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Clinical Chemistry 54: 1226-1233, 2008. First published May 1, 2008; 10.1373/clinchem.2008.103614
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Right arrow Hemostasis and Thrombosis
(Clinical Chemistry. 2008;54:1226-1233.)
© 2008 American Association for Clinical Chemistry, Inc.

Hemostasis and Thrombosis

Relationship between Progression to AIDS and Thrombophilic Abnormalities in HIV Infection

Willem M. Lijfering1,a, Herman G. Sprenger2, Rita R. Georg2, Piet A. van der Meulen2 and Jan van der Meer1

1 Division of Haemostasis, Thrombosis and Rheology and 2 Division of Infectious Diseases, Department of Internal Medicine, University Medical Center Groningen (UMCG), Groningen, The Netherlands.

aAddress correspondence to this author at: Division of Haemostasis, Thrombosis and Rheology, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. Fax 31-50-3611790; e-mail w.lijfering{at}int.umcg.nl.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: HIV-infected patients are at increased risk of venous and arterial thrombosis. We hypothesized that acquired thrombophilic abnormalities that could predispose to thrombosis are most pronounced in patients in advanced stages of HIV infection.

Methods: We included 109 consecutive HIV-infected patients in the study and tested them twice for currently known thrombophilic abnormalities at an interval of at least 3 months (median, 3 months; range, 3–12 months). Detailed information was collected about the date of diagnosis of HIV infection, HIV treatment, and previous episodes of venous and arterial thrombosis.

Results: After HIV infection was diagnosed, 16% of the patients experienced symptomatic thrombosis (venous, 10%; arterial, 6%). Repeated measurements established protein C deficiency in 9% of the patients, increased factor VIII concentrations in 41%, high fibrinogen concentrations in 22%, and free protein S deficiency in 60%. Median factor VIII concentrations were higher in patients with AIDS (CD4 cell counts <2 x 108/L) than in patients with a non–AIDS-defining illness (2260 IU/L vs 1 490 IU/L; P < 0.001), whereas median free protein S concentrations were lower (450 IU/L vs 580 IU/L; P < 0.001). Developing AIDS was associated with increasing factor VIII concentrations and decreasing free protein S concentrations. Increasing factor VIII concentrations were correlated with increasing fibrinogen concentrations and decreasing free protein S concentrations.

Conclusions: Multiple acquired and persistent thrombophilic abnormalities are more frequently observed in HIV-infected patients than in the healthy population. The frequencies of these thrombophilic abnormalities increase with the progression to AIDS. These findings may contribute to the high prevalence of venous and arterial thrombosis in HIV-infected patients.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Several reports have documented an increased risk of venous and arterial thrombosis in HIV-infected patients (1)(2)(3)(4). Patients with AIDS, as documented by CD4 cell counts <2 x 108/L, have a higher risk of thrombosis than HIV-infected patients with a more robust immune system (5)(6)(7). Why HIV-infected patients are at higher risk for thrombosis is largely unknown. A link between infection and thrombosis via endothelial activation has been suggested (8)(9). The same cytokines responsible for endothelial activation are up-regulated during the course of HIV infection (10)(11). These cytokines, including tumor necrosis factor {alpha}, interleukin-1, and interleukin-6, activate coagulation and down-regulate the production of fibrinolytic proteins (12)(13). Increased concentrations of procoagulant proteins and decreased concentrations of anticoagulant proteins have been identified as risk factors for venous and arterial thrombosis (14)(15)(16)(17)(18). Of these proteins, factor VIII and fibrinogen are acute-phase proteins (15)(16) that become risk factors when their concentrations remain increased for a prolonged time (16)(17). Low concentrations of protein C have been reported in various infections, possibly because of the consumption of protein C in its role as an antiinflammatory mediator (19). Inherited protein C deficiency is a strong risk factor for venous thrombosis (18), but whether acquired deficiency is also a risk factor is unknown. Inherited protein S deficiency is another risk factor for venous thrombosis, and possibly for arterial thrombosis as well (16)(18). Approximately 60% of protein S is bound to complement C4b–binding protein, but only free protein S is active as an anticoagulant (20). During infections, the concentration of C4b-binding protein increases up to 400% of its typical concentration (20). Some small studies have shown decreased concentrations of both protein S and protein C in HIV-infected patients (21)(22)(23). Recently, a larger study of 94 HIV-infected women showed that an advancing HIV infection was associated with high factor VIII concentrations and a decrease in protein S activity (24); however, all of the women in this study were tested only once.

