Paroxysmal Nocturnal Hemoglobinuria Treatment & Management

Updated: Dec 26, 2017
  • Author: Emmanuel C Besa, MD; Chief Editor: Koyamangalath Krishnan, MD, FRCP, FACP  more...
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Approach Considerations

According to current understanding of paroxysmal nocturnal hemoglobinuria (PNH), the ideal treatment is to replace the defective hematopoietic stem cell with a normal equivalent by stem cell transplantation; however, this is not realistic for many patients, because stem cell transplantation requires a histocompatible donor and is associated with significant morbidity and mortality. This form of treatment is reserved for severe cases of PNH with aplastic anemia or transformation to leukemia, both of which are life-threatening complications.

In 2007, eculizumab (Soliris), an anti-complement antibody targeting the CD5 complement component, was approved by the US Food and Drug Administration (FDA). Eculizumab alleviates the hemolysis associated with PNH and its sequelae, dramatically improving symptoms, improving quality of life, and eliminating complications of PNH. [8] Eculizumab does not alter the underlying defect of the disease, however; thus, treatment needs to continue life-long or until spontaneous remission, which occurred only in a minority of patients (12 of 80 patients in one study [16] ) before the advent of eculizumab.

Treatment of bone marrow hypoplasia

Bone marrow hypoplasia is a serious cause of morbidity and mortality. It is treated most effectively with bone marrow transplantation; however, if there is no suitable donor available, antithymocyte globulin (ATG) has been used in the treatment of aplastic anemia with considerable success.


Patients with PNH who develop acute thrombosis should immediately be started on eculizumab, if they are not already taking it, as this reduces the risk of thrombosis extension or recurrence. [12] Otherwise, management of thrombotic complications follows standard principles, including using heparin emergently, then maintenance therapy with the use of an oral anticoagulant, such as warfarin. Sometimes, heparin can exacerbate the thrombotic problem, possibly by activating complement. This can be prevented using inhibitors of the cyclooxygenase system, such as aspirin, ibuprofen, and sulfinpyrazone.

Primary prophylaxis of thromboembolism for patients with PNH has been advocated. Whether this approach is safe and effective in all patients with PNH remains controversial, however.


Modulation of complement is controlled poorly by high doses of glucocorticoids. The usual adult dose of prednisone is 20-40 mg/d (0.3-0.6 mg/kg/d) given daily during hemolysis and changed to alternate days during remission. On this regimen, about 70% of adult patients experience improvement in hemoglobin levels, but long-term therapy is fraught with complications.

Investigational agents

Yuan et al reported that two novel small-molecule inhibitors of Factor D, which is a component of the alternative complement pathway, show potential as oral agents for treating PNH. In the Ham test, using cells from PNH patients, the Factor D inhibitors significantly reduced complement-mediated hemolysis at concentrations as low as 0.01 μM. In an animal model, the compound ACH-4471 blocked alternative pathway activity. [27]




The anticomplement agent eculizumab is a humanized monoclonal antibody against terminal protein C5; it has been shown to be highly effective in reducing intravascular hemolysis. [28, 29] Eleven transfusion-dependent patients with PNH were given intravenous (IV) eculizumab at 900 mg over 30 minutes every 2 weeks. The mean lactate dehydrogenase (LDH) level decreased, transfusion requirements fell from 2.1 units per patient per month to 0.0, and a global improvement in quality of life occurred. [29] Long-term analysis showed that these improvements can be maintained over 3 years, and erythropoietin can overcome anemia due to bone marrow failure in patients on the drug.

The 5-year survival of patients with PNH prior to eculizumab therapy in a cohort followed at Leeds Hospital in the United Kingdom was 66.8%. With eculizumab therapy, 5-year survival improved to 95.5%, which is not statistically different from age-matched controls in the general population. [30]

Treatment breakthrough from complement control can occur in small minority (10%) of patients due to an inadequate dosing schedule. The eculizumab level must remain above 35 μg/mL, but trough levels at 2 weeks may fall below this level and cause recurrence of hemolysis.

The recommended adjustment for patients whose eculizumab levels fall into this category is to increase the dose to 900 mg every 12 days or 1200 mg every 2 weeks. Withdrawal hemolysis can occur by stopping therapy for any reason, as accumulation of PNH RBC increases over time by protecting type II and III PNH cells from destruction due to therapy, which can potentially trigger a massive hemolysis.

