Original Article
Kinetic Studies of the Mechanism of Thrombocytopenia in Patients with Human Immunodeficiency Virus Infection
N Engl J Med 1992; 327:1779-1784December 17, 1992
- Abstract
- Abstract
Background.
Isolated thrombocytopenia accompanied by increased amounts of platelet-associated antibody is a common manifestation of human immunodeficiency virus (HIV) infection, and the thrombocytopenia often improves with zidovudine. It is not clear whether the mechanism of HIV-related thrombocytopenia primarily involves autoimmune destruction of platelets or reduced platelet production by megakaryocytes.
Methods.
We studied the survival of 111In-labeled autologous platelets and performed platelet imaging in 24 men with isolated HIV-related thrombocytopenia (16 who received no treatment and 8 who received zidovudine). We also studied 20 HIV-infected men with normal platelet counts (10 who received no treatment and 10 who received zidovudine) and studied 12 healthy seronegative men as controls.
Results.
Mean (±SD) platelet survival was significantly decreased in both the untreated and the zidovudine-treated patients with HIV-related thrombocytopenia (to 92±33 and 129±44 hours, respectively; both P<0.001), as compared with the normal controls (198±15 hours). Mean platelet survival was also significantly decreased in the HIV-infected patients with normal platelet counts (untreated, 162±23 hours, P<0.01; zidovudine-treated, 166±35 hours, P<0.05). Imaging studies, however, revealed no evidence of increased clearance of autologous platelets in the liver or spleen in any of these groups. Mean platelet production was significantly depressed in the untreated patients with thrombocytopenia (23,000±11,000 platelets per cubic millimeter per day, P<0.001) as compared with the healthy controls (45,000±6,000 per cubic millimeter per day). Mean platelet production was significantly increased, however, in the men treated with zidovudine, both in those with thrombocytopenia (60,000±31,000 platelets per cubic millimeter per day, P<0.01 vs. controls) and in those without thrombocytopenia (68,000±22,000 per cubic millimeter per day, P<0.01).
Conclusions.
Although there was a moderate reduction in platelet survival in HIV-infected persons, these patients, regardless of platelet counts, also had decreased production of platelets, possibly due to viral infection of the megakaryocytes. Zidovudine appears to improve platelet production. (N Engl J Med 1992;327:1779–84.)
Media in This Article
Figure 1
Platelet Counts in Patients with HIV Infection.Article Activity
- Article
ISOLATED thrombocytopenia associated with human immunodeficiency virus (HIV) infection has been well described.1 2 3 Numerous studies have identified increased amounts of platelet-associated IgG, IgM, C3,4 5 6 and immune complexes4 , 7 on autologous platelets in patients with this infection. The finding of isolated thrombocytopenia associated with increased platelet-associated antibody and normal numbers of megakaryocytes in the bone marrow has led to the premise that HIV-associated thrombocytopenia is a form of autoimmune thrombocytopenia. A number of factors, however, suggest that there are basic pathophysiologic differences between this disorder and classic idiopathic thrombocytopenic purpura. Increased platelet-associated immunoglobulin is a nonspecific finding in HIV-positive patients who have thrombocytopenia, as well as in those who do not.4 , 5 , 7 Furthermore, in HIV-positive patients there is no specificity for platelet-specific antigens, in contrast to the findings in patients with idiopathic thrombocytopenic purpura.5 , 8 9 10 11 12 Morphologic abnormalities of megakaryocytes have been described in HIV-related thrombocytopenia,13 unlike idiopathic thrombocytopenic purpura,14 and there are decreased numbers of megakaryocyte progenitors.15 , 16 Finally, zidovudine, a drug normally toxic to the bone marrow, improves the platelet count in many patients with HIV-associated thrombocytopenia.17 18 19 20
Preliminary kinetic studies of platelets in patients with HIV-related thrombocytopenia revealed both diminished platelet production and shortened platelet survival.21 Zidovudine appeared to increase the platelet count by stimulating platelet production. These results suggested that HIV may affect thrombopoiesis directly. We examined this possibility further by using techniques of kinetic analysis and imaging to study platelets in both HIV-positive patients with thrombocytopenia and those without it.
