Risk Factors for Venous Thromboembolism in Patients with Human Immunodeficiency Virus Infection

Katie L. Kiser, Pharm.D.; Melissa E. Badowski, Pharm.D.


Pharmacotherapy. 2010;30(12):1292-1302. 

In This Article

Viral Risk Factors

CD4+ Cell Count and Viral Load The reported frequency of VTE in HIV-infected individuals varies widely, from 0.19–7.63%/year, with most estimates reported to be 1–2%. Progression of HIV disease, as manifested by plummeting CD4+ cell counts and immuno-suppression, is known to contribute to the occurrence of VTE.[12,13,20,21,33,56] Although the frequency of VTE is higher in the presence of lower CD4+ cell counts, there are reports of thrombosis occurring with CD4+ cell counts as high as 800 cells/mm3, suggesting that the risk of thrombosis was not limited to advanced disease.[20] When differentiating on the basis of the severity of the HIV infection, the frequency of VTE found in one investigation was 0.096% in the HIV population and increased to 1.9% in the AIDS population.[16] One group of authors established that 24% of their study population that met the definition of AIDS, with a CD4+ cell count less than 200 cells/mm3 and the presence of opportunistic infections, developed thrombosis compared with 1.1% of HIV-positive individuals with a higher CD4+ cell count.[21] Based on the presence of immunologic AIDS (defined as a CD4+ cell count < 200 cells/mm3 without clinical manifestations or complications of the virus) and HIV disease compared with clinical AIDS (defined as a CD4+ cell count < 200 cells/mm3 with clinical manifestations and complications of the virus), the incidence of thrombosis was 1.8/1000 person-years (95% CI 1.2–2.5/1000 person-yrs) and 6.2/1000 person-years (95% CI 5.2–7.2/1000 person-yrs), respectively.[12] Compared with those who have a CD4+ cell count of 200 cells/mm3 or greater, a strong relationship exists between a severely immunocompromised patient with AIDS and thrombosis. Furthermore, those individuals with a simultaneous opportunistic infection in the presence of a CD4+ cell count less than 200 cells/mm3 are at increased risk for the development of a thrombotic event.[21] From a pathophysiologic standpoint, decreased CD4+ cell levels, specifically less than 200 cells/mm3, can account for worsening of the procoagulant state perceived with disease progression.

New antiretroviral guidelines recommend that treatment be started when CD4+ cell counts are less than 350 cells/mm3.[57] It will be interesting to observe whether the incidence of thrombosis decreases as the guidelines are followed.

Another indicator of high disease burden of HIV infection is viral load, also known as HIV RNA level. Low CD4+ cell counts and high viral loads are predictive of progression of HIV and typically complement each other in the absence of treatment. One group of authors concluded that a higher viral load, and lower CD4+ cell count, was associated with a higher risk of thrombosis.[20]

Opportunistic Infections

The history or presence of active opportunistic infections in a patient with AIDS has been proposed as a potential risk factor in the development of thromboembolism.[11,12,15,21,33,56,58–60] Individuals with AIDS are at the greatest risk for developing opportunistic infections secondary to their immunocompromised status. As previously described, lower CD4+ cell counts are thought to be associated with a higher frequency of thromboembolism.[12,13,20,21,33,56] The combination of advanced HIV infection and the presence of opportunistic infections appears to serve as an increased risk for thromboembolic events.[21] Although the mechanism of association is unknown, many analyses report disease-inherited abnormalities present in the clotting cascade of HIV-infected individuals.[11,13,15,36] The presence of an acute opportunistic infection also affects proinflammatory and coagulation factors in HIV-positive individuals.[21,27,51,53,58,61]

One group of authors evaluated the occurrence of thrombosis in individuals receiving highly active antiretroviral therapy (HAART) and discovered a significantly increased OR for thrombosis in individuals with an AIDS-defining opportunistic infection (OR 1.5, 95% CI 1.1–2.2).[12] Another group evaluated the association of VTE with HIV in a population of veterans and observed a similar risk for thrombosis in both HIV-positive individuals with opportunistic infections and HIV-negative individuals.[17] They also did not detect an association of VTE with monotherapy compared with combination treatment for HIV infection.

Thrombosis in the presence of cryptococcus, Mycobacterium avium complex, and toxoplasmosis in HIV-infected individuals has been observed; however, VTE is most commonly reported with cytomegalovirus and Pneumocystis jiroveci pneumonia (PCP).[20,51,62]

Cytomegalovirus Although cytomegalovirus is not as common as it was in the pre-HAART era, the incidence has decreased substantially to less than 6 cases/100 person-years.[63] Several investigators have reported that cytomegalovirus disease is a risk factor for venous thrombosis in previously healthy individuals.[51,62] Only two investigations have linked cytomegalovirus as a risk factor in the development of thromboembolism in immunocompromised HIV-positive individuals. According to one group, the frequency of thromboembolism in the presence of cytomegalovirus in HIV-positive individuals is approximately 9.8%, with the majority of thrombosis associated with gastrointestinal-related disease compared with retinitis-related disease.[64] Similarly, another group reported an adjusted OR of 1.9 (95% CI 1.2–2.9) for VTE in those with AIDS and cytomegalovirus.[12] A possible mechanism behind this interaction involved how cytomegalovirus affects the coagulation cascade through infecting the endothelium and altering the procoagulant and anticoagulant balance. Cytomegalovirus-infected endothelial cells stimulate the release of procoagulant agents and the expression of adhesion molecules.[12,65] Specifically, cytomegalovirus has been postulated to cause acquired anticardiolipin antibodies.[51,58]

In addition to cytomegalovirus, Mycobacteriumavium-intracellulare infection in HIV-positive individuals may induce anticardiolipin antibodies.[58] Those with these antibodies are thought to be at increased risk for developing a thromboembolism.[51] Declining levels of anticardiolipin antibodies seem to occur after the initiation of effective treatment with anticoagulation and management and treatment of underlying infection.[51,58]

Although these investigations demonstrate a correlation between cytomegalovirus and thrombosis, substantial research data are lacking with respect to the actual incidence of thrombotic events in patients with cytomegalovirus. With the implementation of effective antiretroviral therapy, and as long as the incidence of cytomegalovirus remains low, it is unlikely that additional research focusing on an association between cytomegalovirus and VTE will be conducted.

Pneumocystis jiroveci Pneumonia Many reports have highlighted the concurrent diagnosis of VTE and active PCP[11,21,58,60] in addition to a remote history of PCP.[11,21] Thromboembolism associated with PCP may be secondary to a hypercoagulable state in patients with AIDS. Pneumocystis jiroveci pneumonia is associated with the presence of antiphospholipid antibodies, lupus anticoagulant in particular.[58,61,64–66] Lupus anticoagulant appears to return to normal limits when infections subside or are successfully treated.[58,61] Although lupus anticoagulant has not been shown to be linked to the development of VTE, antiphospholipid syndrome has. Since patients with HIV who have PCP have been shown to have a high rate of concurrent antiphospholipid syndrome, these individuals are at increased risk for developing VTE. Venous thromboembolism, specifically pulmonary embolism, in this population may remain underdiagnosed because of similar signs and symptoms of presentation between pulmonary embolism and PCP. These conditions may be clinically indistinguishable from each other unless cultures and imaging are performed.


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