scholarly journals Relationship between Progression to AIDS and Thrombophilic Abnormalities in HIV Infection

2008 ◽  
Vol 54 (7) ◽  
pp. 1226-1233 ◽  
Author(s):  
Willem M Lijfering ◽  
Herman G Sprenger ◽  
Rita R Georg ◽  
Piet A van der Meulen ◽  
Jan van der Meer
Keyword(s):  
Hiv Infection ◽  
Factor Viii ◽  
Arterial Thrombosis ◽  
Protein S ◽  
Hiv Treatment ◽  
Repeated Measurements ◽  
Healthy Population ◽  
Free Protein ◽  
Cell Counts ◽  
Increased Risk

Abstract 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 × 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.

Severe Arterial Cerebral Thrombosis in a Patient with Protein S Deficiency (Moderately Reduced Total and Markedly Reduced Free Protein S): A Family Study

1989 ◽  
Vol 61 (01) ◽  
pp. 144-147 ◽  
Author(s):  
A Girolami ◽  
P Simioni ◽  
A R Lazzaro ◽  
I Cordiano
Keyword(s):  
Arterial Thrombosis ◽  
Protein C ◽  
Protein S ◽  
Protein S Deficiency ◽  
Protein C Deficiency ◽  
Free Protein ◽  
Her Family ◽  
S Deficiency ◽  
Increased Risk ◽  
Patient Reported

SummaryDeficiency of protein S has been associated with an increased risk of thrombotic disease as already shown for protein C deficiency. Deficiencies of any of these two proteins predispose to venous thrombosis but have been only rarely associated with arterial thrombosis.In this study we describe a case of severe cerebral arterial thrombosis in a 44-year old woman with protein S deficiency. The defect was characterized by moderately reduced levels of total and markedly reduced levels of free protein S. C4b-bp level was normal. Protein C, AT III and routine coagulation tests were within the normal limits.In her family two other members showed the same defect. All the affected members had venous thrombotic manifestations, two of them at a relatively young age. No other risk factors for thrombotic episodes were present in the family members. The patient reported was treated with ASA and dipyridamole and so far there were no relapses.

Associations Between Free Protein S and Factor VIII Levels with Traditional Arterial Thrombotic Risk Factors and Their Risk On Arterial Thrombosis. Results From a Retrospective Family Cohort Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 25-25
Author(s):  
René Mulder ◽  
Inge M van Schouwenburg ◽  
Bakhtawar Khan Mahmoodi ◽  
Nic J.G.M. Veeger ◽  
André B Mulder ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Risk Factors ◽  
Cohort Study ◽  
Factor Viii ◽  
Arterial Thrombosis ◽  
Protein S ◽  
Cumulative Distribution ◽  
Thrombotic Risk ◽  
Free Protein ◽  
Age And Sex

