Impact of patient selection in clinical trials: application of ROCKET AF and ARISTOTLE criteria in GARFIELD-AF.

BACKGROUND: The extent to which differences in results from Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) and Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial (ROCKET) atrial fibrillation (AF)-the landmark trials for the approval of apixaban and rivaroxaban, respectively, for non-valvular AF-were influenced by differences in their protocols is debated. The potential influence of selection criteria on trial results was assessed by emulating these trials in data from the Global Anticoagulant Registry in the Field (GARFIELD)-AF registry. METHODS: Vitamin K antagonist (VKA) and non-vitamin K oral antagonist (NOAC) users from GARFIELD-AF were selected according to eligibility for the original ARISTOTLE or ROCKET AF trials. A propensity score overlap weighted Cox model was used to emulate trial randomisation between treatment groups. Adjusted HRs for stroke or systemic embolism (SE) within 2 years of enrolment were calculated for each NOAC versus VKA. RESULTS: Among patients on apixaban, rivaroxaban and VKA, 2570, 3560 and 8005 were eligible for ARISTOTLE, respectively, and 1612, 2005 and 4368, respectively, for ROCKET AF. When selecting for ARISTOTLE criteria, apixaban users had significantly lower stroke/SE risk versus VKA (HR 0.57; 95% CI 0.34 to 0.94) while no reduction was observed with rivaroxaban (HR 0.98; 95% CI 0.68 to 1.40). When selecting for ROCKET AF criteria, safety and efficacy versus VKA were similar across the NOACs. CONCLUSION: Apixaban and rivaroxaban showed similar results versus VKA in high-risk patients selected according to ROCKET AF criteria, whereas differences emerged when selecting for the more inclusive ARISTOTLE criteria. Our results highlight the importance of trial selection criteria in interpreting trial results and underline the problems faced in comparing treatments across rather than within clinical trials.

Selected inflammatory and coagulation biomarkers pre-viral suppression in people with human immunodeficiency virus (HIV) infection without overt cardiovascular disease: Is there a need to redefine reference indices?

BACKGROUND: Human immunodeficiency virus (HIV) infection is prevalent in Africa and causes morbidity and mortality despite antiretroviral therapy (ART). Non-communicable complications of HIV infection include cardiovascular disease (CVD) with thromboses throughout the vascular tree. Ongoing inflammation and endothelial dysfunction in people living with HIV (PLWH) probably contribute significantly to HIV-related CVD. OBJECTIVES: A systematic review was conducted to inform interpretation of 5 biomarkers commonly measured in PLWH namely interleukin-6 (IL-6), tumour necrosis factor alpha (TNF-α), D-dimers, and soluble intracellular and vascular adhesion molecules-1 (sICAM-1 and sVCAM-1) to attempt to define a range for these values in ART naïve PLWH without overt CVD or additional comorbid diseases. METHODS: A systematic search was conducted for all studies documenting the levels of the above biomarkers in ART naïve PLWH published on the PubMed database from 1994 to 2020. RESULTS: The number of publications that reported medians above the assay values was: 4/15 for D-dimer; 0/5 for TNF-α, 8/16 for IL-6, 3/6 for sVCAM-1, and 4/5 for sICAM-1. CONCLUSION: The clinical utility of biomarkers is reduced by the lack of standardisation of the measurement of these parameters, absence of normal reference indices and the lack of uniformity of study protocols in different research centres. This review supports the ongoing use of D-dimers to predict thrombotic and bleeding events in PLWH since the weighted averages across study assays suggest that the median levels do not exceed the reference range. The role of inflammatory cytokine monitoring and measurement of endothelial adhesion markers is less clear.

Pregnancy Related Venous Thromboembolism-Associated with HIV Infection and Antiretroviral Therapy.

