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CME/CE

Anemia, Neutropenia, and Thrombocytopenia: Pathogenesis and Evolving Treatment Options in HIV-Infected Patients

  • Authors: Author: Alexandra M. Levine, MD
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Target Audience and Goal Statement

This activity is intended for front-line primary care physicians and specialists, pharmacists, advanced nurse clinicians and nurse practitioners, as well as generalists in these professions, who have an understanding of HIV/AIDS.

The goal of this activity is to present a comprehensive review of the pathogenesis and treatment of anemia, neutropenia and thrombocytopenia in HIV-infected patients.

Upon completion of this activity, participants should be able to:

  1. Summarize the causes of anemia, neutropenia, and thrombocytopenia in HIV-infected patients.

  2. Describe the impact of HAART in the prevention and treatment of anemia.

  3. Outline the role of G-CSF and GM-CSF in the treatment of neutropenia.

  4. List therapeutic strategies for thrombocytopenia.


Author(s)

  • Alexandra M. Levine, MD

    Professor of Medicine, Chief of the Division of Hematology, University of Southern California (USC) School of Medicine, Los Angeles, California; Medical Director, USC/Norris Cancer Hospital, Los Angeles, California

    Disclosures

    Disclosure: Alexandra M. Levine, MD, has disclosed that she has received grants for clinical research and educational activities, and has served as an advisor or consultant for Ortho Biotech. She has also disclosed that she owns stock in ILEX Oncology.


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CME/CE

Anemia, Neutropenia, and Thrombocytopenia: Pathogenesis and Evolving Treatment Options in HIV-Infected Patients

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Thrombocytopenia

Thrombocytopenia is relatively common during the course of HIV infection, occurring in approximately 40% of patients and serving as the first symptom or sign of infection in approximately 10%.[87,88] Sullivan and colleagues[88] recently evaluated the 1-year incidence of thrombocytopenia (< 50,000/mm3) in a group of 30,214 HIV-infected patients as part of the retrospective 10-city Adult and Adolescent Spectrum of Disease Project, sponsored by the CDC. The incidence of thrombocytopenia during 1 year was 8.7% in patients with clinical AIDS, 3.1% in patients with immunologic AIDS (CD4+ cell count < 200 cells/mm3), and 1.7% in patients with neither condition. Over time, development of thrombocytopenia was associated with clinical or immunologic AIDS, history of injection drug use, history of anemia or lymphoma, and African American race. After controlling for multiple factors (AIDS, CD4+ cell count, anemia, neutropenia, antiviral therapy, receipt of prophylaxis against P carinii), thrombocytopenia was significantly associated with shorter survival (risk ratio, 1.7: 95% confidence interval = 1.6-1.8).

The major cause of thrombocytopenia in HIV disease is idiopathic thrombocytopenic purpura (ITP), in which antibody-coated platelets are removed from the circulation by the macrophages in the spleen. The resulting thrombocytopenia may result in bleeding or bruising, predominantly from the mucous membranes or skin. However, the majority of patients with HIV-related ITP do not actually experience bleeding or have had only minor bleeding manifestations.[87] Furthermore, the likelihood of clinical bleeding is very low until the platelet count drops below 10,000/mm3. Nonetheless, the potential risk of life-threatening bleeding into the central nervous system does exist in the setting of ITP, serving to render this a condition of some concern.

 

Mechanisms of Thrombocytopenia: "de novo" ITP

In usual de novo ITP occurring in people who are not HIV-infected, the disease is caused by the production of antibodies with specificity against certain platelet antigens, such as the IIb/IIIa receptor on the platelet surface. The variable portion of the antibody molecule (Fab) attaches directly to the specific auto-antigen on the platelet surface, while the constant portion of the antibody molecule (Fc) remains free (Figure 4).

