Tips to help with your thrombocytopenia

Hiv And Thrombocytopenia

Acquired immunodeficiency syndrome (AIDS) is a systemic disorder caused by human immunodeficiency virus (HIV) and is characterized by severe impairment and progressive damage of both cellular and humoral immune responses (

). Besides immunological complications of HIV disease, altered hematopoiesis occurs in patients with HIV infection. This change affects all three cell lines (red blood cells, white blood cells, and platelets) and, consequently, these patients may suffer from anemia, leucopenia, thrombocytopenia, or any combination of these three (

). Thrombocytopenia is a frequent hematologic disorder in patients infected with HIV and can occur independently of other cytopenias and at all stages of HIV infection (

). It is the second most frequent complication of HIV infection, occurring in about 4–40% of HIV-infected patients and the degree is generally mild to moderate; however, severe reduction of a platelet count <50,000/μL also occurs (

).

The underlying mechanisms for the development of thrombocytopenia have not yet been well described (

). The possible mechanisms that have been reported are immune-mediated destruction of platelets by antibodies, impaired megakaryocytosis/direct infection of megakaryocytes leading to low production of platelets from those precursor cells, hypersplenism, opportunistic infections, malignancy, and toxic and myelosuppression effects of HIV medications (

,

). The immune mechanism underlying short platelet survival involves not only an antibody-mediated clearance of platelets in the reticulum-endothelial system, but also impaired T-cell immunity, the complement activation, and the clearance of platelets opsonized by immunoglobulin (

). Thrombocytopenia in HIV infection can either be due to primary HIV-associated thrombocytopenia or secondary thrombocytopenia; the former is the most common cause and may occur at any stage of HIV disease. In the early stages of infection, the clinical picture may be identical to immune thrombocytopenia purpura, with accelerated platelet destruction related to immune complexes and cross-reacting platelet antibodies (

,

). Mature megakaryocytes can be infected by HIV through binding the CD4 receptor, and HIV genomes have been detected in megakaryocytes purified from the bone marrow of HIV-positive patients (

). In addition to these direct effects of HIV on the MK cell lineage, HIV also supports chronic thrombocytopenia through autoimmune mechanisms, particularly manifesting in the early stages of the disease (

,

). In HIV infection, thrombocytopenia has been associated with circulating immune complexes that contain platelet membrane components and anti-platelet membrane antibodies (

). The presence of cross-reactions between gp120 of HIV and gp3a thrombocytes has been identified as a contributing factor of thrombocyte depletion (

). Similarly, HIV-p24 antibodies cross-react with platelets (60%). Platelet destruction by these antibodies has been associated with the generation of peroxide and other reactive oxygen species (

).

Thrombocytopenia may represent the first manifestation of HIV infection and it may progress over time and lead to severe bleeding (

). The risk associated with thrombocytopenia is not limited to increased morbidity, but also includes increased mortality (

). The development of thrombocytopenia depends on the clinical stage of the disease and is more prevalent in individuals at an advanced disease stage (

,

). It still remains an important issue, not only because of the risk of bleeding: it also complicates other treatments for diseases such as hepatitis infection and use of myelosuppressive agents in these patients (

). Additionally, severe thrombocytopenia limits the medications used to treat HIV disease and AIDS-related malignancies (

). Thrombocytopenia is also associated with accelerated deterioration in CD4 counts and accelerated progression to AIDS (

). It may therefore be suggestive of an increase in viremia, an alteration of the immune system, and could also be due to the type of antiretroviral therapy (ART) and the effects of opportunistic infections (

). Hematological abnormalities in ART-naive HIV-infected patients result in poor ART outcomes and otherwise strongly predict mortality (

,

).

The use of ART could positively or negatively affect these parameters, depending on the choice of combination used. Although many drugs used for the treatment of HIV-related disorders are myelosuppressive, severe cytopenia is most often related to the use of zidovudine (

). Before the advent of HAART, the incidence of HIV-associated thrombocytopenia was estimated at 10–30%, and thrombocytopenia was the initial manifestation of HIV in approximately 10% of cases (

). Studies have reported that HAART has reduced the prevalence of thrombocytopenia (

,

). However, there are also considerable numbers of reports that have shown an ongoing occurrence of this hematological abnormality, even in patients receiving HAART (

).

Although hematological abnormalities may have a considerable impact on a patient’s well-being, treatment and care, few studies on hematological parameters in HIV-infected people have been undertaken. The results of previous studies respecting the prevalence of thrombocytopenia in HIV/AIDS do not provide a comprehensive framework for clinical decision‑making, since they were conducted in small cohorts of populations. Therefore, this study aimed to systematically review the previous studies on the prevalence of thrombocytopenia among HIV/AIDS adults and thereby determine the global prevalence of thrombocytopenia among HIV/AIDS adults and its association with HAART.

