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 Low ADAMTS13 Activity Correlates with Increased Mortality in COVID-19 Patients

2021 ◽  
Vol 156 (Supplement_1) ◽  
pp. S6-S7
Author(s):  
Joseph Sweeney ◽  
Mohammad Barouqa ◽  
Gregory Krause ◽  
Jesus Gonzalez Lugo ◽  
Shafia Rahman ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Hospitalized Patients ◽  
Activity Level ◽  
Activity Levels ◽  
Adamts13 Activity ◽  
Cut Point ◽  
Von Willebrand ◽  
The Relationship ◽  
Willebrand Factor ◽  
D Dimer

Abstract Systemic inflammation and coagulopathy are characteristic hallmarks of COVID19. “COVID coagulopathy” manifests mainly as a prothrombotic state affecting both large and small blood vessels, and presenting as arterial, venous, and microangiopathic thrombotic events with von Willebrand factor (VWF) and soluble thrombomodulin increased in hospitalized patients. The causes of coagulopathy are poorly understood. Aim: To investigate the relationship between von Willebrand factor (VWF) biomarkers, intravascular hemolysis, coagulation, and organ damage in COVID19 patients and to study their association with disease severity and mortality. Methods: 181 hospitalized adult COVID19 patients were randomly selected with a balanced distribution of survivors and non-survivors during the period of March 26th 2020 to May 5th 2020. The medical records and laboratory values were reviewed. Statistical analysis was performed using R studio V.3.6.2. Results: Patients who died (n=90) had significantly lower ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity, elevated lactate dehydrogenase levels, increased schistocyte/RBC fragment counts, and elevated VWF antigen and activity levels compared to patients discharged alive (n=91). In 31 patients, we measured several of these biomarkers on two or more occasions. The trending of ADAMTS13 activity illustrated that it is not steady throughout the hospitalization course. ADAMTS13 activity levels tended to improve and/or reach normal levels in patients that survived, yet ADAMTS13 activity levels worsened in most patients that died. Likewise, the VWF antigen and activity levels tended to decrease in patients that survived whereas tended to increase well above the normal range (2-3 folds) in patients that died. D-Dimer levels trended downwards in survivors, sometimes to levels less than 1 µg/ml, yet tended to increase in patients who died. Given the relationship between ADAMTS13 activity and mortality, we wanted to determine a cut-point of initial ADAMTS13 activity (within 72 hours from admission) to predict mortality. 102 patients in our cohort had an ADAMTS13 activity measurement within this timeframe. We determined that this optimal cut-point of initial ADAMTS13 activity was 43% using Youden’s J statistic. Only 30% of patients who had an ADAMTS13 activity level of less than 43% on admission survived, yet 60% of patients survived who had an ADAMTS13 activity level of greater than 43% on admission. Conclusions: COVID-19 may present with low ADAMTS13 activity in a subset of hospitalized patients. Presence of schistocytes/RBC fragment and elevated D-dimer levels on admission may warrant a work-up for ADAMTS13 activity and VWF antigen and activity levels. These findings indicate the need for future investigation to study the relationship between endothelial and coagulation activation and the efficacy of treatments aimed at prevention and/or amelioration of microangiopathy in COVID-19.

scholarly journals Characterization of ADAMTS13 and von Willebrand factor levels in septic and non-septic ICU patients

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0247017
Author(s):  
Kanwal Singh ◽  
Andrew C. Kwong ◽  
Hasam Madarati ◽  
Sharumathy Kunasekaran ◽  
Taylor Sparring ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Protein C ◽  
Specific Activity ◽  
Coagulation System ◽  
Adamts13 Activity ◽  
Icu Patients ◽  
Icu Discharge ◽  
Life Threatening ◽  
Von Willebrand ◽  
Willebrand Factor

Sepsis is a life-threatening disease characterized by excessive host response to infection that can lead to activation of the coagulation system. Von Willebrand Factor (VWF) and ADAMTS13 are important regulators of hemostasis and their dysregulation during sepsis progression is not well understood. Herein we characterize ADAMTS13 and VWF in septic and non-septic patients. ADAMTS13 activity, ADAMTS13 antigen, VWF antigen, myeloperoxidase, and protein C, were measured in plasma collected from 40 septic patients (20 non-survivors and 20 survivors) and 40 non-septic patients on the first and last day of their ICU stay. ADAMTS13 activity and ADAMTS13 antigen were reduced, whereas VWF antigen was elevated among septic patients compared to non-septic patients and healthy controls. Non-septic patients also exhibited elevated VWF antigen and reduced ADAMTS13 activity, but to a lesser extent than septic patients. Non-survivor septic patients exhibited the lowest levels of ADAMTS13 activity. ADAMTS13 activity:antigen ratio was similar across all patient cohorts suggesting that the specific activity of ADAMTS13 remains unchanged. Therefore, reduced ADAMTS13 function in circulation is likely due to a reduction in circulating levels. We suggest that massive release of VWF in response to inflammation consumes limited circulating ADAMTS13, resulting in the imbalance observed between VWF and ADAMTS13 among septic and to a lesser extent in non-septic ICU patients. Changes to ADAMTS13 did not correlate with myeloperoxidase or protein C levels. Reduced ADAMTS13 activity and antigen, and elevated VWF antigen observed among all patient cohorts on admission remained unchanged in survivors at ICU discharge. Prolonged reduction in ADAMTS13 activity and antigen in septic patients coincides with elevated levels of VWF. The persistent abnormalities in ADAMTS13 and VWF in sepsis patients discharged from the ICU may contribute to a sustained prothrombotic state.

