We examined the independent association of HCV with the markers of hemostasis in multivariate analyses as described in the statistical methods, adjusting for both HIV status and treatment and other covariates: age, race, smoking status, drug use, alcohol use, hormone use, history of diabetes, history of ADI, and BMI. In addition, we adjusted for WIHS site and date of laboratory test. Significant associations from multivariate analysis are shown in Table 3. HCV was independently significantly associated with higher levels of Factor VIII% (adjusted difference +11.70%, P = 0.008) and lower levels of TPS (adjusted difference −7.55%, P < 0.0001) after adjustment. Thus, an HCV-positive woman would have 11.70% higher Factor VIII% compared with an HCV-negative woman with all other variables in the model equal. An HCV-positive woman would have 7.55% lower TPS compared with an HCV-negative woman with all other variables equal. HCV was not significantly associated with PAI-1 or log10 D-dimer (P = 0.34 and P = 0.91, respectively). HCV remained an independent predictor of Factor VIII and TPS even after adjusting for FIB-4.
In these multivariate models, HIV status/VL was significantly and independently associated with higher Factor VIII% and log10 D-dimer and lower TPS but was not statistically associated with PAI-1. In models restricted to HIV-infected women, higher tertiles of VL were statistically associated with higher Factor VIII% and log10 D-dimer levels (data not shown). Self-reported HIV treatment category was also significantly associated with TPS, for example, compared with no treatment HAART was associated with higher TPS levels (4.92%, P = 0.05) after adjustment for all other variables in the model.
Higher log FIB-4 scores were independently associated with higher Factor VIII% and lower TPS (in the direction of worse thrombosis) (P = 0.0014 and P < 0.0001, respectively). Age, race, smoking, drug use, hormone use, and BMI were significant independent predictors for some of the markers of hemostasis in multivariable models. In particular, higher BMI was significantly associated with higher Factor VIII%, PAI-1, and also TPS (all P < 0.05). Hormone use was independently associated with a lower level of Factor VIII% (adjusted difference 6.71% lower, P = 0.04), and current smoking was independently associated with greater PAI-1 (adjusted difference 6.87 ng/mL, P = 0.02). Black compared with white race was independently associated with higher Factor VIII% and log10 D-dimer (adjusted differences 22.23% and 0.09 µg/mL higher, P < 0.0001 and P = 0.01, respectively). Older age was associated with higher Factor VIII and TPS (adjusted differences 5.25% and 4.65% higher per 10 years, P = 0.068 and P < 0.0001, respectively).
This study of 868 women in the WIHS cohort found a highly statistically significant association of hepatitis C infection, defined by HCV viremia, with both higher Factor VIII% and lower TPS, independent of HIV infection. Higher Factor VIII% and D-dimer and lower TPS were strongly associated with HIV infection and levels of HIV viremia, independent of HCV infection. Greater levels of Factor VIII% and lower TPS are consistent with hypercoagulability. Thus, both HCV and HIV infection were each independently associated with markers of hypercoagulability. Coinfection with both HCV and HIV was associated with greater Factor VIII% among women with low and medium VL and lower TPS across all tertiles of VL, compared with HIV infection alone. To our knowledge, this is the first study to examine the associations of these markers of hemostasis in a large cohort of HIV-infected and uninfected women with and without HCV infection.
These markers have not been well characterized in general HCV infection. Previous studies examined the association between advanced HCV disease state and hemostasis marker levels. Abdo et al91 found significant differences in TPS levels in a small number of patients with HCV and elevated liver enzymes and patients with liver cirrhosis. In a study of markers of hemostasis among 34 patients with HCV and extensive fibrosis and/or cirrhosis compared with 34 patients with HCV but without extensive fibrosis and/or cirrhosis, Factor VIII% was significantly elevated in the group with more advanced disease (160% vs. 120%, respectively).92 Among patients with cirrhosis, including those with HCV, Fimognari et al12 found higher levels of D-dimer associated with advanced liver disease. Hepatocellular damage from HCV may explain some of these marker levels, as HCV targets primarily hepatocytes in vivo.93,94 Hepatocytes are the primary site for synthesis of Protein S, PAI-1, and fibrinogen, the source of the fibrin degradation product, D-dimer,1,95,96 whereas Factor VIII is made primarily by sinusoidal epithelial cells.2
We confirmed several other previously observed associations with these 4 markers of hemostasis. Greater age, a known risk factor for thrombosis,114 was associated with higher Factor VIII and lower TPS in our study. Higher BMI, also a known risk factor for thrombosis,114 was significantly associated with all the clotting factors except D-dimer. Interestingly, hormone use was associated with lower Factor VIII%. One previous study has shown no association of oral or transdermal contraception with Factor VIII% levels.54
We found that self-reported antiretroviral therapy was associated with an increase in TPS levels compared with no treatment. Monotherapy and HAART were significantly associated with this increase but combination therapy was not, perhaps reflecting type 2 error. There is some prior evidence that HAART is associated with increases in Protein S.115 However, Protease inhibitors have also been linked to an increase in thrombotic events and a decrease in Protein S.4,21 Viral replication may play a role in modulating these markers; others have found that interruptions in HAART based on CD4 counts, compared with continuous treatment, resulted in increases in D-dimer.116
This study has several limitations. We cannot make any causal inferences from the study, as it is a cross-sectional design. The generalizability of this study to the modern HIV era may be limited as nearly 40% of HIV-infected women were not treated and only 23% were taking HAART. However, new studies have suggested that markers of hemostasis such as D-dimer are elevated in those not on continuous HAART,116 and we would hypothesize that the overall effect of HAART would lead to markers of hemostasis in the direction of decreased thrombosis. In addition, the WIHS cohort may not be representative of women living with HIV or HCV in the United States, and caution must be used in applying these results from this cohort study to the general population. Finally, very few patients were receiving treatment for HCV; so, this article cannot address whether HCV treatment improves markers of hemostasis. We also acknowledge that FIB-4 is an imperfect measure of fibrosis and may not be completely capturing the influence of fibrosis on these markers of hemostasis.
In summary, in a large group of women with and without HCV defined by viremia, we found an independent association of HCV infection with 2 markers of hemostasis, Factor VIII and TPS, independent of HIV infection. We have also found a significant association of level of HIV viremia with 3 of these markers, Factor VIII%, D-dimer, and TPS. These findings suggest that prior studies demonstrating an association of markers of hemostasis with HIV infection may have been partially confounded by coinfection with HCV. Future studies of hemostatic markers in HIV/HCV-coinfected populations should control for both level of HIV viremia and HCV infection. Further investigation of HCV and markers of hemostasis in clinical outcomes is warranted.
Data were collected by the Women's Interagency HIV Collaborative Study Group with centers (Principal Investigators) at New York City/Bronx Consortium (Kathryn Anastos); Brooklyn, NY (Howard Minkoff); Washington, DC, Metropolitan Consortium (Mary Young); The Connie Wofsy Study Consortium of Northern California (Ruth Greenblatt); Los Angeles County/Southern California Consortium (Alexandra Levine); Chicago Consortium (Mardge Cohen); Data Coordinating Center (Stephen Gange).
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