Thrombosis used to be the main identifiable cause of death in patients with PNH, prior to the introduction of complement protein C5 inhibitors. In the current treatment era, the rates of thrombosis are substantially lower. As seen in an analysis of a large database from the National Health Service in the United Kingdom and reported at this year's ASH meeting, only 4.5% of patients with PNH developed thrombosis while on eculizumab or ravulizumab (abstract 2566). Case records spanned from May 2002 to July 2022, revealing a total of 509 patients with PNH who were treated with eculizumab or ravulizumab. A 79% survival rate was reported, with 91 deaths, and infection was associated with the cause of death in 48.4% of these individuals. 

Still, thrombosis may occur in patients with PNH, and it is important to optimize anticoagulation strategies when it does. In abstract 3818, also presented at the conference, Gurnari et al investigated the efficacy of direct oral anticoagulants in patients with classical hemolytic PNH. In this cohort study, researchers found that 33 of 106 patients (31%) experienced thrombotic events, with 84% occurring as the initial manifestation of PNH that led to the patient seeking treatment, 13% occurring during a temporary discontinuation of anticomplement treatment, and 3% occurring during treatment. Individuals with superficial thrombotic events promptly began treatment with anticomplement therapy, while the other patients improved with additional anticoagulation. The anticoagulation strategies in patients with PNH were warfarin (50%), direct oral anticoagulants (29%), and low-molecular-weight heparin (21%), with a median treatment duration of 44 months. Further, researchers reported that low-molecular-weight heparin was preferred in those with thrombocytopenia. Notably, 42% of patients were able to successfully discontinue anticoagulation therapy with the use of anticomplement therapy without a recurrence of thrombotic events. 

In an attempt to characterize the inpatient burden and outcomes associated with venous thromboembolism (VTE) among patients with PNH, Grewal and colleagues analyzed the National Inpatient Sample, which included data from inpatient hospitalizations in the United States from 2016 to 2019 (abstract 3571). Overall, 9.6% of PNH hospitalizations were linked to VTE. Lower extremity deep vein thrombosis, hepatic vein thrombosis/Budd Chiari syndrome, portal vein thrombosis, pulmonary embolism, and upper extremity deep vein thrombosis were among the most common sites of VTE. Patients with VTE were, on average, younger and had a higher prevalence of comorbid obesity and chronic liver disease compared with those without VTE.  

Over the long-term, there are a variety of other complications that may be associated with PNH. For instance, some patients may develop renal dysfunction. It is thought that chronic hemolysis and hemosiderin deposition in the renal tubules are a part of that process. Individuals with PNH may develop chronic kidney disease and, rarely, renal failure. Pulmonary hypertension is another complication of PNH. Patients with pulmonary hypertension can present with shortness of breath, chest pain, and, perhaps, some heart failure. 

Despite the success of anticomplement therapy, patients with PNH are at risk for breakthrough intravascular hemolysis, especially in the setting of complement-amplifying conditions such as infection or surgery, for instance. Additionally, some individuals experience extravascular hemolysis and persistent anemia while on the standard-of-care treatments. We saw evidence of breakthrough hemolysis and extravascular hemolysis in the UK cohort from abstract 2566, in a subset of patients on C5 inhibition. Episodes of acute hemolysis are also a concern with C3 inhibition, and these were observed in a subset of patients participating in clinical trials with pegcetacoplan. In fact, Griffin et al explored intensive pegcetacoplan dosing and maintenance regimens for such patients and reported their findings at the ASH meeting (abstract 1255). They concluded that lactate dehydrogenase levels can be rapidly controlled with these regimens. 

Of note, in a late-breaking abstract by Peffault de Latour and colleagues (abstract LBA-2), iptacopan monotherapy showed superiority vs the standard of care in both of the trial’s primary end points and in several secondary end points, including transfusion avoidance, absolute reticulocyte count, and rates of clinical breakthrough hemolysis. Researchers noted that headache and diarrhea were more commonly reported among patients on iptacopan, whereas infections and breakthrough hemolysis events were more commonly reported among those on the standard of care.

From the perspective of patient care, my view is that if you have a patient on ravulizumab or eculizumab and they are doing very well (ie, their hemoglobin is normal or near normal and they feel great), there is no need to change anticomplement therapies. If they have breakthrough hemolysis, moderate to severe anemia, for example, a hemoglobin of 10 g/dL or lower, or substantial symptoms, then we may want to consider a different drug. Of course, if a patient is on anticomplement therapy and is doing well and then one day develops anemia, we also have to consider other common causes of anemia. Is the individual iron deficient? If yes, then perhaps the iron deficiency is causing the anemia rather than a lack of efficacy of the anticomplement drug. Is the patient becoming vitamin B₁₂ deficient? Is the patient bleeding? What is the patient’s renal status, erythropoietic capacity, and bone marrow function? 

The other major point, from a patient care perspective, is cost. We are excited about the emerging therapies. It is almost unprecedented to have so many promising agents for such a rare disease, and it would be outstanding if we get multiple new US Food and Drug Administration approvals. However, PNH is a costly disease to treat, and I am not confident that the costs will substantially come down with these new agents.