Severe Malaria and Leptospirosis Are Associated with a Deficiency of the Von Willebrand Factor Cleaving Protease, ADAMTS13

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3912-3912
Author(s):  
Ester C Lowenberg ◽  
Sophie Cohen ◽  
Bert-Jan H van den Born ◽  
J.C.M. Meijers ◽  
Marcel Levi ◽  
...  
Keyword(s):  
Cerebral Malaria ◽  
Severe Malaria ◽  
Thrombotic Microangiopathy ◽  
Scrub Typhus ◽  
Endothelial Activation ◽  
Adamts13 Activity ◽  
P Values ◽  
Adamts13 Deficiency ◽  
Normal Controls

Abstract The thrombotic microangiopathy observed in severe malaria and leptospirosis shows resemblance to that of thrombotic thrombocytopenic purpura (TTP) and haemolytic uremic syndrome (HUS), respectively. The pathophysiology of these complications remains incompletely understood. TTP and (in some cases) HUS are associated with a deficiency of ADAMTS13, a metalloprotease that cleaves large prothrombotic VWF multimers. We hypothesized that ADAMTS13 may be deficient in cerebral malaria and leptospirosis, and that the severity of ADAMTS13 deficiency may be associated with the degree of endothelial activation. We investigated a series of patients with cerebral malaria (n=9) and leptospirosis (n=18). Patients with scrub typhus (n=12) representing a disease that is accompanied by endothelial activation, but without the clinical features of TTP-HUS, and healthy blood donors served as controls. Baseline characteristics did not significantly differ between study groups, except for BUN values which were higher in cerebral malaria than in leptospirosis (p-value 0.046). The Glasgow Coma Scale (GCS) score was evidently lower in cerebral malaria, with a median score of 4 (interquartile range 3–6) while subjects with leptospirosis, scrub typhus and normal controls had (near) maximum scores of 15. ADAMTS13 levels were significantly reduced in both cerebral malaria and leptospirosis, compared to scrub typhus and normal controls, with a significantly more severe deficiency in cerebral malaria than in leptospirosis (data in figure). VWF antigen and VWF propeptide levels were elevated in all three disease groups in comparison to healthy controls (p-values < 0.001), and most markedly increased in cerebral malaria. ADAMTS13 activity inversely correlated with both VWF antigen and VWF propeptide levels (p-values <0.001 and 0.005). No significant correlation was apparent between ADAMTS13 activity and hemoglobin (Hb) concentration or platelet count. Free Hb levels were not elevated in any of the patient groups, hence it seems highly unlikely that free Hb is involved in the observed reduction of ADAMTS13 activity in cerebral malaria and leptospirosis. The results of this study indicate that ADAMTS13 levels are decreased in patients with cerebral malaria and leptospirosis providing direct support to the hypothesis of a role of ADAMTS13 in the pathogenesis of the thrombotic microangiopathy associated with these diseases. Further research seems warranted to establish the role of ADAMTS13 deficiency in the development and the severity of these diseases, and to evaluate its prognostic significance. Potentially, ADAMTS13 function might serve as a risk marker of disease severity and it may be speculated that the administration of exogenous (recombinant) ADAMTS13 can be used as an adjunctive therapeutic strategy in the clinical management of patients with cerebral malaria and severe leptospirosis. Figure Figure

scholarly journals Real-world data of thrombotic microangiopathy management: The key role of ADAMTS13 activity and complement testing

2021 ◽  
Vol 3 ◽  
pp. 100043
Author(s):  
Eleni Gavriilaki ◽  
Eudoxia-Evaggelia Koravou ◽  
Thomas Chatziconstantinou ◽  
Christina Kalpadaki ◽  
Nikoleta Printza ◽  
...  
Keyword(s):  
Real World ◽  
Thrombotic Microangiopathy ◽  
Adamts13 Activity ◽  
Real World Data ◽  
World Data

