Page 2494 - Hematology_ Basic Principles and Practice ( PDFDrive )

2226 Part XIII Consultative Hematology

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In a recent analysis of 13,449 admissions at US children’s hospitals, incidence rate for symptomatic thrombosis was 5.2%. As opposed
the majority (63%) of patients with venous thromboembolism (VTE) to other types of cancer, cerebral venous thrombosis and stroke are
had one or more complex chronic conditions, most commonly frequently seen in ALL, particularly in the setting of asparaginase
cardiovascular disease (28%), followed by malignancy (14%) and therapy. Asparaginase, an essential component of induction chemo-
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neuromuscular (11%) and respiratory (7%) diseases. This review therapy, reduces the synthesis of both coagulation factors and inhibi-
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focuses on four childhood illnesses commonly associated with throm- tors as a consequence of asparagine depletion. Higher incidences
boembolism: malignancy, CHD, nephrotic syndrome, and SLE. In of thrombosis appear to be associated with lower doses of asparaginase
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addition to the diseases discussed in this review, other chronic ill- given over longer treatment durations, as well as prednisone. In a
nesses of childhood have been associated with thromboembolism, large Italian cohort (n = 2042), VTE occurred in 2.4% of patients
including sickle cell anemia, IBD, diabetes, and CF. Children receiv- and was associated with male sex and the presence of factor V Leiden
ing home total parental nutrition also have an increased risk of and prothrombin G20210A. 257a Similarly to other studies, 40 of the
thrombosis because of the combination of a central venous catheter 48 events occurred during the induction cycle of chemotherapy, likely
and infusion of hyperosmolar solutions that can injure the vascular due the prothrombotic effects of active disease, asparaginase, and
endothelium. 239,240 As the incidence of pediatric VTE increases, the prolonged steroid therapy. A predictive model incorporating high-
concept of thromboprophylaxis in hospitalized children is receiving dose prednisone, asparaginase in combination with steroids, the
increased attention. The end of this section reviews the small but presence of a central venous catheter, and the presence of inherited
growing body of literature on this topic. thrombophilias has demonstrated validity in the ability to identify
children at high risk of thrombosis in a large population of children
with ALL, although modifications are likely necessary when treat-
Thromboembolism in Pediatric Cancer ment protocols vary. As a secondary outcome of this study, high-
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risk patients without low-molecular-weight heparin (LMWH)
Although thrombosis is a well-known complication of pediatric prophylaxis showed significantly reduced thrombosis-free survival
malignancy, the overall incidence is low compared with adults with during induction therapy compared with those who did receive
cancer. Most epidemiologic studies in this area have been limited to prophylaxis; LMWH was administered according to preference of the
single-center experiences or specific cancer types. The reported inci- treating physician (see box How to Manage Thromboembolism in
dence of thromboembolism in pediatric cancer ranges from 2% to the Setting of Pediatric Cancer).
14% when based on clinical symptoms and up to 44% to 50% when The incidence of thromboembolism in sarcoma ranges from 14%
children undergo routine radiographic screening. 241–248 In a report of to 16%. 259,260 Thrombotic events in sarcoma are frequently detected
17 years’ experience at McMaster Children’s Hospital, 7.9% (95% at the time of presentation and may be asymptomatic. Patients with
confidence interval, 6.0%–10.0%) of oncology patients experienced greater disease burden or metastatic disease appear to be at highest
thromboembolism. Increasing age, certain cancer types (hematologic risk. Brain tumors, the most common solid tumor in children, have
malignancies and sarcomas), intrathoracic disease, and catheter dys- a relatively lower risk of thrombosis in children than in adults.
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function were associated with a higher risk of thromboembolism. Researchers in pediatric and adolescent studies have reported an
Because many thrombotic events in pediatric cancer are catheter incidence of only 0.5% to 2.8% as opposed to the 18% to 28%
related, the majority of thrombosis described in the literature is incidence of thrombosis in adults with brain tumors. 248,261–263
located in the upper venous system. Because the incidence of thromboembolism increases with age,
Factors associated with an increased risk of catheter-related cancer-related thrombosis is of particular concern in adolescents and
thrombosis include insertion of peripherally inserted central catheters young adults with cancer, an increasing number of whom are cared
or Hickman catheters and a history of catheter occlusion and infec- for at children’s hospitals. In a study of 2001 to 2008 national dis-
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tion. There is increasing evidence of a bidirectional relationship charge data from US children’s hospitals, 5.3% of adolescents and
between catheter-associated infection and thrombosis, and ongoing young adults (15–24 years of age) with cancer had a discharge
clinical studies are underway to better delineate the relationship diagnosis of VTE. 264
250
between occlusion, infection, and thrombosis in central lines.
Right atrial thrombi are also frequently seen, with a reported inci-
dence of 9% to 14% in children with indwelling catheters. 245,251 Thromboembolism in Congenital Heart Disease
Typically asymptomatic, these thrombi are often found incidentally
on routine surveillance echocardiograms of children receiving anthra- Although CHD affects only 1% of live births, almost 50% of infants
cycline chemotherapy. Patients with asymptomatic catheter-related younger than 6 months of age and 30% of older children who
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thrombosis are at risk for postthrombotic syndrome (persistent pain, develop VTE have underlying cardiac disorders. Also, the majority
swelling, or skin changes) after catheter removal, and screening cancer of children receiving prophylactic anticoagulation are those with
survivors for these symptoms should be part of the long-term complex CHD, prosthetic heart valves, or severe acquired cardiac
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follow-up care for these patients. The occurrence of postthrombotic diseases such as cardiomyopathy. Children with CHD are at risk of
syndrome is associated with a history of catheter occlusion, history venous, arterial, and intracardiac thrombosis, as well as embolism to
of catheter-related VTE, and the use of two or more catheters, and the central nervous system. CHD is also the most common associated
is also a predictor of decreased health-related quality of life. 252 diagnosis among children hospitalized with arterial ischemic stroke
There are several mechanisms by which malignancy increases the in the United States. 266
risk of thromboembolism. 253,254 These include direct activation of Cardiac catheterization is the most common procedure performed
the coagulation system; inhibition of fibrinolysis through secretion in children with CHD, and it is used for both diagnostic and thera-
of plasminogen activator inhibitor-1; and the release of cytokines, peutic purposes. Access is typically obtained through the femoral
which themselves induce procoagulant and antifibrinolytic activity. artery. Historically, thromboembolism of the femoral artery was a
Studies have also documented increased thrombin generation at the common complication of this procedure, particularly in younger
time of cancer diagnosis that persists for several months after initiating patients. In the 1970s, a randomized clinical trial demonstrated that
therapy. Malignant cells can also adhere to platelets, leukocytes, and the use of unfractionated heparin prophylaxis reduced the incidence
the endothelium through adhesion molecules present on their surfaces. of femoral artery thrombosis from 40% to 8% in children younger
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Finally, as tumors increase in size, they may compress or occlude blood than 10 years of age. Even when heparin prophylaxis is the standard
vessels, leading to reduced blood flow and stasis. Non–catheter-related of care, postthrombotic syndrome is commonly identified in children
lower-extremity VTE can occur as a result of immobilization. 255 after cardiac catheterization, although fortunately most children have
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Published studies indicate that patients with hematologic malig- mild manifestations. The Fontan procedure, which diverts systemic
nancies and sarcomas appear to have the highest risk of thromboem- venous return directly to the pulmonary arteries, is the definitive
bolism. In a meta-analysis including 1752 children with ALL, the palliative surgical treatment for most congenital univentricular heart