792199/
6.    Alwan F, Vendramin C, Liesner R, Clark A, Lester W, Dutt T, et al. Characterization and treatment of congenital thrombotic thrombocytopenic purpura. Blood [Internet]. 2019 Apr 11 [cited 2025 Mar 3];133(15):1644–51. Available from: https://pubmed.ncbi.nlm.nih.gov/30770395/
7.    Coppo P, Scully M, Kremer Hovinga JA, Jose Aragon M, Patwari P, Wang LT, et al. Clinical Outcomes of Congenital Thrombotic Thrombocytopenic Purpura: A Multinational Chart Review Study. Blood [Internet]. 2023 Nov 2 [cited 2025 Mar 3];142(Supplement 1):4006–4006. Available from: https://dx.doi.org/10.1182/blood-2023-189416
8.    Borogovac A, Reese JA, Gupta S, George JN. Morbidities and mortality in patients with hereditary thrombotic thrombocytopenic purpura. Blood Adv [Internet]. 2022 Feb 8 [cited 2025 Mar 3];6(3):750–9. Available from: https://pubmed.ncbi.nlm.nih.gov/34807988/
9.    Matsumoto M, Miyakawa Y, Kokame K, Ueda Y, Wada H, Higasa S, et al. Diagnostic and treatment guidelines for thrombotic thrombocytopenic purpura (TTP) in Japan 2023. Int J Hematol [Internet]. 2023 Nov 1 [cited 2025 Mar 3];118(5):529–46. Available from: https://pubmed.ncbi.nlm.nih.gov/37689812/
 

NEW Recommendation:
For patients with congenital TTP who are in remission, the ISTH guideline panel recommends recombinant ADAMTS13 over fresh frozen plasma infusion. (A strong recommendation in the context of moderate certainty evidence)

Remark: The guideline panel acknowledged the methodological limitations of the Scully et al study (1), but also the extremely rare nature of the condition, and the objective current and future barriers to generating new evidence in the field. A strong recommendation based on moderate quality evidence was issued for the high likelihood of critically important benefit in a potentially life-threatening condition against a low likelihood of side effects. 

The evidence to address this question comes from the interim analysis of a single prospective phase 3, multicenter, open-labeled, randomized, controlled, cross-over trial assessing the efficacy and safety of prophylaxis with recombinant ADAMTS13 among children and adults with cTTP (1). The guideline panel felt confident in the balance of benefits and harms given the available evidence. While there was no significant difference in patient relevant beneficial outcomes such as mortality and acute TTP events, there was a marked difference observed in the prespecified TTP manifestations (e.g., thrombocytopenia, elevated lactate dehydrogenase (LDH), increased creatinine, neurological symptoms, and abdominal pain) and exploratory outcomes (e.g., composite TTP manifestations and other TTP manifestations), which favored recombinant ADAMTS13. In addition, the levels of plasma ADAMTS13 activity (surrogate outcome) were much higher and sustained at levels greater than 10% in patients who received recombinant ADAMTS13 compared to those who were treated with FFP.  ADAMTS13 activity levels correlate with age of onset and disease severity (2), as well as with long term organ function outcomes as supported by external observational evidence (3-6). Additionally, patients tend to prefer recombinant ADAMTS13 over FFP when considering safety, burden of care, feasibility and acceptability. The guideline panel acknowledges the lack of pricing and cost-effectiveness data for recombinant ADAMTS13 and recognizes that these may be barriers to its adoption. In summary, the guideline panel believes, after weighing the evidence and practical considerations, that a strong recommendation for the use of recombinant ADAMTS13 over FFP should be issued. 


Click here to view the recommendation's Summary of Findings Table and Evidence-to-Decision Table for further information.