Risk Factors for Recurrence of Thrombotic Thrombocytopenic Purpura.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1060-1060 ◽  
Author(s):  
Flora Peyvandi ◽  
Silvia Lavoretano ◽  
Roberta Palla ◽  
Hendrik B. Feys ◽  
Tullia Battaglioli ◽  
...  
Keyword(s):  
Risk Factors ◽  
Relative Risk ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Disease Recurrence ◽  
Acute Episode ◽  
Adamts13 Activity ◽  
Thrombocytopenic Purpura ◽  
Neutralizing Activity ◽  
Adamts13 Deficiency

Abstract The introduction of plasma exchange therapy in early 1970s significantly reduced the rate of mortality in patients affected by thrombotic thrombocytopenic purpura (TTP), a disease characterized by thrombocytopenia and microangiopathic hemolytic anemia. A similar improvement was never achieved in the prevention of the disease recurrence. Still, 20–50% of patients, who survived the fatal disease, experience a relapse one month or even years after the acute episode of TTP. There is no pathognomic marker or laboratory test that can be used for the surveillance of TTP during remission and predict which patients will relapse. We have retrospectively analyzed for the first time at remission the role of ADAMTS13, anti-ADAMTS13 autoantibodies and von Willebrand Factor (VWF) in 109 patients who survived the acute episode of TTP. ADAMTS13 activity and ADAMTS13 antigen levels were measured as described by Gerritsen et al (TH 1999) and Feys HB et al. (JTH 2006), respectively. The total anti-ADAMTS13 autoantibodies (with and without neutralizing activity) were measured by western blot analysis and the presence of neutralizing anti-ADAMTS13 autoantibodies was checked according to Gerritsen et al (TH 1999). VWF antigen was measured using an ELISA assay and VWF multimers analysis was carried out using low-resolution SDS-agarose gel electrophoresis and exposing gels to human anti-VWF antibodies labeled with I125 for autoradiography (Ruggeri & Zimmerman, Blood 1981). All variables have been statistically analyzed in 2 subgroups of patients with or without TTP recurrence, in order to understand the role of each variable as a potential predictor marker for recurrence. Univariate and multivariate analysis were carried out to evaluate adjusted and unadjusted odds ratios (Ors) with 95% confidence intervals (CI) as a measure of the relative risk of relapse associated with the risk factors under investigation. Our data showed that the median value of ADAMTS13 activity and antigen levels at remission were significantly lower in patients with recurrent TTP than in patients with no relapse (ADAMTS13 activity: 12% vs. 41%; p=0.007; ADAMTS13 antigen: 36% vs 58%; p=0.003). Furthermore, the prevalence of patients with severe ADAMTS13 deficiency (≤10%) was significantly higher in the group of patients who relapsed (OR=2.9 CI95% 1.3–6.8, p=0.01). The prevalence of anti-ADAMTS13 autoantibodies (with or without neutralizing activity) resulted to be significantly higher in patients with recurrent TTP (OR= 3.1 CI 95% 1.4–7.3, p=0.006). A higher VWF antigen levels or the presence of ultralarge VWF (ULVWF) multimers at remission did not increase the risk of recurrence (p=0.4 for VWF:Ag and p=0.7 for ULVWF multimers). In conclusion, our data showed that the association of severe ADAMTS13 deficiency and the presence of anti-ADAMTS13 autoantibodies is a negative prognostic marker at remission and increases the relative risk of TTP recurrence by 3.6 times (OR=3.6 CI95% 1.4–9). Therefore our results would suggest that our efforts should go in the direction of maintenance therapy which aims at reducing or abolishing the presence of antibodies during remission and increasing the level of ADAMTS13 in plasma in order to prevent the recurrence of TTP.

scholarly journals Synergistic effects of ADAMTS13 deficiency and complement activation in pathogenesis of thrombotic microangiopathy

Blood ◽  
2019 ◽  
Vol 134 (13) ◽  
pp. 1095-1105 ◽  
Author(s):  
Liang Zheng ◽  
Di Zhang ◽  
Wenjing Cao ◽  
Wen-Chao Song ◽  
X. Long Zheng
Keyword(s):  
Complement Activation ◽  
Thrombotic Microangiopathy ◽  
Synergistic Effects ◽  
Adamts13 Deficiency

Abstract This study in mice suggests a synergistic role of ADAMTS13 deficiency and complement “hyperactivatability” in the pathogenesis of thrombotic microangiopathy.

