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418 Part IV Disorders of Hematopoietic Cell Development

in protecting cells from complement. Red blood cells from individu- thrombosis and accumulation of iron deposits. Acute renal failure
als with the Inab phenotype, a blood group antigen, lack CD55, yet following massive hemolysis occurs infrequently and usually resolves
these individuals have no clinical hemolysis. In contrast, patients with in days to weeks.
congenital CD59 deficiency have complement-mediated hemolytic
anemia.
The classic manifestation from which PNH derives its name— Thrombosis and PNH
paroxysmal bouts of reddish, brownish, or “cola-colored” urine that
strikes predominantly overnight—is described by a minority of PNH Thrombosis is an ominous complication of PNH and was the leading
patients. Most PNH patients have no noticeable hemoglobinuria or cause of death before the availability of terminal complement inhibi-
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have intermittent episodes of hemoglobinuria with no relation to the tion. Thrombosis occurs in approximately 40% of PNH patients and
time of day. Early speculation that the nocturnal hemoglobinuria was most commonly involves the venous system, but arterial clots may
a function of a mild drop in pH that occurs with sleep has not been also occur. Patients with a large percentage of PNH cells and classical
validated. Patients with a history of hemoglobinuria are more likely symptoms (hemolytic anemia and hemoglobinuria) have a greater
to have a large PNH clone and less likely to have a markedly hypocel- propensity for thrombosis than patients with a small percentage of
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lular bone marrow. PNH cells. According to logistic regression modeling, for a 10%
Although hemolysis is often the most conspicuous feature in change in PNH clone size, the odds ratio for risk of thrombosis is
patients with classical PNH, many patients, particularly those with estimated to be 1.64. Patients with PNH granulocyte clones of
coexisting bone marrow failure, exhibit mild to barely detectable greater than 60% appear to be at greatest risk for thrombosis. The
hemolysis. The hemoglobin concentration can range from normal mechanism of thrombosis in PNH is not entirely understood and
to severely depressed. The reticulocyte count is often elevated but probably multifactorial, but similar to other manifestations of the
usually lower than expected for the degree of anemia. Patients with disease, it is probably related to the GPI anchor protein deficiency
PNH manifest all the usual clinical and laboratory signs of chronic and activation of complement. Indeed, C5a is proinflammatory and
hemolytic anemia: weakness, fatigue, pallor, and dyspnea on exertion. may increase the risk for thrombosis. Furthermore, nitric oxide deple-
In patients with prominent hemolysis, the magnitude of fatigue can tion (as a consequence of intravascular hemolysis and nitic oxide
be out of proportion to the degree of anemia. Morphologically, the scavenging) has been associated with increased platelet aggregation,
red cells appear normal, although some cases display mild to moderate increased platelet adhesion, and accelerated clot formation. In an
poikilocytosis and anisocytosis. The haptoglobin levels are usually low, attempt to repair damage, PNH platelets undergo exocytosis of the
and the lactate dehydrogenase (LDH) is frequently elevated, some- complement attack complex. This results in the formation of
times greater than 3000 IU/L, depending on the degree of hemolysis. microvesicles with phosphatidylserine externalization, a potent in
Multiple factors influence the degree of hemolysis in PNH, vitro procoagulant. These prothrombotic microvesicles have been
including the size and type of the PNH clone and the degree of detected in the blood of PNH patients. Fibrinolysis can also be
complement activation. In general, the percentage of PNH erythro- perturbed in PNH given that PNH blood cells lack the GPI-anchored
cytes correlates with the degree of hemolysis. However, the type of urokinase receptor. Although the mechanism of thrombosis in PNH
PNH erythrocytes may also influence the degree of hemolysis. Type is not entirely clear, the sites of venous thrombosis in PNH are
III erythrocytes are more readily lysed than type II erythrocytes and manifold with the splanchnic veins and the cerebral veins being the
almost always constitute a larger percentage of the PNH red cells. most commonly involved regions. It should be noted that thrombin
Thus patients with a large percentage of type III erythrocytes tend to itself can cleave C3 and also act as a C5 convertase. This can initiate
have more hemolysis than patients with a large percentage of type I a viscous cycle of thrombin activating complement, leading to
or type II cells. Finally, hemolysis is frequently exacerbated by infec- increased hemolysis and more generation of C5a that predisposes to
tions (especially gastrointestinal infections), surgery, strenuous exer- even more thrombosis.
cise, excessive alcohol intake, blood transfusions, and anything else
that increases complement activation.
Liver
Smooth Muscle Dystonia and Nitric Oxide Hepatic vein thrombosis (Budd-Chiari syndrome) is a common site
of thrombosis in PNH and may be fatal without appropriate therapy.
Many clinical manifestations of PNH are readily explained by The clinical manifestations of hepatic vein thrombosis include
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hemoglobin-mediated nitric oxide scavenging. Failure of comple- abdominal pain, hepatomegaly, jaundice, ascites, and weight gain.
ment regulation on the PNH erythrocyte membrane leads to intra- The onset of symptoms can be abrupt or insidious. Hepatic vein
vascular hemolysis resulting in the release of large amounts of free thrombosis in PNH tends to inexorably progress with periodic
hemoglobin into the plasma. Free plasma hemoglobin leads to exacerbations followed by intervals of relatively stable disease.
increased consumption of nitric oxide resulting in manifestations that Although some patients live many years with the condition, it fre-
include fatigue, abdominal pain, esophageal spasm, erectile dysfunc- quently results in death unless complement inhibition or bone
tion, and possibly thrombosis. Indeed, hemoglobinuria, thrombosis, marrow transplantation is initiated. The best noninvasive tests to
erectile dysfunction, and esophageal spasm are more common in confirm the diagnosis include computed tomography scanning,
patients with large PNH populations (>60% of granulocytes) than magnetic resonance imaging, and ultrasonography. Thrombosis can
in patients with relatively small PNH populations. In a study of 49 involve the small hepatic veins, large-sized hepatic veins, or both.
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PNH patients diagnosed using flow cytometry, Moyo et al. demon- Thrombolytic therapy has been used successfully to restore venous
strated that large PNH clones were associated with an increased risk patency and reverse the hepatic congestion; however, because of the
for thrombosis, hemoglobinuria, abdominal pain, esophageal spasm, potential danger of this approach, it should be used judiciously.
and male impotence. Thus many of the clinical manifestations of Patients with acute onset disease, preserved platelet counts (>50,000
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PNH appear to be a direct consequence of intravascular hemolysis, cells/mm ), and large vessel involvement are the best candidates for
leading to the release of free hemoglobin, scavenging of nitric oxide, thrombolysis. For patients with massive ascites who are not suitable
and smooth muscle dystonias. candidates for thrombolytic therapy, transjugular intrahepatic portal-
systemic shunting or surgical shunting can successfully palliate some
patients. Orthotopic liver transplantation was once considered con-
Renal Manifestations traindicated in PNH, but now that the thrombotic risk can be miti-
gated using complement inhibition, this is no longer true. Long-term
PNH patients have a greater than sixfold increased risk of chronic survival following liver transplantation and eculizumab administra-
kidney disease. Renal tubular damage is caused by microvascular tion has been reported.