Abstract Abstract 25 Introduction: Accumulating evidence shows that venous and arterial thrombosis may be viewed as two diseases with similar pathophysiological entities. Both high factor VIII and low free protein S levels are risk factors for venous thrombosis, but if, and in what way, these thrombophilic factors also increase the risk of arterial thrombosis is unknown. Patients and Methods: In a single-center retrospective cohort study of families with thrombophilia, we performed a post-hoc analysis to identify if relatives with high factor VIII or low free protein S levels were at risk of arterial thrombosis. Clinical data were collected before laboratory testing. To avoid bias, all probands were excluded from the analyses. In addition, relatives with protein S deficiency type I were excluded from analysis when analyzing effects of free protein S. Factor VIII:C levels were measured by one-stage clotting assays and were considered increased at levels above 150 IU/dL. Free protein S antigen levels were measured by enzyme-linked immunosorbent assay after precipitation of protein S complexed with C4b-binding protein with polyethylene glycol. Free protein S antigen levels were considered decreased at levels below the normal range (< 65 IU/dL). Coronary and peripheral arterial disease had to be symptomatic and angiographically proven, whereas myocardial infarction was diagnosed according to clinical, enzymatic and electrocardiographic criteria. Known risk factors for arterial thrombosis were recorded and included: hypertension, hyperlipidemia, the presence of diabetes mellitus, smoking habits or obesity. Absolute risks of first arterial thrombosis in relatives with high factor VIII or low free protein S levels were calculated. Linear regression was used to determine the relation between factor VIII levels and free protein S levels, respectively, combined with traditional arterial thrombotic risk factors. Adjustments were made for age and sex. Cumulative distribution functions were constructed to visualize a possible relationship between factor VIII and free protein S levels, respectively, and BMI Results: Of 1468 relatives tested for thrombophilia, 1399 were analyzed on factor VIII and 1143 on free protein S. Forty-six percent were male. Mean age at enrollment was 45 years. Mean factor VIII level was 146 IU/dL and mean free protein S level 80 IU/dL. High factor VIII levels were observed in 39% of relatives and low free protein S levels in 23% of relatives. First arterial thrombotic events were documented in 86 relatives at a mean age of 57 years. Annual incidence of arterial thrombosis in relatives with high factor VIII levels was 0.29% (95%CI, 0.22-0.38) compared to 0.13% (95%CI, 0.09-0.19) in relatives with normal factor VIII levels. In relatives with low free protein S levels, this risk was 0.26% (95%CI, 0.16-0.40), compared to 0.14% (95%CI, 0.10-0.20) in relatives with normal free protein S levels. Relatives with hypertension, diabetes mellitus, and obesity had mean factor VIII levels (age and sex adjusted) that were 11 IU/dL, 18 IU/dL, and 21 IU/dL higher than relatives without these arterial thrombotic risk factors, which were statitically significant findings. In addition, a dose response relation could be demonstrated between increasing factor VIII and body mass index (Figure). None of these associations were shown for free protein S. Conclusions: Both high factor VIII and low free protein S levels were a risk factor for arterial thrombosis in thrombophilic families. High factor VIII levels were particularly observed in relatives with traditional arterial thrombotic risk factors, suggesting that increase of these levels were acquired. Free protein S levels were not influenced by these arterial thrombotic risk factors which assumes that low free protein S levels were genetically determined. Disclosures: No relevant conflicts of interest to declare.

Increased Prothrombotic State in Patients with Advancing HIV Disease.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2274-2274
Author(s):  
Willem M. Lijfering ◽  
Herman G. Sprenger ◽  
Rita R. Georg ◽  
Piet A. van der Meulen ◽  
Jan van der Meer
Keyword(s):  
Factor Viii ◽  
Arterial Thrombosis ◽  
Protein C ◽  
Normal Population ◽  
Protein S ◽  
Time Interval ◽  
Hiv Disease ◽  
Prothrombotic State ◽  
Free Protein ◽  
S Deficiency

Abstract HIV-infected patients are at high risk for venous and arterial thrombosis. We hypothesized that advancing stages of HIV are associated with thrombophilic abnormalities that could predispose to thrombosis. A total of 109 consecutive HIV infected patients were included in the study and twice screened for currently known thrombophilic defects with a time interval of at least 3 months. Ten percent of HIV infected patients had confirmed decreased protein C levels (< 65 IU/dL), 41% had confirmed elevated factor VIII levels (> 150 IU/dL), 22% had confirmed high fibrinogen levels (> 3.5 g/L) and 60% had a confirmed free protein S deficiency (< 65 IU/dL). Median factor VIII levels were higher in patients with AIDS defining illness compared to non AIDS defining illness (226 IU/dL versus 149 IU/dL; P< 0.001), while median free protein S levels were lower in these subgroups (45 IU/dL, versus 58 IU/dL; P< 0.001). Advancing HIV, stratified by CD4 levels of > 500 cells/μL, 200–500 cells/μL or < 500 cells/μL, respectively, was associated with increasing factor VIII levels, fibrinogen levels and decreasing free protein S levels (Figure 1). When factor VIII levels were < 100 IU/dL, median fibrinogen levels were 2.4 g/L, which was 0.3 g/L lower than when factor VIII levels were 100–150 IU/dL (P=0.033) and 0.9 g/L lower than when factor VIII levels were > 150 IU/dL (P< 0.001). Free protein S levels were 70 IU/dL when factor VIII levels were < 100 IU/dL, which decreased to 60 IU/dL when factor VIII levels were 100–150 IU/dL (P=0.010) and to 52 IU/dL when factor VIII levels were > 150 IU/dL (P< 0.001). We conclude that HIV infected patients have multiple prolonged thrombophilic abnormalities compared to the normal population, which increase with advancing HIV disease, thus providing a biologic mechanism for the increased prevalence of venous and arterial thrombosis in HIV. Figure Figure