scholarly journals An IAP retrotransposon in the mouse ADAMTS13 gene creates ADAMTS13 variant proteins that are less effective in cleaving von Willebrand factor multimers

Blood ◽  
2007 ◽  
Vol 110 (3) ◽  
pp. 886-893 ◽  
Author(s):  
Wenhua Zhou ◽  
Eric E. Bouhassira ◽  
Han-Mou Tsai
Keyword(s):  
Von Willebrand Factor ◽  
Full Length ◽  
Carboxyl Terminus ◽  
Mouse Strains ◽  
Activity Levels ◽  
Adamts13 Activity ◽  
Severe Deficiency ◽  
Type Particle ◽  
Von Willebrand ◽  
Willebrand Factor

AbstractSevere deficiency of ADAMTS13, a von Willebrand factor (VWF)–cleaving metalloprotease, causes thrombotic thrombocytopenic purpura. When analyzed with VWF multimers, but not with an abbreviated VWF peptide (VWF73) as the substrate, the plasma ADAMTS13 activity levels of mouse strains segregated into a high and a low group that differed by approximately 10 fold. Low ADAMTS13 activity was detected in mice containing 2 alleles of intracisternal A-type particle (IAP) retrotransposon sequence in the ADAMTS13 gene. Molecular cloning of mouse ADAMTS13 identified 2 truncated variants (IAP-a and IAP-b) in the low-activity mice. Both of the IAP variants lacked the 2 carboxyl terminus thrombospondin type 1 repeat (TSR) and CUB domains of full-length ADAMTS13. The IAP-b variant also had splicing abnormalities affecting the spacer domain sequence and had miniscule enzymatic activity. Compared with full-length ADAMTS13, the IAP-a variant was approximately one ninth as active in cleaving VWF multimers but was only slightly less active in cleaving VWF73 peptide. Recombinant human ADAMTS13 was also less effective in cleaving VWF multimers than VWF73 when the C-terminal TSR sequence was deleted. In summary, the carboxyl terminus TSR sequence is important for cleaving VWF multimers. Assay results should be interpreted with caution when peptide substrates are used for analysis of variant ADAMTS13 proteins.

A Rapid Sensitive Assay for Measuring ADAMTS13 Activity in Plasma Utilizing a Novel Recombinant Alexa488-vWF86 (Q1599\P1611C) FRET Substrate.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4040-4040
Author(s):  
Enriqueta R. Guinto ◽  
Nicholas Grafos ◽  
John Owen ◽  
Heather L. Lawson ◽  
Robert S. Greenfield
Keyword(s):  
Von Willebrand Factor ◽  
Limit Of Detection ◽  
Resonance Energy ◽  
Cysteine Residues ◽  
Activity Levels ◽  
Analytical Sensitivity ◽  
Adamts13 Activity ◽  
Von Willebrand ◽  
A2 Domain ◽  
Willebrand Factor