Infection prophylaxis

Consequences of complement inhibition include an increased risk of infections from Neisseria meningitides, as seen in inherited terminal complement deficiency. [8] Before the administration of eculizumab, all patients should be vaccinated with a serogroup B meningococcal vaccine. [31] Alashkar et al suggest that serologic response testing after vaccination is warranted, because immunological response to vaccines varies, and that re-vaccination with a tetravalent conjugate vaccine every 3 years is essential, or should be based on response rates, in patients on eculizumab therapy. [32]

Despite vaccination, patients may develop meningococcal septicemia (not meningitis). Although this is rare, occurring at a rate of 0.5 cases per 100-patient years, prophylactic antibiotics are recommended to prevent this complication. One study used penicillin V, 500 mg twice daily orally, or erythromycin 500 mg twice daily for patients intolerant to penicillin. [33]

Effect on thromboembolic complications

Eculizumab treatment reduces the risk of clinical thromboembolism in patients with PNH (the leading cause of death in PNH) and is recommended for PNH patients with a history of prior thromboembolism. [34] The rate of thrombotic complications prior to eculizumab was 5.6 per 100 patient years; after eculizumab, it dropped to 0.8 per 100 patient years.

In an international multi-institutional cooperative study involving 195 PNH patients, the thromboembolic (TE) event rate per 100 patient-years with eculizumab treatment was 1.07, compared with 7.37 events (P <0.001) prior to eculizumab treatment, a relative absolute reduction of 85%. With equalization of duration of exposure before and during treatment for each patient, TE events were reduced from 39 before eculizumab to 3 during eculizumab (P <0.001). The TE event rate in antithrombotic-treated patients (n = 103) was reduced from 10.61 to 0.62 events/100 patient-years with eculizumab treatment (P <0.001).

One study has documented elevated D-dimer levels in PNH patients with a history of thrombosis. D-dimer levels decreased immediately after initiation of eculizumab therapy. [35]

Continuation of anticoagulation in patients with PNH with a previous thrombosis while on eculizumab is recommended, as stopping therapy has not been studied. However, patients with no previous thrombosis have discontinued warfarin after starting eculizumab, with no thrombotic sequelae. [33, 36]

Eculizumab and renal dysfunction

Chronic hemosiderosis and/or microvascular thrombosis from PNH causes kidney dysfunction at an incidence of 65% for renal dysfunction or damage, defined by stages of chronic kidney disease (CKD), in a large cohort of PNH patients. Eculizumab treatment was safe and well-tolerated in patients with renal dysfunction or damage and resulted in the likelihood of improvement as defined as categorical reduction in CKD stage (P <0.001) compared with baseline and placebo (P = 0.04).

Improvement in renal function was more commonly seen in those with less severe impairment. Improvements occurred quickly and were sustained for at least 18 months of treatment. Administration of eculizumab to patients with renal dysfunction or damage was well tolerated and was usually associated with clinical improvement. [37]


Monitoring iron even if the patients no longer require transfusions is recommended, because hemosiderinuria—a protective mechanism in PNH to excrete iron—no longer occurs with eculizumab. Measuring serum ferritin is recommended and chelation therapy may be necessary in patients with high levels.


Treatment of Anemia

The anemia of PNH may have three components: intravascular hemolysis, inadequate erythropoiesis, and superimposed iron deficiency (massive iron loss through hemoglobinuria). In view of increased rate of erythropoiesis, give 5 mg/d of folic acid orally. Assess iron stores with the use of the transferrin saturation index (TSI) and give oral ferrous sulfate if the result is <20%. (Ferritin levels should not be used for this purpose, as ferritin is an acute-phase reactant and levels can be misleading.)

Determine steady-state hemoglobin levels after correction for iron deficiency. When appropriate, transfuse packed red blood cells (RBCs) with leukocytes depleted by filter. Washing RBCs is no longer necessary, and use of irradiated blood products is recommended for future stem cell transplantation.

Supportive care for severe anemia includes blood transfusion using leuko-depleted packed RBCs to prevent alloimmunization. Development of alloantibodies can be a problem with future transfusions because of activation of complement and delayed hemolysis of transfused blood.


