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Chapter 31 Paroxysmal Nocturnal Hemoglobinuria 423

or antithymocyte globulin and cyclosporine. Young patients (i.e., <30
Approach to Diagnosing PNH
years of age) with an HLA-matched sibling should be transplanted;
PNH has an estimated incidence of 2 to 5 per million in the United for older patients and for those without an HLA-matched sibling,
States. This, coupled with its protean manifestations, make diagnosing high-dose cyclophosphamide or antithymocyte and cyclosporine
PNH a challenge for even the most astute diagnostician. However, is appropriate. Alternative donor transplants with posttransplant
given the ease and specificity of modern diagnostic assays, the most immunosuppression is showing promising results, but more experi-
important attribute a physician can possess in diagnosing PNH is to ence with this approach in severe aplastic anemia is needed before
maintain a high level of suspicion and to be cognizant of the various this can be recommended as initial therapy. If the patient’s cytopenias
presentations of the disease. A small sample of peripheral blood sent do not fulfill criteria for severe aplastic anemia, supportive care or a
to an experienced flow cytometric laboratory is usually sufficient to trial of immunosuppressive therapy is appropriate.
establish or exclude the diagnosis of PNH. These assays are fast, reli-
able, and inexpensive. If monoclonal antibodies are used to establish
the diagnosis, it is imperative that two or more antibodies be used on at
least two different lineages. Assaying granulocytes is the most reliable Classical PNH
method to diagnose PNH as they are not affected by blood transfu-
sions. I prefer to use FLAER in conjunction with monoclonal antibodies Symptoms in patients with classical PNH vary from mild to severely
on granulocytes and monocytes because of the improved sensitivity debilitating to acutely life-threatening. Hence therapy should be
and specificity; anti-CD59 is the most reliable marker on erythrocytes. directed toward the specific manifestations (e.g., anemia, thrombosis,
PNH populations less than 1% are not usually relevant, but if present etc.). Allogeneic stem cell transplantation, preferably from an HLA-
on multiple lineages in the setting of a hypocellular bone marrow may matched sibling, is appropriate for patients with debilitating or life-
help to establish an immune-mediated form of aplastic anemia. threatening disease. In general, these are patients with recurrent
Classical PNH is usually more conspicuous than hypoplastic PNH.
Patients typically present with a direct antiglobulin negative hemolytic thrombosis or those with clonal evolution to either MDS or acute
anemia, hemoglobinuria, and mild to moderate cytopenias. Obscure leukemia. Patients with less severe disease should not be transplanted
paroxysms of back pain, abdominal pain, fatigue, and/or headaches because of the morbidity and mortality of the procedure. Antithy-
are often present. The bone marrow is typically normocellular to mildly mocyte globulin and cyclosporine or high-dose cyclophosphamide
hypercellular with intense erythroid hyperplasia and mild to moderate does not appear to benefit patients with classical PNH.
dyserythropoiesis. Bone marrow iron stores are frequently, but not
always, absent. PNH patients can also present with abrupt, severe
abdominal pain and jaundice caused by thrombosis. All patients pre- Anemia
senting with unexplained hepatic vein, portal vein, mesenteric vein, or
portal vein thrombosis should be screened for PNH.
It is important to distinguish PNH from MDS. Most patients with All patients with classical PNH should be placed on folic acid
refractory anemia should be screened for PNH, especially those with (1–2 mg/d). Patients with absent iron stores, usually because of
moderate to severe cytopenias, an elevated LDH, and a hypocellular chronic intravascular hemolysis, should be treated with oral iron
bone marrow. In addition, all patients diagnosed with aplastic anemia supplementation. Eculizumab has become the standard-of-care to
should be screened for PNH. As few as 3% of PNH erythrocytes may treat selected patients with classical PNH. It is the only drug dem-
result in an elevated LDH. In rare instances myelofibrosis or auto- onstrated in a randomized study to benefit PNH patients. Eculizumab
immune hemolytic anemias can mimic PNH. Patients with a history of has been shown to decrease the need for transfusions, decrease par-
aplastic anemia—especially those managed with immunosuppressive oxysms, and improve quality of life in patients with classical PNH;
therapy—should be monitored closely for the outgrowth of PNH.
however, it has not been shown to benefit patients with hypoplastic
PNH. In classical PNH, eculizumab is recommended for patients
with disabling fatigue, thromboses, transfusion dependence, frequent
APPROACH TO TREATMENT pain paroxysms, renal insufficiency, or other end organ complications
from disease. Watchful waiting is appropriate for asymptomatic
patients or those with mild symptoms.
Classification of PNH: Classical PNH Versus Hypoplastic PNH
It useful to classify PNH patients as either “classical” or “hypoplastic”. Thrombosis
This can usually be accomplished by ordering a complete blood count,
reticulocyte count, LDH, peripheral blood flow cytometry for PNH, Patients who present with acute life-threatening or organ-threatening
and a bone marrow aspirate, biopsy, and cytogenetics. Patients with thrombosis should be considered for thrombolytic therapy followed
classical PNH tend to have mild to moderate cytopenias, a normocel- by long-term anticoagulation. Thrombosis is probably the most
lular to hypercellular bone marrow, an elevated reticulocyte count, compelling reason to start eculizumab in PNH patients. Whether or
a markedly elevated LDH, and a relatively large PNH granulocyte
population (>30%). In contrast, hypoplastic PNH patients present with not anticoagulation can be safely discontinued after eculizumab
manifestations similar to that of aplastic anemia or hypoplastic MDS. induction is still unknown, but patients who respond well to eculi-
These patients typically present with moderate to severe cytopenias, zumab therapy may not need long-term anticoagulation.
a hypocellular bone marrow (<25% cellularity), a decreased corrected
reticulocyte count, a normal or mildly elevated LDH, and a relatively
small (<20%) PNH granulocyte population. Most, but not all, patients REFERENCES
can be readily subdivided into classical versus hypoplastic PNH, a
distinction that aids with therapeutic decisions.
1. Brodsky RA: Paroxysmal nocturnal hemoglobinuria. Blood
124(18):2804–2811, 2014.
1a. Marchiafava E: Anemia emolitica con emosiderninuria perpetua.
Policlinico [Med] 35:105–117, 1928 (in Italian).
Hypoplastic PNH 1b. Enneking J: Eine neue form intermittierender haemoglobinurie (Hae-
moglobinuria paraoxusmalis nocturia). Klin Wochenschr 7:2045, 1928.
1c. Ham T: Chronic hemolytic anemia with paroxysmal nocturnal
Because bone marrow failure is the major risk for patients with hemoglobinuria. A study of the mechanism of hemolysisin relation to
hypoplastic PNH, therapy is directed towards the pancytopenia. If, acid-based equilibrium. N Eng J Med 217:915–917, 1937.
in addition to the PNH, the patient fulfills criteria for severe aplastic 2. Takeda J, Miyata T, Kawagoe K, et al: Deficiency of the GPI anchor
anemia (see Chapter 30), appropriate therapeutic options include allo- caused by a somatic mutation of the PIG-A gene in paroxysmal nocturnal
geneic bone marrow transplantation, high-dose cyclophosphamide, hemoglobinuria. Cell 73:703–711, 1993.