Abstract ADAMTS13 (von Willebrand Factor cleaving protease) is a zinc metalloprotease that cleaves the Tyr(1605)/Met(1606) bond within the A2 domain of von Willebrand Factor (vWF). Low levels of ADAMTS13 activity (<5%) are strongly associated with the life threatening hemostatic condition thrombotic thrombocytopenic purpura (TTP). A rapid clinical assay for ADAMTS13 is necessary to provide critical information for the early diagnosis of TTP and to guide and monitor the treatment of TTP. Present methods for measuring ADAMTS13 activity (e.g. collagen binding, vWF multimer analysis and ELISA) are cumbersome, take a long time to complete and lack sensitivity. A fluorescence resonance energy transfer (FRET) assay for ADAMTS13 has been described, which uses the costly and difficult to synthesize truncated A2 domain VWF73aa peptide as substrate (1). However, the lower limit of detection of ADAMTS13 assays using VWF73 FRET substrate is only about 5–10% of normal ADAMTS13 activity levels (1,2). Recently, Zhang et al (3) reported a novel recombinant VWF A2 FRET substrate of 86 amino acids in which cysteine residues were substituted for residues Q1599 and P1611, respectively. The cysteine residues were chemically labeled with fluorescein maleimide to produce a FRET substrate whereby the two fluorescein dyes flanking the ADAMTS13 Tyr/Met cleavage site interact sufficiently such that auto-quenching of fluorescence occurs. In this study, we developed a rapid more sensitive fluorescent assay for ADAMTS13 using a novel recombinant VWF86(Q1599C/P1611C) FRET substrate. VWF86(Q1599C/P1611C) peptide was chemically coupled via the cysteine residues to the brighter, more photostable Alexa488 fluorochrome. Assay conditions were optimized to obtain higher analytical sensitivity < 5% normal ADAMTS13 activity (0.5 ng/ml) and shorter assay times (20–30 minutes). ADAMTS13 activity in 50 normal individuals as well as subjects with TTP, thrombosis and lupus anticoagulant will be presented. The rapid FRET assay using the novel recombinant Alexa488-vWF86 (Q1599\P1611C) substrate should prove clinically useful for quantitation of ADAMTS13 activity and the rapid diagnosis of TTP.

Determination of ADAMTS13 Antigen and Activity Levels in Patients with Acute Myocardial Infarction and Acute Ischemic Stroke.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3987-3987
Author(s):  
Ningzheng Dong ◽  
Fang Liu ◽  
Shundong Ji ◽  
Changgeng Ruan
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Ischemic Stroke ◽  
General Population ◽  
Von Willebrand Factor ◽  
Arterial Thrombosis ◽  
Activity Levels ◽  
Adamts13 Activity ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract von Willebrand factor-cleaving protease (ADMTS13) is a metalloproteases regulating von Willebrand factor multimers size in plasma, its activity decrease has been reported in many physiological and pathological conditions. But information on ADAMTS13 in arterial thrombosis disease and in the general population is limited. In this study, we investigated the ADAMTS13 antigen and activity levels in 87 healthy control subjects of different ages, in 93 patients with acute myocardial infarction (AMI) and in 30 patients with acute ischemic stroke (AIS). ADAMTS13 Antigen levels were measured using a sandwich ELISA, and ADAMTS13 activity levels were analyzed by the FRETS-VWF73 method. A pool of plasma obtained from 40 blood donors was used as reference and was defined to contain 100% of the protease. The individual subject of the pool was not included in the study. Compared with 50 sex- and age-matched control subjects, ADAMTS13 antigen and activity levels were significantly lower in patients with arterial thrombosis diseases. Antigen levels were 87.8±19.8%, 61.8±18.8%, and 70.2±15.5% respectively in control, AMI and ASI patients. ADAMTS13 activity were 81.7±13.9%, 59.2±22.1% and 65.4±15.8% respectively. In the 87 healthy subjects, the range of ADAMTS13 activity is from 46.3% to 119.0%, and antigen is from 60.8% to 141.9%. In different age groups (17 to 20 years old, 21 to 40 years old, 41 to 60 years old, and older than 60 years old), ADAMTS13 antigen levels were 76.0%, 109.7%, 99.3%, and 74.5% respectively, and activity levels were 80.8%, 81.1%, 77.9%, and 87.3% respectively. It seems the antigen reached the highest level in people from 21 to 40 years old, then gradually decreased with age. The antigen and activity mean in males (87.1% and 80.8%) was lower than that in females (94.7% and 86.1%), but the difference is not significant (p=0.145 and p=0.124). In conclusion, the decrease of ADAMTS13 antigen and activity in AMI and AIS patients indicated ADMATS13 might contribute to arterial thrombosis, and the plasma ADAMTS13 antigen level in the general population was significantly affected by age.

Severe secondary deficiency of von Willebrand factor–cleaving protease (ADAMTS13) in patients with sepsis-induced disseminated intravascular coagulation: its correlation with development of renal failure

Blood ◽  
2006 ◽  
Vol 107 (2) ◽  
pp. 528-534 ◽  
Author(s):  
Tomoko Ono ◽  
Jun Mimuro ◽  
Seiji Madoiwa ◽  
Kenji Soejima ◽  
Yuji Kashiwakura ◽  
...  
Keyword(s):  
Renal Failure ◽  
Von Willebrand Factor ◽  
Disseminated Intravascular Coagulation ◽  
Activity Levels ◽  
Adamts13 Activity ◽  
Intravascular Coagulation ◽  
Disease States ◽  
Adamts13 Deficiency ◽  
Von Willebrand ◽  
Willebrand Factor

