**4. Specific settings for thrombotic events**

### **4.1. Autoimmune background**

Autoimmune disturbances have emerged in the setting of immunological reconstitution and constant antigenic viral stimulation in HIV-infected patients. Different types of autoantibodies have been observed, including aCL, anti-Beta2-glycoprotein I and antiprothrombin antibodies [**27**]. Clinical challenges can arise when the two conditions coexist.

HIV-Infected Patients and Potential Impact on Thrombotic Events 229

**4.3. Acute coronary artery disease and non-bacterial thrombotic endocarditis** 

mechanisms might be involved independent of these drugs.

**4.4. Non cirrhotic portal hypertension** 

hypercoagulate state.

**4.6. Other settings** 

**5. Management** 

**4.5. Pregnancy-puerperium** 

to HIV-negative pregnant women.

In addition to the issues referred above, protease inhibitors [**29**] have also been implicated in direct endothelial damage, which may be mediated by reduced nitric oxide production or release. The development of CVD risk factors such as insulin resistance, hyperlipidemia and fat redistribution syndrome, may exacerbate already existing underlying atherosclerotic risk in patients using these medications. However, necropsy studies de- monstrated *premature CVD in HIV-infected patients even before the advent of protease inhibitors*, indicating that other

Other authors could not demonstrate relation between a patient's human immunodeficiency

A multifactorial mechanism has been proposed to explain the pathogenesis of noncirrhotic portal hypertension (NCPH) in HIV-infected patients, and we have reviewed it and described two cases, in a previous published paper [**32**]: prothrombotic state, by HIV as a direct cause or through anti-protein S antibodies, leading to protein S deficiency; as well as didanosine, an ARTdrug, adenosine analogue, which has been postulated as an independent predictor of developing NCPH through cumulative dosing or idiosyncratic mechanisms. It results in an obliteration of the small portal venules and liver regenerative hyperplasia. Considering the data regarding prothrombotic abnormalities in HIV-infected patients, we wondered if patients with HIV and NCPH should be evaluated for

Annual incidence of VTE within 3 months postpartum in a cohort of 41 consecutive HIVinfected pregnant women [33], was 313 per 1000 person-years (95% CI, 65- 915). This risk is 120-fold higher than in HIV-positive controls, whereas the risk is 157-fold higher compared

Thrombophilia might have a limited role in the development of osteonecrosis in HIVpositive, according a case - control study [34], being only significantly associated with

Notably, the 2008 American College of Chest Physicians (ACCP) guidelines on antithrombotic and thrombolytic therapy, are silent regarding HIV-infected patients [**35**]. Anyway, the

management of proven VTE should be the same as for the non HIV-patients [**3**].

osteonecrosis: nadir of CD4(+) < 60 cells/microL and steroid use.

virus status and valve thrombosis [**30**] or non-bacterial thrombotic endocarditis [**31**].

Lupus anticoagulants were first described in AIDS and asymptomatic HIV-infected individuals (in whom they could be transient), by Bloom et al. in 1986. The association between aCL and HIV infection in men who have sex with men was reported in 1991. Falco et al., in 1993, found that, on the contrary to systemic lupus erythematosus (SLE), in the HIV-positive serum samples, reduced aCL binding capacity was evident if the cofactor (beta2-glycoprotein I) was added. Canoso et al. reported in 1997, aCL positivity in association with human T cell lymphotropic virus type 3 infection.

The presence of SLE and HIV infection in the same individual is being increasingly reported, particularly in Africa and Asia. This coexistence has been associated with remissions or amelioration of SLE symptoms, with advancing HIV infection during pre-Highly Active ART (HAART) era (before 1996 and introduction of protease inhibitors); or with flares in immune reconstitution, during effective HAART, through a cross-reactive mechanism between inflammatory factors and common nuclear antibodies.

Overlapping features between SLE and HIV infection can include: arthralgias and arthritis, polyclonal B cell activation, antibodies against double-stranded DNA, anti-Smith antibodies, antiphospholipid antibodies and autoimmune haemolytic anemia with positive Coombs test; however, low complement has not been detected in HIV infection. In addition, patients with SLE without previous exposure to retroviral infection may express antibodies against retroviral proteins, including gag, env, nef and p24 of HIV-1, with false-positive results of ELISA and Western blot for detection of HIV. Some authors have suggested that these antibodies directed against HIV proteins may protect SLE subjects from exogenous infection.

