Autoantibodies to ADAMTS13 in human immunodeficiency virus-associated thrombotic thrombocytopenic purpura.

BACKGROUND AND OBJECTIVES: Thrombotic thrombocytopenic purpura (TTP) is a potentially fatal thrombotic microangiopathic disorder that can result from human immunodeficiency virus (HIV) infection. The pathogenesis involves a deficiency of the von Willebrand factor (vWF) cleaving protease ADAMTS13 (a disintegrin and metalloprotease with thrombospondin motifs member 13) and the presence of anti-ADAMTS13 autoantibodies. However, there is insufficient information regarding the epitope specificity and reactivity of these autoantibodies. This study aimed to perform epitope-mapping analysis to provide novel insights into the specific epitopes on ADAMTS13 domains affected by autoantibodies. MATERIALS AND METHODS: The study analysed 59 frozen citrate plasma samples from HIV-associated TTP patients in South Africa, measuring ADAMTS13 activity using Technozyme® ADAMTS13 activity test, total immunoglobulin (Ig) M and IgA antibodies levels using ELISA kit and purifying IgG antibodies using NAb™ Protein G spin columns. A synthetic ADAMTS13 peptide library was used for epitope mapping. RESULTS: Overall, 90% of samples showed anti-ADAMTS13 IgG autoantibodies, with 64% of these antibodies being inhibitory, as revealed by mixing studies. Samples with ADAMTS13 antigen levels below 5% showed high anti-ADAMTS13 IgG autoantibody titres (≥50 IU/mL), whereas those with 5%-10% levels had low autoantibody titres (<50 IU/mL).The metalloprotease, cysteine-rich and spacer domains were 100% involved in binding anti-ADAMTS13 IgG antibodies, with 58% of samples containing antibodies binding to the C-terminal part of the ADAMTS13 disintegrin-like domain, indicating different pathogenic mechanisms. CONCLUSION: The metalloprotease, cysteine-rich and spacer domains are the primary targets for anti-ADAMTS13 IgG autoantibodies in patients with HIV-associated TTP. These findings suggest potential effects on the proteolytic activity of ADAMTS13, highlighting the complex nature of the pathogenic mechanisms involved.

Verification of a Benchtop Hematology Analyzer with a 5-Part Differential Count: There is Nothing Wrong with Being Small.

BACKGROUND: The benchtop ADVIA 560 AL hematology analyzer (Siemens Healthineers Tarrytown, NY, USA) offers a small footprint and ease of operation making it suitable for satellite laboratories and intensive care units. A verification study of this analyzer was performed. METHODS: Between- and intra-run precision, carry-over, linearity, and throughput were evaluated on the ADVIA 560 AL. Accuracy was assessed on 94 patient samples by comparing the results obtained on the ADVIA 560 AL to the results on the reference Sysmex XN1000 analyzer (Sysmex Corporation, Kobe, Japan). RESULTS: The ADVIA 560 AL showed acceptable imprecision on control material and minimal bias in comparison to the XN 1000 on patient samples with a throughput of 60 samples per hour. The percentage carryover was not significant and the linearity was within acceptable limits. CONCLUSIONS: The ADVIA 560 AL bench-top analyzer is suitable for acute care centers and satellite laboratories owing to its small footprint, ease of use, and reproducible and accurate results.

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.

Assessing Biomarkers in Viral Infection.

Current biomarkers to assess the risk of complications of both acute and chronic viral infection are suboptimal. Prevalent viral infections like human immunodeficiency virus (HIV), hepatitis B and C virus, herpes viruses, and, more recently, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) may be associated with significant sequelae including the risk of cardiovascular disease, other end-organ diseases, and malignancies. This review considers some biomarkers which have been investigated in diagnosis and prognosis of key viral infections including inflammatory cytokines, markers of endothelial dysfunction and activation and coagulation, and the role that more conventional diagnostic markers, such as C-reactive protein and procalcitonin, can play in predicting these secondary complications, as markers of severity and to distinguish viral and bacterial infection. Although many of these are still only available in the research setting, these markers show promise for incorporation in diagnostic algorithms which may assist to predict adverse outcomes and to guide therapy.

