1. health and fitness
2. disease

ACQUIRED HEMATOPOIETIC DISORDERS: COMPLEMENT-MEDIATED BLOOD DISORDERS
Management of Paroxysmal Nocturnal Hemoglobinuria
in the Era of Complement Inhibitory Therapy
Charles J. Parker1
1Hematology
Division, Department of Internal Medicine, The University of Utah School of Medicine,
Salt Lake City, UT
Despite the availability of safe, effective targeted therapy that controls intravascular hemolysis, the management of
paroxysmal nocturnal hemoglobinuria (PNH) remains complicated because of disease heterogeneity and close
association with BM failure syndromes. The purpose of this review is to provide a framework for individualizing
treatment based on disease classification. According to the recommendations of the International PNH Interest Group,
patients can be placed into one of the following 3 categories: (1) classic PNH, (2) PNH in the setting of another BM
failure syndrome, or (3) subclinical PNH. The PNH clone in patients with subclinical disease is insufficiently large to
produce even biochemical evidence of hemolysis, and consequently, patients who fit into this category require no
PNH-specific therapy. Patients with PNH in the setting of another BM failure syndrome (usually aplastic anemia or
low-risk myelodysplastic syndrome) have at least biochemical evidence of hemolysis, but typically the PNH clone is
small (⬍ 10%) so that hemolysis does not contribute significantly to the underlying anemia. In these cases, the focus of
treatment is on the BM failure component of the disease. Intravascular hemolysis is the dominant feature of classic
PNH, and this process is blocked by the complement inhibitor eculizumab. The thrombophilia of PNH also appears to
be ameliorated by eculizumab, but the drug has no effect on the BM failure component of the disease. Low-grade
extravascular hemolysis due to complement C3 opsonization develops in most patients treated with eculizumab, and
in some cases is a cause for suboptimal response to treatment. Allogeneic BM transplantation can cure classic PNH,
but treatment-related toxicity suggests caution for this approach to management.
Introduction
Paroxysmal nocturnal hemoglobinuria (PNH) has a special place in
the fields of hematology and complementology because identification of the molecular basis of the hemolytic anemia that is the
clinical hallmark of this disease led to a remarkable number of
discoveries that helped to identify and characterize the alternative
pathway and define the physiology of the complement system in
humans.1 The discoveries began with the seminal observations of
Thomas Hale Ham in the late 1930s that suggested a novel,
antibody-independent mechanism for complement activation. Subsequently, Ham’s observations contributed to elucidation of the
properdin pathway (now known as the alternative pathway) by
Louis Pillemer while the two were on the faculty at Case Western
Reserve University in the 1950s. Systematic investigation of the
aberrant regulation of complement on PNH erythrocytes contributed
to the identification and characterization of the complement regulatory proteins decay accelerating factor (DAF, CD55) and membrane
inhibitor of reactive lysis (MIRL, CD59) in the 1970s and 1980s and
ultimately led to the development of the first successful targeted
therapy for a complement-mediated disease when eculizumab was
approved for treatment of PNH in 2007.2
In contrast to all other intrinsic abnormalities of the erythrocyte,
PNH is an acquired disorder; and although the focus of this review is
on the complement-mediated hemolytic anemia component of the
disorder, PNH is actually a disease of the hematopoietic stem cell.
PNH arises as a result of the nonmalignant clonal expansion of one
or several hematopoietic stem cells that have acquired a somatic
mutation of the X-chromosome gene PIGA that is required for
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synthesis of the glycosyl phosphatidylinositol (GPI) moiety that
anchors some proteins to the cell surface. As a consequence of
mutant PIGA, the progeny of affected stem cells (erythrocytes,
granulocytes, monocytes, platelets, and lymphocytes) are deficient
in all GPI-anchored proteins (GPI-APs) that are normally expressed
on hematopoietic cells (and all GPI-APs that are normally expressed
on hematopoietic cells are deficient on the progeny of PIGA mutant
stem cells). Among the GPI-APs that are deficient in PNH are DAF
(CD55) and MIRL (CD59), the 2 primary erythrocyte membrane
regulators of complement. Deficiency of CD55 and CD59 accounts
for the complement-mediated intravascular hemolysis that is the
hallmark of the disease. The clinical manifestations of PNH are
hemolytic anemia, thrombophilia, and BM failure, but only the
hemolytic anemia is unequivocally a direct consequence of somatic
mutation of PIGA.
