Thrombotic thrombocytopenic purpura medical therapy
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sogand Goudarzi, MD [2] Anum Ijaz M.B.B.S., M.D.[3]
Overview
Immune thrombotic thrombocytopenic purpura (iTTP) is a medical emergency, and treatment should begin as soon as the diagnosis is suspected without waiting for ADAMTS13 results. First-line therapy consists of daily therapeutic plasma exchange with corticosteroids, with adjunctive rituximab and caplacizumab used in most patients. Plasma exchange removes anti-ADAMTS13 antibodies and restores enzyme activity, rituximab suppresses ongoing autoantibody production, and caplacizumab rapidly inhibits vWF-mediated platelet adhesion to control microvascular thrombosis. After remission, patients require ADAMTS13 monitoring and relapse prevention, commonly with preemptive rituximab when enzyme activity declines.
Medical Therapy
Treatment of Acute Initial Episode:
For a first acute iTTP episode, 2020 International Society on Thrombosis and Haemostasis (ISTH) guidelines recommend first-line treatment with therapeutic plasma exchange plus corticosteroids (strong recommendation), and suggest adding rituximab and caplacizumab (conditional recommendation).[1]
Therapeutic plasma exchange (TPE)
- Therapeutic plasma exchange removes anti-ADAMTS13 antibody and provides ADAMTS13 via donor plasma.[2],[3]
- Therapeutic plasma exchange decreases acute iTTP mortality from >90% to approximately 9%–20% and should be initiated prior to ADAMTS13 reporting when clinical suspicion is intermediate or high.[4]˒[1]
- Therapeutic plasma exchange is typically initiated using 1 to 1.5 plasma volumes per procedure and continued daily until clinical response (sustained platelet count ≥150 × 10⁹/L) or until an alternate diagnosis is established (eg, iTTP ruled out by ADAMTS13 activity >20%).
- Therapeutic plasma exchange requires an apheresis catheter and is associated with risks including bleeding, arterial injury, pneumothorax, central line infection, and thrombosis, as well as plasma-related transfusion reactions including anaphylaxis.[5]˒[6]˒[7]
- For patients awaiting emergent transfer to a center capable of therapeutic plasma exchange, plasma infusion may be used as a temporizing measure to replace ADAMTS13.[2]˒[8]
Corticosteroids
- Corticosteroids suppress production of autoantibodies to ADAMTS13 and are used with therapeutic plasma exchange in iTTP.[1]˒[9]
- The ISTH guideline panel estimated fewer deaths with corticosteroids plus therapeutic plasma exchange versus therapeutic plasma exchange alone, although the certainty of evidence was very low due to small, heterogeneous observational studies.[1]
- ISTH guidelines do not specify a single corticosteroid agent, dose, or duration; oral prednisone 1 mg/kg daily is commonly used.[1]
- Some experts treat high-risk iTTP (eg, severe neurologic features or elevated troponin level) with intravenous methylprednisolone 1000 mg/day for 3 days.[1]
- Corticosteroids are generally continued during therapeutic plasma exchange and until ADAMTS13 activity increases to >10%–20%, followed by a rapid taper to limit toxicity (optimal taper duration has not been studied).[8][10]
Rituximab
- Rituximab (anti-CD20) reduces autoantibody production to ADAMTS13 and helps restore ADAMTS13 activity.[11]
- Although ISTH guidelines do not mandate dosing, most studies used rituximab 375 mg/m² weekly for 4 doses.[12]˒[13]
- Because rituximab is associated with viral infection risk including hepatitis B reactivation, patients should be screened (total hepatitis B core antibody and hepatitis B surface antigen) and receive antiviral prophylaxis if positive.[14]
- Other anti-CD20 therapies (eg, ofatumumab, obinutuzumab) have been used when rituximab causes infusion reactions or serum sickness.[15]
Caplacizumab
- Caplacizumab is a nanobody that binds the A1 domain of von Willebrand factor (vWF) and blocks platelet glycoprotein 1b-IX-V binding, thereby preventing microvascular thrombosis during acute iTTP.[16]˒[17]
- Caplacizumab was approved by the US Food and Drug Administration (FDA) in 2019 for adults with iTTP in combination with therapeutic plasma exchange and immunosuppression (eg, corticosteroids and rituximab).