Human immunodeficiency virus (HIV) infection in pregnancy is associated with substantial morbidity and mortality. Improved access to effective antiretroviral therapy (ART) has shifted the spectrum of pregnancy-related complications among HIV-infected pregnant women. In addition to placental vascular complications and preterm delivery, increased rates of venous thromboembolism (VTE) have been described. HIV infection is characterized by immune activation, inflammation, and endothelial dysfunction, which contribute to the activation of coagulation and its prothrombotic consequences. Indeed, activated coagulation factors have been reported to be increased and natural anticoagulants reduced in HIV. Several mechanisms for this persistent prothrombotic balance on ART have been identified. These may include: co-infections, immune recovery, and loss of the gastrointestinal mucosal integrity with microbial translocation. In addition to the direct effects of HIV and ART, traditional venous and obstetric risk factors also contribute to the risk of VTE. A research priority has been to understand the mechanisms of VTE in HIV-infected pregnant women receiving suppressive ART and to translate this into HIV-specific thromboprophylaxis recommendations. Management requires a multidisciplinary approach and further studies are indicated to guide the prevention and management of pregnancy-associated VTE in this population. The current review describes the epidemiology, mechanisms, and management of VTE in HIV-infected women in pregnancy and the postpartum period.

Evaluation of markers of fibrinolysis and coagulation in pregnant women with human immunodeficiency virus.

INTRODUCTION: Human immunodeficiency virus (HIV) in pregnant women is characterized by immune activation and inflammation despite suppressive antiretroviral therapy (ART). The extent to which ongoing inflammation contributes to activation of coagulation and fibrinolysis is unknown. MATERIALS AND METHODS: This cross-sectional study included pregnant women in the following three groups: HIV negative (n = 109), HIV infected virologically suppressed (n = 109) and HIV infected with HIV viral load (VL) of >50 copies/mL (n = 80). Fibrinolytic activity was evaluated by measuring d-dimer and plasminogen activator inhibitor-1 (PAI-1) as well as thrombin-antithrombin (TAT) complex concentrations, as an index of coagulation, in the first, second and third trimesters. RESULTS: In this population, with a mean age of 33 ± 6 years, pregnancy outcomes were recorded for 277 (93.0 %) participants with live births. HIV infected participants with virological suppression and VL of >50 copies/mL showed significantly increasing levels of d-dimer and PAI-1 in the first, second and third trimesters, as compared to HIV negative participants. No significant differences were observed between HIV infected participants with virological suppression and HIV infected participants with VL > 50 copies/mL for levels of first and third trimester d-dimer and PAI-1 in each trimester. In addition, TAT complex levels in the first trimester were significantly increased in HIV infected virologically suppressed participants as compared to HIV negative participants. CONCLUSION: HIV infected virologically suppressed pregnant women show evidence of persistently impaired markers of fibrinolysis. Future research should explore the risk of adverse pregnancy complications among HIV infected pregnant women in the modern era of ART.

Profile of antiphospholipid antibodies in HIV-infected and HIV-uninfected women with a history of thrombosis.

INTRODUCTION: Increased antiphospholipid antibodies (aPL) have been described in human immunodeficiency virus (HIV) infection. However, the association between aPL and the increased risk of thrombosis in HIV requires further clarification. METHODS: We reviewed the medical records of 215 consecutive women with a history of thrombosis and/or obstetric complications (158 HIV-uninfected and 57 HIV-infected) between July 2017 and March 2021. Participants (n = 215) without clinical criteria manifestations for antiphospholipid syndrome were included as matched controls. Testing for lupus anticoagulant (LAC), anticardiolipin (aCL) and anti-beta2-glycoprotein1 (aß2GP1) IgM and IgG was performed. RESULTS: Thirty-two (10.1%) HIV-uninfected and 15 (13.2%) HIV-infected participants were positive at baseline for one of the five criteria aPL, with no statistically significant difference. The profile of the HIV-infected participants with thrombosis (n = 11) included LAC in 15.8%, aCL IgG in 3.5% and aß2GP1 IgG in 1.8%. In contrast, the HIV-infected controls (n = 4), included aCL IgM in 1.8% and aß2GP1 IgM in 5.3%. Only LAC was significantly associated with thrombosis (p < 0.003). On repeat testing, in a HIV-infected sub-population, 2/7 with thrombosis were positive, while 3/3 controls tested negative. CONCLUSION: In contrast to earlier reports, the prevalence and expression of aPL in HIV-infected women with a history of thrombosis in the present study, in the era of antiretroviral therapy, were similar to HIV-uninfected women. Baseline LAC positivity was associated with a significantly increased risk for thrombosis in HIV. Future studies are recommended to explore additional coagulation abnormalities in HIV.

