The advent of HAART has dramatically increased life spans of HIV-infected individuals [1,2]. Concurrently, the incidence of AIDS-defining illnesses and opportunistic infections has declined, whereas noninfectious causes of morbidity and mortality have emerged, including an increased risk of thrombotic disease [3–6].
HIV-infected patients are two-fold to 10-fold more likely to have a venous thromboembolism (VTE) compared with the general population [7–9]. Epidemiologic studies have linked traditional risk factors including ongoing non-HIV infections and hospitalizations [7,10] and, to a lesser extent, protease inhibitors to thrombotic events [11,12]. Mounting evidence, however, suggests that HIV-specific factors are more heavily implicated in the pathogenesis of venous thrombotic disease [5,7,13].
HIV-related chronic immune activation and inflammation may contribute to vascular dysfunction and VTE risk [14–18]. A wide spectrum of procoagulant abnormalities including increased levels of D-dimer, soluble thrombomodulin, P-selectin, von Willebrand factor (vWF), monocyte tissue factor expression, and anticardiolipin antibodies  have been observed in HIV-infected compared with uninfected individuals [15,20–23]. Many of these abnormalities correlate with the degree of immunodeficiency and concomitant presence of opportunistic infection [11,24]. Case reports implicating co-infection with cytomegalovirus (CMV) in clot formation date back to the beginning of the HIV epidemic . This may be due to impaired endothelial function and inflammation  of the venous vasculature .
Results of the Strategies for the Management of Anti-Retroviral Therapy (SMART) study showed that higher levels of pro-inflammatory cytokines and acute phase reactants [interleukin (IL)-6 and C-reactive protein (CRP), and D-dimer products of fibrinolysis], which are known to be associated with the coagulation pathway, were associated with increased all-cause mortality, cardiovascular, and opportunistic disease . It is unclear whether these markers will be helpful in predicting specifically venous thrombotic disease.
In this retrospective, case–control study of HIV-infected participants with incident VTE, we hypothesized that chronic inflammation, induced by HIV infection and coexisting opportunistic disease, may contribute to the elevated risk of VTE.
Patient identification and definitions
A retrospective review of all HIV-infected participants (N = 2072) enrolled in National Institute of Allergy and Infectious Diseases (NIAID) intramural research protocols between January 1995 and April 2010 was conducted. Participants who experienced an incident VTE while participating in a research study were identified from the NIAID electronic research database. Thromboembolic events were identified and validated by detailed chart review and imaging. Events were defined by the Justification for the Use of Statins in Primary Prevention: Interventional Trial of Rosuvastatin (JUPITER) trial criteria as described elsewhere . Deep venous thromboses (DVTs) were confirmed at the time of the documented event by venous ultrasonogram or venogram, pulmonary embolism by angiogram, computed tomographic scan, or ventilation–perfusion scan, and portal vein thrombosis (PVT) by abdominal ultrasonogram. Validation methods used to identify patients were the use of anticoagulation therapy and a determination of sudden death attributed to pulmonary embolism by autopsy.
Exclusion criteria included experiencing a VTE prior to enrollment in NIH research protocols or prior to documented HIV seroconversion.
Patients with a first occurrence of VTE and cryopreserved plasma available at a pre-VTE event time point were matched 1: 3 with HIV-infected controls by sex, age (within 5 years), and date of NIAID study enrollment (within 3 years). Controls were eligible for inclusion if they had not experienced a VTE and had cryopreserved plasma available at the time of the matching event.
Active infection was classified as the treatment and/or diagnosis of any non-HIV infection within 3 months of the matching event. Provocation was defined as any trauma, surgery, central line placement, or hospitalization within 3 months of the event date. Hypertension was identified by the use of any antihypertensive agent, or documented blood pressure reading of more than 140 mmHg SBP or more than 90 mmHg DBP on two or more occasions prior to the event date. BMI was computed using the most recent weight and height measurements preceding the matching event. Smoking history was assessed positive if patient reported smoking of more than 100 lifetime cigarettes and classified as current if patient reported cessation of less than 1 month prior to the event date. Diabetes was identified by use of an antidiabetic agent, random glucose level of more than 200 mg/dl, or a fasting glucose level of more than 126 mg/dl on two separate occasions. Family history of a coagulopathy was classified as any history of VTE or coagulation disorder in a first-degree relative documented prior to the matching event. History of malignancy was defined as any cancer diagnosis excluding squamous cell and basal cell skin carcinomas and was classified as current if the patient was diagnosed and/or treated within 5 years of the VTE event date. History of cardiovascular disease was defined as any history of myocardial infarction, arterial revascularization, stroke, or coronary heart disease risk equivalent using the 2004 National Cholesterol Education Program guidelines. Injection drug use (IDU) was considered positive if patients reported any lifetime use of injection drugs. Cumulative antiretroviral exposures were determined by prescribing information and detailed chart review. Antiretroviral drug use was classified as current if the patient was documented as actively taking an agent within 1 month of the matching event. Immunological AIDS and opportunistic infections were defined according to current Department of Health and Human Services (DHHS) guidelines. The most recent clinical and laboratory values preceding the matching event were used in comparative tests. Deaths were verified using the Social Security Death Index database.