We studied a group of HIV-infected patients primarily to ascertain whether progression to AIDS was associated with an increased frequency and/or severity of thrombophilic abnormalities and secondarily to determine the overall risk of venous and arterial thrombosis in HIV-infected patients.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
patients
Between May 2006 and December 2006, we asked 120 consecutive HIV-infected patients treated at the outpatient clinic of our university hospital to participate in our study. The study was approved by the institutional review board of our hospital, and informed consent was obtained from all of the participants. Detailed information about the date of HIV diagnosis, HIV status, HIV treatment, previous episodes of venous and arterial thrombosis, exposure to risk factors for thrombosis, and anticoagulant treatment was retrospectively collected by physicians at the outpatient clinic via a questionnaire and review of medical records. In women, the use of oral contraceptives and their obstetric histories were also documented, considering that oral contraceptives and pregnancy are risk factors for venous thrombosis and may be associated with thrombophilic abnormalities. Clinical data were collected before laboratory testing to avoid bias in assessing clinical outcome events. To determine whether HIV status was correlated with thrombophilic abnormalities, we simultaneously collected blood samples for measurements of CD4 cell counts and HIV RNA, and for thrombophilia testing. Thrombophilia tests included those for the following: deficiencies in antithrombin, protein C, total protein S, and free protein S; factor V Leiden; the prothrombin G20210A mutation; increased concentrations of fibrinogen and factor VIII; and lupus anticoagulant. We also measured anticardiolipin antibodies and measured C-reactive protein (CRP)1 to assess the effects of acute-phase inflammatory reactions. We repeated all tests with a second blood sample collected after an interval of at least 3 months (median, 3 months; range, 3–12 months) to confirm the concentrations of proteins and CD4 cell counts obtained in the first set of measurements.

laboratory studies
Lymphocyte subsets (CD3, CD4, CD8) were analyzed within 24 h of collection with standard flow cytometry techniques. Plasma concentrations of HIV RNA were measured with the NucliSENS HIV RNA assay (detection limit, 4 x 104 copies/L; Organon Teknika). CRP was measured by nephelometry (BN II; Dade Behring); CRP concentrations ≥5 mg/L were used to identify acute-phase inflammatory reactions. We measured the activities of antithrombin (COATEST; Chromogenix) and protein C (Berichrom Protein C; Behring) with chromogenic-substrate assays and measured the concentrations of protein C and protein S with ELISAs (Dako). We defined antithrombin deficiency as a decreased antithrombin activity (<650 IU/L), protein C deficiency as a decreased protein C antigen concentration (<650 IU/L) and/or activity (<650 IU/L), and protein S deficiency as decreased concentrations of total protein S antigen (<650 IU/L) and/or free protein S antigen (<650 IU/L), corresponding to plasma concentrations below the lower limit of their reference intervals (18). We used a 1-stage clotting assay (Amelung) to measure factor VIII:C. We considered a factor VIII:C concentration above 1 500 IU/L to be increased because this concentration has been identified to confer an increased risk of both venous and arterial thrombosis (15). Fibrinogen concentrations were measured according to the Clauss method (Baxter) and were considered increased at concentrations >3.5 g/L. Reference intervals were determined from measurements in healthy volunteers who had no personal or family history of venous thrombosis, were not pregnant, and had not used oral contraceptives during the preceding 3 months. PCR analyses were used to demonstrate factor V Leiden and prothrombin G20210A (25)(26). We used 3 different phospholipid-dependent coagulation tests to screen for lupus anticoagulant: the dilute Russell viper venom time, the activated partial thromboplastin time, and tissue thromboplastin inhibition (27). Tests that produced abnormal results were repeated with a 1:1 mixture of patient plasma to plasma from a healthy individual to exclude deficiencies in coagulation factors. If the test result remained abnormal, we confirmed phospholipid dependence with a phospholipid-neutralization test. We used Gradipore reagents (LA-screen and LA-confirm) for the dilute Russell viper venom time test, Actin FSL (Dade Behring) to measure the activated partial thromboplastin time, and Thromboplastin IS (Dade Behring) in 2 dilutions (1 part reagent plus 49 parts diluent and 1 part reagent plus 499 parts diluent) to measure tissue thromboplastin inhibition. The anticardiolipin ELISA was carried out with samples diluted 1 part reagent plus 99 parts diluent in PBS (140.0 mmol/L NaCl, 9.0 mmol/L Na2HPO4, and 1.3 mmol/L NaH2PO4, pH 7.4) containing 100 mL/L fetal calf serum. We performed duplicate measurements of 9 calibrators for IgG and IgM anticardiolipin antibodies (Louisville APL Diagnostics) according to the manufacturer’s instructions to prepare a calibration curve. Concentrations ≥4 x 104 IU/L were considered positive (27). Blood samples were taken from patients undergoing long-term anticoagulant treatment with vitamin K antagonists after treatment had been interrupted; nadroparin was administered subcutaneously in the meantime.