Methods

 Study design and search strategy

Previously published articles were systematically reviewed and analyzed to determine the global prevalence of thrombocytopenia and its association with HAART among HIV-infected adults. To identify published articles, major databases such as PUBMED/MEDLINE, Cochrane library, Web of Science, African Journals Online, Science Direct, Google Scholar, and Google were used accordingly. Publications were also identified from reference lists of relevant studies and manually hand-searched to identify additional relevant studies. The search terms were used separately and in combination using Boolean operators like “OR” or “AND”. The search terms included “thrombocytopenia”, OR “hematological profile”, OR “hematological abnormalities” AND “HIV”, OR “HIV/AIDS”. The Search terms were pre-defined to allow a comprehensive search strategy that included all fields within records, and Medical Subject Headings (MeSH) terms were used to help expand the search in advanced PubMed search (Table S1). The PRISMA checklist (

) was used to report the results of this systematic review and meta-analysis (Table S2).

 Inclusion and exclusion criteria

Cross-sectional and cohort studies that have been published in different peer-reviewed journals on the prevalence of thrombocytopenia among HIV-infected adults on HAART were included. Articles were included if they were the reports of original research, included data on the prevalence of thrombocytopenia among HIV/AIDS-infected adults, were in English, and had been published from 01 January 2001 to 30 September 2020. Case reports, case reviews, and studies addressing specific groups such as HIV-infected adults with tuberculosis were excluded from the study.

 Operational definitions of outcomes

The primary outcome of this systematic review and meta-analysis was to determine the prevalence of thrombocytopenia among HIV-infected adults in the global setting. Thrombocytopenia was defined as a total platelet count <150 × 103 cells/μL (

).

 Study selection and quality assessment

In this systematic review and meta-analysis, retrieved articles were imported to EndNote X7 (Thomson Reuters, New York, USA) to collect and organize search outcomes and remove duplicate articles. Articles were then screened by their titles and abstracts by three reviewers (TA, MA and BB) independently. Discussions and mutual consensus were in place when possible arguments were raised and a fourth reviewer (SG) was involved if required. The quality of articles was assessed using the JBI critical appraisal checklist for simple prevalence (

). The checklist consists of nine items: (1) Was the sample frame appropriate to address the target population? (2) Were study participants sampled appropriately? (3) Was the sample size adequate? (4) Were the study subjects and the setting described in detail? (5) Was the data analysis conducted with sufficient coverage of the identified sample? (6) Were valid methods used for the identification of the condition? (7) Was the condition measured in a standard, reliable way for all participants? (8) Was there an appropriate statistical analysis? (9) Was the response rate adequate? Based on this, individual studies were assigned a score in line with the review objectives. The responses were scored 0 for “Not appropriate and not reported” and 1 for “Yes”; total scores ranged 0−9. Studies with high and medium quality (fulfilling 50% of quality assessment) were included for analysis (Table S3).

 Data extraction

Relevant studies that fulfilled the eligibility criteria were subjected to data extraction by two authors (SG and TA), independently, and summarized into an excel spreadsheet. The data abstraction format included the following items: first author’s name, year of publication, study area, study period, age of study participants, study design, HAART status, and sample size. The proportion of thrombocytopenia was also retrieved from each included study.

 Statistical analysis

Extracted data were entered into Microsoft Excel and then exported to STATA version 11 statistical software for further analysis. Forest plots were utilized to estimate the pooled effect size and weight of each recruited study with 95% CI to show a graphic summary of the data. The degree of heterogeneity between the included studies was evaluated by the index of heterogeneity (I2 statistics). I2 values of 25%, 50%, and 75% were assumed to represent low, medium, and high heterogeneity, respectively (

). Because of the high heterogeneity observed among the studies included in the meta-analysis, a random-effect model was used to estimate pooled effect size and effect of each study with their 95% CI. A sub-group analysis and sensitivity analysis were conducted to determine the potential sources of heterogeneity. Funnel plot analysis and Egger weighted regression tests were conducted to detect publication bias. A P-value <0.05 in Egger’s test was considered to be evidence of statistically significant publication bias (

,

).

Results

 Identified studies

A total of 1823 articles were retrieved through database literature searching, including manual searching. Of these, 423 articles were exclude due to duplication and 1357 unrelated articles were excluded by their title and abstract. The remaining 43 full-text articles were assessed for inclusion; of them, 23 full-text articles were excluded with reason. After excluding non-relevant articles, 20 full-text articles were included for qualitative and quantitative (meta-analysis) synthesis (Figure 1).