Severe malaria is associated with a deficiency of von Willebrand factor cleaving protease, ADAMTS13

2010 ◽  
Vol 103 (01) ◽  
pp. 181-187 ◽  
Author(s):  
Prakaykaew Charunwatthana ◽  
Sophie Cohen ◽  
Bert-Jan van den Born ◽  
Joost Meijers ◽  
Emran Yunus ◽  
...  
Keyword(s):  
Severe Malaria ◽  
Falciparum Malaria ◽  
Von Willebrand Factor ◽  
Activity Levels ◽  
Adamts13 Activity ◽  
Life Threatening ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Severe Falciparum Malaria ◽  
Normal Controls

SummarySevere falciparum malaria remains a major killer in tropical countries. Central in the pathophysiology is mechanical obstruction in the micro-circulation caused by cytoadherence and sequestration of parasitized erythrocytes. However, the pathogenesis of many features complicating severe malaria, including coma, renal failure and thrombocytopenia, remains incompletely understood. These disease manifestations are also key features of thrombotic thrombocytopenic purpura, a life-threatening disease strongly associated with a deficiency of the von Willebrand factor (VWF) cleaving protease, ADAMTS13. We measured plasma ADAMTS13 activity, VWF antigen and VWF propeptide levels in 30 patients with severe falciparum malaria, 12 patients with uncomplicated falciparum malaria and 14 healthy Bangladeshi controls. In patients with severe malaria ADAMTS13 activity levels were markedly decreased in comparison to normal controls (mean [95%CI]: 23% [20–26] vs. 64% [55–72]) and VWF antigen and propeptide concentrations were significantly elevated (VWF antigen: 439% [396–481] vs. 64% [46–83]; VWF propeptide: 576% [481–671] vs. 69% [59–78]). In uncomplicated malaria VWF levels were also increased compared to healthy controls but ADAMTS13 activity was normal. The results suggest that decreased ADAMTS13 activity in combination with increased VWF concentrations may contribute to the complications in severe malaria.

scholarly journals Marked elevation in plasma osteoprotegerin constitutes an early and consistent feature of cerebral malaria

2016 ◽  
Vol 115 (04) ◽  
pp. 773-780 ◽  
Author(s):  
Kristina Gegenbauer ◽  
Jamie M. O’Sullivan ◽  
Alain Chion ◽  
Owen P. Smith ◽  
Roger J. S. Preston ◽  
...  
Keyword(s):  
Cerebral Malaria ◽  
Severe Malaria ◽  
Critical Role ◽  
Fatal Outcome ◽  
Prognostic Significance ◽  
Clinical Signs ◽  
Marked Elevation ◽  
Consistent Feature ◽  
Lactate Levels

SummaryAdherence of infected erythrocytes to vascular endothelium causes acute endothelial cell (EC) activation during Plasmodium falciparum infection. Consequently, proteins stored in Weibel-Palade (WP) bodies within EC are secreted into the plasma. Osteoprotegerin (OPG) binds to VWF and consequently is stored within WP bodies. Given the critical role of EC activation in the pathogenesis of severe malaria, we investigated plasma OPG levels in children with P. falciparum malaria. At presentation, plasma OPG levels were significantly elevated in children with cerebral malaria (CM) compared to healthy controls (means 16.0 vs 0.8 ng/ml; p<0.01). Importantly, OPG levels were also significantly higher in children with CM who had a fatal outcome, compared to children with CM who survived. Finally, in children with CM, plasma OPG levels correlated with other established prognostic indices (including plasma lactate levels and peripheral parasite density). To further investigate the relationship between severe malaria and OPG, we utilised a murine model of experimental CM in which C57BL/6J mice were infected with P. berghei ANKA. Interestingly, plasma OPG levels were increased 4.6 fold within 24 hours following P. berghei inoculation. This early marked elevation in OPG levels was observed before any objective clinical signs were apparent, and preceded the development of peripheral blood parasitaemia. As the mice became increasingly unwell, plasma OPG levels progressively increased. Collectively, these data suggest that OPG constitutes a novel biomarker with prognostic significance in patients with severe malaria. In addition, further studies are required to determine whether OPG plays a role in modulating malaria pathogenesis.