- In randomized trials, caplacizumab (10 mg) was administered intravenously once prior to therapeutic plasma exchange and continued subcutaneously after daily therapeutic plasma exchange for at least 30 days.[16]˒[17]
- Across 2 clinical trials, caplacizumab shortened time to platelet count recovery and reduced exacerbations and refractory iTTP during the first 30 days after therapeutic plasma exchange cessation.[18]
- Bleeding is the major adverse effect of caplacizumab; in trials, treatment-emergent bleeding was more frequent with caplacizumab than standard care.[19]˒[18] With clinically significant bleeding, caplacizumab was held until resolution or permanently discontinued, and vWF concentrate was used in at least one reported case.[16]
Summary of first-line treatment for acute episode of iTTP is given in the table below:[20]
First-Line Therapies in Addition to Therapeutic Plasma Exchange for an Initial Episode of TTP
| Therapy type | Medication and dosing | Mechanism | Time to normalization of platelet count, d | Incidence of refractory TTP | Incidence of TTP exacerbation | Incidence of TTP relapse | Adverse eventsa |
| Immunosuppression | Prednisone (1 mg/kg/d orally)
or methylprednisolone (1000 mg intravenously daily ×3 d) for severe features such as neurologic symptoms |
Decrease
auto-antibody production |
NR | NR | NR | NRb | Infection: NR
Mood disorders: NR Hypertension: NR Weight gain: NR Myopathy: NR Decreased bone density (>6 wk of use) Glaucoma (>6 wk of use) |
| Rituximab (375 mg/m2 weekly
×4 doses)c |
Deplete CD20+ B
cells to decrease auto-antibody production |
NR | NR | NR | Rituximab:
22/139[11] Control: 74/226[11] OR, 0.4 (95% CI, 0.19-0.85)[11] |
Infections: 19%-63%[21]
Infusion reactions: 12%-77%[21] Hypogammaglobulinemia: 51%-72%[21] Lymphocytopenia: 48%[21] Hepatitis B reactivation (screen and give antiviral prophylaxis) | |
| Anti-vWF | Caplacizumab (11 mg
intravenously prior to therapeutic plasma exchange, then 11 mg subcutaneously for 30 d following therapeutic plasma exchange administration or until ADAMTS13 recovery)d |
Nanobody blocks
binding of platelets to A1 domain of von Willebrand factor |
Caplacizumab
(median days): Pooled mean difference (days): −0.66 (95% CI, −0.90 to −0.43)[18] |
Caplacizumab:
Pooled risk difference: −8% (95% CI, −13% to −2%)[18]e |
Caplacizumab:
Pooled risk difference: −29% (95% CI, −42% to −14%)39[18]e |
Caplacizumab:
Pooled risk difference: 14% (95% CI, 0%-27%)[18] |
Any bleeding: 58.5%[19]
Serious bleeding: 11.3%[19] Parasthesias: 12.3%[19] Constipation: 11.3%[19] |
| Abbreviations: ADAMTS13, a disintegrin and metallopeptidase with thrombospondin type 1 motif 13; NR, not reported; OR, odds ratio; TTP, thrombotic thrombocytopenic purpura; vWF, von Willebrand factor.
a Adverse events from studies specifically of patients with thrombotic thrombocytopenic purpura. When unavailable, incidence of adverse events of medication reported from product labeling. b While some observational studies have reported relapse risk with corticosteroid use as per International Society on Thrombosis and Haemostasis treatment guideline panel, overall quality of evidence is very low, supported by only small studies with a heterogenous population and varied interventions. Thus, relapse risk with corticosteroids is not reported. c Off-label use, indication not approved by the US Food and Drug Administration. d The clinical trial reported using caplacizumab (10 mg), but a posttrial dose-recovery study showed that the mean dose that can be withdrawn from the vial and reconstituted is 11 mg. Thus, labeling of the commercial product labeling is 11 mg, which is equivalent to the dose used in the study. e Only data from randomized trials included. | |||||||
Treatment of TTP Exacerbation
- Exacerbation is an early recurrence (within 30 days of stopping therapeutic plasma exchange or caplacizumab) and occurs because therapeutic plasma exchange and caplacizumab are temporizing measures that do not treat the underlying autoimmunity.[17],[8]
- With an exacerbation of iTTP, therapeutic plasma exchange should be reinitiated. Caplacizumab initiated at the time of iTTP exacerbation (if not used initially) showed a high response rate in retrospective data.
