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Frequency and Significance of HIV Infection among Patients Diagnosed with Thrombotic Thrombocytopenic Purpura

  1. Melody Benjamin1,
  2. Deirdra R. Terrell1,2,
  3. Sara K. Vesely2,
  4. Gene W. Voskuhl3,
  5. Bruce J. Dezube4,
  6. Johanna A. Kremer Hovinga5,
  7. Bernhard Lämmle5, and
  8. James N. George1,2
  1. 1Department of Medicine, College of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City
  2. 2Department of Biostatistics and Epidemiology, College of Public Health, The University of Oklahoma Health Sciences Center, Oklahoma City
  3. 3Mercy Memorial Health Center, Ardmore, Oklahoma
  4. 4Department of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, Massachusetts
  5. 5Department of Hematology and Central Hematology Laboratory, Inselspital, Berne University Hospital and University of Berne, Berne Switzerland
  1. Reprints or correspondence: Dr. James N. George, The University of Oklahoma Health Sciences Center, College of Health Bldg., Rm. 358, PO Box 26901, Oklahoma City, OK 73126–0901 (james-george{at}ouhsc.edu).
 
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Abstract

Background. Case series of patients with a diagnosis of thrombotic thrombocytopenic purpura (TTP) have reported different frequencies of human immunodeficiency virus (HIV) infection; some series suggest that HIV infection may cause TTP.

Methods. We systematically reviewed all reports of HIV infection in case series of patients with TTP. We analyzed data from the Oklahoma TTP-HUS (hemolytic uremic syndrome) Registry, an inception cohort of 362 consecutive patients, for 1989–2007.

Results. Nineteen case series reported the occurrence of HIV infection at the time of diagnosis of TTP in 0%–83% of patients; individual patient data were rarely described. The Oklahoma TTP-HUS Registry determined the HIV status at the time of diagnosis of TTP in 351 (97%) of 362 patients. HIV infection was documented in 6 (1.84%; 95% CI, 0.68%–4.01%) of 326 adult patients (age, 26–51 years); follow-up data were complete for all 6 patients. The period prevalence of HIV infection among all adults in the Oklahoma TTP-HUS Registry region for 1989–2007 was 0.30%. One patient had typical features of TTP with 5 relapses. Five patients had single episodes; in 4, the clinical features that had initially suggested the diagnosis of TTP were subsequently attributed to malignant hypertension (in 3 patients) and disseminated Kaposi sarcoma (in 1 patient).

Conclusions. HIV infection, similar to other inflammatory conditions, may trigger acute episodes of TTP in susceptible patients. More commonly, acquired immunodeficiency syndrome–related disorders may mimic the clinical features of TTP. If the diagnosis of TTP is suggested in a patient with HIV infection, there should be careful evaluation for alternative diagnoses and cautious consideration of plasma exchange, the required treatment for TTP.

Soon after the first reports of AIDS, there were reports of thrombotic thrombocytopenic purpura (TTP) in patients with HIV infection, suggesting that TTP was a “new manifestation of infection with HIV” [1, p. 195]. Recent case series of TTP that reported a high frequency of patients who also had HIV infection have suggested that HIV-associated TTP is a specific entity [2–5], that HIV infection can cause TTP [6–8], and that TTP may be an AIDS-defining disorder [9]. However, a different interpretation, based on analysis of 350 consecutive hospitalized patients with HIV infection, was that the characteristic clinical features of TTP, microangiopathic hemolytic anemia, thrombocytopenia, and abnormal renal function, were manifestations of advanced HIV infection [10]. These different perspectives reflect the fact that the diagnosis of TTP is often uncertain, especially in patients with other complex medical problems, because of the absence of specific diagnostic criteria for TTP [11].

In patients with TTP, the only consistent abnormalities are microangiopathic hemolytic anemia, which is defined by schistocytes (fragmented RBCs on the peripheral blood smear) and a negative direct antiglobulin test result, and thrombocytopenia—features that can occur in other conditions. Severely deficient activity of ADAMTS13, a plasma von Willebrand–cleaving protease, caused by autoantibody inhibition is characteristic of TTP and was initially thought to be diagnostic of TTP [12]. However, measurements of ADAMTS13 activity are not sufficiently sensitive or specific to consistently distinguish TTP from other severe systemic disorders [11].