 

As the platelet travels through the slow circulation of the sinusoids of the spleen, it comes in contact with the macrophages that line these sinusoids. The macrophage possesses receptors for the Fc portion of the antibody molecule, allowing attachment of the platelet-antibody complex to the macrophage, which then internalizes the platelet via phagocytosis. The platelet is destroyed within the macrophage. The resulting thrombocytopenia is thus a consequence of increased peripheral destruction of platelets. In an attempt to overcome this increased rate of platelet destruction, a compensatory increase in platelet production is expected, as demonstrated by increased numbers of megakaryocytes in the marrow. In most cases, this compensatory increase in platelet production does not fully correct for the increased platelet destruction, and significant thrombocytopenia becomes evident in the peripheral blood.[89]

Although the platelet count is low in ITP, it is rather unusual for patients to develop extensive bleeding manifestations. The reason for this finding relates to the fact that new platelets, just released from the marrow, are large and highly functional. Thus, as the normal platelet circulates within the bloodstream during its normal 7- to 10-day life span, it becomes progressively smaller and less functional. In ITP, once the platelet is coated with antibody, it is removed from the circulation rather quickly. As a result, the platelets that are present in the circulation are new, fresh from the marrow, and highly functional. It is for this reason that the usual patient with ITP does not actually experience substantial bleeding.

 

Mechanisms of Thrombocytopenia in HIV-Related ITP

Increased platelet destruction. As in de novo ITP, HIV-infected patients with ITP also demonstrate increased platelet destruction via phagocytosis by macrophages in the spleen.[89] In HIV-related ITP, however, several mechanisms for platelet-associated antibody have been described, often occurring simultaneously in a given patient. Thus, presence of platelet-specific antibodies, immunochemically characterized as anti-glycoprotein (gp) IIb and/or gp-IIIa, have been detected in HIV-infected patients with ITP, indicating a similar mechanism to that described in de novo disease.[90] However, cross-reactive antibody between HIV-gp 160/120 and platelet gp IIb/IIIa has also been demonstrated.[91] Thus, Bettaieb and colleagues[91] found that serum antibodies against HIV-gp 160/120 could be eluted from platelets of patients with HIV-related ITP, and that these HIV-specific antibodies shared a common epitope with antibodies against platelet gp IIb/IIIa on the platelet surface. It is thus apparent that molecular mimicry between HIV-gp 160/120 and platelet gp IIb/IIIa may be operative in the immune destruction of platelets in some cases of HIV-related ITP. A further mechanism of antibody-induced destruction of platelets arises from the absorption of immune complexes against HIV onto the platelet Fc receptor, thus providing a "free" Fc portion for subsequent macrophage binding and phagocytosis.

Decreased platelet production. Kinetic studies of platelet production and destruction have been performed in patients with HIV-related ITP, and the results were compared with those for normal controls and for patients with de novo ITP.[89] Mean platelet survival was found to be significantly decreased in patients with HIV-ITP, occurring to the same extent in patients receiving zidovudine or in those who were untreated. Of interest, mean platelet survival was also significantly decreased in HIV-infected patients with normal platelet counts. In addition to this increased destruction of platelets, mean platelet production was also found to be significantly decreased in patients with untreated HIV-ITP, although those patients receiving zidovudine demonstrated a major increase in platelet production, occurring even in zidovudine-treated HIV-infected individuals without thrombocytopenia. Thus, it is apparent that patients with HIV-ITP, although experiencing a moderate increase in platelet destruction, are also faced with significant decreases in platelet production, which occur even in those individuals with normal platelet counts.[89]

Infection of the megakaryocyte by HIV. The cause for this reduced production of platelets in the setting of HIV infection may be direct infection of the megakaryocyte by HIV. Thus, Kouri and colleagues[92] first demonstrated that human megakaryocytes bear a CD4 receptor capable of binding HIV-1, while Zucker-Franklin and associates[93] showed that HIV-1 could be internalized by human megakaryocytes. Wang and colleagues[94] have demonstrated the presence of CXCR4, a chemokine receptor known to be important as the coreceptor for HIV on megakaryocytic progenitors, megakaryocytes, and platelets. Furthermore, employing in situ hybridization techniques and a 35S HIV riboprobe (antisense to an HIV env sequence), HIV transcripts have been detected in megakaryocytes of 5 of 10 patients with HIV-ITP, indicating that the megakaryocyte had been infected by HIV in these cases.[95] Expression of viral RNA within the megakaryocytes was also detected in 10 of 10 patients, using in situ hybridization techniques. Specific ultrastructural damage in the HIV-infected megakaryocytes has also been noted, consisting of blebbing and vacuolization of the surface membrane.[96] The documentation of significant increases in platelet production after receipt of zidovudine in patients with HIV-ITP[97] would be consistent with the hypothesis that a major mechanism of this disorder is the direct infection of the megakaryocyte by HIV.