Prevalence and Trajectory of COVID-19-Associated Hypercoagulability Using Serial Thromboelastography in a South African Population.

INTRODUCTION: The coagulation abnormalities resulting from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been attributed to inflammation and subsequent cytokine storm. Thromboelastography (TEG) is a point-of-care test used to assess clot formation and degradation in whole blood and is an indicator of the overall real-time coagulopathic state of the patient. METHODS: A single-centre, prospective, observational cohort study was conducted in South Africa, analysing the coagulation patterns of 41 patients with hypoxia related to SARS-CoV-2 using serial thromboelastography (TEG) on admission, after 48 hours, and at resolution of hypoxia/day 10. Results: Two-thirds (n = 26) were women. The median age was 61 (IQR 50-67), and the majority (88%) were Black patients. Almost half (22) of the patients were critically ill and ventilated, with median SOFA and SAPS2 scores of 3 and 22 (IQR2-4 and 18-30), respectively. The prevalence of hypercoagulability was 0.54 (95% CI 0.46-0.62), whilst 29/41 (0.71, CI 0.64-0.78)) met the definition of hypofibrinolysis. Differences between the hypercoagulable (HC) and non-hypercoagulable groups remained apparent at 48 hours after anticoagulation. At this time point, the K time was significantly lower (p ˂ 0,01), and the α-angle (p ˂ 0,01) and maximum amplitude (MA) (p ˂ 0,01) were significantly higher in the HC cohort. At resolution of hypoxia, or day 10, only MA was significantly higher in the hypercoagulable group compared to the non-hypercoagulable group (p = 0.01). The initial impairment in fibrinolysis (Ly30), α angle, and MA were significantly associated with mortality, with p values of 0.006, 0.031, and 0.04, respectively. CONCLUSIONS: In this South African population, hypercoagulability was a highly prevalent phenomenon in COVID-19 disease. It was typified by hypofibrinolysis and a persistently elevated MA, despite anticoagulation therapy.

von Willebrand factor propeptide-to-antigen ratio in HIV-infected pregnancy: Evidence of endothelial activation.

BACKGROUND: Endothelial activation has been proposed as a potential mechanism for the increased risk of venous thromboembolism (VTE) in human immunodeficiency virus (HIV)-infected pregnancy. OBJECTIVES: To assess the state of endothelial activation in HIV-infected pregnancy by measuring the von Willebrand factor (VWF) propeptide-to-antigen ratio, as an index of acute endothelial activation. METHODS: VWF antigen and VWF propeptide were measured in HIV-negative participants (n = 85), HIV-infected virologically suppressed participants, (n = 89) and HIV-infected participants with HIV viral load (VL) of >50 copies/ml (n = 63) in each trimester. Results were correlated with multimer patterns and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13) antigen, activity, and antibody levels. RESULTS: VWF propeptide-to-antigen ratio was increased, in the first, second, and third trimester, in the HIV-infected virologically suppressed group (1.7 ± 0.7, 1.7 ± 0.4, 1.6 ± 0.5) and the HIV-infected group with VL > 50 copies/ml (1.9 ± 0.9, 1.7 ± 0.9, 1.6 ± 1.1) compared to the HIV-negative group (1.4 ± 0.6, 1.3 ± 0.4, 1.2 ± 0.3, P < .05). Increased high molecular weight multimers were observed in the HIV-infected groups, despite only a mild reduction in ADAMTS-13 activity compared to the HIV-negative group (P < .001). No correlation was observed between VWF antigen or VWF propeptide and ADAMTS-13 activity. CONCLUSION: HIV-infected virologically suppressed pregnant participants showed persistent endothelial activation. Future research should focus on whether endothelial activation contributes to the excess risk of pregnancy-related VTE.