To investigate the association of HIV infection and TTP, we had 4 objectives. First, to provide a comprehensive background, we systematically reviewed case series of patients with TTP to document the reported frequency of HIV infection. Second, to describe our experience of HIV infection among patients who have received a diagnosis of TTP, we analyzed data from the Oklahoma TTP-HUS (hemolytic uremic syndrome) Registry, an inception cohort of all 362 consecutive patients with an initial episode of clinically diagnosed TTP within a defined geographic region in 1989–2007 [13, 14]. Third, to interpret our experience, we compared the frequency of HIV infection among registry patients with the prevalence of HIV infection among all adults in the registry region. Fourth, to determine possible reasons for an association of HIV infection and TTP, we analyzed the clinical course and continuous follow-up of each patient in the registry who had HIV infection at the time of his or her diagnosis of TTP.

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Methods

Systematic literature review. OVID software was used to search the Medline database on 30 May 2008. Articles containing both a keyword or medical subject heading in the title or available text for TTP (“thrombotic thrombocytopenic purpura,” “TTP,” “hemolytic-uremic syndrome,” “HUS,” “thrombotic thrombocytopenic purpura–hemolytic uremic syndrome,” “TTP-HUS,” “thrombotic microangiopathy,” “TMA,” “microangiopathy,” “intravascular hemolysis,” and “plasma exchange”) and also for HIV (“human immunodeficiency virus,” “HIV,” “acquired immunodeficiency syndrome,” and “AIDS”) were identified. Case series involving ⩾10 patients with TTP that reported data on the presence or absence of HIV infection were selected for review. The bibliographies of the selected articles were searched to identify additional articles.

To search for additional articles that may have reported HIV infection, we identified all case series involving ⩾25 patients with TTP published since 1981 by reviewing the titles and relevant abstracts of English-language articles that were retrieved by the search terms “thrombotic thrombocytopenic purpura” and “TTP.”

Oklahoma TTP-HUS Registry patients. The Oklahoma TTP-HUS Registry includes data on all consecutive patients for whom the Oklahoma Blood Institute was requested to provide plasma exchange treatment for patients with a diagnosis of TTP or HUS since 1 January 1989 [13, 14]. The Oklahoma Blood Institute is the sole provider of plasma exchange services for all hospitals in 58 of the 77 Oklahoma counties. Because the standard practice in this region is to treat all adult patients who have received a diagnosis of either TTP or HUS with plasma exchange, the registry is an inception cohort of consecutive patients for whom a diagnosis of TTP or HUS was made and for whom plasma exchange treatment was requested. Because these syndromes in adults are commonly known as TTP [11], we describe patients in this report as having TTP. Serum samples were obtained for HIV testing and ADAMTS13 assays immediately before the first plasma exchange; ADAMTS13 activity and its inhibition were measured by previously described methods [12, 15]. Deficiency of ADAMTS13 was defined as activity of <10% [14]. The Oklahoma TTP-HUS Registry is approved by the institutional review boards of the University of Oklahoma Health Sciences Center and each participating hospital.

Prevalence of HIV infection in the Oklahoma TTP-HUS Registry region. Data regarding the cumulative frequency of people with HIV infection who are currently or were living in each county of Oklahoma during 1989–2007 were available from the Oklahoma State Department of Health. We limited our analysis to adults (age, ⩾20 years), because the patients in the Oklahoma TTP-HUS Registry with HIV infection were all adults and because the prevalence of HIV infection was much lower among children. To calculate period prevalence for 1989–2007, we used 2000 US Census data for population estimates for each of the 58 counties of the registry region.

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Results

Systematic literature review. The keyword search retrieved 78 articles; 7 retrospective case series involving ⩾10 patients with a diagnosis of TTP were identified that specifically described the presence of HIV infection [1–4, 8, 16, 17]. The search terms “thrombotic thrombocytopenic purpura” and “TTP” retrieved 3317 articles; 65 additional retrospective case series published after 1981 that described ⩾25 patients were identified: 43 (66%) did not mention HIV infection, 10 (15%) specifically excluded patients with HIV infection, and 12 (19%) [5–7, 18–26] described the presence (9 articles) or absence (3 articles) of patients with HIV infection at the time of diagnosis of TTP. These 19 case series are presented in table 1. In 4 articles, all patients were tested for HIV, and the reported frequencies of HIV infection were 0% [22], 22% [17], 48% [4], and 83% [8]. In the other 15 articles, the number of patients tested for HIV infection was not reported. Most articles described HIV infection as an associated condition or cause of TTP. Only 2 studies presented individual patient data [2, 17, 27]. In 1 article [17], 3 of 4 patients with HIV infection had potential causes other than TTP for their clinical features: malignant hypertension [28], sepsis [14], and cocaine intoxication [29]. Eight (44%) of 18 patients in the other study had cytomegalovirus infection [2, 27].