PNH and complement
Thoughtful management of patients with PNH is facilitated by an
understanding of the mechanisms involved in the activation and
regulation of complement on the erythrocyte surface (Figure 1). The
chronic intravascular hemolysis of PNH is mediated by the alternative pathway of complement (APC). A component of innate
immunity, this ancient system evolved to protect the host against
invasion by pathogenic microorganisms.3 Unlike the classical
complement pathway that is part of the system of acquired
immunity and requires antibody for initiation of activation, the APC
is in a state of continuous activation, armed always to protect the
host.4 The APC cascade can be divided into 2 functional components, the amplification C3 and C5 convertases and the cytolytic
membrane attack complex (MAC) (Figure 1). The C3 and C5
21
Figure 1. Complement-mediated lysis of PNH erythrocytes. Top panel shows that the C3 convertase (left blue rectangle) of the APC consists of
activated C3 (C3b), activated factor B (Bb, the enzymatic subunit of the complex), and factor P (a protein that stabilizes the complex, formally called
properdin). The C5 convertase (right blue rectangle) has the same components as the C3 convertase except that 2 C3b molecules are required to bind
and position C5 for cleavage by activated factor B (Bb). C3a and C5a are bioactive peptides that are generated by cleavage of C3 and C5,
respectively, by their specific activation convertases. The C3 and C5 convertases greatly amplify complement activation by cleaving multiple substrate
molecules. The MAC (red rectangle) consists of activated C5 (C5b), C6, C7, C8, and multiple molecules of C9 (C9n). The MAC is the cytolytic unit of
the complement system. The GPI-anchored complement-regulatory protein CD55 restricts the formation and stability of both the C3 and the C5
amplification convertases by destabilizing the interaction between activated factor B (Bb) and C3b (indicated by the blue arrows), whereas GPIanchored CD59 blocks formation of the MAC by inhibiting the binding of C9 to the C5b-8 complex (indicated by the brown arrow). Inhibition of MAC
formation by the humanized anti-C5 mAb eculizumab (indicated by the red arrow) ameliorates the intravascular hemolysis of PNH. Bottom panel shows
that normal erythrocytes (left) are protected against complement-mediated lysis (lightning bolts) primarily by CD55 (blue circles) and CD59 (green
circles). Deficiency of these GPI-anchored complement-regulatory proteins results in APC activation on PNH erythrocytes (right). Consequently, MACs
form pores in the red cell membrane, resulting in colloid osmotic lysis and release of hemoglobin (red circles) and other contents of the red cell,
including LDH, into the intravascular space.