Pregnancy-related venous thromboembolism and HIV infection.

OBJECTIVE: To assess risk factors for venous thromboembolism (VTE) in African women in order to guide thromboprophylaxis. METHODS: A case-control study was performed at a specialist obstetric unit in South Africa from July 1, 2017 to June 30, 2020. We identified 128 cases with VTE and 640 controls, matched for gestation. RESULTS: Prepartum risk factors associated with VTE included; medical comorbidities (odds ratios [OR] 5.32, 95% confidence intervals [CI] 1.82-15.56), human immunodeficiency virus (HIV) (OR 2.84, 95% CI 1.50-5.41), and hospital admission or immobility (OR 5.33, 95% CI 1.17-24.22). Postpartum, the following were identified as significant risk factors; medical comorbidities (OR 23.72, 95% CI 8.75-64.27), hospital admission or immobility (OR 13.18, 95% CI 5.04-34.49), systemic infection (OR 4.48, 95% CI 1.28-15.68), HIV (OR 3.20, 95% CI 1.49-6.87), pre-eclampsia and fetal growth restriction (OR 2.74, 95% CI 1.18-6.36), and postpartum hemorrhage (OR 4.38, 95% CI 1.75-10.97). Antiretroviral therapy, opportunistic infections, and viral load >50 copies/ml, however, were not associated with VTE risk among HIV-infected participants. CONCLUSION: HIV was a significant risk factor for pregnancy-related thrombosis. This was independent of traditional HIV risk factors. As such, future studies are recommended to explore the mechanisms of thrombosis associated with HIV infection.

Safety and efficacy of adjusted-dose enoxaparin in pregnant patients with increased risk for venous thromboembolic disease.

OBJECTIVE: To assess the efficacy and safety of anti-Xa guided dose-adjusted low molecular weight heparin (LMWH) thromboprophylaxis in at-risk pregnant women. METHODS: This single-center retrospective study was conducted at a quaternary hospital in Johannesburg, South Africa. We analyzed clinical and laboratory data for pregnant patients referred between January 1, 1999, and May 1, 2017, with an increased risk of venous thromboembolic disease (VTED) and treated with prophylactic LMWH adjusted according to anti-Xa levels. The efficacy endpoint was pregnancy-related VTED and/or pregnancy loss despite anti-Xa guided dose-adjusted LMWH thromboprophylaxis. RESULTS: We reviewed data for 113 consecutive pregnant patients with 151 pregnancies referred for prophylactic LMWH. Prevalence of pregnancy-related VTED was 1.3% (95% confidence interval [CI] 0.1-4.7), which is lower than that reported in the literature for fixed-dose thromboprophylaxis in similar at-risk groups. One venous thromboembolism event occurred in the antenatal period (despite adequate prophylaxis) and the second in the postpartum period (related to prolonged labor). Prevalence of pregnancy-related bleeding was 2% (95% CI 0.4-5.7) with all bleeding events considered to be minor and unrelated to LMWH therapy. CONCLUSION: This study demonstrated the efficacy and safety of anti-Xa dose-adjusted LMWH thromboprophylaxis in at-risk pregnant patients.

Utility of reticulocyte haemoglobin content and percentage hypochromic red cells as markers of iron deficiency anaemia among black CKD patients in South Africa.

