PAROXYSMAL NOCTURNAL HEMOGLOBINURIA
DEFINITION:
A disorder of blood cells characterized by nocturnal
hemoglobinuria, chronic hemolytic anemia, and thrombosis.
EPIDEMIOLOGY:
- incidence: rare
- age of onset:
- childhood -> adulthood with peak in the 3rd-5th decades
- risk factors:
- familial - ?
- chrom.#: Xp22.1
- gene: phosphatidylinositol glycan (PIG-A)
- M = F
PATHOGENESIS:
- Paroxysmal Nocturnal Hemoglobinuria (PNH) is an acquired
bone marrow disorder expressed in myeloid and erythroid
progenitor cells and subsequently affects erythrocytes,
platelets, monocytes, and granulocytes
- there are many different types of proteins anchored to the
cell membrane of these cells and one particular class of
proteins is anchored by molecules of
glycosyl-phosphatidylinositol via phosphatidylinositol linkages
- PIG-A is a component of glycosyl-phosphatidylinositol
biosynthesis and a defect in the PIG-A gene will interfere with
the synthesis of glycosyl-phosphatidylinositol, a deficiency
which results in a deficient surface expression of a particular
class of proteins including:
- Decay-Activating Factor (DAF) - CD55 and CD59
- C8 Binding Protein
- Membrane Inhibitor of Reactive Lysis (MIRL)
- RBC Acetylcholinesterase
- CD55 is a membrane glycoprotein that inhibits both classic
and alternate pathway complement-mediated cell lysis by
inhibiting C3 convertases and a deficiency of this glycoprotein
results in increased complement-mediated lysis of the affected
cells, i.e, erythrocytes, platelets, monocytes, and granulocytes
2. Genetic Defect
- gene defect -> defective synthesis of PIG-A -> defective syn-thesis
of glycosyl-phosphatidylinositol -> failure to anchor CD55 to
the cell membrane -> failure to protect affected blood cells
from the action of complement -> complement-mediated hemolysis
of the affected cells
- deletions and point mutations have been identified in the
PIG-A gene isolated from PNH patients (Miyata et al., New
England Journal of Medicine 330(4): 249-255, 1994)
CLINICAL FEATURES:
- classic presentation is an acute hemolytic episode with
hemoglobinuria and abdominal pain
- most common presentation is chronic intravascular
hemolysis of varying severity
- may also have acute-on-chronic intravascular hemolysis
- hemolysis is characteristically worse during sleep
resulting in nocturnal and morning hemoglobinuria
- associated symptoms:
- iron deficiency (due to chronic loss of iron in urine)
- abdominal, back, and musculoskeletal pain
2. Hemolytic Thrombocytopenia
- may be the initial manifestation of PNH & mild to moderate
- complications:
- hemorrhage
- venous thromboses
- may be due to some aspect of complement-platelet
interaction
- hepatic (Budd-Chiari Syndrome), portal, splenic,
cerebral, mesenteric
- may be responsible for episodes of abdominal, back,
head, and musculoskeletal pain
- common cause of death in these patients
3. Complications
- PNH should be considered in any patient with pancytopenia
or aplastic anemia
- PNH may arise from or evolve into other dysplastic bone
marrow diseases such as aplastic anemia, sideroblastic anemia,
and myelofibrosis
- PNH may also evolve into acute leukemia
- pyogenic infections due to leukopenia
INVESTIGATIONS:
- an acid hemolysin test in which normal serum of compatible
blood type, acidified to pH 6.4, lyses PNH cells (the
acidification facilitates complement activation)
2. Positive Sucrose Hemolysis Test
- by reducing ionic strength, sucrose induces lysis by
facilitating binding of complement to the PNH cells
2. Serum
- normocytic or microcytic anemia +/- reticulocytosis
- mild to moderate thrombocytopenia
- leukopenia, granulocytopenia
- negative Coombs Test
3. Urine
- intermittent nocturnal or morning hemoglobinuria
- hemosiderinuria
4. Biopsy
- variable from hyperplastic to hypocellular or aplastic
2. Kidney
MANAGEMENT:
2. Danazol
2. Transfusion
2. Iron Deficiency
- oral or parenteral iron supplements
- may increase hemolysis due to the release of a new
population of sensitive RBC's from the bone marrow
3. Thrombolic Episodes
- acute - streptokinase or urokinase
- chronic - long-term anticoagulation
4. Experimental
- allogenic bone marrow transplantation
5. Prognosis
- variable clinical course depending on the degree and
duration of anemia, venous thromboses, and other complications
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