Absolute risk of venous and arterial thromboembolism in thrombophilic families is not increased by high thrombin-activatable fibrinolysis inhibitor (TAFI) levels

2008 ◽  
Vol 100 (07) ◽  
pp. 38-44 ◽  
Author(s):  
Michiel Coppens ◽  
Nic J. G. M. veeger ◽  
Victor J. J. Bom ◽  
Saskia Middeldorp ◽  
Karly Hamulyak ◽  
...  
Keyword(s):  
Factor Viii ◽  
Arterial Thrombosis ◽  
Absolute Risk ◽  
Protein S ◽  
Adjusted Relative Risk ◽  
Thrombin Activatable Fibrinolysis Inhibitor ◽  
Arterial Thromboembolism ◽  
Increased Risk ◽  
Fibrinolysis Inhibitor ◽  
Prothrombin 20210A

SummaryHigh levels of thrombin-activatable fibrinolysis inhibitor (TAFI) are a supposed risk factor for thrombosis. However, results from previous studies are conflicting. We assessed the absolute risk of venous and arterial thromboembolism in subjects with high TAFI levels (>126 U/dl) versus subjects with normal levels, and the contribution of other concomitant thrombophilic defects. Relatives from four identical cohort studies in families with either deficiencies of antithrombin, protein C or protein S, prothrombin 20210A, high factor VIII levels, or hyperhomocysteinemia were pooled. Probands were excluded. Of 1,940 relatives, 187 had high TAFI levels. Annual incidences of venous thromboembolism were 0.23% in relatives with high TAFI levels versus 0.26% in relatives with normal TAFI levels (adjusted relative risk [RR] 0.8; 95% confidence interval [CI], 0.5–1.3). For arterial thrombosis these were 0.31% versus 0.23% (adjusted RR 1.4; 95% CI, 0.9–2.2). High levels of factor VIII, IX and XI were observed more frequently in relatives with high TAFI levels. Only high factor VIII levels were associated with an increased risk of venous and arterial thrombosis, independently of TAFI levels. None of these concomitant defects showed interaction with high TAFI levels. High TAFI levels were not associated with an increased risk of venous and arterial thromboembolism in thrombophilic families.

scholarly journals Differential haemostatic risk factors for pregnancy-related deep-vein thrombosis and pulmonary embolism

2012 ◽  
Vol 108 (12) ◽  
pp. 1165-1171 ◽  
Author(s):  
Anders Dahm ◽  
Anne Flem Jacobsen ◽  
Leiv Sandvik ◽  
Per Morten Sandset ◽  
Astrid Bergrem
Keyword(s):  
Risk Factors ◽  
Pulmonary Embolism ◽  
Deep Vein Thrombosis ◽  
Factor Viii ◽  
Protein S ◽  
Factor Ix ◽  
Free Protein ◽  
Vein Thrombosis ◽  
Increased Risk ◽  
Deep Vein

SummaryLimited data exist on thrombophilia and the risk of venous thrombosis (VT) during pregnancy and postpartum. The objectives of the present study were to investigate the role of haemostatic risk factors for pregnancy-related VT and their phenotypic expression in deep-vein thrombosis (DVT) and pulmonary embolism (PE). Total 313 cases with objectively verified first time VT and 353 controls were selected from a source population of 377,155 women with 613,232 pregnancies. The adjusted odds ratio (aOR) for pregnancy-related VT was 1.7 (95% confidence interval [CI] 1.1–2.8) for women with factor VIII >90th percentile. The aOR for VT for endogenous thrombin potential and D-dimer values >90thpercentiles were 1.8 (95% CI 1.1–3.0) and 2.1 (95% CI 1.3–3.3), respectively. Factor IX >90thpercentile or free protein S ≤the 5th percentile increased the risk for PE, and the aORs were 2.4 (95% CI 1.1–5.0) and 3.1 (95% CI 1.3–7.2), respectively. Women carrying the factor V Leiden (F5 rs6025) polymorphism, or who had reduced sensitivity to activated protein C (aPC) in the absence of F5 rs6025, had increased risk for DVT, with unadjusted ORs 7.7 (95% CI 4.7–12.7) and 3.5 (95% CI 2.2–5.4), respectively. Women with a history of pregnancy-related VT showed activation of coagulation and had elevated factor VIII. Furthermore, high levels of factor IX and low levels of free protein S were associated with increased risk for PE, whereas aPC resistance and F5 rs6025 were risk factors for DVT and not PE.

