The Use of Caplacizumab in COVID-19-Related TTP

Introduction

Thrombotic Thrombocytopenic Purpura (TTP) is a rare but feared hematological disorder encountered in the inpatient setting. COVID-19-associated TTP is a lesser understood phenomenon, with slightly different symptomology and clinical course. Prompt identification is essential since TTP is a medical emergency which carries a 90% risk of mortality if untreated. Several aspects of treatment, including the use of agents like caplacizumab as monotherapy and therapy duration, are poorly defined in the literature. In this case report, we discuss one such case of post-COVID TTP and explore the therapeutic challenges that clinicians should be aware of when using caplacizumab.

Case

A 49-year-old female presented with brief changes in mentation and confusion, as well as an associated headache, sore throat, myalgias, and fever for 10 days. The patient tested positive for the COVID-19 antigen 3 days prior to presentation. The patient was hemodynamically stable on arrival, although tachycardic to 94 beats per minute. Initial labs revealed acute normocytic anemia (Hb 7.4 g/dl from a baseline of 12.1 g/dl) and acute, severe thrombocytopenia (9 K/ul from a baseline of 217 K/ul) with schistocytes present on peripheral blood smear. Elevated lactate dehydrogenase (LDH) and low haptoglobin suggested hemolysis. PT, INR, PTT, d-dimer, fibrinogen, and fibrin degradation product (FDP) did not suggest disseminated intravascular coagulation (DIC). TTP was highly suspected with a PLASMIC score of 7. Therapeutic plasma exchange (TPE) was started emergently on day of admission. Additional treatments that were administered include methylprednisolone (1g daily for 3 days), rituximab (375mg/m2), and caplacizumab (11mg before and after TPE on Day 1, then 11 mg daily thereafter). Caplacizumab was administered daily through Day 4, then stopped because our hospital pharmacy could not procure the drug. Nevertheless, by day 4, platelets had improved to >150 K/ul and LDH to <200 IU/l for 2 consecutive days. From Day 4 to Day 10, TPE was given every other day. However, on day 10 the platelets decreased to 11 K/ul. Both daily TPE and caplacizumab was re-initiated. ADAMTS 13 level was <2% at admission and Day 9, later increased to 54.1% on Day 15. ADAMTS 13 antibody levels were >164 U/ml on the day of admission, 67 U/ml on Day 9, and undetectable on Day 15. The patient was discharged on Day 22 and completed a 30-day course of caplacizumab. Follow-up showed sustained remission at 2.5 months with ADAMSTS13 level of 90.8%, platelet count 130 K/ul and the LDH level of 136 U/l.

Discussion

Caplacizumab is a bivalent anti-VWF immunoglobulin approved in 2019 for treating acquired TTP in conjunction with TPE and other immunosuppressive therapies. The TITAN trial showed significantly lower 30-day exacerbations in the caplacizumab group compared to the placebo group, but a higher rate of relapse in the caplacizumab group in the following month. Patients in the caplacizumab group received fewer TPE sessions overall. Paradoxically HERCULES trial showed 67% lower recurrence in the caplacizumab group. These results in the HERCULES trial were attributed to caplacizumab treatment lengths that could be expanded based on ADAMTS13 activity <10%. In our case, given the high bleeding risk and lack of cost-effectiveness while inpatient, caplacizumab was discontinued and TPE decreased to alternate day dosing following adequate clinical response. It is difficult to predict whether premature discontinuation of caplacizumab or early weaning of TPE triggered recurrence, since both therapies were discontinued on Day 5. This case demonstrates a clinical conundrum of whether caplacizumab can lead to early discontinuation of TPE with inadequate clearance of ADAMTS13 antibody, leading to early relapses. A review of current literature and our experience suggest that Caplacizumab may be very effective in improving platelet count and reducing relapse rates, especially when decisions to discontinue the drug are based on ADAMTS-13 levels. However, lack of cost-effectiveness is a limiting factor, and high bleeding risks must be considered before deciding to start caplacizumab in patients with refractory or severe TTP.