Page 2201 - Hematology_ Basic Principles and Practice ( PDFDrive )

1948 Part XII Hemostasis and Thrombosis

proinflammatory and antiinflammatory cytokines, upregulation or
First-Line Therapy
downregulation of various Fc receptors, and the induction of soluble
An 8-year-old girl is brought to the emergency department because immune complexes. In a mouse model of ITP, transfer of IVIg-primed
her mother noticed bruising on her legs. She has had a sore throat dendritic cells recapitulated the effect of IVIg.
and fever for the past 7 days but is otherwise well and not taking any Based on the results of a metaanalysis of randomized controlled
medications. On physical examination, there are a few small bruises trials that included 410 children, the probability of achieving a
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on her legs but no petechiae on her skin or purpura in her mouth. platelet count above 20 × 10 /L at 48 hours was higher with IVIg
Neurologic examination findings are normal, and the spleen is not than corticosteroids (relative risk for corticosteroids, 0.74; 95% CI,
palpable. The platelet count is 23 × 10 /L. The presumed diagnosis is 0.65–0.85). Similar results have been observed in adults. Common
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ITP without significant bleeding; thus the decision is made to observe side effects of IVIg include headache, hypertension, and chills.
the child in the hospital with no specific treatment. The next day, the Hemolysis, thrombosis, renal impairment, and neutropenia are rare
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platelet count is 33 × 10 /L. On day 2, it is 37 × 10 /L, and the child
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is discharged home. One week later, the platelet count is 66 × 10 /L, complications.
and 1 month later, it is up to 155 × 10 /L. Anti-D (50–75 IU/kg) and IVIg have similar efficacy in children.
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Hemolysis is expected with anti-D administration, and rarely, intra-
vascular hemolysis can be severe or even fatal. Consequently, the
United States Food and Drug Administration has issued a black box
patients present with bleeding, such as epistaxis or mucosal hemor- warning about the use of anti-D for the treatment of ITP, and the
rhage, treatment is required. For adults, a period of observation may drug has been removed from certain European markets. In general,
be reasonable if there is no evidence of bleeding and the platelet count the use of anti-D is restricted to nonsplenectomized patients who are
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is above 20 × 10 /L; however, most adults will require treatment Rh-positive and have a negative direct antiglobulin test.
because spontaneous remissions are rare. To reflect current practice,
the ASH 2011 guidelines recommend using a platelet count below
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30 × 10 /L as the threshold for starting treatment. Second-Line Therapy
Splenectomy
Corticosteroids
Splenectomy was first proposed as a treatment for ITP in 1913
The conventional starting dose of prednisone is 1–2 mg per kg for and was subsequently shown to be an effective means of rapidly
2–4 weeks followed by tapering over a several week period once the increasing the platelet count in most ITP patients. In a systematic
platelet count improves. In general, 60% to 70% of adults with acute review, approximately two-thirds of patients achieved a platelet count
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ITP achieve an initial response with corticosteroids. Sustained platelet response after splenectomy, usually within days. Despite the high
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count responses (platelet count >100 × 10 /L at 6 months) with success rate with splenectomy, patients (and physicians) are often
corticosteroids are infrequent in practice, but have been reported to reluctant to undertake an invasive procedure such as splenectomy,
be as high as 47% in some studies. The risk of relapse increases with when pharmacologic alternatives are available. Only younger age
longer duration of follow up. Low-dose prednisone (0.5 mg/kg per has been identified as a predictor of splenectomy success, although
day followed by a taper) may be as effective as the conventional dose some investigators have found a correlation between prior response
for initial ITP treatment, but long-term remissions are rare. The to IVIg and a splenic pattern on radiolabeled platelet sequestration
optimal duration of prednisone treatment and the optimal tapering studies.
schedule have yet to be established. With currently available minimally invasive surgical techniques,
High-dose dexamethasone, typically administered at a dose of complications after splenectomy are uncommon. The overall mortal-
40 mg/day for 4 consecutive days, is also effective. In one study that ity rate is approximately 1% with open surgery and about 0.2% after
included 125 adults with ITP, approximately 40% of patients had a laparoscopic splenectomy. The most frequent perioperative complica-
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sustained response that lasted 2–5 years. Repeated cycles of high- tions include pneumonia, subphrenic abscess or pleural effusion
dose dexamethasone (once per month for 6 months) may result in (4%), major bleeding (1.5%), and thromboembolism (1%). With
even higher rates of durable remissions, although this effect may laparoscopic techniques, patients have less postoperative pain, shorter
simply reflect the total corticosteroid exposure. High-dose dexa- hospital stays, and fewer wound complications.
methasone is associated with side effects that may limit the use of Because the spleen is involved in clearance of encapsulated bacte-
this treatment including hypertension, muscle weakness, insomnia, ria, asplenic individuals are at risk for infection with Streptococcus
and impaired cognition. In a systematic review of randomized trials pneumoniae, Neisseria meningitides, and Haemophilus influenzae type
comparing high dose dexamethasone and prednisone in adults with b. Therefore all patients undergoing splenectomy should receive
previously untreated ITP (n = 533), treatment with dexamethasone vaccinations against these bacteria at least 2 weeks before surgery.
resulted in improved overall (79% vs. 59%; P = .048) and complete Poor compliance and vaccine failures contribute to the ongoing risk
platelet count response (64% vs. 36%; P = .040) without excess of serious postsplenectomy infections. The lifetime risk of over-
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toxicity. Sustained responses at 6 months were not different between whelming postsplenectomy infection is estimated to be 1% to 3%
groups, but platelet count responses occurred more rapidly with high with the risk being higher in children younger than 15 years of age
dose dexamethasone. and in patients with hematologic malignancies. Although the risk of
an infection requiring hospitalization was highest in the first 90 days
after splenectomy in a cohort of 3812 splenectomized patients in
Intravenous Immunoglobulin and Anti-D Denmark, this risk remained 2.5 times higher than that in the general
population even after 90 days.
The predominant mechanism of action of high-dose IVIg and anti-D The ITP International Working Group and the revised ASH
is thought to be via RES blockade. Individuals with low plasma IgG guidelines consider splenectomy an acceptable second-line therapy
levels exhibit more rapid clearance of sensitized red blood cells (RBCs) for ITP. However, the former group considers splenectomy equal to
(indicating enhanced RES capacity) than those with high levels of other medical options, whereas the ASH guidelines favor splenectomy
plasma IgG, such as those achieved with high-dose IVIg. A competitive (grade 1B evidence) over rituximab or TPO receptor agonists (grade
model of RES clearance would also explain why anti-D administration 2C evidence). Splenectomy leads to a high rate of durable remission.
to Rhesus (Rh)-positive individuals is effective in improving platelet In a systematic review, 1731 (66%) of 2623 adults with ITP achieved
counts in patients with ITP. Thus IgG-sensitized RBCs compete a complete response following splenectomy at a median follow up of
for Fc receptor occupancy. Other potential mechanisms of action 28 months (range 1–153 months) and this response rate was main-
of IVIg or anti-D include antiidiotypic antibodies, stimulation of tained for 10 years or more after splenectomy.