definitions
Patients were classified into 3 groups according to their HIV status (28). Patients with CD4 cell counts >5 x 108/L after repeated measurement were classified as having asymptomatic HIV infection; patients with CD4 cell counts between 2 x 108/L and 5 x 108/L were classified as having early symptomatic HIV disease; and patients with CD4 cell counts of <2 x 108/L were classified as having AIDS. Venous thrombosis was considered established if deep vein thrombosis was confirmed by compression ultrasound or venography, and pulmonary embolism was confirmed by ventilation and perfusion lung scanning, spiral computed tomography scanning, or pulmonary angiography. Coronary and peripheral arterial disease had to be symptomatic and angiographically proven, and myocardial infarction was diagnosed according to clinical, enzymatic, and electrocardiographic criteria. Ischemic stroke was defined as the onset of rapidly developing symptoms and signs of loss of cerebral function that lasted at least 24 h and had an apparent vascular cause, as demonstrated by computed tomography scanning or magnetic resonance imaging. If a cerebral event completely resolved within 24 h without the demonstration of cerebral lesions at scanning, it was classified as a transient ischemic attack. Risk factors for atherosclerosis included known diabetes mellitus, hyperlipidemia, hypertension, and active smoking.

statistical analysis
Data for continuous variables are expressed as medians and ranges, and categorical data are expressed as counts and percentages. Differences between groups were evaluated with the Student t-test or the Mann–Whitney U-test, depending on whether the data were normally distributed, for continuous data and with the Fisher exact test for categorical data. A 2-tailed P value of <0.05 was considered statistically significant. Medians and interquartile ranges for protein concentrations were calculated by group. The interquartile range included the 25th and 75th percentile values, which represented the variation in the data without undue emphasis on extreme values, which can occur when the data are highly skewed. In box plots, whiskers extended to 1.5 times the interquartile range. Annual incidences of venous and arterial thrombosis were calculated by dividing the number of events by the number of observation years. Observation time was defined as the period from the age of HIV diagnosis until the first thrombotic episode or until the end of the observation period. We ignored the occurrence of arterial thrombosis when calculating the annual incidence of venous thrombosis, and vice versa. We calculated 95% confidence intervals (CIs) around the incidence rates by assuming a Poisson distribution.

Because 2 blood samples were collected, we categorized our results as "single abnormality," indicating a specific result in at least one blood sample, and as "confirmed abnormality," indicating a specific result in both blood samples.

Statistical analyses were performed with SAS software (version 9.1; SAS Institute).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
We asked 120 consecutive HIV-infected patients to participate in the study. Two of these patients failed to provide informed consent, 4 refused collection of a second blood sample, 2 died (one from liver cell carcinoma and another from non-Hodgkin lymphoma in combination with deep vein thrombosis), and 3 were lost to follow-up for geographic reasons. The data for the remaining 109 patients were analyzed. The median interval between HIV diagnosis and the date of study entry was 5 years (range, 0–20 years). The clinical characteristics of the patient population are summarized in Table 1 . Sixty-six percent were men, and the median age at HIV diagnosis was 34 years (range, 16–73 years). Eleven patients (10%) were discovered to have venous thrombosis while they were HIV positive, and arterial thrombosis was found in 6 patients (6%). Seventy-five percent of the patients received highly active antiretroviral therapy (HAART). The median CD4 cell count was 4.3 x 108/L (range, 0.2–12.2 x 108/L) for the first blood sampling and 4.0 x 108/L (range, 0.3–12.2 x 108/L) for the second blood sampling, with an individual median difference of 0.6 x 108/L (range, 0–3.4 x 108/L) indicating stable CD4 cell counts during the study period. The median interval between the blood collections was 3 months (range, 3–12 months).


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  		Table 1. Clinical characteristics of 109 HIV-infected patients.1