#### **4.2. Immune reconstitution inflammatory syndrome (IRIS)**

When ART is started, a striking immune restoration inflammatory response can appear. In this setting, there could be a predisposition to thrombotic events, as in the case reported as follows [**28**]. A 26-year-old HIV-infected man who had started HAART a few months earlier, developed multiple linear nodules following the superficial veins in both legs. Histopathologic examination demonstrated a mostly septal panniculitis with features of superficial thrombophlebitis. Authors propose that superficial thrombophlebitis should be added to the list of clinical manifestations of this newly observed immune reconstitution disease.

#### **4.3. Acute coronary artery disease and non-bacterial thrombotic endocarditis**

In addition to the issues referred above, protease inhibitors [**29**] have also been implicated in direct endothelial damage, which may be mediated by reduced nitric oxide production or release. The development of CVD risk factors such as insulin resistance, hyperlipidemia and fat redistribution syndrome, may exacerbate already existing underlying atherosclerotic risk in patients using these medications. However, necropsy studies de- monstrated *premature CVD in HIV-infected patients even before the advent of protease inhibitors*, indicating that other mechanisms might be involved independent of these drugs.

Other authors could not demonstrate relation between a patient's human immunodeficiency virus status and valve thrombosis [**30**] or non-bacterial thrombotic endocarditis [**31**].

#### **4.4. Non cirrhotic portal hypertension**

228 Immunodeficiency

**4. Specific settings for thrombotic events** 

[**27**]. Clinical challenges can arise when the two conditions coexist.

association with human T cell lymphotropic virus type 3 infection.

mechanism between inflammatory factors and common nuclear antibodies.

**4.2. Immune reconstitution inflammatory syndrome (IRIS)** 

Autoimmune disturbances have emerged in the setting of immunological reconstitution and constant antigenic viral stimulation in HIV-infected patients. Different types of autoantibodies have been observed, including aCL, anti-Beta2-glycoprotein I and antiprothrombin antibodies

Lupus anticoagulants were first described in AIDS and asymptomatic HIV-infected individuals (in whom they could be transient), by Bloom et al. in 1986. The association between aCL and HIV infection in men who have sex with men was reported in 1991. Falco et al., in 1993, found that, on the contrary to systemic lupus erythematosus (SLE), in the HIV-positive serum samples, reduced aCL binding capacity was evident if the cofactor (beta2-glycoprotein I) was added. Canoso et al. reported in 1997, aCL positivity in

The presence of SLE and HIV infection in the same individual is being increasingly reported, particularly in Africa and Asia. This coexistence has been associated with remissions or amelioration of SLE symptoms, with advancing HIV infection during pre-Highly Active ART (HAART) era (before 1996 and introduction of protease inhibitors); or with flares in immune reconstitution, during effective HAART, through a cross-reactive

Overlapping features between SLE and HIV infection can include: arthralgias and arthritis, polyclonal B cell activation, antibodies against double-stranded DNA, anti-Smith antibodies, antiphospholipid antibodies and autoimmune haemolytic anemia with positive Coombs test; however, low complement has not been detected in HIV infection. In addition, patients with SLE without previous exposure to retroviral infection may express antibodies against retroviral proteins, including gag, env, nef and p24 of HIV-1, with false-positive results of ELISA and Western blot for detection of HIV. Some authors have suggested that these antibodies directed against HIV proteins may protect SLE

When ART is started, a striking immune restoration inflammatory response can appear. In this setting, there could be a predisposition to thrombotic events, as in the case reported as follows [**28**]. A 26-year-old HIV-infected man who had started HAART a few months earlier, developed multiple linear nodules following the superficial veins in both legs. Histopathologic examination demonstrated a mostly septal panniculitis with features of superficial thrombophlebitis. Authors propose that superficial thrombophlebitis should be added to the list of clinical manifestations of this newly observed immune reconstitution

**4.1. Autoimmune background** 

subjects from exogenous infection.

disease.

A multifactorial mechanism has been proposed to explain the pathogenesis of noncirrhotic portal hypertension (NCPH) in HIV-infected patients, and we have reviewed it and described two cases, in a previous published paper [**32**]: prothrombotic state, by HIV as a direct cause or through anti-protein S antibodies, leading to protein S deficiency; as well as didanosine, an ARTdrug, adenosine analogue, which has been postulated as an independent predictor of developing NCPH through cumulative dosing or idiosyncratic mechanisms. It results in an obliteration of the small portal venules and liver regenerative hyperplasia. Considering the data regarding prothrombotic abnormalities in HIV-infected patients, we wondered if patients with HIV and NCPH should be evaluated for hypercoagulate state.

#### **4.5. Pregnancy-puerperium**

Annual incidence of VTE within 3 months postpartum in a cohort of 41 consecutive HIVinfected pregnant women [33], was 313 per 1000 person-years (95% CI, 65- 915). This risk is 120-fold higher than in HIV-positive controls, whereas the risk is 157-fold higher compared to HIV-negative pregnant women.