Methods
Study Participants
HIV-positive patients were referred to the study from the AIDS [acquired immunodeficiency syndrome] Care Group at St. Paul's Hospital in Vancouver. All were homosexual men with no history of intravenous drug abuse. The study was approved by the ethics committees of the University of British Columbia and St. Paul's Hospital, and all the patients gave informed consent.
The patients with HIV-associated thrombocytopenia met the following criteria for inclusion: isolated thrombocytopenia; increased levels of autologous platelet-associated IgG, as determined in an enzyme-linked platelet-antibody assay21; normal numbers of megakaryocytes on bone marrow aspiration or biopsy, without infiltrates; clinical stability, with no evidence of concomitant opportunistic infection; no use of medications other than as outlined in this study; and no evidence of microangiopathy or active hemorrhage.
Two groups of patients with HIV-associated thrombocytopenia were studied. The 16 patients in the no-treatment group were not receiving medication for their thrombocytopenia. Eleven of these patients were in Group II, and five were in Group III, of the Centers for Disease Control and Prevention (CDCP) classification system for HIV infection.22 The mean (±SD) CD4+ lymphocyte count for these patients was 319±217 per cubic millimeter (range, 70 to 600).
The eight patients in the zidovudine group were studied while receiving zidovudine (200 mg orally every four hours); all these patients met the criteria for HIV-associated thrombocytopenia before the institution of zidovudine therapy. Two patients were in CDCP Group II, and four were in Group III. One patient had AIDS-related complex, and one was given a diagnosis of AIDS23 13 months before the study. The mean CD4+ lymphocyte count for these patients was 230±210 per cubic millimeter (range, 30 to 450). The mean platelet count for this group before the start of therapy with zidovudine was 53,000 per cubic millimeter; during zidovudine therapy, it was 127,000 per cubic millimeter (P<0.01).
The HIV-positive patients without thrombocytopenia had no history or current evidence of thrombocytopenia. Among these patients, two groups were studied. The 10 patients in the no-treatment group were clinically well, with no evidence of active opportunistic infection, and they were taking no medications. Seven of them were in CDCP Group II, and three were in Group III. The 10 patients in the zidovudine group were clinically well, with no evidence of opportunistic infection. These patients were receiving 200 mg of zidovudine orally every four hours. They were receiving no other medication at the time of the study. Two of these patients were in CDCP Group II, three were in Group III, three had AIDS-related complex, and two had been given diagnoses of AIDS 6 and 11 months before the study.
The 12 patients with idiopathic thrombocytopenic purpura were given diagnoses of classic chronic idiopathic thrombocytopenic purpura and had undergone studies of platelet kinetics and sequestration in the past five years. All these patients were studied before they received any treatment. They were matched with respect to platelet count with 12 patients in the group with untreated HIV-associated thrombocytopenia (r = 0.99). None of the patients with idiopathic thrombocytopenic purpura were at risk for HIV infection, and all were seronegative for antibodies to HIV.
The 12 normal control subjects were healthy men with normal platelet counts and no history or serologic evidence of HIV infection or exposure.
Platelet Counts
Platelet counts were performed with an electronic particle counter (Coulter S Plus 4) in fresh samples of whole blood collected in EDTA (10 percent). Platelet counts below 30,000 per cubic millimeter (30×109 per liter) were confirmed by phase-contrast microscopy.