HIV-associated thrombotic thrombocytopenic purpura (HIV-TTP): A practical guide and review of the literature.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP), a serious thrombotic microangiopathy (TMA), is prevalent in the South African HIV-infected population. The exact pathogenesis of HIV-associated TTP (HIV-TTP) is however still unclear with diagnostic and therapeutic inconsistancies. METHODS: A systematic review of the published literature regarding HIV-TTP was performed. RESULTS: HIV-TTP is still associated with significant morbidity and mortality in Africa despite the availability of anti-retroviral therpy (ART). Diagnosis of HIV-TTP requires the presence of a micro-angiopathic haemolytic anaemia with significant red blood cell schistocytes and thrombocytopenia in the absence of another TMA but background activation of the coagulation system and inflammation in HIV infected people can result in diagnostic anbiguity. Plasma therapy in the form of infusion or exchange is successful but expensive, associated with side-effects and not widely available. Adjuvant immunosuppression therapy may of benefit in patients with HIV-TTP and ART must always be optimised. Endothelial dysfunction caused by chronic inflammation and complement activation most likely contributes to the development of HIV-TTP. CONCLUSION: The role of adjuvant immunomodulating therpy, the therapeutic targets and pathogenic contribution from endothelial dysfunction in HIV-TTP requires further investigation.

Von Willebrand Factor Multimer Patterns in People Living with Human Immunodeficiency Virus Infection.

BACKGROUND: Endothelial dysfunction contributes to hypercoagulability in people with HIV (PWH). A surrogate marker of this is elevated von Willebrand factor (VWF) which has been documented in PWH. This study compared VWF multimer patterns in PWH who were anti-retroviral therapy (ART) naive and immune reconstituted on ART. METHODS: VWF multimer analysis was performed with a semi-quantitative electrophoresis assay on plasma from 79 PWH (39 ART-naive and 40 virally suppressed on ART) and 25 normal control samples. RESULTS: The total optical density mean VWF level was significantly increased in PWH and higher in ART-naive versus ART-exposed, virally suppressed patients (p < 0.0001). No quantitative difference was demonstrated in the multimer distribution pattern between the groups. CONCLUSIONS: Our findings suggest that there is no difference in multimer distribution between ART-naive and virally suppressed PWH. Due to a small sample size, confirmation in a larger study is required.

Distinguishing and overlapping laboratory results of thrombotic microangiopathies in HIV infection: Can scoring systems assist?

BACKGROUND: Patients with Human Immunodeficiency Virus (HIV) infection are at risk of thrombotic microangiopathies (TMAs) notably thrombotic thrombocytopenic purpura (TTP) and disseminated intravascular coagulation (DIC). Overlap between laboratory results exists resulting in diagnostic ambiguity. METHODS: Routine laboratory results of 71 patients with HIV-associated TTP (HIV-TTP) and 81 with DIC with concomitant HIV infection (HIV-DIC) admitted between 2015 and 2021 to academic hospitals in Johannesburg, South Africa were retrospectively reviewed. Both the PLASMIC and the International Society of Thrombosis and Haemostasis (ISTH) DIC scores were calculated. RESULTS: Patients with HIV-TTP had significantly (P < .001) increased schistocytes and features of hemolysis including elevated lactate dehydrogenase (LDH)/upper-limit-of-normal ratio (median of 9 (interquartile range [IQR] 5-12) vs 3 (IQR 2-5)) but unexpectedly lower fibrinogen (median 2.8 (IQR 2.2-3.4) vs 4 g/L (IQR 2.5-9.2)) and higher D-dimer (median 4.8 (IQR 2.4-8.1) vs 3.6 g/L (IQR 1.7-6.2)) levels vs the HIV-DIC cohort. Patients with HIV-DIC were more immunocompromised with frequent secondary infections, higher platelet and hemoglobin levels, more deranged coagulation parameters and less hemolysis. Overlap in scoring systems was however observed. CONCLUSION: The laboratory parameter overlap between HIV-DIC and HIV-TTP might reflect a shared pathogenesis including endothelial dysfunction and inflammation and further research is required. Fibrinogen in DIC may be elevated as an acute phase reactant and D-dimers may reflect the extensive hemostatic activation in HIV-TTP. Inclusion of additional parameters in TMA scoring systems such the LDH/upper-limit-of-normal ratio, schistocytes count and wider access to ADAMTS-13 testing may enhance diagnostic accuracy and ensure appropriate utilization of plasma.

