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580 Part VI: The Erythrocyte Chapter 40: Paroxysmal Nocturnal Hemoglobinuria 581

approximately 35 percent. Overall survival for unselected PNH patients thromboembolism during pregnancy in women with PNH is approxi-
who undergo transplantation using an human leukocyte antigen (HLA)- mately 10 percent, and these events are associated with a high risk of
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matched sibling donor is in the range of 50 to 60 percent. 28 mortality. 77,78 Similar to nonpregnant patients with PNH, cerebral and
hepatic veins are commonly involved sites of thrombosis. Thrombolytic
MANAGEMENT OF THE THROMBOPHILIA therapy should be considered for those with Budd-Chiari syndrome.
The role of prophylactic anticoagulation for pregnant women with
OF PAROXYSMAL NOCTURNAL PNH has not been studied prospectively; however, because of the sig-
HEMOGLOBINURIA nificant morbidity and mortality associated with thromboembolism in
Thromboembolic complications are the leading cause of morbidity and this setting, prophylaxis is recommended. Coumadin is contraindicated
mortality in PNH. Prophylaxis against thromboembolic events in because of teratogenic potential in the first trimester and hemorrhagic
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patients with PNH is an issue of active debate. Current estimates of risks later in gestation (Chap. 8). Anticoagulation with heparin should
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risk are based on retrospective analysis, 54,70–73 but risk appears to correlate begin immediately once the pregnancy is documented. Low-molecular-
with size of the PNH clone (based on flow cytometric determination of weight heparin has a hypothetical advantage over unfractionated hep-
the percentage of GPI-AP–deficient PMNs), leading to the recommen- arin because of a lower incidence of drug-induced thrombocytopenia
dation that patients with greater than 50 to 60 percent GPI-AP–deficient and less osteopenia (Chap. 118). Careful monitoring of the platelet
PMNs be offered prophylactic anticoagulation. 70,71 Treatment with war- count is required because thrombocytopenia may worsen during the
farin with a goal international normalized ratio (INR) of between 2.0 and period of anticoagulation. Anticoagulation can be discontinued briefly
3.0 is recommended for patients with PNH who require chronic antico- around the time of delivery. However, it should be restarted as soon as is
agulation either for treatment of a thromboembolic event or for prophy- feasible and continued for at least 6 weeks into the postpartum period,
laxis. There are no empiric data to guide the use of low-molecular-weight as thrombosis during the puerperium is a major concern. 77,78 Most
heparin or novel oral anticoagulants in these settings, but their use can deliveries can be accomplished vaginally, although premature delivery
be considered in patients with adequate renal function who fail warfarin may be necessary. Despite the many concerns surrounding PNH and
or in patients have difficulty maintaining a consistent therapeutic INR. pregnancy, successful outcomes appear to be the rule rather than the
Although arterial thrombosis may be observed, thromboembolic exception 72,77 ; however, management is complicated and should involve
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events in patients with PNH usually involve the venous system. Acute the combined efforts of a knowledgeable hematologist and an obstetri-
thrombotic events require anticoagulation with heparin. Systemic cian experienced in dealing with high-risk pregnancies. 27
thrombolytic therapy, 74,75 or thrombolytic therapy delivered via canal-
ization directly to the affected site, should be strongly considered in PEDIATRIC PAROXYSMAL NOCTURNAL
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patients with acute onset of Budd-Chiari syndrome. HEMOGLOBINURIA
Thrombocytopenia often complicates PNH, and this issue should
be addressed when formulating an anticoagulation management plan. PNH can occur in the young (approximately 10 percent of patients are
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Thrombocytopenia is a relative contraindication to anticoagulation, younger than age 21 years at the time of diagnosis). A retrospective
and transfusions should be given to maintain the platelet count in a safe analysis of 26 cases, underscored the many similarities between child-
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range rather than withholding therapy. Patients with PNH who expe- hood and adult PNH. Signs and symptoms of hemolysis, marrow
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rience a thromboembolic event should be anticoagulated indefinitely. failure, and thrombosis dominate the clinical picture, although gross
Recurrent, life-threatening thrombosis merits consideration of mar- hemoglobinuria as a presenting symptom may be less common in young
row transplantation, but such patients are at high-risk for transplanta- patients. A generally good response to immunosuppressive therapy was
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tion-related adverse events (see Table 40–4). 61 observed, but based on poor long-term survival, hematopoietic cell
Eculizumab reduces the risk of thromboembolic complications. transplantation is the recommended treatment for childhood PNH.
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For patients being treated with eculizumab who have no prior history of One study confirmed the common presentation of marrow failure in
thromboembolic complications, prophylactic anticoagulation may not 11 children with PNH, and reported that five patients eventually under-
be necessary. went hematopoietic cell transplant (three matched unrelated donors and
two matched family donors), of whom four were long-term survivors. In
PREGNANCY AND PAROXYSMAL NOCTURNAL another study of 12 young patients over an 18-year period, 10 presented
with evidence of marrow failure and only one with hemoglobinuria.
40
HEMOGLOBINURIA There were six children with thrombosis and five with myelodysplastic
Women with PNH can have serious morbidity and increased mortality features, indicating that the clinical presentation may be more similar to
during pregnancy. 77,78 Because of concerns about fetal/maternal risks adult PNH than previously recognized. The safety and effectiveness of
from exposure to potentially toxic therapy, anticoagulation and trans- eculizumab in pediatric patients below the age of 18 years has not been
fusion have been the mainstay of management. Eculizumab has been established, however, there are anecdotal reports of its use in pediatric
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assigned to pregnancy category C (risk cannot be ruled out) by the FDA. patients with PNH. Although eculizumab is not approved for PNH
There are no controlled studies of the use of eculizumab in human preg- patients younger than age 18 years, approval will likely be sought once
nancy; however, anecdotal reports and small series have identified no pharmacodynamic and pharmacokinetic characteristics of the drug are
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significant adverse effects when eculizumab is used during pregnancy, defined for the pediatric/adolescent population. The availability of
including early in gestation and, in one case, from the time of concep- eculizumab for pediatric PNH may be particularly advantageous as a
tion. 51,79,80 Nonetheless, until more is known about the safety of eculi- bridge prior to implementation of more definitive therapy.
zumab in pregnancy, it seems prudent to restricted use of the drug to
the third trimester and then only for patients who are at high-risk for COURSE AND PROGNOSIS
thrombosis and who have no acceptable therapeutic alternatives.
Moderate to severe thrombocytopenia may complicate the The clinical course of PNH is enormously variable. In rare instances, the
pregnancy, and clinically significant bleeding in this setting necessi- patient may succumb to this disease within a few months of the first onset
tates platelet transfusion. The incidence of clinically apparent venous of symptoms. Most patients experience a chronic course in which the

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