#### **4.6. Other settings**

Thrombophilia might have a limited role in the development of osteonecrosis in HIVpositive, according a case - control study [34], being only significantly associated with osteonecrosis: nadir of CD4(+) < 60 cells/microL and steroid use.

#### **5. Management**

Notably, the 2008 American College of Chest Physicians (ACCP) guidelines on antithrombotic and thrombolytic therapy, are silent regarding HIV-infected patients [**35**]. Anyway, the management of proven VTE should be the same as for the non HIV-patients [**3**].

Some special issues must be considered:

#### **5.1. Antiretroviral therapy and warfarin drug interaction**

Interactions between warfarin and ART (non-nucleoside reverse transcriptase inhibitors-NNRTIs and protease inhibitors-PIs), are through influence of ART on CYP2C9, the enzyme responsible for the metabolism of the more active S-enantiomer of warfarin [3]. Among the NNRTIs, induction of warfarin metabolism is likely with nevirapine. Inhibition of warfarin metabolism may occur with efavirenz o etravirine. Interactions involving ritonavir-boosted PIs are most frequent when warfarin is initiated in patients receiving concurrent efavirenz therapy [**36**]. International Normalized Ratio (INR) response should be used to guide warfarin dosage requirements; otherwise, low-molecular-weight heparin (LMWH) could be considered as a safer choice, although always keeping in mind that HIV infection may be an independent risk factor for the development of heparin-induced thrombocytopenia (HIT).

HIV-Infected Patients and Potential Impact on Thrombotic Events 231




traditional screening methods and management strategies applicable in HIV?

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

*Novoa Santos, Sanitary Area of Ferrol, A Coruña, Spain* 

J Hematol Infect Dis 2011; 3; Open Journal System.

*Infectious Diseases Unit, Department of Internal Medicine, Hospital Arquitecto Marcide-Profesor* 

[1] Ahonkhai AA, Gebo KA, Streiff MB et al. Venous thromboembolism in patients with HIV/AIDS: a case-control study. J. Acquir Immune Defic Syndr 2008; 48 (3):

[2] Jacobson MC, Dezube BJ, Aboulafia DM et al. Thrombotic complications in patients infected with HIV in the era of Highly Active Antiretroviral Therapy: a case series. CID

[3] Bibas M., Biava G. and Antinori A. HIV-associated venous thromboembolism. Mediterr

[4] Lijfering WM, Sprenger HG, Georg RR et al. Relationship between progression to AIDS and thrombophilic abnormalities in HIV infection. Clin Chem 2008; 54 (7): 1226-33. [5] Saif M and Greenberg B. HIV and thrombosis: a review. Aids Patient Care STDS 2001;

[6] Santos JL, Cruz I, Martín F et al. Trombosis coronaria recurrente, síndrome antifosfolípido primario, factor V Leiden y virus de la inmunodeficiencia humana. Rev

[7] Ramos-Casals M, Cervera R, Lagrutta M et al. Clinical features related to antiphospholipid syndrome in patients with chronic viral infections (hepatitis C

[8] Bernasconi E, Uhr M, Magenta L et al. Homocysteinaemia in HIV-infected patients treated with highly active antiretroviral therapy. AIDS 2001;15 (8): 1081-1082.

virus/HIV infection): description of 82 cases. CID 2004; 38: 1009-1016.

anticoagulation?

it?

**Author details** 

**7. References** 

310-4.

2004; 39: 1214-1222.

15 (1): 15-24.

Esp Cardiol 2004; 57 (10): 997-9.

#### **5.2. Warfarin-induced skin necrosis (WISN)**

The presentation of WISN, a condition due to decrease protein C levels by warfarin, in HIV-1 infected patients, is a novel clinical entity, reported recently [**37**]. Six cases of WISN occurred in 973 patients receiving warfarin therapy for venous thrombosis (0.62%, 95% CI 0.25 - 1.37%) at a referral hospital in Cape Town, South Africa. All 6 cases occurred in HIV-1 infected women (median age 30 years, range 27 - 42) with microbiologically confirmed tuberculosis (TB) and venous thrombosis. All were profoundly immunosuppressed (median CD4+ count at TB diagnosis 49 cells/microl, interquartile range 23 - 170). Of the 3 patients receiving combination ART, 2 had TB-IRIS. The occurrence of 6 WISN cases in a 40-month period may be attributed to: hypercoagulability secondary to HIV-1(above all if associated to decreased protein C levels) and TB, short concurrent heparin and warfarin therapy and high loading doses of warfarin. Active prevention and appropriate management of WISN are likely to improve the morbidity and mortality of this unusual condition.