INTRODUCTION: Iron deficiency anaemia (IDA) worsens the prognosis and outcomes of chronic kidney disease (CKD). However, while the haemoglobin level is unreliable for early detection of IDA, reticulocyte haemoglobin content (CHr) and hypochromic red cells (%HYPO) are early markers of IDA. METHODS: This was a cross sectional study of black adult participants (n = 258) with CKD and apparently healthy members of staff and patients' relatives (n = 141) at the Charlotte Maxeke Johannesburg Academic Hospital, South Africa, between 1 June 2016 and 31 December 2016. Serum iron, serum ferritin and transferrin were measured using standard laboratory methods, while the haematology analyser was employed to measure CHr and %HYPO. The validity of CHr and %HYPO as markers of IDA were evaluated. Multivariable binary logistic regression was conducted to determine predictors of the relationship between IDA, CHr and %HYPO. The area under the receiver operator characteristics (ROC) curve (AUC) of the final models were utilised to evaluate the discriminatory value of CHr and %HYPO respectively. RESULTS: About one-quarter (26.1%) of the participants had IDA which was more than three times more frequent among CKD patients, compared to controls (35.3% vs 9.2%); 32.3% (95%CI: 27.90%- 37.10%) of the study population had iron deficiency without anaemia and the prevalence of iron deficiency without anaemia was lower in CKD patients compared to controls (29.5% vs 37.6%). The mean age of CKD patients was higher than in controls (52.7 ±14.3 vs 40.4 ±12.6 years, P-value<0.001). The sensitivity and specificity for diagnosing IDA among CKD participants was 62.6% and 80.2% respectively for CHr (at a cut-off value of <28pg) and 63.3% and 79.8% respectively for %HYPO. CKD participants with CHr levels >28pg were 82% less likely to be diagnosed as having IDA as compared to those with CHr levels ≤ 28pg) (adj odds ratio = 0.18, 95% CI: 0.09-0.37). The AUC of CHr (0.81, 95% CI: 0.76-0.87) was higher than the AUC of %HYPO (0.76, 95%CI: 0.70-0.82). CONCLUSION: The diagnostic usefulness of CHr and the screening performance of %HYPO in predicting IDA among CKD patients are high. Their lower cost compared to conventional markers of ID recommend their use in clinical practice. Further cost effectiveness studies of these parameters are warranted.

Conservative Management of Overanticoagulation in Patients With Low-Moderate Risk for Bleeding Complications.

Despite long-standing experience with warfarin, anticoagulation clinic services are often confronted with the challenging clinical situation of patients with overanticoagulation. This requires repeat international normalized ratio (INR) monitoring and in some cases administration of vitamin K to minimize the risk of bleeding. A study was performed to determine the safety and efficacy of outpatient management in order to provide guidance on the management of patients with prolonged INRs. Patients on stable warfarin therapy for more than 1 month attending a dedicated academic hospital anticoagulation clinic who had an INR ≥5 were identified over a 1-year period. Follow-up INR results and outcomes were recorded for 30 days. One hundred and ninety-five episodes of overanticoagulation in 148 patients were identified. Patients were classified as low risk (n = 85, 57.4%) and moderate risk of bleeding (n = 63, 42.6%). The mean index INR was 7.22 (1.88). Management with low-dose oral vitamin K (n = 32, 16.4%) did not significantly result in a more rapid correction of the INR when compared to conservative management (n = 163, 83.6%; P = .103). Follow-up INR testing was performed at a mean of 11.1 (8.9) days from the index measurement. A mean of 1.6 (0.9) follow-up INR tests were performed per episode. During the 30-day follow-up, there was 1 (0.5%) episode of major bleeding and 1 (0.5%) death. The management of asymptomatic outpatients with overanticoagulation is associated with a low risk of major bleeding within 30 days. Conservative management of overanticoagulation is as effective as utilizing low-dose oral vitamin K.

The impact of risk assessment on the implementation of venous thromboembolism prophylaxis in foot and ankle surgery.

