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2008 Part XII: Hemostasis and Thrombosis Chapter 117: Thrombocytopenia 2009

thrombocytopenia, fatal gastrointestinal, cerebral, and pulmonary in several ways: by decreasing production in the marrow, by increased
bleeding have been reported. Among the many potential contributors to immune destruction, or by inducing microangiopathy as seen in
thrombocytopenia in SLE patients, platelet destruction by autoantibod- patients with infection induced DIC or HUS. In addition, drugs used
ies is the major mechanism. Antiplatelet antibodies are present in up to for the treatment of an infection can contribute to thrombocytopenia
60 percent of SLE patients. 280,281 The presence of antiplatelet antibodies (see “Drug-Induced Thrombocytopenia” below).
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is correlated with low platelet counts and increased disease severity. Viral infections are an important cause of secondary ITP. ITP can
Besides the antiplatelet antibodies, APLAs (see “Thrombocytopenia in be seen after a viral infection, especially in children, and usually resolves
the Antiphospholipid Syndrome” above) and circulating immune com- within 2 to 8 weeks. In patients with viral infections such as rubella,
plexes that bind platelets may nonspecifically accelerate platelet destruc- mumps, and infectious mononucleosis, thrombocytopenia can be pres-
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tion. Specific antiplatelet antibodies, especially those against integrin, ent with other clinical signs and symptoms. Adult patients with isolated
have an important role in the pathogenesis of thrombocytopenia in thrombocytopenia with no obvious causes should be screened for HIV,
SLE patients. 280,281,283 In general, marrow megakaryocytes are normal or HCV and, in endemic areas, for HBV. Because other clinical symptoms
increased, and platelet production is not affected in SLE patients with and signs associated with infection with these viruses may not be pres-
thrombocytopenia. However, decreased numbers of megakaryocytes ent initially, and it may not be possible to distinguish these cases from
and even amegakaryocytic thrombocytopenia have been reported. 86,284 primary ITP.
High levels of TPO in the plasma, and both anti-TPO and anti-TPO HIV is a leading cause of isolated thrombocytopenia in Western
receptor antibodies have been reported in SLE patients, 285,286 the latter countries. Thrombocytopenia associated with HIV infection has
associated with a decrease in marrow megakaryocytes and thrombocy- numerous causes, many of which can be present simultaneously. These
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topenia. Thrombocytopenia in SLE is associated with serious organ include accelerated platelet destruction primarily related to immune
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pathology, leading to neuropsychiatric disease, renal disease, 288,289 complexes, decreased platelet production, especially in advanced dis-
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and APS, and is an independent indicator of poor prognosis. 289,291,292 ease, splenic sequestration, and, rarely, platelet consumption associ-
A study of selected SLE families in which at least one affected member ated with TTP. Medications, concurrent infections such as hepatitis C,
was thrombocytopenic reported genetic linkage to loci at chromosomes and hematologic malignancies may contribute to the development of
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11p13 and 1q22–23. A severe lupus phenotype was much more com- thrombocytopenia (Chap. 83). 304–307
mon in patients with thrombocytopenia and their affected family mem- HCV is another important cause of thrombocytopenia in adults. It
bers than in patients from families with no thrombocytopenic patients. is a hepatotrophic RNA virus of the Flaviviridae family. HCV infection is
Therefore, thrombocytopenia in a family member may herald severe chronic in approximately 85 percent of the infected individuals and pro-
lupus in familial SLE. gresses to cirrhosis in 20 percent of these individuals. The World Health
There are no well-established treatment strategies for severe throm- Organization (WHO) estimates that approximately 3 percent of the
bocytopenia in patients with SLE. Because SLE ranges in severity from world’s population is infected with HCV, the prevalence ranging from
milder forms with easily controlled symptoms and signs to severe forms 0.5 to 2 percent in Western countries to 20 percent in some underde-
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that can be fatal, the treatment of severe thrombocytopenia should be veloped countries. HCV causes thrombocytopenia through different
tailored to the individual patient. Patients with severe thrombocytope- mechanisms, including hypersplenism, decreased TPO level associated
nia are generally treated with glucocorticoids as first-line therapy, but with liver insufficiency, the effect of drugs (pegylated interferon [IFN]
sustained remission is infrequent. Because most patients with severe and ribavirin), and immune-mediated platelet destruction. Immune
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thrombocytopenia also have nephritis and neurologic symptoms, they dysregulation in HCV is associated with several autoimmune disorders,
receive immunosuppressive therapy either alone or combination with including arthritis, Sjögren syndrome, cryoglobulinemia, and immune
glucocorticoids. 294–297 IVIG is reserved for use in patients with severe cytopenias. As a potential mechanism of immune destruction, one
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bleeding. 298,299 It is well-known that B lymphocytes play an important study demonstrated binding of both free and IgG-complexed HCV to
role in the pathogenesis of SLE. Although lymphopenia is common in platelets. In secondary ITP associated with HCV infection, antiviral
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patients with active SLE, autoantibody-producing B cells have been therapy with pegylated IFN and ribavirin will decrease viral load and
shown to be expanded, and B cells were found to be more sensitive may also treat thrombocytopenia. However, platelet counts can be unaf-
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to inflammatory cytokines. B-cell targeted therapy—rituximab—is fected or even decrease after these therapies. Severe thrombocytopenia
effective in the treatment of refractory SLE patients, especially those interferes with optimal HCV treatment, and may increase bleeding risk.
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with nephritis and severe thrombocytopenia. A retrospective study In this situation, the ASH 2011 guideline recommends IVIG as a first-
evaluating the long-term effects of rituximab therapy in 65 patients with line therapy, because glucocorticoids may increase viral load. Gluco-
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refractory ITP associated with SLE and mixed connective tissue disease corticoids and splenectomy both appear to be effective treatments for
reported an overall response rate of 80 percent. Although case series thrombocytopenia, but their use should be balanced against other con-
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indicate that splenectomy yields sustained remission in 61 percent of siderations after discussion with a hepatologist. TPO receptor agonists
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SLE patients with severe thrombocytopenia and is relatively safe in may increase the risk of abdominal thrombosis in HCV patients with
terms of perioperative complications, splenectomy may increase liver cirrhosis. 312
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the risk of thrombotic complications in SLE patients, and may also The potential role of H. pylori in the pathogenesis of chronic ITP
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increase the risk of infection if the patients require further immunosup- is controversial. Japanese and Italian studies showed that eradication of
pressive therapy. H. pylori with antibiotics resulted in marked platelet count increases in
patients with ITP. However, this success was not reproduced in Amer-
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THROMBOCYTOPENIA IN INFECTIOUS ican and other European studies. It appears that response rates are
higher in countries where H. pylori infection is endemic. ITP patients
DISEASES treated for H. pylori had higher platelet counts than untreated ITP
The first recorded observation of purpura was made in patients with patients, even if the therapy was unsuccessful in eradicating the infec-
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fever, and purpura was accepted as a sign of severe infections for cen- tion. It has therefore been speculated that the antibiotic therapy,
turies. Thrombocytopenia can be seen in patients with viral, bacterial, rather than eradication of H. pylori, may be the factor improving platelet
fungal and parasitic infections. Infection can decrease platelet levels counts. However, meta-analysis found that H. pylori eradication therapy

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