Acquired thrombotic thrombocytopenic purpura

Section editors
	Shruti Chaturvedi, MBBS, MSCI Johns Hopkins University Baltimore, MD LinkedIn		Benjamin Tillman, MD Vanderbilt University Nashville, TN

5 regimens on this page 7 variants on this page

Initial therapy

Plasma exchange

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Regimen

Study	Evidence	Comparator	Efficacy
Rock et al. 1991	Phase III (E)	Plasma infusion	Seems to have superior OS

Supportive therapy

• Total plasma exchange as follows (minimum of 7 treatments in first 9 hospital days):
  • Treatments 1 to 3: Exchange of 1.5 times the predicted plasma volume
  • Treatments 4 onwards: Exchange of 1.0 times the predicted plasma volume

Supportive medications

• Dipyridamole (Persantine) 400 mg (route not specified) once per day for at least two weeks
• Aspirin 325 mg PO once per day for at least two weeks

References

1. Rock GA, Shumak KH, Buskard NA, Blanchette VS, Kelton JG, Nair RC, Spasoff RA; Canadian Apheresis Study Group. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. N Engl J Med. 1991 Aug 8;325(6):393-7. link to original article contains verified protocol PubMed

Caplacizumab monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy
Peyvandi et al. 2016 (TITAN)	Phase II	Placebo	Reduced time to response compared to placebo (p=0.005).
Scully et al. 2019 (HERCULES)	Phase III (E)	Placebo	Shorter median time to platelet count normalization. Lower composite outcome events (death, relapse).

Supportive therapy

• Caplacizumab (Cablivi)
• Plasma exchange with discontinuation of plasma exchange five days after normalization of platelet count.

References

1. TITAN: Peyvandi F, Scully M, Kremer Hovinga JA, Cataland S, Knöbl P, Wu H, Artoni A, Westwood JP, Mansouri Taleghani M, Jilma B, Callewaert F, Ulrichts H, Duby C, Tersago D; TITAN Investigators. Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura. N Engl J Med. 2016 Feb 11;374(6):511-522. link to original article PubMed
2. HERCULES: 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; HERCULES Investigators. Caplacizumab Treatment for Acquired Thrombotic Thrombocytopenic Purpura. N Engl J Med. 2019 Jan 24;380(4):335-346. Epub 2019 Jan 9. link to original article PubMed

Maintenance/Preemptive treatment

Rituximab monotherapy

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Regimen

Study	Evidence
Hie et al. 2014	Registry

Note: this prospective registry trial left precise dosing details to physician discretion.

Immunosuppressive therapy

• Rituximab (Rituxan)

References

1. Hie M, Gay J, Galicier L, Provôt F, Presne C, Poullin P, Bonmarchand G, Wynckel A, Benhamou Y, Vanhille P, Servais A, Bordessoule D, Coindre JP, Hamidou M, Vernant JP, Veyradier A, Coppo P; French Thrombotic Microangiopathies Reference Centre. Preemptive rituximab infusions after remission efficiently prevent relapses in acquired thrombotic thrombocytopenic purpura. Blood. 2014 Jul 10;124(2):204-10. Epub 2014 May 28. link to original article PubMed
   1. Update: Jestin M, Benhamou Y, Schelpe AS, Roose E, Provôt F, Galicier L, Hié M, Presne C, Poullin P, Wynckel A, Saheb S, Deligny C, Servais A, Girault S, Delmas Y, Kanouni T, Lautrette A, Chauveau D, Mousson C, Perez P, Halimi JM, Charvet-Rumpler A, Hamidou M, Cathébras P, Vanhoorelbeke K, Veyradier A, Coppo P; French Thrombotic Microangiopathies Reference Center. Preemptive rituximab prevents long-term relapses in immune-mediated thrombotic thrombocytopenic purpura. Blood. 2018 Nov 15;132(20):2143-2153. Epub 2018 Sep 10. link to original article PubMed

Relapsed or refractory

These treatments are usually used in addition to therapeutic plasma exchange, not in its place. There are also many treatments reported at the case report or case series level; the reader is guided to the 2015 Blood article, "How I treat refractory thrombotic thrombocytopenic purpura" for further details.

