Not So Benign
Paroxysmal Nocturnal Hemoglobinuria: Many Targets, Many Drugs

Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal, complement-mediated hemolytic anemia associated with bone marrow failure and thrombophilia.¹  Clonal expansion of a hematopoietic stem cell with a somatic mutation in PIGA underlies virtually all cases. The PIGA gene product is required to make glycosylphosphatidylinositol-anchored proteins (GPI-AP). CD55 and CD59 are complement regulatory proteins that are decreased or absent on PNH blood cells; their absence explains the chronic alternative pathway of complement-mediated hemolysis and acute paroxysms often triggered by classical complement-amplifying conditions such as infection or surgery. These paroxysms exacerbate hemoglobinuria (release of free hemoglobin) and smooth muscle dystonia due to tissue depletion of nitric oxide via free hemoglobin scavenging.²  Thrombophilia in PNH is multifactorial, but recent data suggest that the release of ADP, which is associated with intravascular hemolysis, leads to strong platelet activation.³ 

Clinical manifestations of PNH are manifold, and the classical presentation characterized by intermittent bouts of hemoglobinuria is observed in less than 35% of patients.⁴  Some patients are asymptomatic and are diagnosed following the detection of mild anemia, neutropenia, and thrombocytopenia on routine blood counts. Bone marrow failure consistent with moderate or severe aplastic anemia is a common presentation. Other cases manifest with smooth muscle dystonias (e.g., erectile dysfunction, dysgeusia, esophageal spasm, or abdominal pain), and both microvascular and macrovascular forms of thrombosis are frequently observed.^5,6  Thrombosis predominantly involves the abdominal (portal, hepatic, splenic, mesenteric) and cerebral veins; dermal vein thrombosis, deep venous thrombosis, and pulmonary emboli are less common.⁷  Arterial thrombosis is rare. Fatigue and dyspnea often out of proportion to the degree of anemia are common. Regardless of the presenting symptoms, most patients will have laboratory evidence of intravascular hemolysis (normocytic or macrocytic anemia with a lactate dehydrogenase [LDH] level 1.5 to 10 times the upper limit of normal, elevated indirect bilirubin, and low haptoglobin), mild to moderate bone marrow suppression, and fatigue.

The diagnostic evaluation for PNH should include a complete blood count (CBC), differential, reticulocyte count, biochemical profile, lactate dehydrogenase levels, d-dimer, and peripheral blood flow cytometry for PNH.^8,9  If the CBC suggests underlying bone marrow failure, a bone marrow evaluation to rule out acquired aplastic anemia is indicated. Imaging of the abdominal veins and head is indicated if the patient presents with localized pain symptoms in these areas, especially when d-dimer levels are elevated. Hemolytic or classical PNH is diagnosed in patients with a large PNH granulocyte clone (usually >50%) based on flow cytometry, an LDH level greater than 1.5 times the upper limit of normal, a reticulocyte count greater than 120,000, and relatively well-preserved peripheral blood counts. In the setting of aplastic anemia, PNH is diagnosed based on the presence of a PNH clone (usually less than 20%) in conjunction with a hypocellular marrow, pancytopenia, and low corrected reticulocyte count. In such cases, the LDH level is often less than 1.5 times the upper limit of normal. Patients with subclinical PNH usually present with asymptomatic cytopenias, very mild hemolysis, and a PNH granulocyte clone of 0.1 to 10%. Although several classification schemes for PNH have been established, all are imperfect given the dynamic nature of the disease. In patients with PNH who have underlying aplastic anemia and those with subclinical PNH, the disease may evolve to hemolytic PNH over weeks to years, while hemolytic PNH can also evolve to aplastic anemia.

Observation is appropriate for patients with asymptomatic or minimally symptomatic PNH.¹⁰  Thrombosis is an urgent indication for complement inhibition. Patients with bothersome symptoms (fatigue, dyspnea, pain, etc.) due to a large PNH clone and evidence of intravascular hemolysis should also be treated. For patients with a PNH clone whose symptoms are primarily caused by underlying acquired severe aplastic anemia, the disease should be managed with immunosuppressive therapy or allogeneic bone marrow transplantation.¹¹  Ravulizumab, a C5 inhibitor, is my firstline agent of choice for classical PNH due to its rapid onset of action, long half-life, good safety profile, and ability to mitigate classical pathway-amplifying triggers of complement.¹²  C5 inhibition is highly effective in preventing thrombosis.^13,14  However, a drawback of all C5 inhibitors is that roughly 20% of patients continue to require intermittent red cell transfusions and have symptomatic anemia due to extravascular hemolysis.¹⁵  Upstream complement inhibitors that target the alternative complement pathway at C3 (pegcetacoplan),¹⁶  factor B (iptacopan),¹⁷  or factor D (danicopan)¹⁸  are now available. For patients with PNH who have symptomatic anemia despite C5 inhibition, both pegcetacoplan and iptacopan alone have been shown to be superior to remaining on C5 inhibition. Both drugs can restore hemoglobin to normal or near-normal levels without the need for transfusions in most cases. Pegcetacoplan is administered via subcutaneous infusion at least twice a week; iptacopan is administered orally twice a day. Danicopan is also an oral complement inhibitor that raises hemoglobin to near-normal levels in patients with PNH who exhibit persistent extravascular hemolysis and anemia despite C5 inhibition; however, it is approved as an “add-on” to C5 inhibitors. Danicopan is taken three times a day. All patients on complement inhibitors should remain current on Neisseria vaccinations, and individuals with high-risk disease should receive antibiotic prophylaxis.

Upstream complement inhibitors that inhibit factors C3, B, and D will increasingly be used to manage hemolytic PNH. At baseline, they may prove to be better than C5 inhibitors in reducing hemolysis. A caveat is that these agents have short half-lives and may leave patients vulnerable to severe hemolysis in the setting of classical pathway amplifiers (infection, surgery, pregnancy, etc.) and missed doses. More data on the use of these drugs in preventing thrombosis are needed.

Twenty years ago, PNH was a life-threatening, debilitating disease due to complement-dependent thrombosis and severe anemia. Fortunately, we now have a variety of options. Complement inhibition saves lives and improves quality of life. As the optimal sequence of these drugs continues to evolve, clinicians must consider the efficacy, safety, cost, and ease of administration.

Dr. Brodsky has received research funding from Alexion and AstraZeneca Rare Disease and is the section editor (red blood cell disorders) for UptoDate.