BACKGROUND: The purpose of this prospective study was to determine whether the more frequently quoted procedure and patient specific risk factors have any impact in the implementation of venous thromboembolism (VTE) prophylaxis following foot and ankle surgery. METHODS: Two hundred and sixteen patients were included in the study. A variety of operative procedures was carried out with the common denominator being a below knee cast for at least 4 weeks and nonweightbearing for an average of 6 weeks in 130 patients. The remainder of the patients (88) had hallux surgery not requiring a cast and were allowed to weightbear. No patient received any form of thromboprophylaxis postoperatively. All patients were subjected to compression ultrasonography for deep vein thrombosis (DVT) between 2 and 6 weeks postoperatively. RESULTS: There was a 5.09% incidence of VTE (0.9% pulmonary embolism) overall. As no VTE (neither DVT nor pulmonary embolus) developed in the hallux subgroup, i.e. patients not requiring immobilization and were allowed to weightbear, the incidence of VTE in the cast/nonweightbearing group was 8.46%. The results are descriptive and only statistically analyzed where possible, as the sample size of the VTE group was small. There was no significant difference in number of risk factors and no association between gender in the VTE and non VTE groups. 90.9% of patients in the VTE group had a total risk factor score of 5 or more and 73.7% of patients in the non VTE group had a total risk factor score of 5 or more. The average timing to the diagnosis of VTE in this current study was 33.1 days. CONCLUSIONS: In view of the unacceptable incidence of VTE and the average total risk factor score of 5 or more (for which thromboprophylaxis is recommended) in the majority of the patients, the authors feel that the routine use of thromboprophylaxis in foot and ankle surgery requiring nonweightbearing in combination with short leg cast immobilization, is warranted. This prophylaxis should continue until the patient regains adequate mobility either by weightbearing (in or out of the cast) or removal of cast immobilization (weightbearing or nonweightbearing), usually between 28 and 42 days.

The Use of VTE prophylaxis in relatioN to patiEnt risk profiling (TUNE-IN) Wave 2 study.

BACKGROUND: The TUNE-IN (The Use of VTE prophylaxis in relatioN to patiEnt risk profiling) study evaluated venous thrombo-embolism (VTE) risk assessment and prophylaxis in private medical and surgical inpatients in Gauteng Province, South Africa. The study concluded that of the 608 patients enrolled, 54.1% were clinically evaluated to be at risk for VTE. A VTE risk assessment model (RAM), the Caprini score, increased the rate to 74.6%. OBJECTIVES: TUNE-IN Wave 2, an extension of TUNE-IN, was conducted on a national level including the public sector, focusing on surgical inpatients. METHODS: The study was a national, prospective, non-interventional, multisite, epidemiological disease registry enrolling 453 surgical inpatients. The perceived clinical VTE risk, VTE risk score on Caprini RAM, VTE prophylaxis and clinical details were documented during a baseline visit. A bleeding risk score was provided. RESULTS: Of the cohort, 269 patients (59.4%) were assessed to be at risk for VTE before applying the RAM. All patients (100%), however, were at risk on the RAM score. Early mobilisation and assessment of the VTE risk as low were the most frequent reasons for non-prescription of prophylaxis. Only 15 patients in the private and 2 in the public sector were assessed as having a bleeding risk. Chemoprophylaxis differed between the healthcare sectors, with low-molecular-weight heparin predominating in the private sector and unfractionated heparin being prescribed only in the public sector. CONCLUSION: VTE risk assessment and prophylaxis need to improve in both the public and the private sectors. A formal RAM will improve identification of patients at risk of VTE.

Oral rivaroxaban for the treatment of symptomatic pulmonary embolism.