Measurement of biomarkers
The most recent cryopreserved plasma specimens available prior to the matching event were used to assess biomarkers and CMV viremia. All plasma samples were collected in EDTA at the time of an NIH study visit, shipped frozen to a central repository and cryopreserved at −70°C. CMV DNA was quantified by real-time PCR using EZ1 Virus Mini kits v2.0 (Qiagen, Germantown, Maryland, USA). Anticardiolipin antibody levels were measured using an ELISA (Inova Quanta Lite, INOVA Diagnostics Inc., San Diego, California, USA). D-dimer was measured using an enzyme-linked fluorescent assay on a VIDAS instrument (bioMerieux Inc., Durham, North Carolina, USA). Hyaluronic acid was measured using HA test kits (Corgenix Inc., Westminster, Colorado, USA). vWF activity was assessed using ELISA Zymutest kits (Aniara, Mason, Ohio, USA). Soluble CD14 and soluble tissue factor (TF) were measured by ELISA (R&D Systems, Minneapolis, Minnesota, USA). Interferon-γ (IFNγ), IL-1b, IL-6, IL-8, IL-10, IL-12p70, tumor necrosis factor-α, eotaxin, eotaxin-3, macrophage inflammatory protein-1b, chemokine (C-C motif) ligand (CCL)-17, IFN-inducible protein 10, monocyte chemotactic protein (MCP)-1, MCP-4, macrophage-derived chemokine, thrombomodulin, intracellular adhesion molecule (ICAM)-1, ICAM-3, vascular cellular adhesion molecule-1, E-selectin, P-selectin, serum amyloid A (SAA) , high-sensitivity CRP, and tissue inhibitor of metalloproteinase-1 (TIMP-1)  were measured by electrochemiluminescence using Human Vascular Injury I kits, Human Vascular Injury II kits, Human ProInflammatory-7 Ultra-Sensitive kits, Human Chemokine-9 Ultra-Sensitive kits, and Human TIMP-1 kits (Meso Scale Discovery, Gaithersburg, Maryland, USA).
Nonparametric Mann–Whitney U-tests and Fisher's exact test were used for comparisons between patients with VTE and HIV-infected controls using values obtained at the time of the matching event. Continuous variables were compared using Mann–Whitney U-tests. Categorical variables were compared with Fisher's exact test. To evaluate whether relevant biomarker values were sensitive to time elapsed between measurement and time of the impending event, the relationship between biomarkers determined to be significantly associated with VTE by univariate analyses and the number of days from specimen collection to the event were evaluated by Spearman's rank-order analysis. To assess the independent association of risk factors with VTE, a logistic regression analysis was performed and included the variables that were identified on univariate analyses: active non-HIV infection, provocation, nadir CD4 cell count, one or more lifetime opportunistic infections, albumin, soluble CD14 (sCD14), D-dimer, P-selectin, thrombomodulin, vWF, SAA, CRP, IL-6, IL-8, thymus and activation-regulated chemokine (TARC), TIMP-1, and hyaluronic acid. Alternative regression models, which included immunological AIDS, HIV viral load, and/or history of CMV disease, were also tested. Odds ratios for VTE were calculated for participants with median biomarker values above the 50th percentile with logistic regression. All P-values reported were two-sided. Statistical analyses were performed using JMP software (version 8.0; SAS Institute, Cary, North Carolina, USA).
Clinical measures of traditional risk factors and HIV-specific characteristics
Twenty-three participants experienced a first-incident VTE from a cohort of 2072 HIV-infected participants followed at the National Institutes of Health between 1995 and April of 2010. Sixty-nine HIV-infected participants with no history of VTE were matched to patients as described. Fifty-six percent of patients had a DVT (N = 13), 35% had a pulmonary embolism (N = 8), one had a biventricular cardiac thrombus (N = 1), and one had a PVT.
Participants who had a VTE were predominantly male and the median age at which an event occurred was 47 years (Table 1). Thirty percent of participants with a VTE and 25% of controls were black.
