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Chapter 31 Paroxysmal Nocturnal Hemoglobinuria 419

Portal vein thrombosis is also common in PNH and can occur disease. PNH granulocytes (0.01–5%) can also be found in up to
with or without hepatic vein thrombosis. Patients frequently present 25% of patients with MDS; however, unlike acquired aplastic anemia,
with nausea, vomiting, abdominal pain, and liver dysfunction. it is extremely rare for PNH to evolve from MDS patients. These
Management is similar to that of hepatic vein thrombosis. small PNH populations in MDS appear to be clinically irrelevant
since the PIGA mutations in MDS are transient and also arise from
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progenitor rather than hematopoietic stem cells. In contrast, PIGA
Other Abdominal Veins mutations in PNH patients and patients with acquired aplastic
anemia arise from a multipotent hematopoietic stem cell and are
Venous thrombosis in PNH has been described in all abdominal found in all lineages, including T lymphocytes.
and retroperitoneal venous systems including the splenic veins, Distinguishing hypoplastic MDS from aplastic anemia is often
mesenteric veins, renal veins, and the inferior vena cava. Throm- difficult; however, quantitative analysis of bone marrow CD34 posi-
bosis of minor veins can also occur and can be difficult to diagnose tive cells is useful for discriminating between these two entities.
because of the protean manifestations and their relapsing and
remitting nature. Often such patients present with recurrent, severe
abdominal pain crises sometimes mimicking intestinal obstruction. The PNH Stem Cell and Clonal Expansion
The consequence of these microthromboses can sometimes be
visualized with esophagogastroduodenal endoscopy or colonoscopy. To cause PNH, PIGA mutations must occur in a self-renewing,
Patients with intestinal thromboses can present with ischemic colitis hematopoietic stem cell and must achieve clonal dominance. The
and can be misdiagnosed as having Crohn disease. Upper gastro- mechanisms leading to the clonal expansion and dominance of PNH
intestinal bleeding can be caused by esophageal or gastric varices stem cells remain a topic of continued investigation. Any hypothesis
that develop as a consequence of portal hypertension or splenic vein must also account for the close pathophysiologic relationship between
thrombosis. PNH and acquired aplastic anemia, a T-cell–mediated autoimmune
disease characterized by depletion of hematopoietic stem cells. The
leading hypothesis is that PNH stem cells have a conditional survival
Cerebral Veins advantage in the setting of an autoimmune attack (e.g., aplastic
anemia) that targets the bone marrow. One hypothesis involves
Cerebral veins, particularly the sagittal veins and sinuses, are also natural-killer group 2 member D (NKG2D)-mediated immunity
highly prone to thrombosis in PNH. Patients can present with severe that is activated by the expression of ligands such as major histocom-
headaches and/or focal neurologic deficits depending on the location patibility complex class I chain-related peptides A and B (MICA/B)
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of the thrombosis. Similar to hepatic vein thrombosis, cerebral vein and cytomegalovirus UL-16 binding proteins (ULBPs). MICA/B
thrombosis is an ominous complication that can result in substantial are transmembrane proteins but the ULBPs are GPI-linked. NKG2D
morbidity and mortality. Magnetic resonance imaging to carefully is a common receptor for MICA/B and the ULBPs. It is expressed on
examine the cerebral blood flow is helpful in establishing the natural killer (NK) cells and CD8+ cytotoxic T cells. Engagement of
diagnosis. NKG2D with its ligands (MICA/B and ULBPs) promotes cell death
of the NKG2D ligand-expressing cells by the NKG2D+ effectors;
thus PNH cells would be relatively spared from effector cell-mediated
Other Sites killing because they lack GPI-anchored ULBPs. Recently, it has been
proposed that CD1d-restricted, GPI-specific T cells might be respon-
Dermal venous thrombosis can occur virtually anywhere on the body. sible for the immune killing in PNH. Under this scenario, PNH cells
Patients usually complain of pain, discolorations, and swelling. The would be spared immune-mediated killing because CD1d has been
lesions can reach several centimeters in diameter and are firm and shown to associate with GPI. Others have shown that mutations
tender. Necrosis and the formation of a black eschar can occur. that confer a survival advantage to the PNH clone can contribute
Anticoagulation and warm compresses can ameliorate the attacks. to clonal outgrowth.
Pulmonary emboli and deep venous thrombosis have also been Clinical observations also provide clues to understanding clonal
reported in PNH; arterial thrombosis is less common. dominance in PNH and the relationship between aplastic anemia and
PNH. Up to 30% of aplastic anemia patients treated with conven-
CLONALITY AND BONE MARROW FAILURE tional immunosuppressive therapy (antithymocyte globulin and
cyclosporine) will develop PNH or MDS, usually several years after
PIGA Mutations in Aplastic Anemia and therapy. In contrast, allogeneic bone marrow transplantation appears
to eliminate the risk for developing PNH in patients with aplastic
Myelodysplastic Syndrome and Healthy Controls anemia. These data suggest that secondary clonal disorders (PNH and
MDS) are part of the natural history of aplastic anemia. Although
Small to moderate PNH clones are found in up to 70% of patients immunosuppressive therapy prolongs survival, it does not prevent
with acquired aplastic anemia, demonstrating a pathophysiologic link these late complications.
between these disorders. Typically, less than 20% GPI anchor protein-
deficient granulocytes are detected in aplastic anemia patients at
diagnosis, but occasional patients can have larger clones. DNA Clonal Transformation
sequencing of the GPI anchor protein-deficient cells from aplastic
anemia patients reveals clonal PIGA gene mutations that arise from PNH patients, similar to aplastic anemia and MDS patients, are at
a multipotent hematopoietic stem cell. Moreover, many of these increased risk for clonal transformation; however, the incidence of
patients exhibit expansion of the PIGA mutant clone and progress to leukemic transformation in PNH is small, probably less than 5%.
clinical PNH. Although it was once thought that PNH evolving from MDS and acute myeloid leukemia are the most common malignan-
aplastic anemia is more benign than classical PNH, this observation cies to evolve from PNH; the leukemic cells may arise from the GPI
is probably a consequence of lead time bias, as many of these patients anchor-deficient clone in many, but not all cases.
eventually develop classical PNH symptoms.
Somatic PIGA mutations arising from hematopoietic cells can be
found at low frequency (~1 in 50,000 granulocytes) in healthy control NATURAL HISTORY
subjects. These mutations arise from hematopoietic progenitor cells.
Since normal and PIGA mutant progenitor cells do not self-renew The natural history of PNH before the era of anticomple-
and only survive for 3 to 4 months, these cells cannot contribute to ment therapy ranged from indolent to severely debilitating and