Page 2486 - Hematology_ Basic Principles and Practice ( PDFDrive )

2218 Part XIII Consultative Hematology

downregulation of the endothelial thrombomodulin–protein C been associated with remission of bleeding manifestations. Complete
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receptor pathway. The severity of protein C deficiency has been resolution without recurrence is the most common event. Thrombosis
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associated with increased morbidity and mortality. There are in the setting of transient postinfectious coagulation inhibitors is rare,
minimal data on the frequency of inherited thrombophilia in children although splenic infarction from aPLs has been reported during
who develop purpura fulminans. In one report, the frequency of infection with EBV and mycoplasma pneumonia. 61,62
factor V Leiden was not different from that in healthy children; the
presence of factor V Leiden was not associated with an increased
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mortality rate, although complications were increased. In another Pancytopenia
study of 16 children with purpura fulminans, 6 (37%) of 16 patients
studied had the factor V Leiden mutation. All of the children in this Pancytopenia in a child should alert the clinician to the possibility of
study survived, but 10 (63%) required amputation. 43 disorders such as leukemia, aplastic anemia, or disseminated neuro-
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Treatment of purpura fulminans consists of antibiotics for sus- blastoma. Infectious causes of pancytopenia are uncommon, and
pected bacterial infection, volume replacement for shock, and disseminated disease is most often present. Organisms implicated in
heparin. Although there is controversy regarding the routine use of patients with pancytopenia include Mycobacterium tuberculosis, atypi-
heparin in DIC, its use in purpura fulminans has been associated cal mycobacteria, Histoplasma capsulatum, Leishmania spp., Salmonella
with an improved outcome when it is started early in the course of enterica subsp. enterica serovar Typhi, Mucor spp., Brucella spp.,
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the disease and continued for 2 to 3 weeks. Theoretically, to improve Fusobacterium necrophorum, Mycoplasma pneumoniae, and Ehrlichia
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the efficacy of heparin, it is reasonable to infuse fresh frozen plasma canis. Virus-associated or reactive hemophagocytic syndrome is an
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or antithrombin III (AT III) concentrates if the AT III level is low. additional, although rare, cause of pancytopenia. Children with HIV
There is anecdotal evidence that infusion of AT III concentrates or infection and concomitant infection with Mycobacterium avium-
protein C concentrates partially corrects or normalizes the hemostatic intracellulare or parvovirus B19 have been reported to have
abnormalities. 46,47 However, in the KyberSept trial, a double-blind, pancytopenia.
placebo-controlled trial of the use of AT III concentrates in 2300
adults with sepsis, researchers found no difference in mortality at day
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28 after diagnosis. In a phase II trial of protein C concentrate in Human Immunodeficiency Virus Infection
the treatment of sepsis and purpura fulminans in children, there was in Children and Adolescents
dose-dependent activation of protein C and normalization of coagu-
lation imbalances. Although there was no improvement in the mor- Infection with HIV is more common in adults but is now recognized
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tality rate, the study was not powered to detect these changes. 49 as a leading cause of immunodeficiency in infants and children.
In initial trials, recombinant human activated protein C (drotre- Acquisition of HIV in a majority of infected children (most of whom
cogin alfa [activated]) reduced the mortality rate in adults with severe are younger than 2 years of age) is by vertical transmission from an
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sepsis, but in pediatric trials, there was no noticeable improvement infected mother to her infant. In a 1989 study of children younger
in mortality (children have a lower mortality rate than adults), and than 13 years of age with acquired immunodeficiency syndrome
there were significant bleeding risks. 50,51 Although activated protein (AIDS), 80% have a parent with AIDS or AIDS-related complex
C has been used in patients with purpura fulminans, the data do not (ARC), 13% have a history of blood transfusion, and 5% have
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suggest a beneficial effect on mortality. 52,53 Use of nonactivated hemophilia or another coagulation disorder. Other “adult” routes
protein C concentrates early in the course of purpura fulminans may, of infection (sexual contact, intravenous needle use) are possible,
however, decrease the need for subsequent skin grafts and amputa- especially in adolescents and sexually abused children.
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tions. In October 2011, this agent was withdrawn from the market Significant advances in the treatment of HIV infection in children
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after a major study showed no efficacy for the treatment of sepsis. have been made since the availability of antiretroviral therapy (ART).
Recombinant tissue plasminogen activator (t-PA) has been used in As a result of programs to prevent mother-to-child transmission,
an attempt to restore organ perfusion by dissolution of diffuse there has been a dramatic decrease in the number of children in the
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microvascular thrombosis ; however, in a retrospective multicenter United States infected with HIV. The Centers for Disease Control
study of 62 patients with meningococcal purpura fulminans treated and Prevention (CDC) estimates the number of children born with
with systemic t-PA, there was a high incidence of intracerebral HIV between 1991 and 2011 decreased from 1650 to 110 cases per
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hemorrhage without proven efficacy in reduction of mortality or year. Rates of death, AIDS, opportunistic infection, and organ-
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incidence of amputation. Other treatments, such as regional sym- specific disease (including thrombocytopenia) have all decreased since
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pathetic blockade, topical nitroglycerin, and local infusion of t-PA, the advent of ART. Reviews of HIV infection in children are
have been used to improve regional blood flow to the affected part. available. 69,70
The mortality rate for postinfectious purpura fulminans has declined The hematologic manifestations of AIDS in children are similar
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from 90% in the past to 18%, but the amputation rate has remained to those in adults (see Chapter 157) and depend on the stage of the
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high. The outcome for patients with acute bacterial sepsis and HIV infection and the presence of coexistent disease. 71,72 Anemia is
purpura fulminans has also improved, but a mortality rate as high as by far the most common finding (seen in 70%–90% of cases),
50% continues to be reported. although the incidence has decreased with effective antiviral
therapy. 73–75 Moderate anemia (hemoglobin less than 8–9 g/dL) has
been identified as an independent risk factor for disease progression
Coagulation Inhibitors in children. Although there have been few studies of severe anemia
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(hematocrit <25%), in one study it correlated with development of
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Acquired inhibitors of coagulation in children with infection are an opportunistic infection and death within 7 months. As in adults,
usually transient and mild but may be associated with severe bleed- inadequate RBC production is the most important pathogenetic
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ing. They are often detected after a viral illness, during antibiotic mechanism for the anemia. The etiology for reduced erythropoiesis
therapy, or incidentally (frequently before tonsillectomy or adenoid- is multifocal, including direct effects of HIV, associated infections,
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ectomy). Both specific inhibitors of coagulation factors (especially medications, and deficiency of micronutrients. Although Coombs-
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factors VIII and IX) and lupus anticoagulants have been demon- positive hemocytic anemia has been described, studies suggest that
strated. Although previously thought to be uncommon, studies have the finding of a positive direct antiglobulin test result is more likely
found 50% to 90% of children with infection have at least one posi- a reflection of hypergammaglobulinemia. Although evidence indi-
tive test result for an antiphospholipid antibody (aPL). 58,59 Significant cates that erythropoietin may improve the hemoglobin and quality
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bleeding is usually seen only in children with specific factor inhibi- of life of patients with HIV and anemia, the evidence is not strong. 80
tors, although hemorrhage also has been described with lupus anti- Leukopenia and neutropenia are commonly seen in HIV-infected
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coagulants. In symptomatic patients, treatment with prednisone has children (occurring in 47% and 41%, respectively), with severe