Treatment of Refractory iTTP
- Refractory iTTP is defined by lack of sustained platelet count increment or platelet count <50 × 10⁹/L with persistently increased LDH (>1.5× upper limit of normal) after ≥5 therapeutic plasma exchange sessions.[22]
- Because refractory iTTP is uncommon, other causes of persistent thrombocytopenia; especially catheter-related infection or drug-induced thrombocytopenia should be considered.[23]
- For patients unresponsive to therapeutic plasma exchange, corticosteroids, and rituximab, higher-dose corticosteroids and other immunosuppressive strategies (eg, cyclosporine, cyclophosphamide, vincristine, daratumumab, bortezomib, splenectomy) have been used, but evidence is limited to case reports and small case series.[23]˒[24]˒[25]
Treatment of iTTP Relapse
- Clinical relapse of immune thrombotic thrombocytopenic purpura (iTTP) refers to recurrence of thrombocytopenia (platelets <150 × 10⁹/L) after a patient previously achieved remission, regardless of whether new ischemic organ injury is present.[22]
- Relapse associated with severe ADAMTS13 deficiency (<10–20%) and thrombocytopenia, with or without organ involvement, should be managed similarly to a first presentation of iTTP.[1]
Treatment of iTTP during Pregnancy
- Management of iTTP during pregnancy includes corticosteroids and therapeutic plasma exchange, with response rates similar to those observed in nonpregnant patients.[26], [27]
- Rituximab is generally reserved for refractory disease after individualized risk–benefit discussion because placental transfer may cause neonatal complications such as lymphopenia or infection.[26],[28]
- Caplacizumab is typically avoided during pregnancy due to concerns for maternal and fetal bleeding.[26]
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 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 treatment of thrombotic thrombocytopenic purpura". J Thromb Haemost. 18 (10): 2496–2502. doi:10.1111/jth.15010. PMC 8091490 Check
|pmc=value (help). PMID 32914526 Check|pmid=value (help). - ↑ 2.0 2.1 Rock GA, Shumak KH, Buskard NA, Blanchette VS, Kelton JG, Nair RC, Spasoff RA (August 1991). "Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group". N Engl J Med. 325 (6): 393–7. doi:10.1056/NEJM199108083250604. PMID 2062330.
- ↑ Bell WR, Braine HG, Ness PM, Kickler TS (August 1991). "Improved survival in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Clinical experience in 108 patients". N Engl J Med. 325 (6): 398–403. doi:10.1056/NEJM199108083250605. PMID 2062331.
- ↑ 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.
- ↑ 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.
- ↑ Rizvi MA, Vesely SK, George JN, Chandler L, Duvall D, Smith JW, Gilcher RO (August 2000). "Complications of plasma exchange in 71 consecutive patients treated for clinically suspected thrombotic thrombocytopenic purpura-hemolytic-uremic syndrome". Transfusion. 40 (8): 896–901. doi:10.1046/j.1537-2995.2000.40080896.x. PMID 10960513.
- ↑ Colling M, Sun L, Upadhyay V, Ryu J, Li A, Uhl L, Kaufman RM, Stowell CP, Dzik WH, Makar RS, Bendapudi PK (April 2020). "Deaths and complications associated with the management of acute immune thrombotic thrombocytopenic purpura". Transfusion. 60 (4): 841–846. doi:10.1111/trf.15721. PMID 32080877 Check
|pmid=value (help). - ↑ 8.0 8.1 8.2 Scully M, Rayment R, Clark A, Westwood JP, Cranfield T, Gooding R, Bagot CN, Taylor A, Sankar V, Gale D, Dutt T, McIntyre J, Lester W (November 2023). "A British Society for Haematology Guideline: Diagnosis and management of thrombotic thrombocytopenic purpura and thrombotic microangiopathies". Br J Haematol. 203 (4): 546–563. doi:10.1111/bjh.19026. PMID 37586700 Check
|pmid=value (help). - ↑ 9.0 9.1 9.2 9.3 Cataland SR, Kourlas PJ, Yang S, Geyer S, Witkoff L, Wu H, Masias C, George JN, Wu HM (October 2017). "Cyclosporine or steroids as an adjunct to plasma exchange in the treatment of immune-mediated thrombotic thrombocytopenic purpura". Blood Adv. 1 (23): 2075–2082. doi:10.1182/bloodadvances.2017009308. PMC 5728286. PMID 29296854.
