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(Version 3.3; last updated April 4, 2022)

Input from Spero Cataland, MD; Paul Coppo, MD, PhD; Marie Scully, MD; Masanori Matsumoto, MD; James George, MD; Bernhard Lämmle, MD; Flora Peyvandi, MD; Ravi Sarode, MD Sarode.

Note: Please review ASH's disclaimer regarding the use of the following information.

Should the initial treatment of immune-mediated thrombotic thrombocytopenic purpura (iTTP) be altered today given the potential for COVID-19 infection? What about the use of rituximab as an adjunct to plasma exchange (PEX) therapy?

Standard PEX should be instituted for iTTP. Despite the initial concerns that corticosteroids could increase the risk of more severe COVID-19 disease, there are no reports to date supporting this hypothesis, and in fact recent data suggest that dexamethasone may improve outcomes in COVID-19 patients requiring ventilator support or oxygen. Therefore, steroids are an integral part of the initial treatment of iTTP and should still be used along with plasma exchange therapy (PEX) as a part of the treatment of an acute iTTP episode.

Caplacizumab is not immunosuppressive and would not be predicted to impact on COVID-19 disease. Rituximab has been associated with viral reactivation and potentially an increased risk of primary viral infections, given impact on antibody production. However, rituximab is an essential part of the treatment of acute iTTP, especially in patients with relapsed iTTP. In these cases, the risk for a more severe infection with COVID-19 should be balanced against the significant benefit of therapy with standard doses of rituximab (375 mg/m² IV × 4 doses over 2-3 weeks). Patients requiring rituximab are currently eligible for administration of prophylactic anti–-COVID-19 monoclonal antibodies to decrease the risk of progression to severe COVID-19 disease, as detailed in the FAQ on COVID-19 Therapies.

In an iTTP patient in remission but at risk for relapse given severely deficient ADAMTS13 activity (<10%), would the potential for infection with COVID-19 impact the decision to give preemptive rituximab therapy?

Patients with iTTP in remission at increased risk for relapse due to severely deficient ADAMTS13 activity may still receive rituximab as preemptive therapy to prevent relapse, given the morbidity and mortality associated with active iTTP. The potential for increased risk for COVID-19 infectious complications and need to receive rituximab in clinic should be balanced against the significant benefit of preventing/delaying relapses of iTTP, which would then require hospitalization and is also associated with significant morbidity and mortality. Patients requiring rituximab are currently eligible for administration of prophylactic anti–COVID-19 monoclonal antibodies to decrease the risk of progression to severe COVID-19 disease, as detailed in the FAQ on COVID-19 Therapies.

Should a patient diagnosed with both TTP and COVID-19 infection be managed differently, and should any special monitoring be performed?

While PEX should be used in the same way as in other patients, the risks and benefits of corticosteroids and rituximab need to be undertaken before use in a patient with active COVID-19. Current data would suggest that standard corticosteroids could be given as a component of standard iTTP therapy. Rituximab could be delayed until the acute COVID-19 infection has cleared and hopefully neutralizing antibodies have already been produced. Although caplacizumab is a temporizing measure that does not improve severely deficient ADAMTS13 activity, this drug could be used in conjunction with PEX to protect from exacerbations and relapses of iTTP until the patient has recovered from acute COVID-19 infection, at which time standard rituximab could be used to decrease anti-ADAMTS13 antibody levels and improve the ADAMTS13 activity.

Although presently there are no issues with availability of plasma for PEX, could patients with TTP be effectively treated if the supply of plasma or access to plasmapheresis was limited?

While it is not anticipated that the frozen plasma supply will be impacted in the short term by COVID-19, if plasma were not available, there are reports of the use of caplacizumab and immune suppressive therapy alone without PEX to successfully treat iTTP.^1,2

If plasmapheresis is not available, ideally, the patient would be transferred to an institution with PEX capabilities. In the interim, one could consider treating such patients with plasma infusions, in association with caplacizumab and immunosuppressive therapy as detailed in this consensus expert approach.

Which patients with iTTP are at greatest risk for infection or complications from COVID-19?

iTTP patients on therapies such as rituximab are likely at increased risk for serious COVID-19 infection based on large series showing significantly worse outcomes in patients on rituximab with other autoimmune disorders such as rheumatoid arthritis and multiple sclerosis, but no large data sets analyzing the impact of this and other chronic immunosuppressive agents yet exist in iTTP. If possible, immunosuppressive treatments should be tapered and stopped as soon as safely possible to minimize this and other risks. As above, the benefits of decreasing the risk for recurrent iTTP episodes must be balanced against these theoretical concerns.

