Guideline sources The following summarized guidelines for the evaluation and management of thrombotic thrombocytopenic purpura are prepared by our editorial team based on guidelines from the International Society on Thrombosis and Haemostasis (ISTH 2020), the American Society for Apheresis (ASFA 2019), the Blood Coagulation Abnormalities Research Team (BCART 2017), the British Committee for Standards In Haematology (BCSH 2012), and the Kidney Disease: Improving Global Outcomes Foundation (KDIGO 2012). 1 2 3 4 5 6 Pathway Calculator Calculator Thrombotic thrombocytopenic p French mortality score in thromb PLASMIC Diagnosis and management Guidelines https://web.pathway.md/diseases/rec61LpJ7bzQVLtfv 1/6 6/24/23, 4:06 PM Thrombotic thrombocytopenic purpura Pathway 1. Diagnostic investigations Initial evaluation: Diagnose TTP on the basis of clinical history, examination and routine laboratory parameters, including blood film review. A Obtain serological tests for human immunodeficiency virus, HBV and HCV, autoantibody screen, and a pregnancy test when appropriate, at presentation. A ADAMTS13 activity and anti-ADAMTS13 antibodies: As per ISTH 2020 guidelines, consider obtaining plasma ADAMTS13 testing (such as ADAMTS13 activity and inhibitors or anti-ADAMTS13 IgG) before initiating therapeutic plasma exchange or any blood product in patients with a high ( 90% pretest probability), intermediate or low clinical suspicion of immune-mediated TTP (based on clinical assessment or a formal clinical risk assessment method) in settings with a timely access to plasma ADAMTS13 activity testing. C As per BCSH 2012 guidelines, obtain pre-treatment samples to measure ADAMTS13 activity levels and detect anti-ADAMTS13 antibodies. Recognize that measurement of ADAMTS 13 antigen levels is also useful in congenital TTP. B 2. Medical management General principles: treat TTP as a medical emergency. A Corticosteroids: As per ISTH 2020 guidelines: Initiate corticosteroids without waiting for the results of ADAMTS13 testing in patients with a high clinical suspicion of immune-mediated TTP. B Consider initiating corticosteroids in patients with an intermediate or low clinical suspicion of immune-mediated TTP, depending on the clinician's judgment and assessment of the individual patient. C As per ISTH 2020 guidelines, add corticosteroids to therapeutic plasma exchange in patients with immune-mediated TTP experiencing a first acute event. B As per BCART 2017 guidelines, initiate corticosteroids either as IV pulse therapy (such as methylprednisolone 1,000 mg/day for 3 days, then tapered) or high-dose oral therapy (such as prednisolone 1 mg/kg/day for 2 weeks, followed by a rapid reduction to 0.5 mg/kg/day, then tapered to the range of approximately 2.5-5.0 mg/week) in the acute phase of TTP. B As per BCSH 2012 guidelines, consider initiating IV methylprednisolone (1,000 mg IV daily for 3 consecutive days in adults) or high-dose oral prednisolone (1 mg/kg PO daily). B Caplacizumab: As per ISTH 2020 guidelines, consider initiating early caplacizumab before receiving plasma ADAMTS13 activity results in patients with a high clinical suspicion of immune-mediated TTP. C https://web.pathway.md/diseases/rec61LpJ7bzQVLtfv 2/6 6/24/23, 4:06 PM Thrombotic thrombocytopenic purpura Pathway Show 4 more As per ISTH 2020 guidelines, consider initiating caplacizumab in patients with immune-mediated TTP experiencing an acute event (first event or relapse). C Rituximab: As per ISTH 2020 guidelines: Consider adding rituximab as early as possible in patients with plasma ADAMTS13 activity < 10 IU/dL (or < 10% of normal) (a positive result) because a majority (> 95%) of these adult patients have autoantibodies against ADAMTS13. C Consider adding caplacizumab and rituximab if ADAMTS13 activity is < 10 IU/dL (or < 10% of normal) with inhibitors or an elevated level of anti-ADAMTS13 IgG (a positive result). C As per ISTH 2020 guidelines, consider adding rituximab to corticosteroids and