Table 1
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Table 1

Case series of patients with thrombotic thrombocytopenic purpura (TTP) that report the occurrence of HIV infection.

Oklahoma TTP-HUS Registry patients. The Oklahoma TTP-HUS Registry enrolled 362 patients with an initial episode of clinically diagnosed TTP during 1989–2007. Tests for HIV infection were performed for 351 patients (97%); HIV infection was documented in 6 patients (age, 26–51 years) at the time of their initial diagnoses of TTP. All 6 patients have been continuously followed up to the present time or until death. Because all patients with HIV infection were adults, all subsequent analyses were limited to adult patients. The period prevalence of HIV infection during 1989–2007 among the 326 adult patients (age, ⩾20 years) who were tested for HIV was 1.84% (95% CI, 0.68%–4.01%) [30]. The period prevalence of HIV infection during 1989–2007 among all adults aged ⩾20 years in the 58 counties of the registry region was 0.30%.

Table 2 describes the 326 adult patients in the Oklahoma TTP-HUS Registry according to clinical categories based on their associated conditions and additional or alternative diagnoses [13]. One hundred thirty patients are described as idiopathic because they had none of the conditions that define the other categories. Two of the patients in the idiopathic category were HIV positive. In 6 patients, the clinical features that had initially suggested the diagnosis of TTP were subsequently attributed to malignant hypertension; 3 were HIV positive. Disseminated malignancy was diagnosed in 12 patients after plasma exchange treatment for TTP was begun; 1 was HIV positive.

Table 2
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Table 2

Clinical categories of 326 adult patients with a clinical diagnosis of thrombotic thrombocytopenic purpura in the Oklahoma TTP-HUS (hemolytic uremic syndrome) Registry, 1989- 2007.

Among the 236 adult patients who were enrolled in the registry since 13 November 1995, when routine testing for ADAMTS13 activity was begun, and who were also tested for HIV infection, ADAMTS13 activity was measured in 226 (96%). Among the 220 HIV-negative patients, ADAMTS13 deficiency was present in 38 (46%) of 82 idiopathic patients and 12 (9%) of 138 patients in other clinical categories. ADAMTS13 activity was measured in all 6 HIV-positive patients. In 2 patients, ADAMTS13 activity was deficient (<10%): 1 with typical relapsing TTP (patient 1, table 3) and 1 whose final diagnosis was disseminated Kaposi sarcoma (patient 4). ADAMTS13 activity was 12% in the other patient (patient 3) in the idiopathic category and 45%-65% in the 3 patients whose presenting clinical features were subsequently attributed to malignant hypertension.

Table 3
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Table 3

Presenting features and clinical course of 6 patients who had HIV infection at the time of their initial diagnosis of thrombotic thrombocytopenic purpura (TTP).

The clinical courses of the 6 HIV-positive patients are presented in table 3. Patients 1 and 3 were assigned to the idiopathic category in table 2. Patient 1 had characteristic clinical features of TTP and responded promptly to plasma exchange treatment. HIV infection was discovered incidentally at the time of TTP diagnosis and progressed to AIDS (defined on the basis of a CD4 cell count of 154 cells/μL). He was not compliant with prescribed HAART. During 9 years, he had 6 episodes of TTP with no apparent preceding infectious or other illnesses. ADAMTS13 deficiency was present in his last 3 episodes. After recovery from his last episode of TTP, he died at home; an autopsy revealed systemic infection with gram-positive cocci and no evidence of recurrent TTP.

Patient 3 had been ill for 6 months with fever and weight loss. AIDS was diagnosed 3 weeks before his diagnosis of TTP, when he developed esophageal candidiasis. Treatment was begun with zidovudine, lamivudine, efavirenz, and fluconazole. He was hospitalized for repeated seizures, became comatose, and required intubation. CT demonstrated cerebral atrophy consistent with HIV encephalopathy. Coagulation studies suggested disseminated intravascular coagulation. When there was no evidence of sepsis, plasma exchange treatment for TTP was begun but was stopped when there was no clinical or hematologic response. Three days after stopping plasma exchange, the patient regained consciousness and subsequently recovered. Although coagulation abnormalities, lack of response to plasma exchange treatment, and recovery after plasma exchange treatment was stopped were not typical of TTP, no alternative diagnosis was discovered. Currently, he is doing well with HAART.

