Abstract

HIV infected patients may be at increased risk for VTE, as shown by case reports, and a recent retrospective, longitudinal medical record review of approximately 42,000 HIV-infected individuals (Sullivan, 2000). There is a well documented association between acute and chronic inflammation and activation of the hemostatic system. Inflammatory cytokines such as TNF alpha, IL-1 and IL-6 have been shown to activate coagulation via the Tissue Factor pathway. Inflammation can also result in a decrease in functional Protein S, and in an increase in Factor VIII coagulant protein. We hypothesized that the inflammatory state associated with more advanced HIV disease would be associated with hemostatic activation, and clinical development of VTE over time.

Methods: We assayed plasma for factor VIII activity levels, functional protein S activity, presence of lupus anticoagulant, and C reactive protein levels in a group of 96 HIV infected women and 50 HIV negative women from the Women’s Interagency HIV Study (WIHS). All assays were performed blinded to subjects HIV status. This cross sectional sample of WIHS participants from the Los Angeles site were studied at their second study visit (1994-5). The sample was selected to represent the following groups: (1) History of clinical AIDS, CD 4< 200; (2) CD4 < 200, no clinical AIDS; (3) HIV positive, CD4 > 200; HIV-negative. Pts were excluded if they were taking any hormones or contraceptives; had been pregnant within 6 weeks of study; had any acute, active infection at the time of study visit. Hemostatic data were correlated with HIV viral load, CD4 cell count, history of clinical AIDS, history of anti-retroviral and other medication use, and levels of serum and plasma C reactive protein (CRP).

Results are depicted below for median (inter-quartile range) values, adjusted for age:

GroupProtein SFactor VIIISerum CRP#
1. Clinical AIDS, CD4 < 200 46* (40,65) 212* (174,253) 2.0 (0.5,4.8) 
2. No Clinical AIDS, CD4 < 200 62^ (55,67) 196+ (150, 234) 0.8 (0.7,2.7) 
3. HIV+, No Clinical AIDS, CD4 > 200 67.5 (59,83) 154^ (111,202) 0.9 (0.4, 3.3) 
4. HIV Negative 75.5 (66,85) 116.5 (97,154) 1.85 (0.8, 5.1) 
GroupProtein SFactor VIIISerum CRP#
1. Clinical AIDS, CD4 < 200 46* (40,65) 212* (174,253) 2.0 (0.5,4.8) 
2. No Clinical AIDS, CD4 < 200 62^ (55,67) 196+ (150, 234) 0.8 (0.7,2.7) 
3. HIV+, No Clinical AIDS, CD4 > 200 67.5 (59,83) 154^ (111,202) 0.9 (0.4, 3.3) 
4. HIV Negative 75.5 (66,85) 116.5 (97,154) 1.85 (0.8, 5.1) 

Models were adjusted for age. Groups are significantly different from HIV negative participants (group 4) at the indicated p-values, determined using Scheffe adjustment

* p<0.0001

^p<.05

+ p<.001

# CRP Medians are not significantly different for the different groups.

No patient or control was found to have a positive assay for the Lupus anticoagulant.

We conclude: (1) Increasing progression of HIV disease, from asymptomatic, to immunologic (CD 4< 200) and then clinical AIDS, is associated with progressive increase in factor VIII activity, and decrease in functional protein S; (2) This progressive hemostatic changes were not associated with elevated CRP levels, suggesting that IL-6 is not involved in this process; (3) An increase in VTE is biologically plausible in the setting of HIV infection; (4) Further prospective study is warranted to determine the full range of hemostatic abnormalities associated with HIV, and to determine any correlation between these abnormalities and development of VTE in time.

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