HIV-associated Thrombotic Thrombocytopenic Purpura Research Articles

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

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. 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. 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. 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.

A CASE OF HIV-ASSOCIATED THROMBOTIC THROMBOCYTOPENIC PURPURA

A CASE OF HIV-ASSOCIATED THROMBOTIC THROMBOCYTOPENIC PURPURA

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

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. 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. 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 4g/L (IQR 2.5-9.2)) and higher D-dimer (median 4.8 (IQR 2.4-8.1) vs 3.6g/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. 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.

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

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. 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. 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. 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. 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.

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

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. A systematic review of the published literature regarding HIV-TTP was performed. 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. The role of adjuvant immunomodulating therpy, the therapeutic targets and pathogenic contribution from endothelial dysfunction in HIV-TTP requires further investigation.

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

BackgroundThe 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).MethodsWe 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.ResultsTwenty-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.ConclusionHIV-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.

Evaluation of a cost-effective ADAMTS13 antigen assay

Thrombotic thrombocytopenic purpura (TTP) is life-threatening and is characterised by platelet deposition in the microvasculature with thrombus formation in particular organs. This results in thrombocytopenia, microangiopathic haemolytic anaemia, kidney failure and neurological symptoms. It is a rare disorder, but can occur in patients infected with the human immunodeficiency virus (HIV). ADAMTS13 is the 13 th member of a disintegrin and metalloprotease with thrombospondin type motifs. Its deficiency causes TTP. Therefore, the measurement of the ADAMTS13 levels in plasma is vital in the diagnosis of TTP and also important in distinguishing it from other thrombotic microangiopathies (TMA’s). Unfortunately, commercial ADAMTS13 antigen assays are expensive for healthcare service providers in developing countries. However, several antibodies and antibody pairs have been produced against ADAMTS13 and are commercially available. In this study, we evaluated an in-house ADAMTS13 antigen assay using two different commercial antibodies and compared the outcomes to that of a commercial ADAMTS13 antigen kit by using the plasma of 40 patients with possible HIV-associated TTP and 40 healthy subjects. The Intra- and inter-assay coefficients of variation were calculated as 8% and 7% respectively. The assay gave linear results between 0.78 to 12.5% ADAMTS13. The limit of detection was 0.2%, and the limit of quantification was 0.8%. The correlation of our assay compared to the commercial test kit was excellent, with a R 2 value of 0.9. In addition, the cost of our ADAMTS13 antigen assay was lower than that of the commercial ADAMTS13 antigen test kit. Our cost-effective in-house ADAMTS13 antigen test also produced reliable results. We therefore recommend that this assay be used to diagnose HIV-associated TTP.

Hemorrhagic Stroke in an Adolescent Female with HIV-Associated Thrombotic Thrombocytopenic Purpura.

HIV-1 infection can trigger acute episodes of Idiopathic Thrombocytoponic Purpura (ITP), and Thrombotic Thrombocytopenic Purpura (TTP), particularly in populations with advanced disease and poor adherence to antiretroviral therapy (ART). These diseases should be distinguished because they respond to different treatments. Previous studies done in adults with HIV-TTP have recommended the prompt initiation or re-initiation of ART in parallel with plasma exchange therapy to improve the clinical outcome of these patients. Here, we describe a case of HIV-TTP resulting in an acute hemorrhagic stroke in a 16 year old female with perinatally acquired HIV infection and non-adherence to ART, who presented with severe thrombocytopenia, microangiopathic hemolytic anemia, and a past medical history of HIV-ITP. Both differential diagnosis and treatments for HIV-ITP and HIV-TTP were considered simultaneously. A decrease in plasma ADAMTS13 activity (<5%) without detectable inhibitory antibodies confirmed the diagnosis of HIV-TTP. Re-initiation of ART and plasma exchange resulted in a marked decrease in the HIV-RNA viral load, recovery of the platelet count, and complete recovery was achieved with sustained virologic suppression.