therapeutic plasma exchange in patients with immune-mediated TTP experiencing a first acute event. C As per BCSH 2012 guidelines, consider initiaitng rituximab, in conjunction with plasma exchange and corticosteroids, in patients with acute idiopathic TTP with neurological or cardiac involvement. B Maintenance of remission: As per ISTH 2020 guidelines, consider initiating rituximab for prophylaxis in patients with immune-mediated TTP in remission having low plasma ADAMTS13 activity with no clinical signs/symptoms. C Show 2 more As per BCSH 2012 guidelines, consider offering elective therapy with rituximab in patients with a documented reduction of ADAMTS 13 activity to < 5%. B Antiplatelet agents: As per BCART 2017 guidelines, consider initiating aspirin (81-100 mg once daily in the morning until the termination of corticosteroids) when the platelet count recovers to > 50, 000/ L. C As per BCSH 2012 guidelines, consider initiating low-dose aspirin (75-81 mg PO daily) during platelet recovery (platelet count has reached > 50, 000/ L). C Thromboprophylaxis: administer thromboprophylaxis with LMWH in patients reached platelet count > 50, 000/ L. B 3. Nonpharmacologic interventions Folate supplementation: initiate folate supplements in patients with active hemolysis. A 4. Therapeutic procedures Plasmapheresis: As per ISTH 2020 guidelines: https://web.pathway.md/diseases/rec61LpJ7bzQVLtfv 3/6 6/24/23, 4:06 PM Thrombotic thrombocytopenic purpura Pathway Perform therapeutic plasma exchange without waiting for the results of ADAMTS13 testing in patients with a high clinical suspicion of immune-mediated TTP. B Consider performing therapeutic plasma exchange in patients with an intermediate or low clinical suspicion of immune-mediated TTP, depending on the clinician's judgment and assessment of the individual patient. C As per BCART 2017 guidelines, perform plasma exchange with FFP (50-75 mL/kg) once daily in the acute phase of TTP, ideally, until 2 days after the platelet count is normalized ( 150, 000/ L). A As per BCSH 2012 guidelines, initiate plasma exchange immediately, preferably within 4-8 hurs, in patients with microangiopathic hemolytic anemia and thrombocytopenia in the absence of any other identifiable clinical cause. B Show 4 more Blood product transfusion: As per BCART 2017 guidelines: Consider administering RBC transfusion in patients with acquired TTP without cardiac disorders in the acute phase if Hgb levels decrease to < 7.0 g/dL. Consider performing RBC transfusion in patients with cardiac disorders if Hgb levels < 8.0 g/dL. B Consider administering platelet transfusion in patients with acquired TTP in the acute phase with life-threatening bleeding. Do not administer prophylactic platelet transfusion in other situations as it may aggravate thrombosis. B As per BCSH 2012 guidelines: Do not administer platelet transfusions in patients with TTP unless there is life-threatening hemorrhage. D Administer PRBC transfusion according to clinical need especially if there is cardiac involvement. A 5. Surgical interventions Splenectomy: consider performing splenectomy in rare cases, during the non-acute period of immune-mediated TTP, recognizing that it has limited proven benefit. C 6. Specific circumstances Pregnant patients: As per ISTH 2020 guidelines, initiate prophylactic treatment in pregnant patients with immune- mediated TTP having decreased plasma ADAMTS13 activity without clinical signs/symptoms. B Show 2 more As per BCSH 2012 guidelines, diagnose TTP and initiate plasma exchange if a thrombotic microangiopathy cannot be fully explained by a non-TTP pregnancy-related thrombotic https://web.pathway.md/diseases/rec61LpJ7bzQVLtfv 4/6 6/24/23, 4:06 PM Thrombotic thrombocytopenic purpura Pathway microangiopathy. B Show 4 more Patients with HIV: measure viral load and closely involve an human immunodeficiency virus physician in the management of patients with TTP and human immunodeficiency virus infection. A Show 4 more Patients with