convertases are enzymatic complexes that initiate and amplify the
activity of the APC and ultimately generate the MAC. The MAC is
the common pore-forming, cytolytic subunit of the classical and
lectin complement pathways and the APC. Because the APC is
always primed for attack, overlapping and redundant mechanisms
for self-recognition and protection of the host against APCmediated injury have evolved. Both fluid-phase and membranebound proteins are involved in these processes. Normal human
erythrocytes are protected against APC-mediated cytolysis primarily by DAF (CD55)5-7 and MIRL (CD59),8 and these proteins act at
different steps in the complement cascade. CD55 regulates the
formation and stability of the C3 and C5 convertases, whereas
CD59 blocks the formation of the MAC (Figure 1).9 Deficiency of
both CD55 and CD59 is the pathophysiological basis of the
Coomb-negative, intravascular hemolysis that characterizes the
disease in its untreated state.9
Phenotypic mosaicism is characteristic of PNH
The peripheral blood of patients with PNH is a mosaic of normal
and abnormal cells (Figure 2). Although PNH is a clonal disease, it
is not a malignant disease and, for reasons that are unclear, the
extent to which the PIGA-mutant clone expands varies widely
among patients.10 As an example, in some cases, ⬎ 90% of the
peripheral blood cells may be derived from the PIGA-mutant clone,
22
whereas in others, ⬍ 10% of the circulating cells may be GPI-AP
deficient. This peculiar feature (variability in the extent of mosaicism) is clinically relevant because patients with small PNH clones
have minimal or no symptoms and require no PNH-specific
treatment, whereas those with large clones are often debilitated by
the consequences of chronic complement-mediated intravascular
hemolysis and respond dramatically to complement-inhibitory
therapy.
Another remarkable feature of PNH is phenotypic mosaicism based
on PIGA genotype,11 which determines the degree of GPI-AP
deficiency.10 PNH III cells are completely deficient in GPI-APs,
PNH II cells are partially (⬃ 90%) deficient, and PNH I cells
express GPI-APs at normal density (putatively, these cells are the
progeny of residual normal stem cells) (Figure 2). Phenotype varies
among patients. Some patients have only type I and type III cells
(the most common phenotype); some have type I, type II, and type
III cells (the second most common phenotype); and some have only
type I and type II cells (the least common phenotype). Further, the
contribution of each phenotype to the composition of the peripheral
blood varies. Phenotypic mosaicism is clinically relevant because
PNH II cells are relatively resistant to spontaneous hemolysis, and
patients with a high percentage of type II cells have a relatively
benign clinical course (Figure 2).
American Society of Hematology
Figure 2. Clinical manifestations of PNH are determined by clone size and erythrocyte phenotype. Mock flow cytometry histograms of
erythrocytes from hypothetical patients with PNH stained with anti-CD59 are illustrated. The proportion and type of abnormal erythrocytes varies greatly
among patients with PNH, and these characteristics are important determinants of clinical manifestations. Patients with a high percentage of type III
erythrocytes have clinically apparent hemolysis (A). If the erythrocytes are partially deficient (⬃ 10% of normal expression) in GPI-AP (PNH II cells),
hemolysis may be modest even if the percentage of the affected cells is high (B). A patient may have a diagnosis of PNH, but if the proportion of type III
cells is low, only biochemical evidence of hemolysis may be observed (C).
The anemia of PNH is multifactorial
The anemia of PNH is multifactorial because an element of BM
failure is present in all patients, although the degree of dysfunction
is variable.12,13 In some patients, PNH arises in the setting of aplastic
anemia. In this case, BM failure is the dominant cause of anemia. In
other patients with PNH, evidence of BM dysfunction may be subtle
(eg, an inappropriately low reticulocyte count), with the degree of
anemia being determined primarily by the rate of hemolysis, which
is determined by the PNH clone size and erythrocyte phenotype
(Figure 2).
Diagnosis of PNH
Once suspected, diagnosing PNH is straightforward because a
deficiency of GPI-APs on peripheral blood cells can be readily
demonstrated by flow cytometry.14 Analysis of both RBCs and
peripheral mononuclear cells is warranted, because clone size will
be underestimated if only RBCs are examined due to the fact that
GPI-AP– deficient red cells are selectively destroyed by complement. Recent transfusion will also affect the estimate of clone size if
only RBCs are analyzed, but delineation of PNH phenotypes (ie, the
percentage of type I, type II, and type III cells) requires flow
cytometric analysis of the erythrocyte population (Figure 2).