HIV-associated Thrombotic Thrombocytopenic Purpura — What We Know So Far

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease characterised by microvascular platelet deposition and thrombus formation in selected organs, resulting in microangiopathic haemolytic anaemia, thrombocytopenia, neurological symptoms and renal failure. Typically a very rare disorder, TTP is being seen with increased frequency in patients infected with the human immunodeficiency virus (HIV). Deficiency of the von Willebrand factor cleavage protease, ADAMTS13, has been implicated as the cause of TTP. However, the pathophysiology of HIV-associated TTP and the thrombotic potential in these patients are not known. This article provides not only an overview of the literature regarding HIV-associated TTP, but also presents new data on this disease. We propose a mechanism for the initial onset of HIV-associated TTP that includes the release of extreme amounts of von Willebrand factor and the downregulation of ADAMTS13 and/or the production of autoantibodies to ADAMTS13.

HIV-Associated Thrombotic Thrombocytopenic Purpura

Abstract 4677Thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening form of microangiopathic hemolysis that can be associated with HIV infection, and has previously been reported to be associated with low CD4 counts. The existing literature on HIV-TTP is very small and largely made up of small case series generated through databases of patients with HIV. As a result, reports have tended to focus on HIV parameters with limited information available regarding the presentation, management and outcome of the TTP itself. We conducted a retrospective review of TTP cases referred to the pheresis units St. Michael's Hospital and Vancouver General Hospital in Vancouver between July 1993 and May 2011. Ten cases of HIV associated TTP were identified (8 male; 2 female). Median age at presentation was 38 years. One patient had been previously diagnosed and treated for TTP at a different institution. Average duration of HIV infection prior to TTP diagnosis was 5 years (range 0 to 11). Median CD4 count at TTP diagnosis was 79 × 106/ml (range 2 to 326). Median platelet count at presentation was 14 × 106/ml (range 5 to 233), median haemoglobin was 74 g/L (range 61 to 133), all patients had an LDH > 2x the upper limit of normal, and all for whom data was available (8/10) had fragmentation on blood film. Creatinine was elevated in 9 of 10 patients. ADAMTS13 was assessed in 3 of 10 patients and was deficient in one. Five of 10 patients had fever. At presentation, 6 of 10 patients had neurological symptoms (most commonly seizures and/or confusion), but none suffered permanent neurological deficits. All patients were treated with plasmapheresis and received a median of 16 exchanges (2-56). Four patients received concurrent steroids, two patients received IVIG, and one patient received pheresis, steroids IVIG, vincristine and rituximab. Eight of 10 patients achieved complete remissions, one patient achieved a partial response, and one died on treatment. Four of the responding patients subsequently relapsed (0.6 to 13.8 months after the initial episode of TTP); two achieved second remissions, and two died on treatment. In conclusion, our series of HIV associated-TTP confirms previous reports that HIV-TTP tends to occur in patients with CD4 counts less than 200. Complete remissions can be achieved with standard management. However, based on our small series, relapses may be more common and mortality greater than in the general TTP population. Disclosures:Leitch: Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees.

The importance of CD4 count, viral load and highly active antiretroviral therapy in HIV-associated thrombotic thrombocytopenic purpura (TTP): Figure 1

A case is reported of HIV-associated thrombotic thrombocytopenic purpura with normal CD4 count but high HIV viral load, developing neurological and cardiac complications up to 36 days after initiation of plasma exchange, but remitting within 18 days of the start of highly active antiretroviral therapy and steroids. In addition to plasma exchange, prompt initiation of highly active antiretroviral therapy in patients with HIV-associated thrombotic thrombocytopenic purpura may be justified despite a normal CD4 count.