BACKGROUND: A fixed-dose regimen of rivaroxaban, an oral factor Xa inhibitor, has been shown to be as effective as standard anticoagulant therapy for the treatment of deep-vein thrombosis, without the need for laboratory monitoring. This approach may also simplify the treatment of pulmonary embolism. METHODS: In a randomized, open-label, event-driven, noninferiority trial involving 4832 patients who had acute symptomatic pulmonary embolism with or without deep-vein thrombosis, we compared rivaroxaban (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with standard therapy with enoxaparin followed by an adjusted-dose vitamin K antagonist for 3, 6, or 12 months. The primary efficacy outcome was symptomatic recurrent venous thromboembolism. The principal safety outcome was major or clinically relevant nonmajor bleeding. RESULTS: Rivaroxaban was noninferior to standard therapy (noninferiority margin, 2.0; P=0.003) for the primary efficacy outcome, with 50 events in the rivaroxaban group (2.1%) versus 44 events in the standard-therapy group (1.8%) (hazard ratio, 1.12; 95% confidence interval [CI], 0.75 to 1.68). The principal safety outcome occurred in 10.3% of patients in the rivaroxaban group and 11.4% of those in the standard-therapy group (hazard ratio, 0.90; 95% CI, 0.76 to 1.07; P=0.23). Major bleeding was observed in 26 patients (1.1%) in the rivaroxaban group and 52 patients (2.2%) in the standard-therapy group (hazard ratio, 0.49; 95% CI, 0.31 to 0.79; P=0.003). Rates of other adverse events were similar in the two groups. CONCLUSIONS: A fixed-dose regimen of rivaroxaban alone was noninferior to standard therapy for the initial and long-term treatment of pulmonary embolism and had a potentially improved benefit-risk profile. (Funded by Bayer HealthCare and Janssen Pharmaceuticals; EINSTEIN-PE ClinicalTrials.gov number, NCT00439777.).

The effect of initiating combined antiretroviral therapy on endothelial cell activation and coagulation markers in South African HIV-infected individuals.

An increased incidence of venous thromboembolism (VTE) is observed in human immunodeficiency virus (HIV)-infected patients. Only a limited number of studies described the effect of combined antiretroviral therapy (cART) on coagulation markers. In a prospective cohort study in cART-naive South African HIV-infected individuals the effect of initiating cART on markers of endothelial cell activation, coagulation and natural anticoagulation was studied. These markers were compared to the reference ranges for an HIV-uninfected control population recruited from hospital staff. A venous ultrasound of both legs was performed to detect asymptomatic deep venous thrombosis (DVT). A total number of 123 HIV-infected participants were included. The patients were predominantly black and severely immuno-compromised. The CD4 cell count increased and the HIV viral load decreased significantly after the initiation of cART (p<0.001). The median follow-up period was 7.2 (± 1.6) months. Laboratory testing before and after initiation of cART was completed by 86 patients. Before initiating cART significantly elevated von Willebrand factor and D-dimer levels, increased activated protein C sensitivity ratio (APCsr) and decreased total and free protein S and protein C levels were observed compared to HIV-negative controls. At follow-up all markers, except APCsr, improved towards the normal range for controls without showing complete normalisation. In a subgroup of 57 patients no asymptomatic DVT was found. Compared to the controls, abnormal levels of coagulation markers were observed in HIV-infected individuals before and after the initiation of cART. Most markers improved after starting cART, but remained significantly different from the controls, indicating a persistent disturbed haemostatic balance.

Human immunodeficiency virus infection and acute deep vein thromboses.

Abnormalities that predispose to a hypercoagulable state with an increased incidence of venous thrombosis have been described in human immunodeficiency virus (HIV) infections and are associated with an increased mortality. A recent systematic review by Klein et al concluded that further studies are essential to elucidate the link between HIV infection and deep vein thrombosis (DVT). We prospectively evaluated 24 consecutive, active people presenting with an acute DVT; 13 consented to HIV testing, revealing an HIV prevalence of 84% (95% confidence interval [CI], 0.65-1.04). In a matched healthy control group, the HIV prevalence was 4% (95% CI, 0.039-0.041). The high HIV prevalence in the DVT group that consented to testing was also significantly higher compared to that in the South African population, estimated to be 10% in 2005. Although the study numbers were low, a statistically significant increased prevalence of HIV infection was found in patients with acute DVTs.

The BEST study--a prospective study to compare business class versus economy class air travel as a cause of thrombosis.