Replacement of nutritional iron, because of increased loss of iron from the hemolysis and the 200-fold increase in iron urinary excretion, is necessary to prevent development of iron deficiency. Iron replacement can stimulate reticulocytosis that can trigger hemolysis by releasing a new cohort of complement-sensitive cells. This process can be prevented by adding prednisone during replacement therapy.

Stimulation of erythropoiesis using androgenic hormones has been successful in patients with a moderate decrease in RBC production. This has been replaced mainly by using recombinant erythropoietin therapy.


Treatment in Pregnancy

Pregnancy in patients with PNH poses very significant risks. There is a very high risk of thrombotic complications for the expectant mother, as well a risk of developing hypoplastic anemia. Maternal mortality in these patients is approximately 20%, mostly from thrombosis and infections, and risk of fetal loss is increased. Consequently, full anticoagulation with low-molecular weight heparin (LMWH) is recommended for pregnant women with PNH. Warfarin may be substituted after the first trimester.

The use of eculizumab in pregnancy has proved beneficial. [38] In a review of 75 pregnancies in 61 women with PNH, Kelly and colleagues reported a high rate of fetal survival and a low rate of maternal complications. No maternal deaths occurred. There were three fetal deaths (4%) and six first-trimester miscarriages (8%). During pregnancy, patients demonstrated increased requirement of red blood cell transfusions, and approximately half required an increase in the eculizumab dosage. Ten hemorrhagic events occurred, and two postpartum thrombotic events. Eculizumab was detected in some infants' cord blood, but not in breast milk. [39]


Hematopoietic Stem Cell Transplantation

Hematopoietic stem cell transplantation (HSCT) using allogeneic donors is the only curative therapy for PNH. With the advent of eculizumab, the indications for HSCT have changed. Clinical results from HSCT from various programs in a rare disease are limited to small numbers of patients. A retrospective analysis of the Italian BM transplantation group in 26 patients with a median age of 32 years (22-60 y, range) with 23 HLA-identical donors (22 siblings, one unrelated) shows a transplant-related mortality of 42%, 8% graft failure, and a 10-year survival (disease-free) of 57% for all patients. [40] The mortality rate remains high, so this form of therapy is reserved for those who are severely hypoplastic and refractory to other forms of therapy.

The International Bone Marrow Transplant Registry (IBMTR) reported a 2-year survival probability of 56% in 48 recipients of HLA-identical sibling transplants between 1978 and 1995. [41] Data using nonmyeloablative conditioning and haploidentical donors was similar to the identical donors, indicating some form of graft-versus-PNH effects. Now that an effective, nontransplant therapy is available, the use of allogeneic HSCT to treat PNH has decreased.

Before the introduction of eculizumab, PNH patients with severe symptoms from classic PNH and patients with AA/PNH with peripheral cytopenias meeting criteria for severe aplastic anemia were considered good candidates for allogeneic bone marrow transplantation, especially if a matched sibling donor was available.

With eculizumab for PNH, the indications for allogeneic HSCT in this setting have changed. First, HSCT should not be offered as initial therapy for most patients with classic PNH, given the high transplant-related mortality, especially when using unrelated or mismatched donors. Exceptions are PNH patients in countries where eculizumab is not available. HSCT is also a reasonable option for patients who do not have a good response to eculizumab therapy. Second, aplastic anemia/PNH patients continue to be reasonable candidates for HSCT if they have life-threatening cytopenias. [42]

An analysis by the International PNH Interest Group reviewed data from 67 patients from single centers and from teo registry studies, with special emphasis in eliminating duplication in patient reporting. [21] Results included the following:

  • Of the seven patients transplanted from a twin syngeneic donor, the four who had no conditioning therapy either failed to engraft or relapsed after transplantation, indicating that a marrow ablative conditioning is necessary before syngeneic transplantation.
  • In 47 of 67 patients, a human leukocyte antigen (HLA)-identical sibling was used as the donor, 1 from a haploidentical family member and 12 from an unrelated donor (matched unrelated donor [MUD]).
  • In the only single-center study providing a Kaplan-Meier analysis, overall survival at 5 years was 58 +/- 13%. This is less favorable than the survival estimate of approximately 75% generated by combining the data from the other reports.
  • Investigation is currently in progress regarding whether reduced-intensity conditioning can improve the outcome.