In addition to flow cytometric analysis, the basic initial evaluation
of a patient with PNH should include: complete blood count to
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assess the effects of the disease on the production of leukocytes,
platelets, and erythrocytes; measurement of serum concentration of
lactate dehydrogenase (LDH), bilirubin (fractionated), and haptoglobin, which are biochemical markers of hemolysis; determination of
iron stores; BM aspirate and biopsy; and cytogenetics. These
diagnostic studies will allow classification into 1 of 3 groups based
on the recommendation of the International PNH Interest Group
(Table 1).13
In patients with classic PNH, the leukocyte and platelet counts are
usually normal or nearly normal, whereas leukopenia, thrombocytopenia, or both invariably accompany PNH in the setting of another
BM failure syndrome. The reticulocyte count is needed to assess the
ongoing capacity of the BM to respond to the anemia. Although the
reticulocyte count is elevated in patients with classic PNH, as noted
above, it may be inappropriately low for the degree of anemia,
reflecting underlying relative insufficiency of hematopoiesis that is
characteristic of the disease. Serum LDH is always markedly
elevated in classic PNH. The degree of serum LDH elevation is
variable in patients with PNH in the setting of another BM failure
syndrome (determined by the size of the PNH clone); however, in a
large majority of patients with PNH/BM failure, the clone size
is ⬍ 10%, with ⬍ 10% of patients with PNH/BM failure having a
clone size of ⬎ 50% (Table 1).15,16
23
Typically no, but some patients
(⬍ 10%) have relatively large clones
and clinically significant hemolysis
and may benefit
No
Benefit from eculizumab
Yes
By definition, patients with subclinical PNH have neither clinical
nor biochemical evidence of hemolysis (Table 1). Patients with
classic PNH may be iron deficient due to chronic hemoglobinuria
and hemosiderinuria. BM aspirate and biopsy are needed to
distinguish classic PNH from PNH in the setting of another BM
abnormality. Nonrandom cytogenetic abnormalities are rare in
classic PNH.17
Management of PNH based on classification
Completing the recommended diagnostic evaluation will allow the
development of a systematic treatment plan (Figure 3) based on
disease classification (Table 1).
24
A close association exists between PNH and aplastic anemia and, to
a lesser extent, between PNH and low-risk myelodysplastic syndrome (MDS). Using high-sensitivity flow cytometry, approximately 60% of patients with aplastic anemia and 20% of patients
with low-risk MDS have been found to have a detectable population
of GPI-AP– deficient erythrocytes and granulocytes.18-20 In ⬃ 80%
of these cases, the proportion of GPI-AP– deficient cells is ⬍ 1.0%
of the total. These patients (designated subclinical PNH patients)
with very small populations of GPI-AP– deficient erythrocytes have
no clinical or biochemical evidence of hemolysis and require no
specific treatment for PNH. However, finding a population of
GPI-AP– deficient erythrocytes in patients with aplastic anemia may
be clinically relevant, because some,19,20 but not all,21 studies
suggest that these patients have a particularly high probability of
responding to immunosuppressive therapy with a more rapid rate of
onset of response compared with patients with aplastic anemia
without a population of GPI-AP– deficient erythrocytes.
PMNs indicates polymorphonuclear cells.
*Based on the recommendations of the International PNH Interest Group.13
†Based on macroscopic hemoglobinuria, serum LDH concentration, and reticulocyte count.
‡Karyotypic abnormalities are uncommon.
§Aplastic anemia or low-risk MDS.
¶Analysis of PMNs is more informative than analysis of RBCs due to selective destruction GPI-AP– deficient RBCs.