Kinetic Studies
Autologous platelets were labeled with [111In]oxine by a standard technique.24 Blood samples were collected at 10, 60, 180, 240, and 300 minutes, and further samples were collected once a day until approximately 40 percent of the initial radioactivity remained. Mean platelet survival was calculated from the curve for the disappearance of activity from the blood with use of curve-fit software supplied by Professor M.G. Lotter (University of the Orange Free State, South Africa). The multiple-hit model was chosen to analyze the curves.25 Platelet recovery was calculated from the total blood radioactivity extrapolated to time zero as a fraction of the injected radioactivity. The rate of platelet production was calculated by the method of Harker and Finch,26 in which, at a constant platelet count, platelet turnover equals platelet production. The following equation was used:
where PS denotes platelet survival and IPR initial platelet recovery.Predicted Platelet Survival
Predicted platelet survival, a function of the patient's platelet count, was calculated for each patient according to the equation of Hanson and Slichter,27 as follows: Mean platelet survival (days) = 2.15 + (8.74×10–5 × P), where P represents the number of platelets per microliter of blood.
Studies of Reticuloendothelial Clearance
Twenty-four hours after the injection of platelets labeled with [111In]oxine, serial anterior and posterior whole-body imaging was performed in both patients and normal controls. A large field-of-view camera was used, capable of collecting both the 174- and the 247-kiloelectron-volt photo peaks of indium-111. Images of the total body, as well as the liver and spleen, were obtained under identical conditions with a scanning speed of 12 cm per minute into a 64×64 computer matrix. Radioactivity in specific organs was expressed as a percentage of total body activity by the geometric-mean method.
Statistical Analysis
Statistical comparisons were made with the unpaired t-test of two means and the two-sample Wilcoxon rank-sum test. Paired t-statistics were used to analyze the studies of patients with thrombocytopenia before and during zidovudine treatment. All data in the Results section are given as means ±SD.
Results
Groups of Patients
As Figure 1Figure 1
Platelet Counts in Patients with HIV Infection. shows, platelet counts averaged 41,000±22,000 per cubic millimeter and 127,000± 49,000 per cubic millimeter in the untreated and the zidovudine-treated groups of patients with thrombocytopenia, respectively. Mean platelet counts for the groups of patients without thrombocytopenia did not differ significantly from those of controls without HIV infection. CD4+ lymphocyte counts did not differ significantly between the untreated and the zidovudine-treated patients with thrombocytopenia.Platelet Survival
Table 1Table 1
Platelet Kinetics in HIV-Positive Patients and Control Subjects.* summarizes the kinetic data in HIV-infected patients. In the patients with thrombocytopenia, the mean platelet survival in both the untreated and the zidovudine groups was significantly shorter than that in the normal controls (P<0.001), with a less marked difference between the two treatment groups (P<0.05). Since it has been recognized that in hypoplastic thrombocytopenia the survival of autologous platelets is diminished in direct relation to the platelet count,27 predicted platelet survival was calculated for all the patients studied. In both the untreated and the zidovudine-treated patients with thrombocytopenia, the measured platelet survival was shortened to 70 percent (P<0.001) and 60 percent (P<0.001), respectively, of the predicted values. The difference between the two groups was not significant.In the patients who did not have thrombocytopenia, there was also a significant shortening of mean platelet survival in both groups as compared with controls without HIV infection. The platelet survival was shortened to approximately 80 percent of the values predicted for the corresponding platelet count.
Platelet Recovery
Mean values for platelet recovery were significantly decreased from the values for normal controls in the groups of patients with thrombocytopenia (untreated, 45±14 percent, P<0.001; zidovudine, 38±8 percent, P<0.001; controls, 60±8 percent). There was no significant difference in platelet recovery between the patients without thrombocytopenia and the normal controls (untreated, 57±11 percent; zidovudine, 55±15 percent).
Platelet Production
As seen in Table 1, the mean rate of platelet production (as measured by platelet turnover) in the untreated patients with thrombocytopenia was significantly below normal (P<0.001). In contrast, the zidovudine-treated patients had significantly increased platelet production over that in both the normal controls (P<0.01) and the untreated patients (P<0.001).