Table 2 summarizes the results of the thrombophilia tests. We confirmed protein C deficiency in 9% of the patients, increased factor VIII concentrations in 41%, and increased fibrinogen concentrations in 22%. After excluding patients with CRP concentrations ≥5 mg/L, we confirmed increased factor VIII and fibrinogen concentrations in 31% and 15% of the patients, respectively. Free protein S deficiency was demonstrated in 74% of the patients and confirmed in 60%. This result was not confounded by oral contraceptive use or pregnancy. None of the female patients used oral contraceptives, were pregnant, or were within 6 months of delivery. The use of oral contraceptives was discouraged because their interactions with antiretroviral therapy make oral contraceptives less reliable. The most frequent thrombophilic abnormalities were analyzed further. Over the entire study period, the median fibrinogen, factor VIII, and free protein S concentrations were 3.6 g/L (range, 1.9–5.5 g/L), 2260 IU/L (range, 1160–3700 IU/L), and 450 IU/L (range, 200–610 IU/L), respectively, in patients with AIDS-defining illness (CD4 cell count <2 x 108/L), vs 2.9 g/L (range, 1.9–5.8 g/L; P = 0.062), 1490 IU/L (range, 480–3920 IU/L; P < 0.001), and 580 IU/L (range, 130–1210 IU/L; P < 0.001), respectively, in patients with non–AIDS-defining illness (CD4 cell count ≥2 x 108/L) (Table 3 ). The prevalences of persistent increased fibrinogen concentrations (P = 0.006), increased factor VIII concentrations (P < 0.001), and free protein S deficiency (P < 0.001) were higher in patients with AIDS than in those with non–AIDS-defining illness.


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  		Table 2. Thrombophilic abnormalities in 109 HIV-infected patients.1


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  		Table 3. Thrombophilic abnormalities related to HIV status.1

At more advanced stages of HIV infection (CD4 cell counts >5 x 108/L vs 2–5 x 108/L vs <2 x 108/L), factor VIII concentrations were significantly higher, whereas free protein S concentrations were significantly lower (Fig. 1 ). The difference was less pronounced for fibrinogen concentrations and was statistically significant only when asymptomatic HIV patients were compared with AIDS patients (P = 0.027). A positive relationship was observed between increasing factor VIII and fibrinogen concentrations, whereas an inverse relationship was observed between increasing factor VIII concentrations and decreasing free protein S concentrations (Fig. 2 ).


Figure 1
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  		Figure 1. The relationship of factor VIII, fibrinogen, and free protein S concentrations to CD4 cell counts in HIV-infected patients.

Data are presented as box-and-whisker plots. The horizontal line within each box represents the median value; the lower and the upper sides of each box represent the first and third quartile, respectively; whiskers are extended to 1.5 times the box width (the interquartile range) and connect the values outside the box within 1.5 interquartile ranges. Dashed horizontal lines represent mean reference concentrations bracketed by the upper and lower limits of reference intervals. The exclusion of results from patients with thrombosis (an asterisk indicates the median concentration) did not alter the results.


Figure 2
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  		Figure 2. Fibrinogen and free protein S concentrations in HIV-infected patients related to factor VIII (FVIII) concentrations.

Data are presented as box-and-whisker plots. The horizontal line within each box represents the median value; the lower and the upper sides of each box represent the first and third quartile, respectively; whiskers are extended to 1.5 times the box width (the interquartile range) and connect the values outside the box within 1.5 interquartile ranges. Dashed lines indicate the mean concentration in the reference (i.e., healthy) population. Excluding patients with thrombosis did not alter the results.

The overall annual incidences of venous thrombosis and arterial thrombosis were 1.61% (95% CI, 0.81%–2.89%) and 0.87% (95% CI, 0.32%–1.88%), respectively. The median age at the time of the first event was 45 years (range, 22–56 years) for venous thrombosis and 53 years (range, 44–59 years) for arterial thrombosis. The median intervals between the onset of venous thrombosis and arterial thrombosis and the time of collection of the first blood sample were 3.2 years (range, 0–11 years) and 5.0 years (range, 1.7–14.1 years), respectively. In a univariate analysis, smoking, hyperlipidemia, hypertension, and diabetes mellitus were not associated with thrombophilic abnormalities.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We confirmed protein C deficiency in 9% of the HIV-infected patients, increased factor VIII concentrations in 41%, increased fibrinogen concentrations in 22%, and free protein S deficiency in 60%. After excluding patients with high CRP concentrations, these prevalences remained high compared with those in the healthy population, which exhibits a <0.4% prevalence for protein C deficiency and a 10% prevalence for increased factor VIII or fibrinogen concentration. The prevalence of a deficiency in free protein S in this population is unknown (14)(17). Conversely, lupus anticoagulant and anticardiolipin antibodies were not observed as frequently as in previous studies, which reported lupus anticoagulant in 60% of HIV-infected patients and anticardiolipin antibodies in 90% (29)(30). These studies were of small populations, however, and did not follow the current strict guidelines for classifying anticardiolipin antibody and lupus anticoagulant concentrations as positive (27). Our finding is in agreement with a more recent study of HIV-infected patients, none of whom was demonstrated to have lupus anticoagulant (24).