Small (⬍ 1%) population of GPI-AP
deficient PMNs detected by
high-resolution flow cytometry
Evidence of a concomitant BM failure
syndrome§
Subclinical PNH
No clinical or biochemical evidence
of intravascular hemolysis
Although variable, the percentage of
GPI-AP–deficient PMNs is usually
relatively small (⬍ 10%)
PNH in the setting of another
BM failure syndrome§
Flow cytometry
Large population (⬎ 50%) of GPIAP–deficient PMNs¶
BM
Cellular BM with erythroid hyperplasia
and normal or near-normal
morphology‡
Evidence of a concomitant BM failure
syndrome§
Rate of intravascular hemolysis†
Florid (markedly abnormal LDH often
with episodic macroscopic
hemoglobinuria)
Mild (often with minimal
abnormalities of biochemical
markers of hemolysis)
Classic PNH
Category
Table 1. Classification of clinical PNH*
Subclinical PNH
The presence of PNH cells has also been observed in patients with
MDS.19,20,22,23 The association between PNH and MDS appears to
be confined to low-risk categories of MDS, particularly the refractory anemia (RA) variant.18-20,22 Using high-sensitivity flow cytometry in which ⱖ 0.003% of GPI-AP– deficient RBCs or peripheral
mononuclear cells was classified as abnormal, Wang et al reported
that 21 of 119 (18%) patients with RA MDS had a population of
PNH cells, whereas GPI-AP– deficient cells were not detected in
patients with RA with ringed sideroblasts, RA with excess of blasts,
or RA with excess of blasts in transformation.20 Compared with
patients with RA without a population of PNH cells, RA patients
with a population of PNH cells had a distinct clinical profile
characterized by the following features: (1) less pronounced morphological abnormalities of the blood cells, (2) more severe thrombocytopenia, (3) a lower rate of karyotypic abnormalities, (4) a higher
incidence of HLA-DR15, (5) a lower rate of progression to acute
leukemia, and (6) a higher probability of response to cyclosporine
therapy. More recently, the findings by Wang et al that a population
of PNH cells was associated only with low-risk MDS variants in
Japanese patients were confirmed in a North-American study of 137
patients classified by World Health Organization criteria.22
When combined with evidence of polyclonal hematopoiesis (based
on the pattern of X-chromosome inactivation in female patients), the
presence of a population of PNH cells in patients with MDS predicts
a relatively benign clinical course and high probability of response
to immunosuppressive therapy.18 A relatively good response to
immunosuppressive therapy for patients with MDS and aplastic
anemia was also predicted by expression of HLA-DR15 in studies
of both North American and Japanese patients.24,25 These observations support the hypothesis that aplastic anemia and a subgroup of
American Society of Hematology
Figure 3. Treatment algorithm based on disease classification. Disease classification is based on the recommendations of the International PNH
Interest Group.13
low-risk MDS are immune-mediated diseases, and that the immune
pathophysiological process provides the selection pressure that
favors the outgrowth of PIGA mutant, GPI-AP– deficient stem cells.
PNH in the setting of another BM failure syndrome
Patients with a BM failure syndrome (aplastic anemia or MDS) and
a PNH clone with clinical/biochemical evidence of hemolysis are
classified as PNH in the setting of another BM failure syndrome
(Table 1). In these patients, BM failure dominates the clinical
picture and hemolysis is primarily an incidental finding.15,16,19 The
large majority of patients with PNH/AA and PNH/MDS have
relatively small PNH clones (⬍ 10%) and require no specific PNH
therapy; in these cases, treatment should focus on the underlying
BM failure syndrome (Table 1 and Figure 3).
The PNH clone will be eradicated by the conditioning regimen in
combination with the GVH effect in patients undergoing allogeneic
transplantation for aplastic anemia or MDS. In most cases, the size
of the PNH clone is unaffected by treatment with immunosuppressive therapy, and the presence of a PNH clone should not deter
immunosuppressive therapy if that approach to treatment of the
underlying BM failure syndrome is considered appropriate.15,16 In
the uncommon cases in which, after immunosuppressive therapy,
the size of the PNH clone is sufficiently large to produce clinical
symptoms, the patient can be managed using the same approach as
for patients with classic PNH.