BACKGROUND: As many as 10% of airline passengers travelling without prophylaxis for long distances may develop a venous thrombosis. There is, however, no evidence that economy class travellers are at increased risk of thrombosis. OBJECTIVES: A suitably powered prospective study, based on the incidence of deep-vein thrombosis (DVT) reported in previous studies on long-haul flights, was designed to determine the incidence of positive venous duplex scans and D-dimer elevations in low and intermediate-risk passengers, comparing passengers travelling in business and economy class. PATIENTS/METHODS: Eight hundred and ninety-nine passengers were recruited (180 travelling business class and 719 travelling economy). D-dimers were measured before and after the flight. A value greater than 500 ng/ml was accepted as abnormal. A thrombophilia screen was conducted which included the factor V Leiden mutation, the prothombin 20210A mutation, protein C and S levels, antithrombin levels, and anticardiolipin antibodies immunoglobulin G (IgG) and immunoglobulin M (IgM). On arrival, lower limb compression ultrasonography of the deep veins was performed. Logistical regression analysis was used to determine the risk factors related to abnormally high D-dimer levels. RESULTS: Only 434 subjects had a full venous duplex scan performed. None had ultrasonic evidence of venous thrombosis. Nine passengers tested at departure had elevated D-dimer levels and these volunteers were excluded from further study. Seventy-four of the 899 passengers had raised D-dimers on arrival. Twenty-two of 180 business class passengers (12%) developed elevated D-dimers compared with 52 of 719 economy class passengers (7%). There was no significant association between elevation of D-dimers and the class flown (odds ratio (OR) 0.61, p = 0.109). The factor V Leiden mutation, factor VIII levels and the use of aspirin were, however, associated with raised D-dimers (OR 3.36, p = 0.024; OR 1.01, p = 0.014; and OR 2.04, p = 0.038, respectively). Five hundred and five passengers were contacted within 6 months and none reported any symptoms of a clinical thrombosis or pulmonary embolus. CONCLUSION: The incidence of ultrasonically proven DVT is much lower than previously reported. However, more than 10% of all passengers developed raised D-dimers, which were unrelated to the class flown. A rise in D-dimers is associated with an inherent risk of thrombosis and/or thrombophilia, demonstrates activation of both the coagulation and fibrinolytic systems during long-haul flights, and may indicate the development of small thrombi.

Risk factors for deep vein thrombosis in short-haul cockpit crews: a prospective study.

BACKGROUND: Venous thrombosis is a concern receiving international attention, especially for passengers traveling on long distance flights. However, there are no data on the effect on cockpit crew of multiple short duration flights. METHODS: Cockpit crew flew two or more internal flights per day. At sign on, 15 ml of blood was venesected from the subjects; at sign off, 20 ml of blood was venesected. All flights originated and terminated at Johannesburg Airport. A full blood count, differential, and D-dimer levels were determined. All participants completed detailed questionnaires stating their ages, alcohol consumption 24 h prior to flight duty, the amount of liquid consumed during flying time, the number of times they went to the toilet, and the amount of time spent sitting during flights. RESULTS: Blood tests on 27 cockpit crew were performed. D-dimers were reduced from 163 ng x ml(-1) to 133 ng x ml(-1) (p = 0.03). Hemoglobin levels dropped from 16.0 g x dl(-1) to 15.8 g x dl(-1) (p = 0.004). Hematocrit levels decreased from 47.2 ml x 100 ml(-1) to 46.9 ml x 100 ml(-1) (p = 0.04). Platelets increased from 221 x 10(9) x L(-1) to 241 x 10(9) x L(-1) (p = 0.001). White cell counts increased from 6.4 x 10(9) x L(-1) to 7.01 x 10(9) x L(-1) (p = 0.0063). Correlation analysis was performed between blood test results and the parameters of the questionnaire. No correlation was found between any of the parameters and the blood results. CONCLUSION: There is no evidence of sub-clinical thrombotic events in this group of subjects. Cockpit crew who fly multiple short duration flights do not suffer sub-clinical thrombotic events as evidenced by an absence of increased D-dimers.