Page 2495 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 152 Hematologic Manifestations of Childhood Illness 2227

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lesions. Unfortunately, thromboembolic events continue to be a symptoms may not always be caused by fluid overload in this popula-
major cause of morbidity and mortality associated with this proce- tion and that pulmonary embolism should at least be considered in
dure. The reported incidence of these complications in cohort studies any nephrotic patient with a significant change in respiratory status.
ranges from 1% to 19% and includes venous thrombosis of the Prophylactic anticoagulation is recommended for adult nephrotic
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Fontan circuit, right atrial thrombosis, and stroke. Thromboem- syndrome as long as the patient has proteinuria or severe hypoalbu-
bolic events may occur anytime after the procedure but often present minemia. However, no studies have been performed to evaluate the
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months to years later. There is no consensus regarding the optimal efficacy or safety of this practice in pediatric patients, and prophylaxis
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type or duration of anticoagulation that Fontan patients should is generally not used in children without a history of thrombosis.
receive, nor are there data that any one prophylactic regimen is One reason for the controversy is that predictors of thrombosis have
effective in reducing thromboembolic complications. Institutional not been clearly established in this population. Even decreased plasma
protocols, if they exist, range from no anticoagulation to aspirin to concentrations of antithrombin, a well-recognized risk factor, are not
warfarin. The American College of Chest Physicians (ACCP) guide- a consistent finding in nephrotic children who develop thromboem-
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lines suggest either therapy with aspirin (1 to 5 mg/kg/day) or thera- bolism. The most consistent biologic risk factor to date is the
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peutic heparin followed by warfarin to achieve a target international presence of severe hypoalbuminemia. Age (infancy or ≥12 years)
normalized ratio of 2.5 but state that the optimal duration of therapy at diagnosis of nephrotic syndrome, membranous histology, severe
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is unknown. In a recently published international randomized trial proteinuria, and history of thromboembolism preceding the diagnosis
of aspirin (5 mg/kg/day) versus warfarin as primary thromboprophy- of nephrotic syndrome have also been identified as significant predic-
laxis in the first 2 years after Fontan surgery, there was no difference tors of thromboembolism. 280,285
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in thrombosis rates between groups. However, the overall throm- Although the traditional duration of anticoagulation for deep
bosis rate was still substantial, suggesting that alternative approaches venous thrombosis (DVT) is 3 months, some form of anticoagulation
need to be considered. In a retrospective cohort of more than 400 should be continued or resumed in the setting of active nephrotic
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Fontan patients, although the total prevalence of thromboembolism disease. To avoid hemoconcentration, diuretics must be avoided or
was low (2.7%), patients with symptomatic thromboembolism had used judiciously in patients who have experienced a thromboembolic
a high mortality rate (73%). The two high prevalence periods for event. Finally, it is important to remember that the efficacy of heparin
thrombosis were within 6 months of surgery and then long-term can be impaired in the setting of decreased antithrombin levels.
thromboembolism occurring more than 15 years from surgery. 273
There is even less data on the role of anticoagulation or antiplatelet
therapy in other cardiac procedures with the potential risk of throm- Thromboembolism in Systemic Lupus
boembolism. These include the placement of endovascular stents and Erythematosus and Antiphospholipid Syndrome
Blalock-Taussig shunts as well as Norwood and Glenn procedures,
which are typically performed before the definitive Fontan procedure. The reported incidence of thromboembolism in pediatric SLE ranges
The ACCP recommends perioperative heparin therapy for these from 9% to 17%, similar to rates reported in adult patients with
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procedures. The need for antiplatelet therapy after these procedures SLE. 287,288 Although DVT of the lower extremities is still the most
remains unknown, although aspirin unresponsiveness has been common manifestation, patients with SLE are more likely than
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associated with postoperative thrombosis. Postoperative chylotho- patients with malignancy, CHD, or nephrotic syndrome to experi-
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rax is also strongly associated with VTE. Finally, thrombosis ence arterial and central nervous system thrombosis. In approximately
remains a significant cause of morbidity in children awaiting cardiac half of cases, thrombosis occurs before or at the time of SLE diagno-
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transplant, and thromboprophylaxis with warfarin should be consid- sis. The significant association between the presence of aPLs and
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ered at the time a patient is placed on the waiting list. 271,276 thromboembolism is well described in patients with SLE. aPLs are
Long-term anticoagulation therapy is clearly indicated for children a heterogeneous group of antibodies directed against plasma proteins
with prosthetic heart valves. Because there are few prospective studies and phospholipid complexes. They most frequently occur in the
and no randomized trials in children, these recommendations are setting of SLE but are also associated with JIA, epilepsy, and other
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based on the high-quality evidence supporting thromboprophylaxis diseases. There are multiple aPLs subtypes, including lupus anti-
in adults. 271 coagulants, anticardiolipin antibodies, anti–β 2 -glycoprotein I anti-
bodies, and antiprothrombin antibodies. The exact mechanism of
aPL-associated thromboembolism has not been elucidated, but recent
Thromboembolism in Nephrotic Syndrome data suggest that lupus anticoagulant antibodies interfere with the
function of the protein C pathway, leading to an acquired activated
The increased risk of thromboembolism in pediatric nephrotic syn- protein C resistance. 292
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drome is multifactorial. The same urinary losses that lead to pro- aPLs are quite common in the pediatric SLE population. Authors
found hypoalbuminemia in these patients also cause acquired of an analysis of 12 published series of children with SLE reported a
deficiencies of anticoagulant proteins such as antithrombin and free global prevalence of 48% for anticardiolipin antibodies and 23% for
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protein S. In addition to deficiencies of anticoagulants, increased lupus anticoagulants. Recent work has been focused on the predic-
levels of procoagulants (fibrinogen, factor V, and factor VIII), hyper- tive value of aPL subtypes for the risk of thromboembolic events. In
cholesterolemia, and increased platelet aggregation have all been a cohort of 58 children with SLE, the presence of lupus anticoagulants
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described in nephrotic syndrome. Finally, the therapeutic interven- had the highest predictive power for thromboembolism. The pres-
tions for nephrotic syndrome can increase the risk of thromboembo- ence of anticardiolipin antibodies was also predictive, but only if they
lism. Diuretics cause reduced intravascular volume, leading to were persistent (positive on at least two occasions 3 months apart).
hemoconcentration, and steroids and cyclosporine increase procoagu- Other studies have confirmed the strong predictive power of aPLs,
lant activities. particularly lupus anticoagulants, for the risk of thromboembo-
The incidence of thromboembolism in pediatric nephrotic syn- lism. 287,294,295 However, pediatric patients with SLE with negative test
drome ranges from 1.8% to 9.2% in published series. 277–281 This results for aPLs rarely develop thrombotic events.
contrasts with adult nephrotic syndrome, in which incidence rates as On the basis of these data, it is recommended that children with
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high as 44% have been reported. The most common locations in SLE routinely be screened for lupus anticoagulants, and if antibodies
children are the deep veins of the lower extremities, renal veins, and are present on more than one occasion, families should be counseled
cerebral veins, and events are frequently associated with the use of on the presenting symptoms of stroke and other thrombotic
central venous catheters. Although pulmonary embolism is clinically events. 295,296 Prophylaxis with low-dose aspirin may be reasonable,
diagnosed in less than 1% of patients, a frequency of 27% (7 of 26) especially in the setting of other thrombotic risk factors. However,
was found in a series of nephrotic children who underwent screening there are not yet data to support routine prophylactic anticoagulation
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with ventilation/perfusion scans. These data suggest that pulmonary with lupus anticoagulants in patients with SLE in the absence of a