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Classic PNH
Patients with classic PNH have a large clone (⬎ 50%), and
consequently this disease subcategory is characterized by florid
intravascular hemolysis as indicated by a markedly elevated serum
LDH (Table 1). Patients may complain of episodic hemoglobinuria,
and most experience ongoing constitutional symptoms dominated
by lethargy, malaise, and asthenia that can be debilitating. The
complement-mediated intravascular hemolysis of PNH can be
inhibited by blocking formation of the MAC (Figure 1). The MAC
consists of complement components C5b, C6, C7, C8, and multiple
molecules of C9. Eculizumab (Soliris; Alexion Pharmaceutics) is a
humanized mAb that binds complement C5, preventing its activation to C5b by the APC C5 convertase and thereby inhibiting MAC
formation (Figure 1).2 In 2007, eculizumab was approved by both
the US Food and Drug Administration and the European Union
Commission for the treatment of the hemolysis of PNH. Treatment
of classic PNH patients with eculizumab reduces transfusion
requirements, ameliorates the anemia of PNH, and improves quality
of life by resolving the debilitating constitutional symptoms associated with chronic complement-mediated intravascular hemolysis
(Figure 3).26-28 After treatment, serum LDH concentration returns to
normal or near normal, with approximately one-half to two-thirds of
patients achieving transfusion independence26,27,29; however, mild
to moderate anemia, hyperbilirubinemia, and reticulocytosis persist
in essentially all treated patients.
25
Figure 4. Generation of C3 opsonins on PNH erythrocytes in patients treated with eculizumab. Deficiency of DAF on PNH cells results in
activation of the APC on PNH erythrocytes. Eculizumab blocks MAC-mediated complement lysis, allowing accumulation of C3 opsonins on PNH cells.
The opsonized erythrocytes are recognized by reticuloendothelial cells of the spleen and liver that express receptors (primarily CR2 for C3dg and CR3
for iC3b), resulting in extravascular hemolysis. The figure illustrates covalent binding of activated C3 (C3b) to glycophorin A on the erythrocyte
membrane surface. The bound C3 serves as the nidus for formation of the APC C3 convertase (C3b, activated factor B [Bb], and factor P) that
enzymatically activates many molecules of C3 to C3b, which then bind covalently via an exposed thioester bond to carbohydrate residues on
glycophorin A. Supported by interaction with sialic acid residues on glycophorin A, the plasma protein factor H binds to C3b and serves as a cofactor
for degradation of C3b to iC3b by the plasma protein factor I. CR1 also binds to C3b and to iC3b and serves as a cofactor for the degradation of C3b to
iC3b and then C3dg by factor I.
Eculizumab appears to reduce the risk of thromboembolic complications.30 For patients being treated with eculizumab who have no
prior history of thromboembolic complications, prophylactic anticoagulation may be unnecessary. Because PNH patients with prior
thrombosis are at higher risk for recurrent thrombosis, anticoagulation for eculizumab-treated patients who experienced a prior
thromboembolic event should be continued.29
Eculizumab is expensive (⬃ $400 000/year in the United States)
and has no effect on either the underlying stem cell abnormality or
on the associated BM failure. Consequently, treatment must continue indefinitely and leukopenia, thrombocytopenia, and reticulocytopenia, if present, persist. Treatment with eculizumab appears to
have a favorable impact on survival,31 because a recent study of 79
patients treated between 2002 and 2010 showed the same survival
rates as those of age- and sex-matched controls from the general
population.29 The contribution of eculizumab to survival cannot be
quantified accurately, however, because a control patient group was
not included in that study.
Reasons for suboptimal response to treatment with
eculizumab
The recommended maintenance dose of eculizumab is fixed (900 mg
every 2 weeks ⫾ 2 days) rather than being based on weight or body
surface area. Some patients may show evidence of breakthrough
intravascular hemolysis (ie, increases in LDH and development of
constitutional symptoms) near the end of a treatment cycle. In these
26
cases, breakthrough hemolysis can be ameliorated by reducing the
length of the treatment cycle from 14 days to 13 or 12 days, and in
some cases, the maintenance dose of eculizumab may also have to
be increased.