Does infection with COVID-19 increase the risk for relapse of iTTP?

While infection with COVID-19 on its own would be unlikely to lead to relapse of iTTP, in patients with pre-existing severely deficient ADAMTS13 activity, an acute infection with COVID-19 could be the “second-hit” that triggers an acute iTTP episode. Measurements from a patient that predate the COVID-19 infection may be required in the short-term to guide therapy.

What are the implications of COVID-19 infection in patients with congenital TTP (cTTP)?

Patients with cTTP that become infected with COVID-19 similarly would be at increased risk for an acute TTP episode as a result of the infection and the secondary inflammatory state. Patients with cTTP and COVID-19 infection should be monitored carefully for hemolysis. cTTP patients with COVID-19 may need an intensified plasma infusion schedule to avoid an acute TTP episode. In cases of plasma shortage, intermediate purity FVIII concentrates could also be considered.

Should patients with TTP receive a COVID-19 vaccination?

While Concerns have been raised by both physicians and patients that COVID-19 vaccination could result in a relapse of TTP in patients with a prior history of the disease. A retrospective study3 of 79 iTTP patients from three universities in the United States demonstrated only one relapse of iTTP within four weeks of COVID-19 vaccination. This individual had undetectable ADAMTS13 activity and had not recovered her ADAMTS13 activity after her initial diagnosis 1.5 years earlier despite treatment with rituximab. This same report from Shah et al searched the Vaccine Adverse Event Reporting System (VAERS) database and concluded that the incidence of iTTP cases was not higher than the incidence of iTTP in the United States (1.7 to 3.7 per million). Similar conclusions regarding the incidence of iTTP following COVID-19 vaccination (regardless of vaccine type) were also reached from retrospective studies in England and France.^4,5

These data support the safety of COVID-19 vaccination in patients with a prior history of iTTP, with the caveat that additional caution should be exercised in patients with a prior history of iTTP and ADAMTS13 activity less than 20 percent. In the specific case of an iTTP with ADAMTS13 activity in remission that is less than 20 percent, a more detailed discussion with the patient regarding the risks and benefits of COVID-19 vaccination, in addition to the indication for and timing of preemptive therapy, should be undertaken. It should also be kept in mind that vaccination within six months of treatment with rituximab may render the vaccination less effective. Patients within six months of rituximab can receive anti–COVID-19 monoclonal antibodies to help protect against progression to severe disease.

In patients with congenital TTP (cTTP), similar concerns have been raised regarding the risk for COVID-19 vaccination to provoke an exacerbation of cTTP and thrombotic complications. In a retrospective study from Hamada et al,⁶ 24 Japanese cTTP patients safely underwent COVID-19 vaccination when it was administered within two weeks of the last fresh frozen plasma infusion. Based upon these data, COVID-19 vaccination is also thought to be safe in patients with cTTP, but it is recommended that the vaccine be given as soon as possible after fresh frozen plasma infusion, preferably within seven days.

For more information, please view the FAQ that addresses frequently asked questions regarding vaccines in immunocompromised patients.

1. Chander DP, Loch MM, Cataland SR, et al. Caplacizumab therapy without plasma exchange for acquired thrombotic thrombocytopenic purpura. N Engl J Med. 2019;381(1):92-94.
2. Sukumar S, George JN, Cataland SR. Shared decision making, thrombotic thrombocytopenic purpura, and caplacizumab. Am J Hematol. 2020;95(4): E76-E77.
3. Shah H, Kim AS, Sukumar S, et al. SARS-CoV-2 Vaccination and Immune Thrombotic Thrombocytopenic Purpura. Blood. 2022.
4. Doyle AJ, Springell D, Dutt T, et al. Acquired thrombotic thrombocytopenic purpura: A rare disease associated with BNT162b2 vaccine: Comment from Doyle et al. J Thromb Haemost. 2022;20(3):781-783.
5. Picod A, Rebibou JM, Dossier A, et al. Immune-mediated thrombotic thrombocytopenic purpura following COVID-19 vaccination. Blood. 2022.
6. Hamada E, Sakai K, Yamada S, Kubo M, Hayakawa M, Matsumoto M. No aggravation of congenital thrombotic thrombocytopenic purpura by mRNA-based vaccines against COVID-19: a Japanese registry survey. Ann Hematol. 2022.

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