We observed a clear relationship between advancing HIV disease and an increase in thrombophilic abnormalities. Patients with AIDS more often had increased factor VIII concentrations, increased fibrinogen concentrations, and free protein S deficiency than patients with non–AIDS-defining illness. These differences may be due to the HIV disease itself, considering that the same cytokines that activate the coagulation system have been described in the setting of progressive HIV (10)(11). Both increased factor VIII concentrations and increased fibrinogen concentrations have been associated with an increased risk of venous and arterial thrombosis (15)(16)(17). Such an association has not been reported for acquired deficiencies in protein C and free protein S. It is remarkable, however, that the combination of high factor VIII and fibrinogen concentrations and decreased free protein S concentrations has been reported in patients with systemic lupus erythematosus (31) and other autoimmune diseases (32), in patients with cytomegalovirus infections (33), and in patients with the nephrotic syndrome (34), conditions that are all associated with an increased risk of venous and arterial thrombosis (31)(32)(33)(34). These thrombophilic abnormalities suggest a link between venous and arterial thrombosis, which has recently been proposed (35). Because of the small numbers of observations, we could not perform a proper multivariate analysis of classic cardiovascular risk factors; however, our patients often had hyperlipidemia or hypertension, which was unusual considering their young median age, and a striking number of the patients were smokers, which is in accordance with the observations of other studies (4)(5).

Sixteen percent of our cohort of 109 consecutive patients with HIV experienced thrombosis during a median follow-up period of 5 years; venous events were documented in 10% of the patients, arterial events in 6%. The annual incidences of venous thrombosis (1.61%) and arterial thrombosis (0.87%) were 5- to 16-fold higher and 2- to 8-fold higher, respectively, than in the healthy population (i.e., 0.1%–0.3% and 0.1%–0.4%) (36)(37)(38). 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 (39), and the median age for arterial thrombosis onset was 53 years, a decade earlier than that documented in the Framingham study (38). Although these results should be interpreted cautiously because of the small size of the study population, they do suggest that HIV-infected patients are at high risk of venous and arterial thrombosis, as has also been demonstrated in other studies (1)(2)(3)(4).

Although our study was of a relatively small number of patients, it is the largest to date that has analyzed acquired thrombophilic abnormalities in HIV-infected patients. Our finding that the development of AIDS was associated with increasing thrombophilic abnormalities may have clinical relevance. HAART is used for (long-term) immunologic reconstitution, which may improve these thrombophilic abnormalities and lead to a decreased risk of venous and arterial thrombosis. Indeed, one study has shown a decreased risk of arterial thrombosis or death in more than 36 000 HIV-infected patients who received HAART (4). Another study reported a decrease in the concentrations of von Willebrand factor, a carrier of factor VIII, after HIV-infected patients began HAART (40). Larger prospective studies that address endothelial activation markers and thrombophilic abnormalities in HIV-infected patients may clarify the relationship between HIV infection and venous thrombosis and the association between venous and arterial thrombosis. Our data suggest that such a link in HIV-infected patients is plausible. Because it is not common practice to screen for thrombophilia in HIV-infected patients, the medical charts often did not provide sufficient information about CD4 cell counts in patients at the time of thrombosis, and therefore we are unable to comment on CD4 cell counts and/or thrombophilic abnormalities at the time of thrombosis in our study. Our small numbers did not enable us to compare the risk of thrombosis in subgroups. Other studies, however, have shown the risk of venous thrombosis to be highest in patients with AIDS, with an odds ratio of 29.9 (95% CI, 3.6–246.3) in patients with AIDS vs patients with non–AIDS-defining illness (5)(6)(7), whereas free protein S deficiency and increased factor VIII concentrations have been reported in 78%–100% of HIV-infected patients at the time of venous thrombosis (3), in apparent agreement with our findings. A further limitation of our data is that patients infected with HIV are a heterogeneous group who have higher rates of coinfections compared with the healthy population, and this factor might have contributed to thrombophilic abnormalities as well. An analysis of these variables was beyond the scope of our study.

We conclude that HIV-infected patients have a higher prevalence of thrombophilic abnormalities and more persistent thrombophilic abnormalities than the healthy population. These abnormalities increase with the development of AIDS and may contribute to the high prevalence of venous and arterial thrombosis in HIV-infected patients.


   Acknowledgments
 
Grant/Funding Support: None declared.

Financial Disclosures: None declared.


   Footnotes
 
1 Nonstandard abbreviations: CRP, C-reactive protein; CI, confidence interval; HAART, highly active antiretroviral therapy.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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W. M. Lijfering, R. Mulder, M. K. ten Kate, N. J. G. M. Veeger, A. B. Mulder, and J. van der Meer
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