All patients with PNH have an element of BM failure, and patients
treated with eculizumab who have higher degrees of relative
reticulocytopenia may remain anemic or even transfusion dependent
despite excellent control of intravascular hemolysis. Iron stores and
serum erythropoietin concentration should be quantified in these
patients, and if iron stores are adequate and serum erythropoietin
concentration is inappropriately low, a trial of recombinant erythropoietin is warranted in patients who have symptomatic anemia or
who are transfusion dependent.
After treatment with eculizumab, serum LDH returns to normal or
near normal, but mild to moderate anemia and laboratory evidence
of hemolysis persist in essentially all treated patients.26,27 A small
subgroup of eculizumab-treated patients experiences little or no
improvement in either anemia or constitutional symptoms. In these
patients, hemolysis is mediated by opsonization of the PNH
erythrocytes by activation and degradation products of complement
C3, which, when tested, are found to be Coomb-positive for C3 but
not IgG.32-34 The known pathophysiology of the PNH predicts that
CD55 deficiency would result in ongoing extravascular hemolysis
of PNH erythrocytes as a consequence of C3 opsonization (Figure
4) because eculizumab does not block the activity of the APC C3
American Society of Hematology
convertase that is unregulated because of DAF deficiency (Figure
1). Support for this hypothesis is provided by the studies of Risitano
et al, who showed that in patients treated with eculizumab, a portion
of the PNH erythrocytes (ie, the CD59-deficient population) had
complement C3 bound.34 Those studies also confirmed the Coombnegative designation of PNH: no C3 was found bound to PNH
erythrocytes before initiation of treatment with eculizumab, implying that PNH erythrocytes upon which complement has been
activated are destroyed directly as a consequence of MAC-mediated
cytolysis. These studies provide a plausible explanation for the
persistent hemolytic anemia observed in PNH patients treated with
eculizumab. By inhibiting the formation of the MAC, eculizumab
prevents direct cytolysis of PNH erythrocytes, allowing the
manifestations of DAF deficiency to become apparent in the form
of aberrant regulation of the APC C3 convertase and the consequent
deposition of activated C3 on the cell surface (Figures 1 and 4).4
Covalently bound activation and degradation products of C3
then serve as opsonins that are recognized by specific receptors on
reticuloendothelial cells, resulting in extravascular hemolysis
(Figure 4).
The extravascular hemolysis of patients with PNH receiving
eculizumab does not require treatment in the absence of constitutional symptoms, symptoms of anemia, or transfusion dependence.
Because the process is extravascular, splenectomy or corticosteroids
may ameliorate the hemolysis in symptomatic or transfusiondependent patients by removing or inhibiting the function of
phagocytic cells (Figure 3).35 Long-term use of corticosteroids is
associated with significant toxicity, however, and concerns about
both postoperative and late complications temper enthusiasm for
splenectomy. It is also conceivable that the primary site of
phagocytosis is hepatic rather than splenic. In such cases, response
to splenectomy would likely be inadequate. Based on experience in
the treatment of refractory autoimmune hemolytic anemia, a trial of
Danazol can be considered; however, Rituxan is not indicated
because the process is mediated by C3 opsonization rather than
opsonization by IgG antibody.
Hematopoietic stem cell transplantation for PNH
Before the availability of eculizumab, the primary indications for
transplantation for PNH were bone failure, recurrent life-threatening thrombosis, and uncontrollable hemolysis.13 The latter process
can be eliminated by treatment with eculizumab and the thrombophilia of PNH may also respond to inhibition of intravascular
hemolysis by eculizumab.30 Nonetheless, transplantation is the only
curative therapy for PNH, and the availability of molecularly
defined, matched unrelated donors; less toxic conditioning regimens; reductions in transplantation-related morbidity and mortality;
and improvements in posttransplantation supportive care make this
option a viable alternative to medical management. The decision of
who should receive a transplantation and when it should be
performed is complex, however, and requires an understanding of
the unique pathobiology of PNH and the input of physicians
experienced in transplantation and medical management of PNH.36
The recent studies of Kelly et al29 showing normal survival for
patients with PNH treated with eculizumab make the decision
concerning medical management versus transplantation even more
challenging.
