There are no guidelines for the management of TTP without plasma transfusion and the optimal strategy is not known.  Ten cases of TTP in Jehovah’s Witness patients managed successfully without plasma transfusion are described in the literature (9-18) (Supplemental Table 1). However, we suspect that there are many cases with poor outcomes that are not reported, as the mortality for TTP prior to PLEX was high.

In all ten cases, long term control was achieved with immunosuppression utilizing a combination of corticosteroids, rituximab, and/or chemotherapy though emergent therapy varied [9-18]. Six cases report use of therapeutic plasma exchange with alternative protein replacement [9,11,13,15,16,18]. Recently, Chander et al. were the first to describe effective TTP treatment in a patient with caplacizumab for 30 days and immunosuppression without PLEX or plasma infusion. Their patient had clinical improvement within 24 hours of caplacizumab administration and normalization of platelet count within three days. On follow up several weeks later, the patient remained in remission [17].

To our knowledge, our patient’s experience is only the second case to report use of caplacizumab without PLEX for successful treatment of TTP. In our patient’s experience, treatment with caplacizumab on Day 5 without therapeutic plasma exchange or plasma transfusion resulted in clinical improvement of TMA with normalization of platelet count and markers of end organ damage (LDH) within three days of administration. These results are similar to those noted by Chander et al. and in the HERCULES study, in which the 75th percentile for platelet normalization was 2.95 days (95% CI 2.85-3.91) and median time to normalization of organ damage markers was 2.86 days (95% CI 1.93-3.86) with PLEX and caplacizumab [6].  Our patient’s ADAMTS13 activity remained undetectable after starting caplacizumab, despite improvement in thrombocytopenia, hemolysis, and end organ damage. At the same time, vWF antigen with high molecular weight multimers were still detectable though vWF activity was low. These data suggest that caplacizumab, independent of ADAMTS13 activity, was effective in preventing platelet and vWF adhesion and thus microvascular thrombosis.

This experience also demonstrates that caplacizumab alone is not sufficient treatment for TTP, but rather a supportive measure until immunosuppression can take full effect. Rituximab has been studied in front line therapy and is used by many physicians to treat acute TTP. It’s benefit has been reported in several cases of Jehovah’s witness patients and in two prospective cohort studies and one retrospective registry study in combination with PLEX and corticosteroids [5,19]. In these studies, remission from TTP has been reported to occur within 14-21 days. In addition, reduced risk for relapse is noted with rituximab use [5,19]. Vincristine, a microtubule inhibitor without megakaryocyte activity, has been noted to have variable efficacy in observational series in both the relapsed and acute setting (20, 21), with combination vincristine and corticosteroids reporting 50-100% response rates. Vincristine use is also reported with success in Jehovah’s Witness patients with TTP [9,10,12]. In our patient’s case, corticosteroids, rituximab, and vincristine were all safely administered concurrently and resulted in eradication of the ADAMTS13 functional inhibitor with restoration of ADAMTS13 activity by Day 30. It is possible that the patient achieved remission prior to Day 30 as she clinically improved, but we did not check data prior to Day 30 as it would not alter our management plan.

Despite favorable outcome, our patient’s case highlights challenges with caplacizumab treatment. The major barrier to caplacizumab use is cost and lack of widespread availability of the drug. At the time of this publication, caplacizumab cost is around US$8000 per dose [22]. With treatment regimens of 30 days and relative rarity of TTP, the drug may not be stocked in many hospitals and may require insurance approval prior to use, which could delay treatment. For patients who present with aggressive disease with end organ damage, high LDH, and high functional inhibitor titer, waiting for drug procurement to start therapy may not be feasible. There are case reports of caplacizumab used as step-up therapy based on ADAMTS13 activity for those failing standard treatment, but no “real-world” cohort or clinical trial data currently exists regarding this approach or delayed treatment [23].

In our patient’s case, caplacizumab was not available for emergent administration and took five days to procure. She presented with renal failure, high LDH, as well as high inhibitor titer suggesting aggressive disease. Studies show that one volume of plasmapheresis removes approximately 45% of circulatory IgG and three to five days of plasmapheresis can remove up to 90% of circulating IgG [4]. We employed therapeutic plasma exchange with albumin replacement in addition to immunosuppression to reduce vWF multimers and circulating antibodies.  With this approach, functional inhibitor titer decreased, but did not resolve and ADAMTS13 activity remained low (<10%). This phenomenon likely resulted from a combination of removal of autoantibody without replenishment of exogenous ADAMTS13 from lack of plasma transfusion in addition to ongoing inhibition of endogenous ADAMTS13 by a strong inhibitor. Markers of hemolysis did not change dramatically in our patient’s case by the last day of plasma exchange, though reduced LDH and improvement in renal function was noted. We believe that while our patient did not experience significant clinical improvement without PLEX, progressive organ dysfunction was likely prevented until caplacizumab was added.

In summary, our case provides additional evidence that caplacizumab with immunosuppression with rituximab, corticosteroids, and vincristine may be a feasible alternative for treatment of TTP without PLEX. This approach could be useful for treatment of patients who are unwilling or unable to accept plasma transfusion but also could also prevent the complications of PLEX including central line placement, infusion reactions, anaphylaxis, and risk for hypocalcemia.  A clinical trial to evaluate use of caplacizumab and immunosuppression without plasma exchange would provide data on the safety and efficacy of this approach.  In addition, our case also provides support for the use of plasma exchange with albumin in patients who cannot get plasma transfusions for emergent management, and also provides additional support for use of caplacizumab as delayed or step-up therapy.