In the other 4 patients, the clinical features that had initially suggested the diagnosis of TTP (thrombocytopenia, anemia with schistocytes, and acute renal failure) were subsequently attributed to other conditions. Patient 4 had been diagnosed as having AIDS 2 weeks previously and began treatment with lamivudine, tenofovir, and efavirenz. Chest radiography demonstrated pulmonary infiltrates; plasma exchange for TTP was begun when evaluation for Pneumocystis species yielded negative results. He subsequently developed violaceous papules on both legs. Plasma exchange was stopped because of no response, and he died 5 days later. Autopsy demonstrated disseminated Kaposi sarcoma; thrombotic microangiopathy characteristic of TTP was not present. In the other 3 patients, the clinical features were subsequently attributed to malignant hypertension; none responded to plasma exchange treatment. Patient 2 had progressive weakness for 4 months. HIV infection was diagnosed during routine testing at the time of TTP diagnosis. A renal biopsy specimen demonstrated diffuse sclerosing glomerulopathy consistent with HIV-associated nephropathy with no thrombotic microangiopathy. The patient developed progressive multifocal leukoencephalopathy and died 10 months after the diagnosis of HIV/AIDS. Patient 5 had progressive weakness for 2 months. He had severe hypertension and bilateral small kidneys. HIV infection was diagnosed during routine testing at the time of TTP diagnosis. He continues to require hemodialysis. He has never taken treatment for HIV infection. Patient 6 had progressive weakness and weight loss for 3 months before her TTP diagnosis. She had received a diagnosis of AIDS 11 years previously and had received HAART for the initial 6 years, but then received no antiretroviral treatment for the next 5 years. She had bilateral pulmonary infiltrates attributed to congestive heart failure. A renal biopsy specimen demonstrated end-stage renal disease with thrombotic microangiopathy attributed to malignant hypertension. She continues to undergo hemodialysis without treatment for her HIV infection.

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Discussion

Although most case series of patients with TTP do not mention HIV infection, some have reported a high frequency of HIV infection among patients diagnosed as having TTP and have suggested that it may cause TTP [6–8]. However, the disparity of reported frequencies of HIV infection among patients who have received a diagnosis of TTP is great (0%–83%) [4, 8, 17, 22]. The reports describing the highest frequency of HIV infection among patients diagnosed as having TTP (48% [4] and 83% [8]) may reflect the high regional prevalence of HIV infection among the population of South Africa [31]. Other reports describing HIV infection among patients in whom TTP has been diagnosed are from hospitals that may also serve populations with a high prevalence of HIV infection (table 1). The lack of individual patient data and follow-up in these reports limits the ability to interpret the relationship between HIV infection and the clinical features suggesting TTP. The reports that describe individual patient data suggest the possibility that other disorders may have caused these clinical features [2, 17, 27]. Because diagnostic criteria for TTP, requiring only the presence of microangiopathic hemolytic anemia and thrombocytopenia with no alternative cause [11], are not specific, and because AIDS-related disorders may cause these abnormalities [10], the diagnosis of TTP is often uncertain in patients with HIV infection.

Although TTP is characterized by systemic microvascular thrombosis that may cause abnormalities of multiple organ systems, some clinical features are uncommon and suggest alternative diagnoses (table 4). The critical initial clinical decision is whether to initiate plasma exchange—the specific treatment for TTP but also a procedure with a high risk of serious complications. A prospective analysis of 206 consecutive patients treated with plasma exchange for TTP documented that 57 patients (28%) had 75 major complications; 5 patients (2.4%) died of these complications: 3 died of complications of central venous catheter insertion, and 2 died of sepsis attributed to the indwelling central venous catheter [32].

Table 4
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Table 4

Clinical features in patients presenting with thrombocytopenia and anemia that are uncommon in thrombotic thrombocytopenic purpura (TTP) and suggest an alternative diagnosis.

ADAMTS13 deficiency is a characteristic abnormality of TTP [14]. However, the interpretation of ADAMTS13 activity levels among our 6 patients with HIV infection was uncertain. Patient 1, who had typical relapsing TTP, had normal ADAMTS13 activity in his first episode before becoming deficient as a result of an inhibitor in later episodes. Patient 4, with disseminated Kaposi sarcoma but no evidence of TTP at autopsy, also had ADAMTS13 deficiency with an inhibitor. ADAMTS13 activity was 12% with a demonstrable inhibitor in patient 3, who was considered to have idiopathic TTP despite atypical clinical features. The 3 patients whose presenting features were subsequently attributed to malignant hypertension had normal ADAMTS13 activity. These data suggest that, among HIV-infected patients, ADAMTS13 activity measurements cannot distinguish patients with typical TTP from patients whose clinical features were subsequently attributed to another diagnosis. Although the frequency of alternative diagnoses among HIV-positive patients is greater than among HIV-negative patients, similar alternative diagnoses occurred [28, 33].