Participants with a VTE were four times more likely to have a history of provocation within 3 months of the matching event and a higher percentage had ongoing, non-HIV infections than controls (Table 1). There were no significant differences in the prevalence of IDU, hypertension, smoking, diabetes, cardiovascular disease, or malignancy between VTE patients and controls. The majority of VTE patients (91%) and their controls (85%) were antiretroviral-experienced, and the median duration of HIV infection was 9 and 10 years, respectively. There were no differences in antiretroviral regimens, cumulative antiretroviral exposure, or co-infection with hepatitis C between groups. Current or previous use of IL-2 and cumulative IL-2 exposure did not differ between the groups (data not shown).
The median CD4 nadir was 40 for VTE patients and 250 for controls (P = 0.0003). Most participants in both groups had a current CD4 cell count of more than 500 cells/μl. VTE patients though were more likely to meet diagnostic criteria for immunological AIDS as determined by the most recent CD4 cell count (and/or percentage of CD4) prior to the matching event. Prevalence of HIV viremia did not differ between the groups (39% patients vs. 35% controls, P = 0.80). The majority of VTE patients had more than one lifetime opportunistic infection (52 vs. 22% in controls, P = 0.008). A significantly higher proportion of VTEpatients had a history of CMV disease. CMV viremia was more prevalent in VTE patients (13.0 vs. 0%, P = 0.02). A history of Mycobacterium avium complex or tuberculosis infection was also more common in VTE patients (Table 2) . Lower albumin was observed in VTE patients and there was a nonsignificant trend for higher platelet levels. Other laboratory variables did not differ significantly between the groups (Table 3).
Pre-event levels of circulating biomarkers differed between venous thromboembolism patients and HIV-infected controls
Plasma available prior to the matching event was obtained for VTE patients and controls at a median of 34 days [interquartile range (IQR) 12–44] vs. 23 days (IQR 10–59), respectively; P-value was equal to 0.26. VTE patients had higher levels of markers of monocyte activation, sCD14; endothelial dysfunction and coagulation including P-selectin, thrombomodulin, and vWF; inflammation, SAA, CRP, IL-6, IL-8, TARC, TIMP-1, and D-dimer; and tissue fibrosis, hyaluronic acid (Fig. 1). There was a trend toward higher MCP-4 in VTE patients than in controls. Plasma levels of the remaining tested markers did not differ between the groups (Table, Supplemental Digital Content 1, https://links.lww.com/QAD/A121). There were no differences in biomarkers for patients on protease inhibitor-containing or, specifically, IDV-containing regimens. Thrombomodulin levels were higher in patients co-infected with hepatitis C virus (HCV) (3.71 vs. 2.61, P = 0.05), although other biomarker measurements were similar. Median biomarker levels in patients co-infected with CMV were not different from those without CMV. Reference values from healthy, HIV-negative participants are provided in Supplemental Digital Content 2, https://links.lww.com/QAD/A121.
The interval from specimen collection to VTE event was significantly correlated with D-dimer (r = −0.44, P = 0.03) and vWF (r = −0.48, P = 0.02) levels. There was no correlation with other biomarkers determined to be significant by univariate analyses.
The frequency of detectable anticardiolipin antibodies  immunoglobulin G (IgG) or IgM was similar in VTE patients and controls (8.7 vs. 9.8%, P = 1.0).
A multivariate regression analysis was performed that included active non-HIV infection, provocation, nadir CD4 cell count, more than one lifetime opportunistic infection, albumin, and all biomarkers determined by univariate analyses to be associated with VTE. P-selectin (P = 0.002), D-dimer (P = 0.01), and hyaluronic acid (P = 0.009) were found to be independently associated with VTE risk. Alternative models including immunologic AIDS, HIV viral load, and CMV disease did not alter these findings.
The odds ratios of incident VTE were calculated for participants with baseline levels of P-selectin, D-dimer, or hyaluronic acid above the median. The odds ratios of VTE for participants with biomarker values exceeding the median value for all participants were 11.4 [95% confidence interval (CI) 3.1–42.3] for D-dimer, 7.6 (95% CI 2.3–24.9) for P-selectin, 1.8 (95% CI 0.7–3.8) for hyaluronic acid, and 11.2 (95% CI; 3.7–33.6) when both D-dimer and P-selectin were above the median (Table 4).
In this case–control study of HIV-infected patients, elevated plasma levels of P-selectin, D-dimer, and hyaluronic acid were strongly and independently linked to risk of subsequent VTE when measured prior to the event occurrence. HIV-specific risk factors including low nadir CD4 cell count, immunological AIDS, history of multiple opportunistic infections, and CMV viremia were associated with thromboembolic events, as well as ongoing, non-HIV infection and the presence of a provocation (recent hospitalization, surgery, or trauma).