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1.    Scully M, Antun A, Cataland SR, Coppo P, Dossier C, Biebuyck N, et al. Recombinant ADAMTS13 in Congenital Thrombotic Thrombocytopenic Purpura. N Engl J Med [Internet]. 2024 May 2 [cited 2025 Mar 3];390(17):1584–96. Available from: https://pubmed.ncbi.nlm.nih.gov/38692292/
2.    Lotta LA, Wu HM, Mackie IJ, Noris M, Veyradier A, Scully MA, et al. Residual plasmatic activity of ADAMTS13 is correlated with phenotype severity in congenital thrombotic thrombocytopenic purpura. Blood [Internet]. 2012 Jul 12 [cited 2025 Mar 3];120(2):440–8. Available from: https://pubmed.ncbi.nlm.nih.gov/22529288/
3.    Sui J, Cao W, Halkidis K, Abdelgawwad MS, Kocher NK, Guillory B, et al. Longitudinal assessments of plasma ADAMTS13 biomarkers predict recurrence of immune thrombotic thrombocytopenic purpura. Blood Adv [Internet]. 2019 Dec 23 [cited 2025 Mar 3];3(24):4177–86. Available from: https://pubmed.ncbi.nlm.nih.gov/31856267/
4.    Upreti H, Kasmani J, Dane K, Braunstein EM, Streiff MB, Shanbhag S, et al. Reduced ADAMTS13 activity during TTP remission is associated with stroke in TTP survivors. Blood [Internet]. 2019 Sep 26 [cited 2025 Mar 3];134(13):1037–45. Available from: https://pubmed.ncbi.nlm.nih.gov/31431443/
5.    Sui J, Zheng L, Zheng XL. ADAMTS13 Biomarkers in Management of Immune Thrombotic Thrombocytopenic Purpura. Arch Pathol Lab Med [Internet]. 2023 Aug 1 [cited 2025 Mar 3];147(8):974–9. Available from: https://pubmed.ncbi.nlm.nih.gov/36223210/
6.    Wu N, Liu J, Yang S, Kellett ET, Cataland SR, Li H, et al. Diagnostic and prognostic values of ADAMTS13 activity measured during daily plasma exchange therapy in patients with acquired thrombotic thrombocytopenic purpura. Transfusion (Paris) [Internet]. 2015 Jan 1 [cited 2025 Mar 3];55(1):18–24. Available from: https://pubmed.ncbi.nlm.nih.gov/24953079/
 

Recommendation 7:
For patients with congenital TTP who are in remission, the ISTH guideline panel suggests plasma infusion over a watch-and-wait strategy. (A conditional recommendation in the context of very-low certainty evidence)

Update: change in direction from neutral to favoring FFP over watch-and-wait strategy (PICO Q 7; 2.5.1 in the original publication).

Remark: Factors to be considered in the Shared-Decision-Making (SDM) process include patient characteristics (e.g., age, which increases the risk of exacerbations; trauma, pregnancy, infections or other factors that may trigger the acute episode), safety and availability of the plasma, feasibility of adopting the treatment, acceptability of the associated burden, patient preferences, and values for the balance of risks and benefits.

While available evidence to address this question was limited in 2019, the standard of care arm in Scully et al 2024 (1) provides sufficient non-comparative evidence showing that the regular prophylactic administration of FFP does prevent mortality and acute events in patients with cTTP. The evidence was judged as non-comparative because a watch-and-wait arm was not included in this trial, leaving the possibility that such an arm would have shown no events as with FFP or recombinant ADAMTS13. For the same reasons, the 2024 Scully et al trial provided only indirect evidence to support the recommendation. However, following the Scully et al publication, the guideline panel felt a conditional recommendation for FFP over watch-and-wait is warranted. Though regular plasma infusion (e.g., 10-15 mL/kg body weight, every 1-3 weeks) requires significant resources and can be burdensome for patients, the guideline panel believed that a Shared-Decision-Making conversation should occur to inform that FFP remains effective, and therefore a conditional recommendation in favor of FFP over watch-and-wait approach should be considered when prevention of acute onset of TTP and the disease-associated manifestations is the goal. Individual patient preferences and clinical circumstances should be taken into consideration to guide the decision-making process.

The guideline panel noted the need for new evidence comparing the efficacy and safety of recombinant ADAMTS13, FFP and watch-and-wait strategy (when an option in the SDM process).

Click here to view the recommendation's Summary of Findings Table and Evidence-to-Decision Table for further information.

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1.    Scully M, Antun A, Cataland SR, Coppo P, Dossier C, Biebuyck N, et al. Recombinant ADAMTS13 in Congenital Thrombotic Thrombocytopenic Purpura. N Engl J Med [Internet]. 2024 May 2 [cited 2025 Mar 3];390(17):1584–96. Available from: https://pubmed.ncbi.nlm.nih.gov/38692292/