- ↑ Akwaa F, Antun A, Cataland SR (August 2022). "How I treat immune-mediated thrombotic thrombocytopenic purpura after hospital discharge". Blood. 140 (5): 438–444. doi:10.1182/blood.2021014514. PMID 35667044 Check
|pmid=value (help). - ↑ 11.0 11.1 11.2 11.3 Owattanapanich W, Wongprasert C, Rotchanapanya W, Owattanapanich N, Ruchutrakool T (2019). "Comparison of the Long-Term Remission of Rituximab and Conventional Treatment for Acquired Thrombotic Thrombocytopenic Purpura: A Systematic Review and Meta-Analysis". Clin Appl Thromb Hemost. 25: 1076029618825309. doi:10.1177/1076029618825309. PMC 6714958 Check
|pmc=value (help). PMID 30808221. - ↑ Scully M, McDonald V, Cavenagh J, Hunt BJ, Longair I, Cohen H, Machin SJ (August 2011). "A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura". Blood. 118 (7): 1746–53. doi:10.1182/blood-2011-03-341131. PMID 21636861.
- ↑ Page EE, Kremer Hovinga JA, Terrell DR, Vesely SK, George JN (June 2016). "Rituximab reduces risk for relapse in patients with thrombotic thrombocytopenic purpura". Blood. 127 (24): 3092–4. doi:10.1182/blood-2016-03-703827. PMID 27060171.
- ↑ Ali FS, Nguyen MH, Hernaez R, Huang DQ, Wilder J, Piscoya A, Simon TG, Falck-Ytter Y (February 2025). "AGA Clinical Practice Guideline on the Prevention and Treatment of Hepatitis B Virus Reactivation in At-Risk Individuals". Gastroenterology. 168 (2): 267–284. doi:10.1053/j.gastro.2024.11.008. PMID 39863345 Check
|pmid=value (help). - ↑ Doyle AJ, Stubbs MJ, Lester W, Thomas W, Westwood JP, Thomas M, Percy C, Prasannan N, Scully M (July 2022). "The use of obinutuzumab and ofatumumab in the treatment of immune thrombotic thrombocytopenic purpura". Br J Haematol. 198 (2): 391–396. doi:10.1111/bjh.18192. PMID 35430727 Check
|pmid=value (help). - ↑ 16.0 16.1 16.2 Scully M, Cataland SR, Peyvandi F, Coppo P, Knöbl P, Kremer Hovinga JA, Metjian A, de la Rubia J, Pavenski K, Callewaert F, Biswas D, De Winter H, Zeldin RK (January 2019). "Caplacizumab Treatment for Acquired Thrombotic Thrombocytopenic Purpura". N Engl J Med. 380 (4): 335–346. doi:10.1056/NEJMoa1806311. PMID 30625070.
- ↑ 17.0 17.1 17.2 Peyvandi F, Callewaert F (June 2016). "Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura". N Engl J Med. 374 (25): 2497–8. doi:10.1056/NEJMc1603180. PMID 27332911.