Assessment of candidate variants causative of inborn metabolic diseases in SUDI cases in South Africa, and a case report.

Sudden unexpected death in infants (SUDI) is a devastating event, and unfortunately is still a burden in many parts of the world, including in South Africa. Due to the absence of routine testing for inborn metabolic diseases in newborns and in a post-mortem context, little is known about the presence of metabolic diseases in local SUDI cases. The aim of this study was to genotype five candidate variants previously associated with metabolic disorders in a cohort of SUDI cases (n = 169) from Salt River Mortuary, Cape Town. DNA was isolated from blood, and SNaPshot® PCR and Sanger sequencing were used to genotype the following variants: ACADM: c.583G > A, ACADM: c.985A > G, GCDH: c.877G > A/T, GALT: c.404C > G/T and GALT: c.563A > G. Four carriers of GCDH: c.877G > A/T were identified, while one infant was homozygous for the founder mutation GALT: c.404C > G/T; the latter which is causative of galactosaemia and was previously undiagnosed. During the follow-up with the family, it emerged that the affected infant's identical twin had subsequently demised. The findings in this study highlight possible new candidate variants to assess in South African SUDI cases, and these results directly contribute to the development of a molecular autopsy which is locally relevant. It is evident that until newborn screening becomes routine and accessible in South Africa, molecular autopsies should include testing for inherited metabolic disorders, as it holds potential to save lives.

The Hemostatic Conundrum of Thrombotic Thrombocytopenic Purpura: a Case Report.

BACKGROUND: In thrombotic thrombocytopenic purpura (TTP), von Willebrand factor (VWF)-platelet rich thrombi form in the microvasculature with ischemia in vital organs. The pathogenesis relates to deficiency of the VWF cleaving protease, ADAMTS-13. METHODS: A case study of a 58-year-old female with previously undiagnosed HIV (human immunodeficiency virus) infection, left hemiparesis, and soft tissue hemorrhages. RESULTS: Investigations revealed microangiopathic hemolytic anemia and a left basal ganglia infarct on magnetic resonance imaging (MRI). A diagnosis of acquired, HIV-related TTP was made and therapeutic plasma exchange and antiretroviral therapy were initiated. CONCLUSIONS: The combined thrombotic and hemorrhagic manifestations of TTP pose therapeutic challenges.

Verification of the Performance of a Fully Automated Coagulation Analyzer and Ongoing Assessment of External Quality Assurance Results in an Academic Laboratory in South Africa.

BACKGROUND: Verification of the performance of analytical platforms is indicated prior to adoption of new Technology for patient sample analysis. Acceptance criteria for the performance of coagulation analytical platforms are not always readily available and is complicated by the multiple assays and test principles in this section of the clinical laboratory. Coagulation samples are also prone to pre-analytical, post-sample collection variables potentially interfering with accuracy analysis. METHODS: This verification study assessed the accuracy of the automated STAGO STA-R Max® coagulation analyzers by means of a comparison study of results obtained on the previously validated STAGO STA-R Evolution® analyzer for 22 coagulation parameters on 40 individual patient samples for each parameter. Within- and between- run reproducibility on commercial control material, carry-over from abnormal to normal samples and the interference of bilirubin, hemoglobin and lipids on the chromogenic analytical channel were also assessed. Ongoing evaluation of the analyzer performance was assessed by External Quality Assurance (EQA) scheme participation. RESULTS: The reproducibility (precision) on 2 levels (Normal and Pathological) commercial control material was acceptable with co-efficient of variance (CV) results below the manufacturer target % CVs. The correlation study demonstrated accuracy of results obtained on the analyzers for all parameters except for D-dimers and coagulation Factor VII. Subsequent EQA performance for these two parameters were however satisfactory. Interference from bilirubin, hemoglobin and lipids did occur in the chromogenic channel. No clinically significant carry over from abnormal to normal samples were observed. CONCLUSIONS: The performance of the STAGO STA-R Max® analyzer is acceptable across the full coagulation test repertoire with the exception of the von Willebrand activity assay. Participation in EQA scheme assessments will be an integral part of ongoing monitoring of the performance of this automated analyzer.

Analytical Performance of a New Immunoturbidimetric Assay for von Willebrand Factor (VWF) Activity Testing.