Associations between high factor VIII and low free protein S levels with traditional arterial thrombotic risk factors and their risk on arterial thrombosis: Results from a retrospective family cohort study

2010 ◽  
Vol 126 (4) ◽  
pp. e249-e254 ◽  
Author(s):  
René Mulder ◽  
Inge M. van Schouwenburg ◽  
Bakhtawar K. Mahmoodi ◽  
Nic J.G.M. Veeger ◽  
André B. Mulder ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cohort Study ◽  
Factor Viii ◽  
Arterial Thrombosis ◽  
Protein S ◽  
Thrombotic Risk ◽  
Free Protein

The Ser460Pro mutation in recombinant protein S Heerlen does not affect its APC-cofactor and APC-independent anticoagulant activities

2004 ◽  
Vol 91 (06) ◽  
pp. 1105-1114 ◽  
Author(s):  
Rory Koenen ◽  
Lucio Gomes ◽  
Guido Tans ◽  
Jan Rosing ◽  
Tilman Hackeng
Keyword(s):  
Recombinant Protein ◽  
Vitamin K ◽  
Dissociation Constants ◽  
Anticoagulant Activity ◽  
Protein S ◽  
Wild Type ◽  
Free Protein ◽  
Increased Risk ◽  
Plasma Factor ◽  
Thrombotic Complications

SummaryProtein S is a vitamin K-dependent plasma protein that functions as an APC-cofactor, but also exhibits anticoagulant activity in the absence of APC. The Heerlen polymorphism of protein S is characterized by a Ser460Pro substitution and lacks glycosylation at Asn458. It is associated with decreased protein S levels due to selective deficiency of free protein S Heerlen.To understand the lack of thrombotic complications associated with the protein S Heerlen mutation, we compared recombinant protein S Heerlen, wild type (wt) protein S and plasmaderived protein S. wt-Protein S and protein S Heerlen each bound 1:1 to C4BP with dissociation constants of 0.27 and 0.33 nM, respectively. Both wt-protein S and protein S Heerlen, either free or in complex with C4BP, were equally active as prothrombinase inhibitors in the absence of APC. All three protein S preparations stimulated APC-catalyzed inactivation of normal FVa, FVa Leiden and FVIIIa to the same extent. If extrapolated to plasma, it is not likely that the decreased free protein S levels in carriers of the protein S Heerlen mutation are compensated by an increased anticoagulant activity of protein S Heerlen-C4BP complexes. It is possible that an unrecognized plasma factor selectively enhances the anticoagulant activity of protein S Heerlen. If not, the reduction of free protein S levels in heterozygous protein S Heerlen-carriers combined with (low) normal total protein S levels apparently minimally affects the total anticoagulant activity of protein S (APC-cofactor and APC-independent activity) and hence is not associated with increased risk of venous thrombosis.

Genetic analysis, phenotypic diagnosis, and risk of venous thrombosis in families with inherited deficiencies of protein S

Blood ◽  
2000 ◽  
Vol 95 (6) ◽  
pp. 1935-1941 ◽  
Author(s):  
Michael Makris ◽  
Michael Leach ◽  
Nick J. Beauchamp ◽  
Martina E. Daly ◽  
Peter C. Cooper ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Protein S ◽  
Structural Defects ◽  
Protein S Deficiency ◽  
Gene Defect ◽  
Thrombotic Risk ◽  
Free Protein ◽  
First Degree Relatives ◽  
S Deficiency ◽  
Increased Risk

Abstract Protein S deficiency is a recognized risk factor for venous thrombosis. Of all the inherited thrombophilic conditions, it remains the most difficult to diagnose because of phenotypic variability, which can lead to inconclusive results. We have overcome this problem by studying a cohort of patients from a single center where the diagnosis was confirmed at the genetic level. Twenty-eight index patients with protein S deficiency and a PROS1 gene defect were studied, together with 109 first-degree relatives. To avoid selection bias, we confined analysis of total and free protein S levels and thrombotic risk to the patients' relatives. In this group of relatives, a low free protein S level was the most reliable predictor of a PROS1gene defect (sensitivity 97.7%, specificity 100%). First-degree relatives with a PROS1 gene defect had a 5.0-fold higher risk of thrombosis (95% confidence interval, 1.5-16.8) than those with a normal PROS1 gene and no other recognized thrombophilic defect. Although pregnancy/puerperium and immobility/trauma were important precipitating factors for thrombosis, almost half of the events were spontaneous. Relatives with splice-site or major structural defects in the PROS1 gene were more likely to have had a thrombotic event and had significantly lower total and free protein S levels than those relatives having missense mutations. We conclude that persons withPROS1 gene defects and protein S deficiency are at increased risk of thrombosis and that free protein S estimation offers the most reliable way of diagnosing the deficiency.

