**HIV-Infected Patients and Potential Impact on Thrombotic Events**

Hortensia Álvarez Díaz, Ana Mariño Callejo and José Francisco García Rodríguez

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/51590

#### **1. Introduction**

There is increasing evidence that infection with HIV may be associated with a hypercoagulate state.

The incidence of thrombotic events in Human Immunodeficiency Virus (HIV)-infected patients is rising as suggested in recent retrospective cohort studies (1%- 2%, which is 10 times that expected among people without HIV) [**1**], but the underlying etiology remains uncertain.

#### **2. Procoagulant mechanisms underlying HIV infection**

Several mechanisms associated with HIV infection that may lead to predispose to a hypercoagulate state, in the absence of classic thrombophilic risk factors [**2**], are emerging.

More than one "hit" seems to be involved [**3**]:

#### **2.1. Host risk factors**

#### *2.1.1. Age*

HIV-infected patients are older than their chronological age, experiencing the so-called "*premature aging* ", with persistent immunological defects and inflammation, even after years of treatment mediated viral suppression (similar to those seen in normal ageing, but they occur at an earlier age than normal): low CD4: CD8 ratio, low *naïve*: memory cell ratio and reduced responsiveness to vaccines. In addition, longevity and life expectancy is increasing due to effective antiretroviral therapy (ART), making HIV infection a chronic disorder.

© 2012 Álvarez Díaz et al., licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2012 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

In a Nederland cohort [**4**] of 109 patients with HIV, the annual incidences of venous and arterial thrombosis were 5- to 16-fold higher and 2- to 8-fold higher, respectively, than in the healthy population. The median age at the onset of venous thrombosis was 45 years, 17 years earlier than the median age of onset for venous thrombosis in non-HIV- infected patients; and the median age for arterial thrombosis onset was 53 years, a decade earlier than that documented in the Framingham study.

HIV-Infected Patients and Potential Impact on Thrombotic Events 223

especially in the setting of ART. It is not sufficient alone to cause thrombosis, but it may add an additional risk among patients with other risk factors for venous

In addition, intravenous drug use (IDU) can induce endothelial injury [**11**]. From a Danish HIV cohort [**12**], the 5-year risk of VTE was 8.0% [95% confidence interval (CI) 5.78-10.74%] in IDU HIV-infected patients, 1.5% (95% CI 1.14-1.95%) in non-IDU HIVinfected patients and 0.3% (95% CI 0.29-0.41%) in the population comparison cohort. In non-IDU HIV-infected patients, adjusted incidence rate ratios (IRRs) for unprovoked and provoked VTE were 3.42 (95% CI 2.58-4.54) and 5.51 (95% CI 3.29- 9.23), respectively, compared with the population comparison cohort. In IDU HIVinfected patients, the adjusted IRRs were 12.66 (95% CI 6.03-26.59) for unprovoked VTE and 9.38 (95% CI 1.61-54.50) for provoked VTE. Low CD4 cell count had a minor impact on these risk estimates, while ART increased the overall risk (IRR 1.93; 95% CI

• High density lipoprotein (HDL). A prospective study from South Africa [**13**] compared thrombotic profiles of 30 HIV-positive and 30 HIV-negative patients with acute coronary syndrome (ACS). Patients with HIV were younger; and besides smoking (73% vs 33%) and low HDL (0.8 ± 0.3 vs 1.1 ± 0.4), they had fewer traditional risk factors. Thrombophilia was more common in HIV-positive patients with lower protein C (PC; 82 ± 22 vs 108 ± 20) and higher factor VIII levels (201 ± 87 vs 136 ± 45). Patients with HIV had higher frequencies of aCL 47% vs 10%) and antiprothrombin

In addition to promoting cholesterol efflux from lipid-filled macrophages (foam cells) and reverse cholesterol transport, HDL protects low density lipoprotein (LDL) from oxidation and decreases expression of adhesion molecules on endothelial cells (including E-selectin and sICAM-1). HDL also improves endothelial function via stimulation of nitric oxide synthase activity, increases prostacyclin production by endothelial cells and inhibits endothelial TF expression, all of which enhance endothelium-dependent vasodilation and down-regulate thrombotic pathways. In this way, HDL possesses anti-inflammatory and antithrombotic properties. A crosssectional study [**14**] was designed to assess large and small high density lipoprotein particle (HDLp) concentrations in persons with untreated HIV infection. Lower small HDLp (primarily responsible for HDL's anti-inflammatory properties and inhibition of

• Endothelial dysfunction: A dysfunctional venous endothelium, induced by HIV, may express heparin cofactor II deficiency and increased amounts of P-selectin, von Willebrand factor, TF, plasminogen activator inhibitor-1 and factor V, all of which may promote blood clotting. Biomarkers of endothelial dysfunction [**9**] (P-selectin, D-dimer and hyaluronic acid), coagulation, and tissue fibrosis may help identify HIV-infected patients at elevated risk of venous thromboembolism (VTE). Other endothelial dysfunction biomarker is asymmetric dimethylarginine (ADMA), a competitive inhibitor for endothelial nitric oxide synthase (eNOS) which seems to be related to an

increased immune activation pathways in HIV-1 infection [**10**].

clots.

1.00-3.72).

antibodies (87% vs 21%).