Harker and colleagues[98] described 3 chimpanzees, infected with HIV-1, who developed ITP associated with elevated levels of antibody against platelet glycoprotein IIIa. Use of recombinant pegylated human megakaryocyte growth and development factor (MGDF) was associated with a decline in antiplatelet antibodies in serum, as well as an increase in peripheral blood platelet counts and an increase in the number of megakaryocytes and megakaryocyte progenitors in the marrow. These changes would imply that the mechanism of ITP in HIV-infected chimps must also include a component of insufficient compensatory expansion of platelet production, similar to what has been described in HIV-infected humans.

 

Therapy for HIV-Related ITP

Zidovudine. The Swiss Group for HIV Studies was the first to demonstrate the efficacy of zidovudine therapy in patients with HIV-ITP.[97] Ten seropositive patients with platelet counts ranging from 20,000 to 100,000/mm3 received zidovudine, at a dose of 2 g/day for 2 weeks, followed by 1 g/day for 6 weeks. This was followed by 8 weeks of placebo. All 10 patients experienced an increase in platelet counts while on zidovudine, with a mean increase of 54,600/mm3 (range, 53,200-107,800/mm3). By contrast, no patient experienced an increase in platelet count while on placebo. The time to onset of response was approximately 8 days, with full response achieved by day 30. These results were subsequently confirmed by others.[99,100]

The appropriate dose of zidovudine in HIV-ITP was studied by Landonio and colleagues,[101] who compared a dose of 500 mg/day in 35 patients with 1000 mg/day in another group of 36 patients. The majority of patients in both groups were injection drug users, with similar mean platelet counts (approximately 23,000/mm3), and mean CD4+ cell counts (approximately 400 cells/mm3). A response rate of 57% was achieved in the low-dose group, with 11% experiencing complete response and 43% experiencing treatment failure. By contrast, a response rate of 72% was achieved in those receiving 1000 mg of zidovudine per day, with complete response in 39% and only 28% experiencing treatment failure. At month 6, a significant difference remained between the groups, with a mean platelet count of 56,000/mm3 in the low-dose group, vs 98,200/mm3 in those receiving high-dose zidovudine. It is apparent from this study that high-dose zidovudine is advantageous in patients with HIV-ITP.[93]

Other antiretroviral agents. Relatively little has been published about the efficacy of other reverse transcriptase inhibitors or protease inhibitors in the treatment of HIV-ITP. Several case reports would suggest the efficacy of didanosine in both adults and children with HIV-ITP, even in 1 patient who had been refractory to prior zidovudine.[102] Increases in platelet counts have been described in 22 patients with advanced HIV disease who were treated with the protease inhibitor indinavir.[103] Platelet counts increased from a mean of 84,000/mm3 (range, 45,000-117,000) to 189,000/mm3 (range, 123,000-325,000) in those patients with chronic ITP. Of importance, Caso and colleagues[104] have recently reported use of HAART in 37 patients with HIV-related ITP. A significant increase in platelet count was observed after 3 months of HAART, independent of the baseline platelet count or the concomitant use of zidovudine. These increases were sustained for at least 6 months. The HAART regimen employed was variable, including indinavir in 60%, saquinavir in 27%, and ritonavir in 14%. In 70% of the treated patients, HIV viral load decreased to nondetectable levels. These data would indicate that use of effective antiretroviral therapy is clearly the treatment of choice in patients with HIV-related ITP.

Interferon-alfa. Interferon-alfa (IFN-alfa) was first shown to be efficacious in patients with refractory de novo ITP in 1988. A prospective, randomized, double-blind, placebo-controlled trial of IFN-alfa, at a dose of 3 million units thrice weekly, given subcutaneously, was subsequently reported by Marroni and colleagues[105] in 15 patients with HIV-related ITP. A platelet response was documented in 66%, with a mean increase of 60,000/mm3. The average time to response was 3 weeks. When interferon therapy was discontinued, platelet counts returned to baseline values within 3 months, indicating the necessity to maintain IFN-alfa therapy over time. In an attempt to ascertain the mechanisms by which IFN-alfa exerts its effects, Vianelli and associates[106] subsequently treated 13 patients with HIV-ITP, noting a partial response in 53% of subjects. In responding patients, IFN-alfa was demonstrated to prolong platelet survival, while no significant increase in platelet production was noted.

