Immune thrombocytopenic purpura (ITP) is an autoimmune disorder characterized by a decreased number of platelets and mucocutaneous bleeding. ITP may be primary (idiopathic) or secondary to an underlying disorder. Secondary disorders are increasingly being recognized as important and significant contributors to immune thrombocytopenia. Disorders associated with ITP include lymphoproliferative disorders, autoimmune and collagen vascular diseases, and chronic infections. The two predominant viral causes of secondary ITP are the human immunodeficiency virus (HIV) and the hepatitis C virus (HCV). It is important to understand the various underlying mechanisms of these disease entities and to recognize that treatment strategies may differ from those for other types of immune thrombocytopenia.
Hepatitis C Virus Infection
In general, studies report a positive HCV serology in 10–36% of patients with chronic ITP.1–6 According to a large series, HCV-positive patients with chronic ITP are characteristically older (54.9±8 versus 40.3±8 years; p=0.001) and more frequently Asian than HCV-negative patients, with an equal distribution between the sexes.4
Multiple pathogenic mechanisms have been elucidated in thrombocytopenia related to chronic HCV infection. In patients with advanced liver disease, thrombocytopenia may result from the sequestration of platelets in spleens enlarged from portal hypertension and the inadequate production of thrombopoietin.7,8 Another mechanism includes the binding to and possible infection of platelets and megakaryocytes by HCV, thereby leading to the phagocytosis of platelets.9,10 Finally, HCV-infected patients may experience an alteration in the regulation of their immune systems, triggering the production of autoantibodies against platelet glycoproteins.11 A compelling argument for this hypothesis is the higher prevalence of thrombocytopenia and antiplatelet antibodies in patients with hepatitis C-induced liver disease than in patients infected with hepatitis B.12
HCV-infected thrombocytopenic patients do not always manifest in a predictable manner. Japanese and American studies were conflicting as to whether the platelet counts in HCV-positive patients were lower or higher than those in HCV-negative patients.2,4 Although the signs and symptoms of thrombocytopenia are less frequent in HCV-positive ITP, major bleeding is more frequent (25 versus 10%; p=0.0059). Serum cryoglobulins and anticardiolipin antibodies are present more frequently in HCV-positive ITP patients (90 and 62%, respectively) and rare in HCV-negative ITP patients (7 and 15%, respectively; p≤0.001) compared with HCV-positive ITP. Cryoglobulins are associated with the development of vasculitis and the combination of cryoglobulinemic vasculitis and thrombocytopenia, which may explain the increased incidence of bleeding in HCV-infected patients. However, in French and Chinese studies the characteristics of ITP in HCV-positive patients did not differ from those of HCV-negative patients.5,6
Although HCV-positive patients respond with improved platelet counts to treatment with intravenous immunoglobulin (IVIg), anti-RhD Ig, and splenectomy,2,5 they respond variably to corticosteroid therapy.2,11,13,14 In addition, caution must be exercised when administering corticosteroids. In one study, six of seven patients (85%) treated with prednisone doubled their hepatic transaminase levels and had increases in their HCV viral loads, two patients developed elevated serum bilirubin levels, and one patient developed overt jaundice.15 Treatment with interferon-α (IFN-α) may increase platelet counts, especially among HCV patients who completely respond to IFN-α treatment.3,15,16 In one study, responders to IFN-α, as opposed to non-responders, experienced decreases in the levels of HCV quantitative ribonucleic acid, hepatic transaminases, and cryoglobulins.15
An association between AIDS and thrombocytopenia was noted before the discovery of HIV.17–20 Prior to the advent of highly active antiretroviral therapy (HAART), the rate of thrombocytopenia (platelet count <150x109/l) was estimated to be between 5 and 30%.21–27 This estimation is likely to be lower because of the frequent and early use of HAART. Recent data from the Women’s Interagency HIV Study documented a reduction in the incidence of anemia and neutropenia in HIV-infected women on HAART therapy, and one could assume a similar reduction in the incidence of thrombocytopenia.28,29
Thrombocytopenia is more prevalent in patients with a clinical diagnosis of AIDS, CD4 lymphocyte count of <200/mcl, and history of intravenous drug abuse.22–27,30,31 Compared with HIV-infected homosexuals, HIV-infected injection drug users have an increased incidence and severity of thrombocytopenia, which may be the result of a higher incidence of co-infection with hepatitis C and underlying liver disease.23–25,30–34
