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Background: Paroxysmal
nocturnal hemoglobinuria (PNH) is a descriptive term for the clinical
manifestation of red cell breakdown with release of hemoglobin into the
urine that is manifested most prominently by dark-colored urine in the
morning. The term "nocturnal" refers to the belief that hemolysis is
triggered by acidosis during sleep and activates complement to hemolyze
an unprotected and abnormal red cell membrane. However, this observation
later was disproved. Hemolysis is shown to occur throughout the day and
is not actually paroxysmal, but the urine concentrated overnight
produces the dramatic change in color.
This disease has been referred to as the great impersonator because
of the variety of symptoms observed during the initial manifestation and
course of the disease. The clinical syndrome can present in 3 types of
symptoms including (1) an acquired intracorpuscular hemolytic anemia due
to the abnormal susceptibility of the red cell membrane to the hemolytic
activity of complement; (2) thromboses in large vessels, such as
hepatic, abdominal, cerebral, and subdermal veins; and (3) a deficiency
in hematopoiesis that may be mild or severe, such as pancytopenia in
aplastic anemia state. The triad of hemolytic anemia, pancytopenia, and
thrombosis makes PNH a truly unique clinical syndrome.
Pathophysiology: PNH currently is reclassified from
purely an acquired hemolytic anemia due to a hematopoietic stem cell
mutation defect. This change in concept was brought about by the
observation that surface proteins were missing not only in the red cell
membrane but also in all blood cells, including the platelet and white
cells.
The common denominator in the disease, a biochemical defect, appears
to be a genetic mutation leading to the inability to synthesize the
glycosyl-phosphatidylinositol (GPI) anchor that binds these proteins to
cell membranes. The corresponding gene PIGA (phosphatidylinositol
glycan class A) in the X chromosome can have several mutations, from
deletions to point mutations. The essential group of membrane proteins
that are lacking in all hematopoietic cells are called
complement-regulating surface proteins, including the decay-accelerating
factor (DAF) or CD55, homologous restriction factor (HRF) or C8 binding
protein, and membrane inhibitor of reactive lysis (MIRL) or CD59. All of
these proteins interact with complement proteins, particularly C3b and
C4b, dissociate the convertase complexes of the classic and alternative
pathways, and halt the amplification of the activation process.
Hemolytic anemia is due to intravascular destruction of red blood cells
(RBCs) by complement with varying degrees.
The classic description of the manifestations of PNH is the presence
of dark urine during the night with partial clearing during the day (see
Image 1); however, hemoglobinuria may occur
every day in severe cases, more frequently in episodes lasting 3-10
days, or, in some cases, not at all. Thrombosis of the veins usually
manifests as a sudden catastrophic complication, with severe abdominal
pain and rapidly enlarging liver and ascites (Budd-Chiari syndrome).
This thrombosis is secondary to a lack of CD59 on platelet membranes
that induces platelet aggregation and is highly thrombogenic,
particularly in the venous system. Deficient hematopoiesis may occur due
to diminished blood cell production with a hypoplastic bone marrow;
thus, patients have a 10-20% chance of developing aplastic anemia in
their course, and patients known to have aplastic anemia eventually
develop PNH in 5% of cases. The nature of the pathogenetic link between
these two diseases still is unknown.
Frequency:
 | In the US: PNH is an uncommon disorder of
unknown frequency both in the United States and worldwide. There is
little information on the incidence of PNH, but the rate is
estimated to be 5-10 times less than that of aplastic anemia; thus,
PNH is a rare disease. Attempts to get a more accurate incidence and
to learn more about its natural course is currently under way under
the auspices of
The Paroxysmal
Nocturnal Hemoglobinuria (PNH) Registry. This is a
comprehensive, observational, multinational effort to document the
clinical outcomes in the treatment of patients with PNH. |
| Internationally: It has been suggested that,
like aplastic anemia, PNH may be more frequent in Southeast Asia and
in the Far East.
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Mortality/Morbidity: The disease process is
insidious and has a chronic course, with a median survival of about 10.3
years. Morbidity depends on the variable expressions of hemolysis, bone
marrow failure, and thrombophilia that define the severity and clinical
course of the disease. In several large studies, the main cause of death
in patients was venous thrombosis, followed by complications of bone
marrow failure; however, spontaneous long-term remission or leukemic
transformation of the PNH clone has been reported and well documented.
| The median survival after diagnosis was 10 years in a series of
80 consecutive patients seen at the Hammersmith Hospital in London
treated with supportive measures, such as oral anticoagulant therapy
after an established thromboses, and transfusions. Sixty patients
died; 28 of the 48 whose cause of death was known died from venous
thrombosis or hemorrhage. Thirty-one patients (39%) had one or more
episodes of venous thrombosis during their illness. No leukemic
transformations occurred in this series. |
| Twenty-two of the 80 patients (28%) survived for 25 years. Of
the 35 patients who survived for 10 years or more, 12 had
spontaneous clinical recovery at which time no PNH-affected cells
were found among the red cells or neutrophils during their prolonged
remission, but a few PNH-affected lymphocytes were detectable in 3
of 4 patients tested. |
Race: The differences among races were shown
comparing 176 American patients seen at Duke University and 209 patients
from Japan. White American patients were younger with significantly more
classic symptoms of PNH including thrombosis, hemoglobinuria, and
infection, while Asian patients were older with more marrow aplasia and
a smaller PNH clone. Survival analysis showed a similar death rate in
each group, although causes of death were different with more thrombotic
deaths seen in American patients. Japanese patients had a longer mean
survival time (32.1 vs 19.4 y), but Kaplan-Meier survival curves were
not significantly different.
| Other geographic ethnic differences were observed in thrombosis
incidence in 64 patients with classic PNH. They found that African
Americans (n=11) and Latin Americans (n=8) had a higher risk or rate
of thrombosis by Cox regression and had an impact on length of
survival compared to others (n=45). |
Sex: Men and women are affected equally, and no
familial tendencies exist.