High-dose intravenous gamma globulin (IVIG). IVIG, at a dose of 1000-2000 mg/kg, has been used effectively in pediatric and adult patients with de novo ITP, resulting in significant rise in platelet counts within 24-72 hours in the majority of individuals.[107] Bussel and Haimi[108] treated 22 patients with HIV-related ITP, employing 1-2 g/kg during a 2- to 5-day period, depending on the platelet response. The average platelet count before therapy was 22,000/mm3, rising to a mean of 182,000/mm3 (range, 10,000-404,000/mm3), within 2-5 days. Only 2 patients did not respond, while 77% experienced an increase to > 100,000/mm3, and 86% had an increase to > 50,000/mm3. However, when IVIG was discontinued, only 25% of patients maintained the increased platelet count, while the remainder required repeat infusions approximately every 21 days. The major problem with IVIG appears to be cost, which is substantial. In addition, the world supply of IVIG has recently been insufficient to meet the increasing demands imposed by the broader clinical indications for its use. For these reasons, IVIG is often reserved for use in patients who are acutely bleeding and require immediate rise in platelet count and in individuals scheduled for an invasive procedure.

Anti-Rh immunoglobulin. The use of anti-Rh immunoglobulin in nonsplenectomized Rh-positive patients with HIV-related ITP represents another potential mode of therapy.[109] After administration of anti-Rh immunoglobulin to such patients, the Rh-positive RBC becomes coated with antibody, with resultant binding to the Fc receptor of the macrophage in the spleen, and subsequent phagocytosis. The binding of these antibody-coated RBCs competes for potential binding sites for the antibody-coated platelets, resulting in the potential for subsequent increase in platelet count. By definition, however, such treatment would result in some degree of RBC hemolysis, with a subsequent decrease in the hemoglobin level. Thus, "requirements" for effective therapy with anti-Rh (D) would include a baseline hemoglobin level adequate to permit a 1- to 2-g decrease due to hemolysis, presence of Rh-positivity in the patient, and presence of a spleen, the site at which RBCs would be preferentially bound to macrophages and phagocytized. Oksenhendler and colleagues[110]treated 14 patients with HIV-ITP, employing 25 mcg/kg IV during 30 minutes on 2 consecutive days. Nine (83%) of 11 patients who were Rh+ responded with a platelet count > 50,000/mm3, with response first noted at a median of 4 days (range, 3-12 days) and a median response duration of 13 days (range, 0-37 days). Maintenance therapy was administered at a dose of 13-25 mcg/kg IV, every 2 to 4 weeks, resulting in long-term response (> 6 months) in 70% of patients. Subclinical hemolysis occurred in all, with a drop of hemoglobin of 0.4 to 2.2 g. Gringeri and associates[109] subsequently confirmed these results, and also studied the use of intramuscular (IM) anti-D immunoglobulin for maintenance treatment after successful induction therapy by the IV route. Patients were asked to self-administer the maintenance anti-Rh, given IM at a dose of 6-13 mcg/kg/week. After induction, 83% of patients had achieved a platelet count > 50,000/mm3. This response was maintained in 85% over time. More recently, a dose of 75 mcg/kg/day was associated with more rapid and durable responses than 50 mcg/kg/day, when administered in a randomized trial in 27 HIV-negative patients.[111] While this regimen has yet to be tested in patients with HIV-ITP, it is apparent that anti-Rh immunoglobulin may be used safely and effectively in patients with HIV-related ITP, providing an alternative that is approximately one tenth the cost of high-dose IVIG.

Danazol. Danazol has been used with some success in patients with de novo ITP, at a dose of 400-800 mg each day.[112-114] The majority of patients experience a response, with platelet counts rising to > 50,000/mm3 in approximately 1-2 months. Although lower doses (50 mg/day) may also be effective in some patients, the average time to response is prolonged, at 3.5 months. Danazol is thought to work via modulation of Fc receptors on the macrophage surface, resulting in fewer available binding sites for antibody-coated platelets. While no large series of patients with HIV-ITP have been studied, anecdotal reports of efficacy have been described. In general, however, danazol use is restricted to patients who have failed other standard therapies.