Other treatments for PNH
Based on anecdotal experience, a portion of patients with classic
PNH responds to Danazol as first-line therapy.37,38 The basis of this
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response is unknown but likely involves complement inhibition
because reduction in hemolysis is observed quickly (within a few
days) after initiation of therapy and PNH WBC clone size does not
change during treatment (C.J.P., unpublished observation). Why
some patients respond dramatically to Danazol whereas others do
not is unknown, but it seems plausible to suggest that responders
produce a metabolite that inhibits complement whereas nonresponders do not (or they produce a subtherapeutic concentration of
the putative inhibitory metabolite).
Although hemolysis is ameliorated in some patients by treatment
with glucocorticoids, the harm that can accrue from long-term use
of prednisone cannot be overemphasized.13 Although their use in the
management of PNH is a matter of ongoing debate, the main value
of glucocorticoids may be in attenuating acute hemolytic exacerbations. Under these circumstances, brief pulses of prednisone may
reduce the severity and duration of the crisis while avoiding the
untoward consequences associated with long-term use.
Because hemolysis is a consequence of a defect intrinsic to a
patient’s erythrocytes, the anemia of PNH responds to transfusion.
In addition to increasing the hemoglobin concentration, transfusion
may lessen hemolysis by suppressing erythropoiesis. Concerns
about inducing a hemolytic exacerbation as a consequence of
infusion of small amounts of donor plasma that may contaminate
red cell preparations appear unwarranted.39
Patients with classic PNH frequently become iron deficient as a
result of renal loss (both hemoglobinuria and hemosiderinuria).38
Clinically important iron loss from hemosiderinuria can occur even
in the absence of gross hemoglobinuria. Concern for inducing a
hemolytic exacerbation should not deter iron repletion, because iron
deficiency not only limits erythropoiesis but also exacerbates the
hemolysis of PNH.38 If hemolytic exacerbation occurs in the setting
of iron repletion, the episode can be controlled by treatment with
corticosteroids or by suppression of erythropoiesis by transfusion.
There is no concern about iron replacement therapy inducing a
hemolytic exacerbation in patients being treated with eculizumab
because the drug inhibits hemolysis. Patients treated with eculizumab should not become iron deficient because treatment will
resolve hemoglobinuria and hemosiderinuria by blocking intravascular hemolysis.
Conclusions and future directions
Systematic investigation of the molecular basis of PNH has
provided a framework for management based on an understanding
of disease pathophysiology and has led to development of targeted
therapy that has improved the lives of patients and changed the
natural history of the disease. Nonetheless, continued investigation
of new approaches to therapy aimed at obviating the extravascular
hemolysis that limits eculizumab efficacy in some patients is
warranted.4 A better understanding of the pathobiology that underlies the thrombophilia of PNH is needed, and defining the complex
relationship between PNH and BM failure syndromes that determine clonal selection and clonal expansion40 may lead ultimately to
therapy that targets the disease at the level of the hematopoietic stem
cell. In particular, an understanding of the molecular basis of clonal
expansion will be facilitated by the availability of next-generation
sequencing that will allow comparison between the genomes of
GPI-AP–positive and GPI-AP–negative cells from individual patients with PNH.
27
Disclosures
Conflict-of-interest disclosure: The author declares no competing
financial interests. Off-label drug use: None disclosed.
Correspondence
Charles J. Parker, Hematology Division, Department of Internal
Medicine, The University of Utah School of Medicine, 30 N 1900 E,
Room 5C402, Salt Lake City, UT 84132; Phone: (801) 585-3229;
Fax: (801) 585-0309; e-mail: [email protected].
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