BACKGROUND: Von Willebrand disease requires laboratory confirmation with quantitative and qualitative measurements of von Willebrand factor (VWF). Qualitative VWF-activity (VWF-Ac) tests have poor inter- and intra-laboratory reproducibility with coefficients of variation (CVs) as high as 64%, often lacking accuracy at low VWF-Ac levels. METHODS: This study evaluated the recently launched immunoturbidometric STAGO® STA-VWF:RCo® reagent for VWF-Ac. Accuracy was evaluated on 32 samples by comparing results using the Siemens® Innovance® reagent. An intra-run reproducibility study was performed on controls. Linearity and lower limit of detection was studied on external-quality-assurance (EQA) material with a known VWF-Ac level. RESULTS: STA-VWF:RCo® reagent results were within clinical interpretation agreement with Siemens® Innovance®. The reproducibility study yielded % CVs of 8.41 for normal and 11.46 for abnormal controls and the assay was linear between 73 and 14.6% and remained linear to 2% with extrapolation. CONCLUSIONS: The STAGO® STA-VWF:RCo® reagent showed clinically meaningful accuracy and acceptable precision.

A Rare Prothrombin Gene Mutation C20209T in a South African Patient with Pulmonary Embolism in Pregnancy: a Case Study and Systematic Review.

BACKGROUND: The G202010A prothrombin gene mutation is a documented prothrombotic risk factor in Caucasian patients. Several other mutations have been described within the prothrombin gene, predominantly in non-Caucasians, including the C20209T mutation. The clinical significance of this mutation is uncertain, but it has been associated with thrombotic events and pregnancy complications. METHODS: We describe a 28-year-old black South African woman who presented with pulmonary embolism during pregnancy. She was investigated for underlying prothrombotic biomarkers. RESULTS: Genetic screening for the prothrombin G202010A mutation by real-time polymerase chain reaction and melting curve analysis demonstrated an atypical mutant peak. Sequencing confirmed a variant C20209T prothrombin mutation. CONCLUSIONS: This is the first report of the C20209T mutation in the Southern African population. It remains uncertain whether genetic testing should be offered routinely to non-Caucasian patients in a resource-limited setting.

Thrombotic thrombocytopenic purpura (TTP)-like syndrome in the HIV era.

BACKGROUND: The thrombotic microangiopathies (TMAs) is a heterogeneous group of relatively uncommon but serious disorders presenting with thrombocytopenia and microangiopathic haemolysis. Thrombotic thrombocytopenic purpura (TTP) is one of these microangiopathic processes. HIV infection is an acquired cause of TTP but the pathogenesis is poorly understood. HIV-associated TTP was previously described to be associated with advanced immunosuppression. The incidence of HIV-related TTP was expected to decline with access to anti-retroviral therapy (ART). METHODS: We undertook an observational study of patients with a diagnosis of TTP admitted to our hospital (CMJAH). The patient demographics, laboratory test results and treatment outcomes were recorded. RESULTS: Twenty-one patients were admitted with a diagnosis of TTP during the study period. All patients had schistocytes and severe thrombocytopaenia. The presenting symptoms were non-specific and renal dysfunction and neurological compromise were uncommon. 77% of the patients were HIV-infected and, in 7 patients, TTP was the index presentation. The remainder of the HIV infected patients were on ART and the majority were virologically suppressed. A significant female preponderance was present. Only 4 of the 21 patients tested HIV negative with a positive Coombs test in 2. All patients in this cohort received treatment with plasma exchange therapy for a median period of 12 days with a 96.5% survival rate. Neither the baseline laboratory features nor the degree of immunosuppression was predictive of the duration of therapy needed for remission. CONCLUSION: HIV-related TTP is still a cause of morbidity and the clinical presentation is heterogeneous which may present a diagnostic challenge in the absence of sensitive biomarkers. Early treatment with plasma exchange is effective but expensive and invasive.

Combination of acquired von Willebrand syndrome (AVWS) and Glanzmann thrombasthenia in monoclonal gammopathy of uncertain significance (MGUS), a case report.