Splenectomy. Splenectomy has been used effectively for years in patients with de novo ITP who are refractory to corticosteroids and is associated with long-term response in approximately 60% of patients. At the onset of the AIDS epidemic, several anecdotal case reports noted a rapid progression to clinical AIDS postsplenectomy, and the procedure was largely abandoned in HIV-infected patients. More recently, Oksenhendler and associates[115] reported long-term experience with splenectomy, performed in 37% of a cohort of 185 patients with HIV-ITP. Splenectomy was eventually performed in 68 such patients, at an average of 13 months from initial diagnosis of HIV-ITP. The mean platelet count presplenectomy was 18,000/mm3, rising to 223,000/mm3 postoperatively. A response was seen in 92% of patients, with complete response (platelet count > 100,000/mm3) in 85%. Maintenance of the elevated platelet count for longer than 6 months was documented in 82%. In comparing the survival or rate of progression to AIDS in the 68 splenectomized patients vs the 117 who did not undergo the procedure, no difference was found, indicating that splenectomy was not associated with more rapid progression of HIV disease. Similar conclusions were made by Kemeny and colleagues[116] in a group of 22 patients with HIV-ITP. Again, the procedure was effective in all and was not associated with more rapid progression to AIDS. Of importance, however, 5.8% of patients undergoing splenectomy in the series by Oksenhendler and colleagues[115] did experience fulminant infection, consisting of Streptococcus pneumoniae meningitis in 2, and Haemophilus influenzae sepsis in 1. It is thus apparent that patients should undergo prophylactic vaccination before splenectomy, and that such surgery may ultimately be safer in those HIV-infected patients who can still achieve an appropriate antibody response to vaccination against S pneumoniae or H influenzae.

Corticosteroids. Corticosteroids remain the initial therapy of choice in non-HIV-infected patients with de novo ITP and at a dose of 1 mg/kg/day are associated with an 80% to 90% response rate. Similar results have been documented in patients with HIV-related disease. However, the immunosuppressive effects of high-dose corticosteroids have made such therapy far from optimal in HIV-infected patients. Furthermore, the potential development of fulminant Kaposi's sarcoma in HIV-infected homosexual/bisexual men co-infected with human herpes type 8 after use of corticosteroids has further dampened enthusiasm for this therapeutic modality.

 

Summary: Treatment Options and Algorithm

Many options currently exist to treat patients with HIV-related ITP (Table 4).

 

Table 4. Treatment Options in HIV-ITP

1. Zidovudine (1000 mg/day)

 

  • Response rate, 70%
  • Best responses with platelets > 20,000/mm3 at baseline
2. Other effective antiretroviral agents and combinations

3. Interferon-alfa

4. Splenectomy

5. IVIG or anti-Rh (D), especially useful when rapid response is required for acute bleeding or procedures

6. Danazol

7. Corticosteroids

8. Can potentially leave untreated if platelets > 20,000/mm3

 

IVIG is extremely useful for obtaining a rapid increase in platelet count, as would be required in a patient who is experiencing bleeding manifestations, or in whom an invasive procedure is planned. While effective, its cost is often prohibitive, especially for long-term use, since maintenance therapy must be administered every 2-4 weeks. Alternatively, anti-Rh immunoglobulin may also be used, at one tenth the cost. However, since subclinical hemolysis is expected with a drop of hemoglobin by 1-2 g/dL, patients with hemoglobin levels < 10 g/dL should not receive this therapy, which is also contraindicated in patients who are Rh-negative and in those who have already undergone splenectomy. Zidovudine remains the drug of choice for initial long-term management of HIV-ITP, although other antiretroviral agents may also be effective. In patients who have failed these interventions, subcutaneous interferon-alfa may be used. Finally, in those patients who have failed all prior therapy, splenectomy may be efficacious, associated with a long-term benefit in approximately 80% -- although postsplenectomy sepsis may occur. Finally, since patients with platelet counts > 20,000/mm3 rarely experience clinical bleeding, such patients may actually remain untreated, although the risk for intracerebral bleeding continues to exist and should be monitored.