Table 2Table 2
Paired Studies of Platelet Kinetics before and during Zidovudine Treatment in Patients with Thrombocytopenia. shows data from four patients with thrombocytopenia studied both before and during the administration of zidovudine. There was an increase in the platelet count that was clearly mediated by an increase in platelet production, with no significant change in platelet survival. The beneficial effect of zidovudine on platelet production was also seen in the patients without thrombocytopenia who were receiving zidovudine (Table 1). Figure 2Figure 2
Platelet-Survival Curves for the Four Patients Studied before Treatment (Upper Panel) and Again after Treatment with Zidovudine (Lower Panel). shows platelet-survival curves for the four patients studied first without treatment and subsequently with zidovudine treatment. The data on platelet survival reveal biphasic exponential survival curves that do not change significantly during treatment with zidovudine.Studies of Reticuloendothelial Clearance
Despite shortened platelet survival, localization studies of 111In-labeled platelets (Table 3Table 3
Reticuloendothelial Clearance of Radio-labeled Platelets.) showed no significant increase in localization in the spleen or in the liver and spleen combined in any group of patients as compared with the normal controls.Comparison of Kinetics in Idiopathic Thrombocytopenic Purpura
As Table 4Table 4
Kinetic Patterns in Matched Patients with Idiopathic Thrombocytopenic Purpura (ITP) and HIV-Associated Thrombocytopenia.* shows, there were significant differences in kinetic patterns between the patients with HIV-associated thrombocytopenia and those with classic idiopathic thrombocytopenic purpura. Although there was no significant difference in the mean rate of platelet turnover (production) between the two groups, 5 of the 12 patients with idiopathic thrombocytopenic purpura (42 percent) had normal-to-increased turnover rates, whereas only 1 of 12 HIV-infected patients (8 percent) had normal platelet turnover, and no HIV-infected patients had evidence of increased platelet production. The patients with idiopathic thrombocytopenic purpura had significantly shorter mean platelet survival (P = 0.001) and significantly increased uptake (P<0.001) of labeled platelets by the spleen and liver as compared with the HIV-infected group.Discussion
In this study, kinetic studies of autologous platelets were performed in HIV-infected men with and without thrombocytopenia. It appears that infection with HIV is associated with a slight shortening in the survival of autologous platelets. There is, however, no associated increase in the uptake of platelets in the liver or spleen. Furthermore, untreated patients with thrombocytopenia were found to have significantly depressed platelet production. This latter condition probably accounts for the decrease in the platelet count as the bone marrow fails to compensate for the accelerated rate of platelet destruction. As others have reported,17 18 19 20 , 28 zidovudine had a beneficial effect on the platelet count. Our data indicate that this is accomplished through increased platelet production. This phenomenon is not restricted to patients with low platelet counts, because we also observed it in the patients receiving zidovudine who did not have thrombocytopenia.
The results of kinetic studies in HIV-associated thrombocytopenia bear some similarities to the findings in classic idiopathic thrombocytopenic purpura. However, there are clear differences. In contrast to the findings in patients with idiopathic thrombocytopenic purpura, impaired thrombopoiesis was found almost universally in patients with HIV-associated thrombocytopenia. The mechanism of decreased platelet production may well differ between the two disorders. There is increasing evidence to suggest that HIV may affect bone marrow progenitor cells directly. Dysplastic hematopoiesis with HIV infection, unrelated to the administration of zidovudine, has been well described.29 30 31 In vitro culture studies of progenitors of red and white cells16 , 32 , 33 and of megakaryocytes15 , 16 show quantitative and qualitative abnormalities in patients with HIV infection. This is not the case in idiopathic thrombocytopenic purpura, in which a normal or expanded compartment of megakaryocyte progenitors is seen and other progenitor lines are normal.14 Morphologic abnormalities of megakaryocytes, not found in idiopathic thrombocytopenic purpura, have also been described in patients with HIV infection.13 Finally, the recent findings of the CD4 receptor on the mature megakaryocyte34 and of HIV RNA in the cytoplasm of megakaryocytes of infected persons35 , 36 strongly suggest that these cells can be infected directly with the virus. Increased platelet production with the administration of zidovudine may be due to a direct antiviral effect or, as recently suggested, to a more nonspecific effect on thrombopoiesis.37