AbstractDeficiency of ADAMTS13 is found in patients with thrombotic thrombocytopenic purpura (TTP), and the genetic defects in the ADAMTS13 gene or the autoantibody against ADAMTS13 is thought to be responsible for the development of TTP. The clinical correlation and mechanisms of secondary ADAMTS13 deficiency in other disease states were investigated. In addition to TTP, ADAMTS13 levels were severely decreased in patients with sepsis-induced disseminated intravascular coagulation (DIC). The incidence of acute renal failure and serum creatinine levels in patients with ADAMTS13 activity levels lower than 20% (incidence, 41.2%; creatinine, 160 ± 150 μM [1.81 ± 1.70 mg/dL]) (P < .05) were significantly higher than they were in patients with ADAMTS13 activity levels higher than 20% (incidence, 15.4%; creatinine, 84 ± 67 μM [0.95 ± 0.76 mg/dL]) (P < .01). Additionally, unusually large von Willebrand factor multimers were detected in 26 (51.0%) of 51 patients with ADAMTS13 activity levels lower than 20%. Lower molecular weight forms of ADAMTS13 were found in the plasma of patients with sepsis-induced DIC, suggesting that the deficiency of ADAMTS13 was partially caused by its cleavage by proteases in addition to decreased synthesis in the liver. These data suggested that severe secondary ADAMTS13 deficiency can be associated with sepsis-induced DIC and may contribute to the development of renal failure.

Population Pharmacokinetic Modeling of von Willebrand Factor Activity in von Willebrand Disease Patients after Desmopressin Administration

2020 ◽  
Vol 120 (10) ◽  
pp. 1407-1416
Author(s):  
Nico C. B. de Jager ◽  
Jessica M. Heijdra ◽  
Quincy Kieboom ◽  
Marieke J. H. A. Kruip ◽  
Frank W. G. Leebeek ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Time Profile ◽  
Von Willebrand Disease ◽  
Activity Level ◽  
Population Pharmacokinetic ◽  
Activity Levels ◽  
Interpatient Variability ◽  
Starting Point ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Objective Most von Willebrand disease (VWD) patients can be treated with desmopressin during bleeding or surgery. Large interpatient variability is observed in von Willebrand factor (VWF) activity levels after desmopressin administration. The aim of this study was to develop a pharmacokinetic (PK) model to describe, quantify, and explain this variability. Methods Patients with either VWD or low VWF, receiving an intravenous desmopressin test dose of 0.3 µg kg−1, were included. A PK model was derived on the basis of the individual time profiles of VWF activity. Since no VWF was administered, the VWF dose was arbitrarily set to unity. Interpatient variability in bioavailability (F), volume of distribution (V), and clearance (Cl) was estimated. Results The PK model was developed using 951 VWF activity level measurements from 207 patients diagnosed with a VWD type. Median age was 28 years (range: 5–76), median predose VWF activity was 0.37 IU/mL (range: 0.06–1.13), and median VWF activity response at peak level was 0.64 IU/mL (range: 0.04–4.04). The observed PK profiles were best described using a one-compartment model with allometric scaling. While F increased with age, Cl was dependent on VWD type and sex. Inclusion resulted in a drop in interpatient variability in F and Cl of 81.7 to 60.5% and 92.8 to 76.5%, respectively. Conclusion A PK model was developed, describing VWF activity versus time profile after desmopressin administration in patients with VWD or low VWF. Interpatient variability in response was quantified and partially explained. This model is a starting point toward more accurate prediction of desmopressin dosing effects in VWD.

scholarly journals Supranormal von Willebrand factor multimers in scleroderma

Blood ◽  
1989 ◽  
Vol 73 (6) ◽  
pp. 1586-1591 ◽  
Author(s):  
PM Mannucci ◽  
R Lombardi ◽  
A Lattuada ◽  
E Perticucci ◽  
R Valsecchi ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Platelet Aggregation ◽  
Von Willebrand Factor ◽  
Dose Aspirin ◽  
Low Dose Aspirin ◽  
Severity Of The Disease ◽  
Partially Occluded ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Normal Controls

Abstract Platelet adhesion-aggregation reactions play an early and pivotal role in the pathogenesis of systemic sclerosis in scleroderma, but the mechanisms are incompletely understood. We determined whether or not plasma from 11 consecutive patients with scleroderma contained a subset of larger than normal (“supranormal”) multimers of von Willebrand factor (vWF) that are potent inducers of platelet aggregation and adhesion. Supranormal multimers were found in all patients on at least one of two different occasions 9 to 12 months apart, whatever the duration and severity of the disease, but in none of the normal controls. Administration of low-dose aspirin (40 mg) to five of the 11 patients for ten days to inhibit the platelet release reaction slightly reduced the amounts of supranormal multimers suggesting that they might originate in part from platelets. Supranormal multimers may contribute to the pathogenesis of systemic sclerosis by inducing platelet aggregation and enhancing adhesion to subendothelium under the conditions of elevated shear stress occurring in the partially occluded vessels of the arterial microcirculation of scleroderma.

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