- ↑ 18.0 18.1 18.2 18.3 18.4 18.5 Djulbegovic M, Tong J, Xu A, Yang J, Chen Y, Cuker A, Pishko AM (May 2023). "Adding caplacizumab to standard of care in thrombotic thrombocytopenic purpura: a systematic review and meta-analysis". Blood Adv. 7 (10): 2132–2142. doi:10.1182/bloodadvances.2022008443. PMC 10196763 Check
|pmc=value (help). PMID 36053773 Check|pmid=value (help). - ↑ 19.00 19.01 19.02 19.03 19.04 19.05 19.06 19.07 19.08 19.09 19.10 19.11 Peyvandi F, Cataland S, Scully M, Coppo P, Knoebl P, Kremer Hovinga JA, Metjian A, de la Rubia J, Pavenski K, Minkue Mi Edou J, De Winter H, Callewaert F (April 2021). "Caplacizumab prevents refractoriness and mortality in acquired thrombotic thrombocytopenic purpura: integrated analysis". Blood Adv. 5 (8): 2137–2141. doi:10.1182/bloodadvances.2020001834. PMC 8095153 Check
|pmc=value (help). PMID 33881463 Check|pmid=value (help). - ↑ Pishko AM, Li A, Cuker A (August 2025). "Immune Thrombotic Thrombocytopenic Purpura: A Review". JAMA. 334 (6): 517–529. doi:10.1001/jama.2025.3807. PMID 40388146 Check
|pmid=value (help). - ↑ 22.0 22.1 Cuker A, Cataland SR, Coppo P, de la Rubia J, Friedman KD, George JN, Knoebl PN, Kremer Hovinga JA, Lämmle B, Matsumoto M, Pavenski K, Peyvandi F, Sakai K, Sarode R, Thomas MR, Tomiyama Y, Veyradier A, Westwood JP, Scully M (April 2021). "Redefining outcomes in immune TTP: an international working group consensus report". Blood. 137 (14): 1855–1861. doi:10.1182/blood.2020009150. PMID 33529333 Check
|pmid=value (help). - ↑ 23.0 23.1 Sayani FA, Abrams CS (June 2015). "How I treat refractory thrombotic thrombocytopenic purpura". Blood. 125 (25): 3860–7. doi:10.1182/blood-2014-11-551580. PMC 4473115. PMID 25784681.
- ↑ van den Berg J, Kremer Hovinga JA, Pfleger C, Hegemann I, Stehle G, Holbro A, Studt JD (February 2022). "Daratumumab for immune thrombotic thrombocytopenic purpura". Blood Adv. 6 (3): 993–997. doi:10.1182/bloodadvances.2021005124. PMC 8945322 Check
|pmc=value (help). PMID 34551063 Check|pmid=value (help). - ↑ Giannotta JA, Artoni A, Mancini I, Agosti P, Carpenedo M, Truma A, Miri S, Ferrari B, De Leo P, Salutari P, Mancini G, Molteni A, Rinaldi E, Bocchia M, Napolitano M, Prezioso L, Cuccaro A, Scarpa E, Condorelli A, Grimaldi D, Massaia M, Peyvandi F (February 2025). "Bortezomib for rituximab-refractory immune-mediated thrombotic thrombocytopenic purpura in the caplacizumab era: an Italian multicenter study". J Thromb Haemost. 23 (2): 704–716. doi:10.1016/j.jtha.2024.10.034. PMID 39549837 Check
|pmid=value (help). - ↑ 26.0 26.1 26.2 Fakhouri F, Scully M, Provôt F, Blasco M, Coppo P, Noris M, Paizis K, Kavanagh D, Pène F, Quezada S, Hertig A, Kissling S, O'Brien P, Delmas Y, Alberio L, Winer N, Veyradier A, Cataland S, Frémeaux-Bacchi V, Loirat C, Remuzzi G, Tsatsaris V (November 2020). "Management of thrombotic microangiopathy in pregnancy and postpartum: report from an international working group". Blood. 136 (19): 2103–2117. doi:10.1182/blood.2020005221. PMID 32808006 Check
|pmid=value (help). - ↑ Scully M, Thomas M, Underwood M, Watson H, Langley K, Camilleri RS, Clark A, Creagh D, Rayment R, Mcdonald V, Roy A, Evans G, McGuckin S, Ni Ainle F, Maclean R, Lester W, Nash M, Scott R, O Brien P (July 2014). "Thrombotic thrombocytopenic purpura and pregnancy: presentation, management, and subsequent pregnancy outcomes". Blood. 124 (2): 211–9. doi:10.1182/blood-2014-02-553131. PMID 24859360.
- ↑ Chakravarty EF, Murray ER, Kelman A, Farmer P (February 2011). "Pregnancy outcomes after maternal exposure to rituximab". Blood. 117 (5): 1499–506. doi:10.1182/blood-2010-07-295444. PMID 21098742.