systemic lupus erythematosus: consider performing plasma exchange in patients with SLE and TTP, as for patients with TTP without SLE. C Patients with malignancy: Do not perform plasma exchange in the management of patients with malignancy and bone marrow transplant-associated thrombotic microangiopathy. D Consider trading the underlying cancer in patients with cancer-associated thrombotic microangiopathy. B Patients with congenital TTP: As per ISTH 2020 guidelines: Administer either plasma infusion or offer watch-and-wait strategy in patients with congenital TTP in remission. B Avoid initiating factor VIII concentrate versus a watch-and-wait strategy in patients with congenital TTP in remission. D As per ISTH 2017 guidelines, administer FFP 5-10 mL/kg once every 2-3 weeks in patients with congenital TTP. B As per BCSH 2012 guidelines, suspect congenital TTP in neonates presenting with severe jaundice. Recognize that presentation may also occur in childhood or as an adult. A Show 4 more 7. Patient education General counseling: counsel patients and provide with verbal and written information about symptoms, signs and risk of relapse before discharge. A Show 2 more 8. Follow-up and surveillance Management of refractory disease: As per BCART 2017 guidelines, consider initiating rituximab in combination with plasma exchange if the platelet count does not increase to 50, 000/ L after five plasma exchange sessions. B Show 3 more As per BCSH 2012 guidelines: https://web.pathway.md/diseases/rec61LpJ7bzQVLtfv 5/6 6/24/23, 4:06 PM Thrombotic thrombocytopenic purpura Pathway Initiate rituximab in patients with refractory immune-mediated TTP. B Consider adding rituximab and increasing the frequency of plasma exchange in patients with refractory TTP. B Management of relapse: As per ISTH 2020 guidelines, add corticosteroids to therapeutic plasma exchange in patients with immune-mediated TTP experiencing a relapse. B Show 2 more As per BCART 2017 guidelines, consider initiating rituximab in combination with plasma exchange if the platelet count decreases to < 50, 000/ L after initially recovering to > 150, 000/ L after five plasma exchange sessions. B Show 3 more As per BCSH 2012 guidelines: Perform plasma exchange at an increased dose and/or add rituximab therapy in patients with relapsing disease. B Consider initiating cyclosporin A as second-line therapy in patients with acute or chronic relapsing acquired TTP. B References 1. X. Long Zheng, Sara K. Vesely, Spero R. Cataland et al. ISTH guidelines for treatment of thrombotic thrombocytopenic purpura. J Thromb Haemost. 2020 Oct; 18 10 2496 2502. Open 2. Scully M, Hunt BJ, Benjamin S et al. Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies. Br J Haematol. 2012 Aug;158 3 323 35. Open 3. X. Long Zheng, Sara K. Vesely, Spero R. Cataland et al. ISTH guidelines for the diagnosis of thrombotic thrombocytopenic purpura. J Thromb Haemost. 2020 Oct; 18 10 2486 2495. Open 4. Matsumoto M, Fujimura Y, Wada H et al. Diagnostic and treatment guidelines for thrombotic thrombocytopenic purpura TTP 2017 in Japan. Int J Hematol. 2017 Jul;106 1 3 15. Open 5. Anand Padmanabhan, Laura Connelly-Smith, Nicole Aqui et al. Guidelines on the Use of Therapeutic Apheresis in Clinical Practice Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Eighth Special Issue. J Clin Apher. 2019 Jun;34 3 171 354. Open 6. KDIGO. Chapter 12 Lupus nephritis. Kidney Int Suppl 2011 . 2012 Jun;2 2 221 232. Open 7. A Li, P R Khalighi, Q Wu et al. External validation of the PLASMIC score: a clinical prediction tool for thrombotic thrombocytopenic purpura diagnosis and treatment. J Thromb Haemost. 2018 Jan;16 1 164 169. Open 8. Ruchika Goel, Karen E King, Clifford M Takemoto et al. Prognostic risk-stratified score for predicting mortality in hospitalized patients with thrombotic thrombocytopenic purpura: nationally representative data from 2007 to 2012. Transfusion. 2016 Jun;56 6 1451 8. Open https://web.pathway.md/diseases/rec61LpJ7bzQVLtfv 6/6