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Paroxysmal Nocturnal Hemoglobinuria
Synonyms and related keywords: PNH, hemolytic anemia,
hemoglobinuria, hemosiderinuria, Marchiafava-Micheli syndrome
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Marchiafava-Micheli
syndrome
Paroxysmal nocturnal haemoglobinuria is an acquired
clonal, benign, haematopoietic stem cell disorder which
results in the formation of defective red cells, white
cells and platelets. It is characterized by
intravascular haemolysis and frequent venous thrombosis
or bleeding.
It is caused by a mutation in an X-linked gene
involved in the formation of membrane phosphatidyl
inositol anchors. The membranes of these cells are
deficient in those proteins normally anchored to the
cell through a phosphatidyl inositol linkage, including
complement deactivating factors.
PNH is a very rare disorder and should be suspected
in confusing cases of haemolytic anaemia. There is a
median survival of 10 years. Source |
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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.
- Internationally: It has been suggested that, like
aplastic anemia, PNH may be more frequent in Southeast Asia and in
the Far East.
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.
Sex: Men and women are affected equally, and no
familial tendencies exist.
Age: PNH may occur at any age from children as young
as 2 years to adults as old as 83 years, but it frequently is found
among young adults. 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.
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History: 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: Pancytopenia can increase the risk for
congestive heart failure in elderly patients or in patients with
infections and bleeding. Thrombosis is a major risk for serious symptoms
and death.
Hemoglobinuria,
Paroxysmal Cold
Hemolytic Anemia
Mesenteric Artery
Ischemia
Mesenteric Artery
Thrombosis
Portal Vein
Obstruction
Renal Vein
Thrombosis
Other Problems to be Considered:
Thrombocytopenia
Special Concerns:
- The disease mimics other conditions and sometimes may be difficult
to diagnose unless it is included in the differential diagnosis. In
cases with unusual large-vein thrombosis, such as Budd-Chiari
syndrome or pancytopenia with hypoplastic bone marrow, patients
should be screened for PNH using a Ham test, a sugar water test,
and, now, a peripheral blood flow cytometry for CD59.
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