232 Successful Treatment of HIV Associated Thrombotic Thrombocytopenic Purpura with Rituximab: A Case Report

232 Successful Treatment of HIV Associated Thrombotic Thrombocytopenic Purpura with Rituximab: A Case Report

Human immunodeficiency virus associated thrombotic thrombocytopenic purpura – favourable outcome with plasma exchange and prompt initiation of highly active antiretroviral therapy

Thrombotic thrombocytopenic purpura (TTP) is an acute prothrombotic disorder. Human immunodeficiency virus (HIV) is an identified precipitant. This study reviewed 30 episodes of HIV-associated TTP in 24 patients from the South-East England Apheresis units, over the last 10 years. All patients were heterosexual Black Africans. First presentation of TTP revealed a new diagnosis of HIV in eight patients. TTP relapse occurred on six occasions (in four patients) as a result of non-adherence to highly active antiretroviral therapy (HAART). Prompt initiation/re-initiation of HAART in parallel with plasma exchange (PEX)±steroid led to prompt remission. Adjunct immunomodulatory agents (e.g. Rituximab) were required in 10% of cases. Once-daily HAART regimens are recommended, being compatible with PEX requirement, maximizing drug exposure between PEX. High viral loads (>500,000 copies/ml) require more PEX to remission. ADAMTS13 activity was reduced (<5%) as detected by collagen-binding assay and anti-ADAMTS13 immunoglobulin G antibodies were raised in 80%. Continued HAART-adherence ensured a durable TTP remission with associated viral control resulting in no evidence of relapse. PEX and HAART are associated with replenishment of ADAMTS13 and viral suppression. More PEX is required in cases with higher viral loads. Continued HAART maintains remission. In a small proportion of cases, further immunomodulatory therapy may be required.

Myocardial injury in HIV-associated thrombotic thrombocytopenic purpura (TTP)

Thrombotic thrombocytopenic purpura (TTP) has been associated with human immunodeficiency virus (HIV) infection. With the high prevalence of HIV in sub-Saharan Africa, HIV-associated TTP is the most common form of this disease seen in the South African population. Several case reports describe myocardial infarction in HIV-negative TTP patients. The case of the first HIV-positive patient who presented with clinical signs and symptoms of TTP and myocardial injury is reported in this study. A patient with fragmentation haemolysis and thrombocytopenia presented with angina. Risk factors for ischaemic heart disease were absent. An electrocardiogram (EKG) revealed ST-segment elevation and a significantly raised Troponin T level. The patient's HIV test was positive and a diagnosis of myocardial injury with HIV-associated TTP was made. The patient was treated with plasma infusion and steroid therapy. Due to poor response, the therapy was changed to plasma exchange. The patient recovered fully and subsequent coronary angiography revealed normal coronary vessels. Treatment of myocardial infarction in TTP is controversial, but the treatment cornerstone should remain plasma infusion or plasma exchange. As patients are often young and do not have the classical risk factors of ischaemic heart disease, a high level of suspicion and routine exclusion of myocardial ischaemia in these patients are advised.

Thrombotic Thrombocytopenic Purpura Associated with Human Immunodeficiency Virus Infection: Demonstration of p24 Antigen in Endothelial Cells

We report a case of thrombotic thrombocytopenic purpura (TTP) in a woman infected with human immunodeficiency virus (HIV) in whose endothelial cells we detected HIV p24 antigen. The patient had an excellent response to conventional therapy for TTP and remained in complete remission 12 months after diagnosis. We also present a review of the literature on the association of TTP with HIV infection and speculate on its nature. The presence of HIV p24 antigen in the endothelial cell might be indicative of a role of virus, yet to be defined, in the pathogenesis of HIV-associated TTP.

Human Immunodeficiency Virus Associated With Thrombotic Thrombocytopenic Purpura: Successful Treatment With Zidovudine

Thrombocytopenia associated with human immunodeficiency virus (HIV) is well described, and two recent reports show a beneficial effect with the antiretroviral agent zidovudine (ZDV). HIV-associated thrombotic thrombocytopenic purpura (TTP) has recently been observed, but the use of ZDV for it has not been previously described. We have reported a case of relapsing TTP in an HIV-positive man who achieved remission with plasmapheresis and antiplatelet therapy initially, but multiple relapses necessitated the addition of vincristine and ZDV to induce a sustained remission.