In HIV-uninfected persons with a first VTE, up to half of all events are unprovoked . In comparison, roughly two thirds of first-time events in our HIV-infected population occurred without an identifiable provocation. The prevalence of non-HIV infection was high in VTE patients and their HIV-positive controls, although substantially higher in VTE patients, consistent with its known relationship to VTE in the general population. Contrary to other traditional clinical risk factors for VTE in patients without HIV, current malignancy, family history of hypercoagulability, and cardiovascular disease were not related to thrombosis in this study. The presence of a provocation or active infection in HIV-infected individuals, even in the absence of other traditional risk factors, has clinical implications for inpatient and outpatient management; extended-distance travel, surgery, hospitalization, and ongoing non-HIV infections necessitate consideration of venous thromboprophylaxis .
At the time of the matching event, the vast majority of patients and controls were receiving ART with a median duration of therapy since HIV diagnosis of 6.9 and 7.3 years, respectively. Most patients had normalized CD4 cell counts (>500 cells/μl) at the time of VTE diagnosis, which is above the threshold at which current DHHS guidelines recommend starting antiretroviral treatment . On the contrary, nadir CD4 cell count was significantly lower and multiple lifetime opportunistic infections were more prevalent among VTE patients than controls, despite a similar duration of HIV infection (9.3 vs. 10.5 years). Combined, these results support the hypothesis that earlier initiation of ART may modify the risk of venous thrombotic disease .
HIV viremia and plasma HIV-RNA levels were not associated with VTE risk in this cohort, although other studies have reported otherwise [7,10]. Persistent low-level viremia has been observed in a majority of individuals with less than 50 copies/μl  and chronic immune activation is evident even in patients with suppressed HIV viremia below detectable levels . The contribution of viral replication to observed biomarker levels and related coagulopathies cannot, thus, be precluded in this study .
Associations between D-dimer products of fibrinolysis and all-cause mortality as well as cardiovascular disease have been well established in HIV-infected and noninfected populations [27,35–38]. The relationship between latest pre-event levels of D-dimer and venous thrombotic disease is likely attributable, in part, to subclinical clot formation. Measurement of D-dimer has significant long-term predictive value in high-risk individuals and is a strategy already used to stratify risk of VTE recurrence. Furthermore, a recent meta-analysis found that timing of testing post-VTE did not affect this association . In a previous report, we linked risk of CVD in HIV to elevated D-dimer levels up to 2 years prior to the index event . Combined with our current findings, these data suggest that there may be clinical utility in D-dimer measurement among HIV-infected patients at elevated risk for venous and arterial thrombosis.
In addition to elevated D-dimer levels observed in HIV-infected participants with an impending VTE, several markers of inflammation (IL-6, CRP, and SAA) were also higher in patients compared with controls.
Increases in IL-6, CRP, and SAA are also related to levels of HIV-RNA , risk of opportunistic infection , and death [27,40], supporting our hypothesis that underlying inflammation, caused by both HIV  and non-HIV infections , contributes to venous thrombotic disease. However, due to the retrospective nature of this study, temporality between biomarkers of inflammation and activation of coagulation and fibrinolytic pathways could not be determined.
A hypercoagulable state often exists among patients with HIV, including a high prevalence of detectable anticardiolipin antibodies . In this study, we evaluated their role in VTE and determined that although anticardiolipin antibodies were detected more commonly in HIV-infected patients than in healthy, uninfected individuals, there was no association with VTE.
The relationship of immunodeficiency with increased coagulation factors may be due to the increased risk of opportunistic infections . In support of this explanation, we found that a history of multiple lifetime opportunistic infections and advanced immunodeficiency were associated with VTE risk in the studied population. Further, CMV viremia was more prevalent among VTE patients than controls. Active CMV infection was recently associated with hypercoagulability independent of stage of HIV disease . These findings suggest that CMV disease, rather than immunodeficiency alone, may result in a heightened inflammatory state leading to activation of the coagulation cascade in co-infected patients.
Another explanation for chronic inflammation in HIV may be related to the ability of HIV to cross the endothelial cell membrane, causing endothelial disruption via induction of intracellular biochemical changes and subsequent activation of inflammatory cascades and expression of endothelial cell adhesion molecules . To investigate the role of endothelial dysregulation in venous clot formation, we quantified circulating levels of P-selectin, vWF, TARC, and TIMP-1 and observed each to be significantly associated with VTE risk. A higher degree of immunodeficiency among VTE patients may in part explain these findings due to its association with impaired vascular function and endothelial inflammation in HIV disease [44,45].
