<em>Hematopoiesis</em>

Refractory Thrombotic Thrombocytopenic Purpura in a Patient with Systemic Lupus Erythematosus

Matty Slaught, MD
PGY-2 Internal Medicine Resident Physician
Virginia Mason Medical Center 
Seattle, WA

Case Presentation

A 47-year-old woman with systemic lupus erythematosus and rheumatoid arthritis (RA) on methotrexate (10 mg weekly) presented to the emergency department with a five-day history of subjective fever, fatigue, and easy bruising. She denied localizing symptoms of infection, sick contacts, or recent medication changes.

Physical examination revealed scattered ecchymoses on the forearms but was otherwise unremarkable. Initial laboratory studies showed profound pancytopenia: hemoglobin 3.7 g/dL, white blood cell count 2.1 × 109/L, and platelet count 1 × 109/L. Peripheral blood smear demonstrated schistocytes. Comprehensive metabolic panel showed a total bilirubin level of 1.5 mg/dL and normal renal function. Lactate dehydrogenase (LDH) was 643 IU/L, reticulocytes 7.9%, and haptoglobin <10 mg/dL. INR was 0.9. A direct antiglobulin test was negative.

Given the constellation of thrombocytopenia, microangiopathic hemolytic anemia, and clinical presentation with easy bruising, subjective fever, and fatigue, thrombotic thrombocytopenic purpura (TTP) was suspected. PLASMIC score on presentation was 6, meeting all criteria except mean corpuscular volume of less than 90 fL, which may have been confounded by the patient’s use of methotrexate for RA. Plasma exchange (PLEX) and high-dose methylprednisolone were initiated. Additionally, the patient's methotrexate was held, and leucovorin was initiated for concern that methotrexate was contributing to pancytopenia. Leucovorin was subsequently discontinued when serum methotrexate levels were found to be low.

Question: What laboratory finding would confirm the diagnosis of TTP?

Clinical Course

ADAMTS13 testing confirmed TTP with 0% protease activity, positive protease inhibition, and ADAMTS13 antibody titer >84 U/mL (reference <12 U/mL). Despite aggressive therapy with daily PLEX and corticosteroids, platelet counts remained well below the target goal of >150 × 109/L for 48 hours, fluctuating between 1-20 × 109/L for the first week. On hospital day 7, caplacizumab 11 mg subcutaneously once daily was initiated due to persistent severe thrombocytopenia. Weekly rituximab 600 mg was added on hospital day 10 given the high antibody titer and refractory disease. Methotrexate remained suspended.

Gradual improvement occurred over subsequent weeks. ADAMTS13 activity remained suppressed at 3% on days 10 and 18, but antibody levels declined from >84 to 71 to 26 U/mL. By day 25, ADAMTS13 activity improved to 34%, with antibody levels falling to 5 U/mL. The platelet goal was liberalized to >90 × 109/L after evaluation of the patient’s baseline levels in the setting of autoimmune disease and methotrexate therapy. Platelet counts stabilized above 100 × 109/L, allowing discontinuation of PLEX on day 26.

The patient was discharged on hospital day 30 on caplacizumab, prednisone 60 mg daily, and trimethoprim-sulfamethoxazole for Pneumocystis jirovecii prophylaxis, with a plan for close follow-up with her primary rheumatologist and hematology clinic. She completed four weekly rituximab doses in total.

Discussion

Answer: ADAMTS13 activity <10% with inhibitory antibodies.

This case illustrates several important teaching points about TTP management:

  1. Early recognition and empiric therapy. Untreated TTP carries up to a 90% mortality rate, as evidenced by the poor survival rate prior to the introduction of plasma exchange.1,2 ADAMTS13 testing should not delay empiric PLEX with adjunctive glucocorticoids and rituximab when clinical suspicion is high.3
  2. Refractory TTP. Defined as persistent or progressive thrombocytopenia despite adequate trial of PLEX,4 with the average patient requiring seven to 10 days.3 Anywhere from 10% to 42% of TTP episodes are refractory to standard therapy.4 Several biomarkers for refractoriness or mortality have been identified, including elevated troponin I level >0.25 mcg/L, prolonged activated partial thromboplastin time, elevated fibrinogen, elevated LDH, and the presence of Bb fragments, soluble C5b-9, or membrane attack complex.5
  3. Caplacizumab: The anti-von Willebrand factor A1 domain nanobody has revolutionized refractory TTP management.6 It prevents platelet adhesion and microthrombi formation, leading to faster platelet count recovery and reduced PLEX duration.6 This case demonstrates caplacizumab's efficacy in stabilizing severe thrombocytopenia while allowing time for PLEX and immunosuppression to reduce ADAMTS13 antibodies. How to best incorporate caplacizumab into clinical practice is uncertain. The International Society on Thrombosis and Haemostasis (ISTH) issued a conditional recommendation for its inclusion in initial therapy;7 however, other experts acknowledge its reasonable omission in some cases, especially given its high cost.3 Glucocorticoids and rituximab are recommended in conjunction with PLEX per the 2020 ISTH guidelines7 and have been shown to reduce the time on PLEX to achieve remission.8

Taken together, multimodal therapy (PLEX, immunosuppression, and caplacizumab) now offers durable remissions for patients with refractory TTP, a historically challenging condition.

  1. Joly BS, Coppo P, Veyradier A. Thrombotic thrombocytopenic purpura. Blood. 2017;129(21):2836-2846.
  2. Hovinga JAK, Vesely SK, Terrell DR, et al. Survival and relapse in patients with thrombotic thrombocytopenic purpura. Blood. 2010;115(8):1500-1511.
  3. Cuker A. Immune TTP: initial treatment. In: Post T, ed. UpToDate. UpToDate; 2025. Accessed June 24, 2025.
  4. Sayani FA, Abrams CS. How I treat refractory thrombotic thrombocytopenic purpura. Blood. 2015;125(25):3860-3867.
  5. Sukumar S, Gavriilaki E, Chaturvedi S. Updates on thrombotic thrombocytopenic purpura: recent developments in pathogenesis, treatment and survivorship. Thromb Update. 2021;5:100062.
  6. Scully M, Cataland SR, Peyvandi F, et al. Caplacizumab treatment for acquired thrombotic thrombocytopenic purpura. N Engl J Med. 2019;380(4):335-346.
  7. Zheng XL, Vesely SK, Cataland SR, et al. ISTH guidelines for treatment of thrombotic thrombocytopenic purpura. J Thromb Haemost. 2020;18(10):2496-2502.
  8. Stanley M, Killeen RB, Michalski JM. Thrombotic thrombocytopenic purpura. In: StatPearls. StatPearls Publishing; 2025. Accessed June 24, 2025.

Disclosure Statement: Dr. Slaught indicated no relevant conflicts of interest.

Acknowledgment: This article was reviewed by Ryan Mack, PhD, and Urshila Durani, MD.