Age: PNH may occur at any age from children (10%) as
young as 2 years to adults as old as 83 years, but it frequently is
found among young adults with a median age at the time of diagnosis was
42 years (range, 16-75 y) from a series in England of 80 consecutive
patients. In childhood through adolescence, patients presented with more
of the primary features of aplastic anemia than the normal adult
population. Other complications, such as infections and thrombosis,
occurred with equal frequency in all age groups.
History: A working
classification has been developed that includes all the variations in
the presentation, clinical manifestations, and natural history among PNH
patients: (1) classic PNH; (2) PNH in the setting of another specified
BM disorder (eg, PNH/aplastic anemia or PNH/refractory anemia-MDS); and
(3) subclinical PNH (PNH-sc) in aplastic anemia are now recognized.
PNH presents in any of the 3 syndromes or sets of symptoms.
| Hemolytic anemia usually is in the form of intravascular
hemolysis. |
 | The most common presentation is the presence of anemia
associated with dark cola-colored urine that is a manifestation
of hemoglobinuria. The latter may be confused with hematuria,
and erroneous treatment could be given for urosepsis.
Hemosiderin nearly always is present in the urine sediment and
can accumulate in the kidneys, which shows up on MRI or CT
scans. |
| Elevated reticulocyte count and serum lactic acid
dehydrogenase (LDH) with a low serum haptoglobin in the absence
of hepatosplenomegaly are the hallmarks of intravascular
hemolysis. Bone marrow usually is markedly erythroid, with
decreased or absent iron stores, depending on how long the
patient has been losing iron in urine. |
| Thrombosis involves the venous system, and it usually occurs in
unusual veins, namely the hepatic, abdominal, cerebral, and
subdermal veins. |
| Hepatic vein thrombosis results in Budd-Chiari syndrome,
which manifests as a sudden and catastrophic event characterized
by jaundice, abdominal pain, a rapidly enlarging liver, and
accumulation of ascitic fluid. This syndrome may be severe and
lead to vascular collapse and death, or it can be slow and
insidious leading to hepatic failure. |
| Abdominal vein thrombosis presents with upper abdominal
pain, or it can occur anywhere in the abdomen, lasting 1-6 days.
It can lead to bowel infarction in severe cases. |
| Cerebral vein thrombosis can range from the mildest form to
a severe headache, depending on which veins are involved. The
sagittal vein is commonly affected, which can give rise to
papilledema and pseudotumor cerebri. |
| Dermal vein thrombosis manifests as raised, painful, and red
nodules in the skin affecting large areas, such as the entire
back, which subsides within a few weeks, usually without
necrosis. In cases that do result in necrosis, skin grafting may
be necessary. |
| Deficient hematopoiesis usually presents with anemia despite the
presence of an erythroid marrow with suboptimal reticulocytosis. In
some cases, neutropenia and thrombocytopenia can occur in a
hypoplastic bone marrow similar to aplastic anemia (aplastic
episodes). |
| Other symptoms include esophageal spasms that occur in the
morning and, like the urine, clear up later in the day. In males,
impotence can occur concomitant with hemoglobinuria, the cause of
which is unknown. |
Physical: Most commonly, pallor suggests anemia,
fever suggests infections, and bleeding, such as mucosal bleeding,
suggests skin ecchymoses in thrombocytopenia similar to aplastic anemia.
| Hepatomegaly and ascites in Budd-Chiari syndrome |
| Splenomegaly if there is splenic vein thrombosis |
| Absent bowel sounds in bowel necrosis |
| Papilledema in cerebral vein thrombosis |
| Skin nodules that are red and painful in dermal vein thrombosis |
Causes: PNH is now known to be a consequence of
nonmalignant clonal expansion of one or several hematopoietic stem cells
that are deficient in GPI-anchor protein (GPI-AP) acquired through a
somatic mutation of PIG-A.
| Recent information has led us to understand that PNH is not a
monoclonal disease with a malignant phenotype. Rather, the clinical
pathology may actually be an epiphenomenon resulting from an
adaptive response to injury such as an immune attack on the stem
cells of hematopoiesis. |
| In PNH, the peripheral blood and bone marrow is a mosaic
composed of GPI-AP+ and GPI-AP- cells; with the GPI-AP-, cells can
be derived from multiple mutant stem cells. The GPI-AP- mutant cells
may appear to dominate hematopoiesis in PNH by providing a
proliferative advantage under some pathological conditions. For
example, if damage to stem cells causing bone marrow failure is
mediated through a GPI-linked surface molecule, the PNH cells
lacking these molecules will survive. The close association with
aplastic anemia and MDS suggests that the selection process arises
as a consequence of this specific type of BM injury. |
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