P-selectin was found to be independently and most strongly associated with thrombosis in this cohort. Stored in endothelial cells and platelet granules, P-selectin interacts with its receptor to promote a hypercoagulable environment by inducing the generation of prothrombotic microparticles from leukocytes and upregulation of tissue factor expression on monocytes [46–49]. Prospective studies in HIV-uninfected participants with malignancies have demonstrated that P-selectin is significantly elevated in patients with an impending or acute VTE. Furthermore, P-selectin has been shown to have comparable diagnostic value to D-dimer in patients with confirmed DVTs .
Plasma levels of the soluble lipopolysaccharide (LPS) receptor sCD14 can be utilized as a marker of monocyte activation . In our cohort, we observed a significantly higher level of sCD14 in VTE patients compared with controls, suggesting that overstimulation of monocytes from increased peripheral exposure to microbial products may contribute to a prothrombotic state in chronic HIV infection. These findings are consistent with a recent study that showed an increased proportion of monocytes expressing surface procoagulants in HIV-infected patients following LPS stimulation . Contrary to expectations, we did not observe any appreciable differences in soluble TF plasma levels between groups. LPS-mediated activation of TF-dependent coagulation pathways may be confined specifically to monocyte surface TF expression.
Monocyte production of inflammatory cytokines may also be induced by hyaluronic acid degradation products through stimulation of the Toll-like receptors (TLR)-2 and TLR4 . A strong indicator of liver fibrosis in HCV co-infected  and mono-infected  individuals, increased hyaluronic acid levels are also predictive of AIDS or death . Although compared with controls, fewer VTE patients in our study were co-infected with HCV, overall hyaluronic acid levels were higher in VTE patients, and in a multivariate analysis, independently linked to VTE disease. These results suggest that hyaluronic acid-mediated tissue injury and inflammation may contribute to VTE risk in patients without other evidence of hepatic injury.
The limitations of our study include a relatively small number of events evaluated and the risk of increased type I error, given the considerable number of variables compared. However, in the multivariate analyses, three biomarkers retained significance: the associations of P-selectin, D-dimer, and hyaluronic acid with VTE remained strong, are biologically plausible, and relevant to other HIV-related adverse outcomes associated with their increased levels.
In summary, indices of endothelial dysfunction, coagulation, and tissue fibrosis were most strongly and independently associated with risk of venous thrombotic disease, although a history of multiple lifetime opportunistic infections, clinical CMV disease and CMV viremia, immunodeficiency, and the presence of an ongoing non-HIV infection or provocation were also related. Our findings suggest that unique risk factors in HIV-infected individuals exist that may contribute significantly to augmented risk of VTE disease. Furthermore, indices of endothelial dysfunction, coagulation, and tissue fibrosis that have been linked to morbidity and mortality in HIV infection were more strongly associated with VTE risk than other covariates examined in this study. Our results present a clinical impetus to further explore both their contributions to immunopathogenesis and the therapeutic role of modulating these biomarkers and associated inflammatory and coagulation pathways to potentially modify risk of noninfectious complications of HIV infection.
This study was funded by the Intramural Program of the NIH, NIAID, Critical Care Medicine Department, and with federal funds from the National Cancer Institute, NIH, under contract number HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.
I.S. and C.H. designed the study, contributed to the analysis and interpretation of the data, and in writing the manuscript. L.W.M. contributed to the study design, clinical and laboratory data acquisition, data analysis and interpretation, and in writing the manuscript. V.S. and T.D.N. contributed to the acquisition of clinical data. A.R. performed laboratory studies. B.O.P. contributed to study conception and revision of the manuscript. S.R.P. provided plasma samples from HIV-negative volunteers. J.S. assisted with the study design and interpretation of statistical analyses. J.M.M. provided clinical management of patients enrolled in NIH protocols that were included in the study. All authors have reviewed and approved the final version of the manuscript for publication.
L.W.M. was a 2009–2010 participant in the Clinical Research Training Program, a public–private partnership supported jointly by the NIH and Pfizer Inc. via a grant to the Foundation for NIH from Pfizer Inc.
The authors would like to thank the study participants at the NIH and the staff of Outpatient Clinic 8 at NIAID, Ven Natarajan and Yunden Badralmaa for CMV testing, Manuel van Deventer and Tracey Bosworth for ACA panel testing, Aaron Richterman for technical assistance, as well as Catherine Rehm and McCamie DeArmon for sample identification.
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