scholarly journals Association between ADAMTS13 deficiency and cardiovascular events in chronic hemodialysis patients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shih-Yuan Hung ◽  
Tsun-Mei Lin ◽  
Hung-Hsiang Liou ◽  
Ching-Yang Chen ◽  
Wei-Ting Liao ◽  
...  
Keyword(s):  
High Density Lipoprotein ◽  
High Density Lipoprotein Cholesterol ◽  
Cardiovascular Events ◽  
Density Lipoprotein ◽  
Normal Subjects ◽  
Adamts13 Activity ◽  
Cholesterol Levels ◽  
Adamts13 Deficiency

AbstractA mild decrease of ADAMTS13 (a disintegrin and metalloprotease with thrombospodin type 1 motif 13) could attribute to stroke and coronary heart disease in general population. However, the role of ADAMTS13 in hemodialysis (HD) patients remains to be explored. This cross-sectional and observational cohort study enrolled 98 chronic HD patients and 100 normal subjects with the aims to compare the ADAMTS13 activity between chronic HD patients and normal subjects, and to discover the role of ADAMTS13 on the newly developed cardiovascular events for HD patients in a 2-year follow-up. Our HD patients had a significantly lower ADAMTS13 activity than normal subjects, 41.0 ± 22.8% versus 102.3 ± 17.7%, p < 0.001. ADAMTS13 activity was positively correlated with diabetes, triglyceride and hemoglobin A1c, and negatively with high-density lipoprotein cholesterol levels in HD patients. With a follow-up of 20.3 ± 7.3 months, the Cox proportional hazards model revealed that low ADAMTS13, comorbid diabetes, and coronary heart diseases have independent correlations with the development of cardiovascular events. Our study demonstrated that chronic HD patients have a markedly decreased ADAMTS13 activity than normal subjects. Although ADAMTS13 seems to correlate well with diabetes, high triglyceride and low high-density lipoprotein cholesterol levels, ADAMTS13 deficiency still carries an independent risk for cardiovascular events in chronic HD patients.

scholarly journals Review of mechanisms of brain injury identified in severe malaria from 2010-2020

2020 ◽  
Vol 3 ◽  
Author(s):  
Minal Patel ◽  
Adnan Gopinadhan ◽  
Katrina Co ◽  
Amy Belvin ◽  
Robert Opoka ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Brain Injury ◽  
Cerebral Malaria ◽  
Severe Malaria ◽  
Case Reports ◽  
Kidney Injury ◽  
Endothelial Activation ◽  
Pubmed Database ◽  
New Research

Background:  Severe malaria manifests as various conditions with severe malarial anemia being the most common and cerebral malaria being the most severe and affecting over 200,000 children annually. A 2010 review highlighted blood brain barrier degradation and decreased cerebral perfusion as contributors to the long-term behavioral, cognitive, and neurological sequalae of severe malaria. Since then, new research has identified various surface marker proteins and cytokines/chemokines playing a role in vascular changes and inflammation that progresses to acute kidney injury, retinopathy, and seizures. Our goal is to summarize the updated research and provide further insight into the mechanisms of brain injury and the outcomes that follow cerebral malaria.      Project Methods:  Hypotheses on future areas of study from the 2010 review were used to generate an outline for the updated review. Search strategies using the PubMed database were developed so that all relevant primary articles pertaining to human (pediatric and adult), murine, and in vitro studies done from 2010-2020 could be identified. The articles were then sorted and inputted into EndNote to generate a library. Review articles, case reports, and articles discussing the treatment of malaria were excluded from this index.    Results:  88 articles remarking on vasculopathy, 88 on leukocytes, 114 on cytokines/chemokines, 11 on seizures, 56 on acute kidney injury, and 35 on retinopathy have been identified as promising literature for this review. The results suggest that infected individuals have increased endothelial activation which promotes red blood cell adherence to vasculature and edema. This reduces blood flow to the brain, kidneys, and eyes and causes injury to the organs.    Conclusion and Potential Impact:  The EndNote library contains current literature on the mechanisms of brain injury secondary to severe malaria, which will be used to write a review article and identify new areas of research to further our understanding of severe malaria pathogenesis and how to target treatments. 