In this study, platelet survival was significantly shorter in the patients with idiopathic thrombocytopenic purpura than in HIV-infected persons with an equal degree of thrombocytopenia. Furthermore, our data confirm the previous findings of increased splenic sequestration in idiopathic thrombocytopenic purpura,14 , 38 a phenomenon not seen in the HIV-positive patients. Heyns et al. have observed reduced recovery in a subgroup of patients with classic idiopathic thrombocytopenic purpura showing a diffuse reticuloendothelial pattern of sequestration39 that fits with our findings in HIV-associated thrombocytopenia. However, membrane alterations related to the expression of viral protein on the platelet surface may also account for the different platelet kinetics and pattern of sequestration in HIV-infected patients. Karpatkin et al.40 and Louache et al.36 have demonstrated the presence of anti-HIV antibody in eluates from platelets of patients with HIV-associated thrombocytopenia, and two groups have documented the expression of viral proteins on the surface of HIV-infected megakaryocytes.36 , 41 Thus, Fc receptor—mediated clearance of platelets related to the presence of membrane-bound antiviral antibodies or viral immune complexes may be a mechanism of platelet destruction in HIV infection. Other viral-associated mechanisms of premature destruction may also be important. Thrombocytopenia is a common consequence of viral infection, and a number of viral infections have been shown to shorten platelet survival, impair platelet production, or do both.42 43 44 45
The improvement of HIV-associated thrombocytopenia with intravenous immune globulin and anti-D antibody would fit the model of Fc-mediated clearance of platelets. These agents, however, may have other beneficial effects that cause a response in the platelet count. For example, it has been shown that the release of thrombopoietic cytokines, such as interleukin-6, may result from the activation of macrophages in the reticuloendothelial system after binding of the Fc receptor with sensitized red cells or intravenous immune globulin.46 47 48 Similarly, both prednisone49 and the postsplenectomy state50 , 51 have been shown to be associated with enhanced thrombopoiesis, through mechanisms that are still unclear. Thus, the pathophysiologic features of the response of patients with HIV-associated thrombocytopenia to these standard interventions require further study.
In conclusion, although classic idiopathic thrombocytopenic purpura and HIV-associated thrombocytopenia share certain features, there are substantial differences between the two disorders. There is good evidence that infection of megakaryocytes may be an important factor in HIV-associated thrombocytopenia, causing decreased platelet production. The slight shortening of platelet survival in HIV infection may be due to direct damage to the platelet, either as a consequence of viral infection or as a result of Fc-mediated clearance of platelets sensitized by the binding of antibodies to viral antigens expressed on the platelet membrane. The success of zidovudine in the treatment of the thrombocytopenia clearly results from its ability to stimulate improved thrombopoiesis. The exact mechanism by which thrombopoiesis and platelet survival are affected by HIV infection requires further study.
Supported by a project grant from the National Health Research and Development Program, Health and Welfare Canada.
We are indebted to Teresa Vozza and Vangie Wiebe for their patience and assistance in the preparation of the manuscript; to Dr. Jim Hogg of the Pulmonary Research Laboratory at St. Paul's Hospital for his constructive and helpful comments; and to the Persons with AIDS Coalition of Vancouver for their interest and assistance.
Source Information
From the Departments of Medicine (P.J.B., A.B., H.C.), Nuclear Medicine (A.B., D.L., B.S.), and Pathology (D.V.D.), St. Paul's Hospital and the University of British Columbia; and the Canadian Red Cross Society Blood Transfusion Service (P.J.B., D.V.D., P.D., K.M.), all in Vancouver, British Columbia, Canada. Address reprint requests to Dr. Ballem at Grace Hospital, 4450 Oak St., Vancouver, BC V6H 3V4, Canada.
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