Multiple mechanisms contribute to the development of thrombocytopenia in the HIV-infected patient, including immune complex disease leading to accelerated platelet clearance,19,35–38 the presence of antiplatelet glycoprotein antibodies,37,39–41 and anti-HIV antibodies that cross-react with platelet membrane glycoproteins (antigenic mimicry).42–45 Additional evidence exists for defective platelet production and direct infection of megakaryocytes, resulting in megakaryocytic apoptosis.46–56
HIV-associated thrombocytopenia of early HIV infection often resembles classic ITP in which thrombocytopenia results primarily from peripheral destruction, whereas patients with immunological AIDS (CD4 lymphocytes <200/mcl) have thrombocytopenia attributable to decreased platelet production and ineffective hematopoiesis.46–48
Thrombocytopenia in HIV patients can precede the development of overt AIDS by several years, manifesting in a form clinically indistinguishable from classic ITP.57 The clinical presentation of HIV-related ITP is often mild, with only a minority of patients having platelet counts of <50x109/l.25–27 Major bleeding is rare and only a few cases of fatal hemorrhage have been reported.59 Severe thrombocytopenia in patients with advanced HIV infection is frequently associated with additional cytopenias.21–23
HIV-related thrombocytopenia is responsive to therapies frequently used in the management of classic ITP. Prednisone therapy produces a major hematological response in the platelet count (100×109/l) of over half the patients treated, although only a minority of patients will maintain platelets above 50×109/l after corticosteroid therapy is discontinued.20,60 There has been no evidence of a deleterious effect of short-term prednisone treatment on HIV-infected, immune-suppressed patients.
IVIg and anti-RhD are equally effective in acutely elevating platelet counts in severely affected patients. Surgical splenectomy, as opposed to splenic irradiation, is safe and effective in HIV patients with refractory thrombocytopenia.17,18,20,31,47,48,62–64
HIV-related hematological disorders correlate with the degree of HIV viral replication as measured by plasma viral load.65 Effective antiretroviral therapies result in improvements in HIV-related cytopenias, including thrombocytopenia.65–71 Zidovudine monotherapy may increase the platelet count in 60–70% of HIV–thrombocytopenic patients.66–68 Other antiretroviral drugs, when given as monotherapy, have been shown to improve hematological parameters to a lesser degree.72,73 HAART, in both de novo and zidovudine-refractory thrombocytopenic patients, can induce sustained platelet responses in association with viral suppression.65,69,70 Responses to zidovudine and HAART may be limited in HIV-infected injection drug users, possibly reflecting the influence of concurrent liver disease and HCV infection.74,30,71 Several trials have shown a benefit of IFN-α in HIV-infected patients with either elevated serum alanine aminotransferase or HCV-infected patients.3,4,74,15,75
Thrombocytopenia is an important finding in patients infected with either HCV or HIV. Platelet destruction in viral infection-associated ITP occurs via various mechanisms, including accelerated platelet clearance as a result of immune complex disease in HIV-infected patients; cross-reactivity of anti-platelet glycoprotein antibodies and viral antibodies in both HIV and HCV-infected patients; and splenic sequestration of platelets secondary to portal hypertension, decreased production of thrombopoietin, and a dysregulated immune system in HCV-infected patients.
All patients presenting with chronic thrombocytopenia with risk factors (multiple sex partners, IV drug abuse, or blood transfusion recipients)76 or from a population sector with a high prevalence of infection should be screened for the presence of HCV and HIV, as these patients will require different treatment strategies from patients with other forms of autoimmune thrombocytopenia.
The use of antiviral therapy in HCV and antiretroviral therapy in HIV lowers the incidence of thrombocytopenia in populations with these infections. In both HIV- and HCV-positive patients, there is often a response to IVIg, anti-RhD Ig, and splenectomy. Although HIV patients will typically respond, at least transiently, to corticosteroid therapy, HCV patients should avoid corticosteroid therapy for as long as possible, because it can increase the viral load and worsen liver damage. In HCV-positive patients without clinically evident liver disease, treatment with IFN-α combination therapy should be considered. ■