ADAMTS13 turns 3

Blood ◽  
2005 ◽  
Vol 106 (1) ◽  
pp. 11-17 ◽  
Author(s):  
Gallia G. Levy ◽  
David G. Motto ◽  
David Ginsburg
Keyword(s):  
Research Effort ◽  
Adamts13 Activity ◽  
Hematologic Disease ◽  
Thrombocytopenic Purpura ◽  
Adamts13 Deficiency ◽  
Normal Hemostasis ◽  
Von Willebrand ◽  
Willebrand Factor

It has now been 3 years since the von Willebrand factor (VWF)–cleaving protease implicated in thrombocytopenic purpura (TTP) pathogenesis was identified as ADAMTS13 (adisintegrin-like and metalloprotease with thrombospondin type 1 motif 13). More than 50 ADAMTS13 mutations resulting in familial TTP have been reported. Considerable progress has also been realized toward understanding the role of ADAMTS13 in normal hemostasis, as well as the mechanisms by which ADAMTS13 deficiency contributes to TTP pathogenesis. Measurement of ADAMTS13 activity in TTP and other pathologic conditions also remains a focus of a substantial clinical research effort. Building on these studies, continued investigation of ADAMTS13 and VWF holds considerable promise for advancing the understanding of TTP pathogenesis and should lead to improved diagnosis and treatment for this important hematologic disease.

Is factor V Leiden a risk factor for thrombotic microangiopathies without severe ADAMTS13 deficiency?

2005 ◽  
Vol 94 (12) ◽  
pp. 1186-1189 ◽  
Author(s):  
Soraya Krieg ◽  
Jan-Dirk Studt ◽  
Irmela Sulzer ◽  
Bernhard Lämmle ◽  
Johanna A. Kremer Hovinga
Keyword(s):  
Risk Factor ◽  
Case Series ◽  
Factor V Leiden ◽  
Factor V ◽  
Adamts13 Activity ◽  
Thrombotic Microangiopathies ◽  
Thrombocytopenic Purpura ◽  
Uremic Syndrome ◽  
Adamts13 Deficiency

SummaryAbout 60% of patients diagnosed with acute thrombotic thrombocytopenic purpura (TTP) display a severe ADAMTS13 deficiency. Recently, Raife et al. concluded from a small case series, that factor V Leiden (FVL) might constitute a risk factor for acute thrombotic microangiopathy (TMA) without severe ADAMTS13 deficiency. Therefore, we determined ADAMTS13 activity and FVL carrier-ship in 256 consecutive patients presenting with various forms of acute TMA, including patients diagnosed with TTP or hemolytic-uremic syndrome (HUS). The overall prevalence of FVL was 8.2% (6.25% among patients diagnosed with TTP, and 9% among those with HUS) concordant with the FVL prevalence reported in Europe. FVL was present in 9.9% of patients with ADAMTS13 activity <10% and in 9.7% of those with normal ADAMTS13 activity (>50%). We conclude that FVL is not more prevalent inTMA patients without as compared to those with severe ADAMTS13 deficiency. The prevalence of FVL carriers in certain HUS subgroups (HUS with ADAMTS13 activity >50%) reaching 12.3% suggests that a contributory role of FVL in the pathogenesis of defined forms of HUS needs further study.

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