The effect of different hormonal contraceptives on plasma levels of free protein S and free TFPI

2013 ◽  
Vol 109 (04) ◽  
pp. 606-613 ◽  
Author(s):  
Frans M. Helmerhorst ◽  
Kathrin Fleischer ◽  
Anders E. A. Dahm ◽  
Frits R. Rosendaal ◽  
Jan Rosing ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Oral Contraceptives ◽  
Acquired Resistance ◽  
Activated Protein C ◽  
Protein S ◽  
Hormonal Contraceptives ◽  
Free Protein ◽  
Routes Of Administration ◽  
Apc Resistance ◽  
Increased Risk

SummaryUse of combined oral contraceptives is associated with a three- to sixfold increased risk of venous thrombosis. Hormonal contraceptives induce acquired resistance to activated protein C (APC), which predicts the risk of venous thrombosis. The biological basis of the acquired APC resistance is unknown. Free protein S (PS) and free tissue factor pathway inhibitor (TFPI) are the two main determinants of APC. Our objective was to assess the effect of both hormonal and non-hormonal contraceptives with different routes of administration on free TFPI and free PS levels. We conducted an observational study in 243 users of different contraceptives and measured APC sensitivity ratios (nAPCsr), free TFPI and free PS levels. Users of contraceptives with the highest risk of venous thrombosis as reported in recent literature, had the lowest free TFPI and free PS levels, and vice versa, women who used contraceptives with the lowest risk of venous thrombosis had the highest free TFPI and free PS levels. An association was observed between levels of free TFPI and nAPCsr, and between free PS and nAPCsr. The effect of oral contraceptives on TFPI and PS is a possible explanation for the increased risk of venous thrombosis associated with oral contraceptives.

scholarly journals Reasons for immunologic inefficiency of antiretroviral therapy in patients with HIV

2014 ◽  
Vol 95 (4) ◽  
pp. 581-588 ◽  
Author(s):  
A F Oleynik ◽  
V Kh Fazylov
Keyword(s):  
Antiretroviral Therapy ◽  
Hiv Infection ◽  
Highly Active Antiretroviral Therapy ◽  
Immunological Response ◽  
Response To Treatment ◽  
Highly Active ◽  
Cell Counts ◽  
Increased Risk ◽  
Long Term Treatment ◽  
Cd4 Lymphocytes

The main component of the treatment of patients with HIV infection is highly active antiretroviral therapy (HAART), which can help to control the disease. The main goal of HAART is to increase the life duration and to maintain the quality of patients’ life. Improved survival among HIV-infected patients receiving highly active antiretroviral therapy is achieved mainly by a decrease of HIV RNA viral load, which increases CD4 lymphocytes count. However, some patients may present with discordant response to treatment, when there is no CD4 lymphocyte count elevation associated with the virus disappearing from the blood. Such patients retain immunodeficiency, despite long-term treatment. The risk of opportunistic infections on the background of insufficient immunological response, despite viral replication suppression, is higher than in patients with good immunological response to treatment. Consistently low CD4 cell counts are associated with an increased risk of AIDS diagnosis. Furthermore, this group of patients shows a slight increase in mortality not associated with AIDS-defining illnesses. The reasons for the low CD4 lymphocytes count increase in some patients achieving virologic response to HAART remain unclear. The immunological efficacy of treatment depends on many factors: baseline CD4 count, duration of HIV infection prior to HAART initiation, age, co-infection with HCV, presence of secondary diseases and comorbidities, HAART regimens, IL-2 use and others. Literature review covers the phenomenon of immunological «non-response» to HAART, factors leading to its development, and possible methods of correction. Currently, there are more questions than answers in the area of immunological non-effectiveness of HAART in HIV-infected patients.

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