BACKGROUND: Autoimmune paraphenomena, are associated with B-cell lymphoproliferative disorders, including monoclonal gammopathy of uncertain significance. These paraphenomena can rarely include acquired bleeding disorders. CASE PRESENTATION: This case study reports an unusual clinical presentation of 2 acquired bleeding disorders, Acquired von Willebrand syndrome (disease) and Acquired Glanzmann's thrombasthenia, in an elderly patient with monoclonal gammopathy of uncertain significance. CONCLUSIONS: Acquired bleeding disorders are often underdiagnosed and a high degree of clinical suspicion is required. The patient in this study demonstrated platelet aggregometry which was atypical for isolated Glanzmann's thrombosthenia because of the severe concomitant endogenous decrease in von Willebrand factor. There was an absence of platelet aggregation to all tested agonists including ristocetin. Once the diagnosis was made, however, the patient showed a partial response to intravenous immunoglobulin confirming the immunological pathogenesis in this case. This case highlights the need to consider acquired bleeding disorders in patients with a possible predisposing factor.

Integrity of Uncapped Routine Coagulation Specimens Processed in an Automated Integrated Laboratory.

BACKGROUND: The validity of laboratory results depends on pre-analytical variables not detected by conventional quality control. Recommendations are for post-centrifugation coagulation samples to remain capped with cappiercing primary tube analysis. Total laboratory automation integrates analytical platforms with potential incompatibilities necessitating changes including pre-analytical uncapping of samples. METHODS: Samples analyzed for Prothrombin Time (PT), activated Partial Thromboplastin Time (aPTT), D-dimers, Antithrombin and Fibrinogen at baseline, and after 60 and 120 minutes were left at ambient temperature, either re-capped or uncapped, in order to simulate changes from baseline that could occur in uncapped samples on an automation track prior to analysis. Changes were compared to the maximal permissible bias. RESULTS: Sample uncapping for up to 120 minutes at ambient temperature post-centrifugation did not result in clinically significant changes in routine coagulation parameters. CONCLUSIONS: Routine coagulation parameters will not change significantly if the primary citrate tubes are uncapped after centrifugation prior to analysis.

External quality assurance experience with Royal College of Pathologists of Australasia Program at an academic hospital in South Africa.

INTRODUCTION: Laboratories use their performance in external quality assurance (EQA) to establish quality planning strategies and to assess whether testing processes require improvement. METHODS: The EQA performance of the hematology and coagulation test parameters on the Royal College of Pathologists of Australasia EQA program was evaluated over a 4-year cycle at an academic hospital in Johannesburg, South Africa. The test performance was determined from analytical quality specification (APS) and/or z-scores. Bias and imprecision were used to calculate sigma (σ) metric scores. Specifications from European Federation of Laboratory Medicine and/or biological variation were applied. RESULTS: The laboratory achieved a mean testing score of 98.7 ± 4.0%. There were 103 (10.7%) unacceptable results. On investigation, root causes included: presurvey issues (83%), transcription errors (9%), random errors (6%), and test performance errors (3%). All test parameters evaluated achieved an acceptable median APS during the study period. The mean z-scores, however, were >2 and unacceptable for mean cell hemoglobin concentration and hematocrit. On investigation, this was attributed to significant delay in transport and storage of full blood count samples. White cell count and d-dimer achieved a σ ≥ 6. CONCLUSION: EQA participation assisted the laboratory in maintaining a quality system. Close monitoring is necessary for international laboratories to avoid sample delays that can affect result quality.

Deciphering the role of endothelial granulocyte macrophage-CSF in chronic inflammation associated with HIV.

People with HIV (PWH) experience endothelial dysfunction (ED) that is aggravated by chronic inflammation and microbial translocation across a damaged gut barrier. Although this paradigm is well-described, downstream pathways that terminate in endothelial dysfunction are only partially understood. This study found increased expression of granulocyte macrophage colony stimulating factor (GM-CSF), toll-like receptor-4 (TLR4), and myeloperoxidase in the aortic endothelium of PWH compared to those without HIV. Bacteria-derived lipopolysaccharide (LPS) heightened glucose uptake and induced GM-CSF expression in primary human endothelial cells. Exposure to sodium-glucose cotransporter-2 (SGLT2) inhibitors reduced glucose uptake, GM-CSF release, and ED in LPS-activated endothelial cells ex vivo, and PWH treated with SGLT2 inhibitors for diabetes had significantly lower plasma GM-CSF levels than non-diabetic PWH not on this medication. The findings suggest that microbial products trigger glucose uptake and GM-CSF expression in the endothelium, contributing to localized inflammation in PWH. Modifying this altered state could offer therapeutic benefits.