Methylprednisolone monotherapy

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Variant #1, "High-dose"

Study	Evidence	Comparator	Efficacy
Balduini et al. 2009	Phase III (E)	Standard-dose methylprednisolone	Might have superior CR rate

Immunosuppressive therapy

• Methylprednisolone (Solumedrol) as follows:
  • Days 1 to 3: 10 mg/kg/day IV
  • Days 4 to 23: 2.5 mg/kg/day IV

Variant #2, "Standard-dose"

Study	Evidence	Comparator	Efficacy
Balduini et al. 2009	Phase III (C)	High-dose methylprednisolone	Might have inferior CR rate

Immunosuppressive therapy

• Methylprednisolone (Solumedrol) as follows:
  • Days 1 to 3: 1 mg/kg/day IV
  • Days 4 to 23: 2.5 mg/kg/day IV

References

1. Balduini CL, Gugliotta L, Luppi M, Laurenti L, Klersy C, Pieresca C, Quintini G, Iuliano F, Re R, Spedini P, Vianelli N, Zaccaria A, Pogliani EM, Musso R, Bobbio Pallavicini E, Quarta G, Galieni P, Fragasso A, Casella G, Noris P, Ascari E; Italian TTP Study Group. High versus standard dose methylprednisolone in the acute phase of idiopathic thrombotic thrombocytopenic purpura: a randomized study. Ann Hematol. 2010 Jun;89(6):591-6. Epub 2009 Dec 23. link to original article contains protocol PubMed

Rituximab monotherapy

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Variant #1

Study	Evidence
de la Rubia et al. 2010	Non-randomized
Clark et al. 2015	Phase II

Full text of de la Rubia et al. 2010 is not available for review.

Immunosuppressive therapy

• Rituximab (Rituxan) 375 mg/m² IV once per week

Supportive medications

• Prednisone (Sterapred) 50 mg PO once prior to Rituximab (Rituxan)
• Diphenhydramine (Benadryl) 50 mg PO once prior to Rituximab (Rituxan)
• Acetaminophen (Tylenol) 325 mg PO once prior to Rituximab (Rituxan)

4-week course

Variant #2

Study	Evidence
Froissart et al. 2012	Non-randomized

Immunosuppressive therapy

• Rituximab (Rituxan) (dose not specified) IV

Four doses in 15 days

References

1. de la Rubia J, Moscardó F, Gómez MJ, Guardia R, Rodríguez P, Sebrango A, Zamora C, Debén G, Goterris R, López R, Peña F, Pujol M, Vidaller A, Del Río-Garma J, Sanz MA; Grupo Español de Aféresis. Efficacy and safety of rituximab in adult patients with idiopathic relapsing or refractory thrombotic thrombocytopenic purpura: results of a Spanish multicenter study. Transfus Apher Sci. 2010 Dec;43(3):299-303. Epub 2010 Oct 12. link to original article contains protocol PubMed
2. Froissart A, Buffet M, Veyradier A, Poullin P, Provôt F, Malot S, Schwarzinger M, Galicier L, Vanhille P, Vernant JP, Bordessoule D, Guidet B, Azoulay E, Mariotte E, Rondeau E, Mira JP, Wynckel A, Clabault K, Choukroun G, Presne C, Pourrat J, Hamidou M, Coppo P; French Thrombotic Microangiopathies Reference Center. Efficacy and safety of first-line rituximab in severe, acquired thrombotic thrombocytopenic purpura with a suboptimal response to plasma exchange: experience of the French Thrombotic Microangiopathies Reference Center. Crit Care Med. 2012 Jan;40(1):104-11. PubMed
3. Review: Lim W, Vesely SK, George JN. The role of rituximab in the management of patients with acquired thrombotic thrombocytopenic purpura. Blood. 2015 Mar 5;125(10):1526-31. Epub 2015 Jan 8. Review. link to original article link to PMC article PubMed
4. Clark WF, Rock G, Barth D, Arnold DM, Webert KE, Yenson PR, Kelton JG, Li L, Foley SR; members of the Canadian Apheresis Group. A phase-II sequential case-series study of all patients presenting to four plasma exchange centres with presumed relapsed/refractory thrombotic thrombocytopenic purpura treated with rituximab. Br J Haematol. 2015 Jul;170(2):208-17. Epub 2015 Apr 8. link to original article contains verified protocol PubMed

Vincristine monotherapy

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Regimen

Study	Evidence
Ferrara et al. 1999	Pilot, <20 patients

Chemotherapy

• Vincristine (Oncovin) 1.4 mg/m² IV once on day 1, then 1 mg IV once per day on days 4 & 7

References

1. Ferrara F, Copia C, Annunziata M, Spasiano A, Di Grazia C, Palmieri S, Prossomariti L, Mele G. Vincristine as salvage treatment for refractory thrombotic thrombocytopenic purpura. Ann Hematol. 1999 Nov;78(11):521-3. contains protocol PubMed