The period prevalence of HIV infection among patients in the Oklahoma TTP-HUS Registry (1.84%; 95% CI, 0.68%–4.01%) was low compared with many published case series but was greater than the period prevalence of HIV infection among adults in the registry region (0.30%). The higher prevalence of HIV infection among patients with a diagnosis of TTP may be related to the fact that the presenting clinical features in 4 of the 6 patients were subsequently attributed to AIDS-related disorders. Also, HIV testing was not performed for all individuals in the registry region population, resulting in the estimate that 25% of patients living with HIV infection in the United States have undiagnosed conditions [34]. In contrast, HIV testing was performed for 97% of patients in the registry.

There may be multiple reasons why patients with HIV infection are diagnosed as having TTP (table 5). First, HIV infection, AIDS-related disorders, or treatment-induced immune reconstitution [35] may trigger episodes of TTP in susceptible patients. This sequence is similar to observations that infections [36], inflammatory conditions [37], and pregnancy [38] can trigger episodes of TTP in patients without HIV infection. This could have been the basis for the association of HIV infection with TTP in patient 1. Second, AIDS-related disorders can mimic the clinical features of TTP; this was the conclusion for patients 2, 4, 5, and 6.

Table 5
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Table 5

Possible reasons why patients with HIV infection may be diagnosed as having thrombotic thrombocytopenic purpura (TTP).

Third, there may be a specific entity of HIV-associated thrombotic microangiopathy [39], suggested by observations of endothelial dysfunction with deposition of thrombi in the vessel wall [40]. Human herpesvirus 8 infection, which is common among HIV-infected patients, involves vascular endothelial cells and may contribute to development of thrombotic microangiopathy [41]. Analogous to HIV-associated thrombotic microangiopathy, transplantation-associated thrombotic microangiopathy, a syndrome that occurs after allogeneic hematopoietic stem cell transplantation and may result from conditioning regimen toxicity, graft-versus-host disease, and infections [42], was also previously considered to be TTP and therefore was treated with plasma exchange. Transplantation-associated thrombotic microangiopathy is now considered to be a specific entity, distinct from TTP, for which plasma exchange treatment is not appropriate [43]. Describing HIV-associated thrombotic microangiopathy as a specific entity could help to avoid plasma exchange treatment in HIV-infected patients whose clinical features are not typical of TTP [39].

HIV-associated thrombotic microangiopathy and AIDS-related disorders that may mimic TTP occur in patients with more advanced HIV infection [10, 44]. This finding is consistent with observations of decreased frequency of the diagnosis of TTP among patients with HIV infection during the HAART era [39, 45, 46]. The ability of HAART to down-regulate inflammation may also contribute to the decreased development of thrombotic microangiopathy [47]. Four of our 6 HIV-infected patients (patients 2, 3, 4, and 6) had AIDS-defining criteria documented before or at the time of their diagnosis of TTP; none had received HAART except for patient 6, and she had not been treated for 5 years.

Strengths of this study are the inception cohort of all 362 consecutive patients with an initial episode of clinically diagnosed TTP in a defined geographic region across 19 years, the documentation of the presence or absence of HIV infection in 97% of these patients, and analysis of the clinical course with complete follow-up of the 6 patients with HIV infection. Limitations are the small number of patients with HIV infection, their complex illnesses, and the nonspecific diagnostic criteria for TTP.

Although HIV infection and AIDS-related disorders may trigger acute episodes of TTP, similar to other infections and inflammatory disorders, our experience does not support the existence of HIV-associated TTP as a specific entity or the hypothesis that HIV infection can cause TTP. If the diagnosis of TTP is suggested in a patient with HIV infection, there should be careful evaluation for alternative origins in addition to appropriate treatment of the HIV infection. Treatment with plasma exchange must be considered cautiously.

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Acknowledgments

We thank Kristen Eberly for providing the data for HIV prevalence from the Oklahoma State Department of Health, Surveillance and Analysis Division, HIV AIDS Reporting System. We also thank the late Margot Kruskall for her encouragement to investigate patients with AIDS-related disorders who had been diagnosed as having TTP.

Financial support. The Hematology Research Fund of the University of Oklahoma and the Swiss National Science Foundation (3200B0–108261).

Potential conflicts of interest. All authors: no conflicts.

  • Received October 22, 2008.
  • Accepted December 5, 2008.
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  1. Clin Infect Dis. (2009) 48 (8): 1129-1137. doi: 10.1086/597471
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