Diagnosis of human immunodeficiency virus associated disseminated intravascular coagulation.

INTRODUCTION: Disseminated intravascular Coagulation (DIC) is a thrombotic microangiopathy which may complicate a number of severe disease processes including sepsis. Development of microvascular thromboses results in consumption of coagulation factors and platelets and ultimate bleeding. Patients with HIV infection (PWH) often present with baseline dysregulation of the coagulation system which may increase severity and derangement of DIC presentation. Previously, we have shown that HIV is a significant risk factor for development of DIC. METHODOLOGY: We conducted a retrospective record review of all DIC screens submitted to our tertiary coagulation laboratory in Johannesburg, South Africa, over a one year period and compared the laboratory presentation of DIC in PWH with presentation of DIC in patients without HIV infection. RESULTS: Over the year, 246 patients fulfilled the International Society of Thrombosis and Haemostasis (ISTH) diagnostic criteria for DIC- 108 were confirmed HIV-infected and 77 were confirmed uninfected. PWH and DIC presented at a significantly earlier age (41 vs 46 years respectively, p<0.02). The prothrombin time was significantly more prolonged (30.1s vs 26.s), the d-dimer levels were substantially higher (5.89mg/L vs 4.52mg/L) and the fibrinogen (3.92g/L vs 1.73g/L) and platelet levels (64.8 vs 114.8x109/l) were significantly lower in PWH. PWH also showed significant synthetic liver dysfunction and higher background inflammation. CONCLUSION: PWH who fulfil the diagnostic criteria for DIC show significantly more dysregulation of the haemostatic system. This may reflect baseline abnormalities including endothelial dysfunction in the context of inflammation and liver dysfunction.

Thrombotic thrombocytopenic purpura in HIV-infected patients: new twists on an old disease.

OBJECTIVE: Investigate the presence of inflammation, endothelial dysfunction and complement activation in patients with HIV-associated thrombotic thrombocytopenic purpura (HIV-TTP) to support the hypothesis that these processes probably contribute to the development of this thrombotic microangiopathy. DESIGN: A prospective, investigational cohort study of 35 consecutive patients diagnosed with HIV-associated TTP presenting to three academic, tertiary care hospitals in Johannesburg, South Africa over 2 years. METHODS: The patients with HIV-TTP received therapeutic plasma therapy and supportive treatment. Demographic data, the results of routine investigations and patient outcomes were recorded. Peripheral blood samples were collected prior to and on completion of plasma therapy and the following additional parameters were assessed at both time points: activity of the von Willebrand factor (VWF) cleaving protease, a-disintegrin-and-metalloproteinase-with-thrombospondin-motifs 13 (ADAMTS-13) and the presence of ADAMTS-13 autoantibodies, levels of pro-inflammatory cytokines, interleukin-6 and tumour necrosis factor-alpha, and two endothelial cell adhesion molecules. Complement activation was assessed by sequential measurement of C3 and C4 as well as levels of the complement inhibitor, factor H. RESULTS: The inflammatory and endothelial activation markers were significantly ( P  < 0.001) elevated in the cohort of patients prior to plasma therapy compared with levels on discharge. Complement was activated and normalized with therapy. The ADAMTS-13 levels were reduced with significant auto-antibodies to this protease at presentation. CONCLUSION: Inflammation in HIV mediates endothelial damage and complement activation. This study proposes that these processes are probably contributory to the development of HIV-TTP, which can therefore be characterized in part as a complementopathy, resembling TTP-like syndrome.

Good Fences Make Good Neighbors: Human Immunodeficiency Virus and Vascular Disease.

Cardiovascular disease, venous thrombosis, and microvascular disease in people with HIV (PWH) is predicted to increase in an aging HIV-infected population. Endothelial damage and dysfunction is a risk factor for cardiovascular events in PWH and is characterized by impaired vascular relaxation and decreased nitric oxide availability. Vascular disease has been attributed to direct viral effects, opportunistic infections, chronic inflammation, effects of antiretroviral therapy, and underlying comorbid conditions, like hypertension and use of tobacco. Although biomarkers have been examined to predict and prognosticate thrombotic and cardiovascular disease in this population, more comprehensive validation of risk factors is necessary to ensure patients are managed appropriately. This review examines the pathogenesis of vascular disease in PWH and summarizes the biomarkers used to predict vascular disease in this population.