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.

von Willebrand factor cleaving protease (ADAMTS13) is deficient in recurrent and familial thrombotic thrombocytopenic purpura and hemolytic uremic syndrome

Blood ◽  
2002 ◽  
Vol 100 (3) ◽  
pp. 778-785 ◽  
Author(s):  
Giuseppe Remuzzi ◽  
Miriam Galbusera ◽  
Marina Noris ◽  
Maria Teresa Canciani ◽  
Erica Daina ◽  
...  
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Acute Phase ◽  
Von Willebrand Factor ◽  
Adamts13 Activity ◽  
Thrombocytopenic Purpura ◽  
Uremic Syndrome ◽  
Adamts13 Deficiency ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Whether measurement of ADAMTS13 activity may enable physicians to distinguish thrombotic thrombocytopenic purpura (TTP) from hemolytic uremic syndrome (HUS) is still a controversial issue. Our aim was to clarify whether patients with normal or deficient ADAMTS13 activity could be distinguished in terms of disease manifestations and multimeric patterns of plasma von Willebrand factor (VWF). ADAMTS13 activity, VWF antigen, and multimeric pattern were evaluated in patients with recurrent and familial TTP (n = 20) and HUS (n = 29). Results of the collagen-binding assay of ADAMTS13 activity were confirmed in selected samples by testing the capacity of plasma to cleave recombinant VWF A1-A2-A3. Most patients with TTP had complete or partial deficiency of ADAMTS13 activity during the acute phase, and in some the defect persisted at remission. However, complete ADAMTS13 deficiency was also found in 5 of 9 patients with HUS during the acute phase and in 5 patients during remission. HUS patients with ADAMTS13 deficiency could not be distinguished clinically from those with normal ADAMTS13. In a subgroup of patients with TTP or HUS, the ADAMTS13 defect was inherited, as documented by half-normal levels of ADAMTS13 in their asymptomatic parents, consistent with the heterozygous carrier state. In patients with TTP and HUS there was indirect evidence of increased VWF fragmentation, and this occurred also in patients with ADAMTS13 deficiency. In conclusion, deficient ADAMTS13 activity does not distinguish TTP from HUS, at least in the recurrent and familial forms, and it is not the only determinant of VWF abnormalities in these conditions.

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.

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 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 (&lt;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 &lt; 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.

Von Willebrand factor–cleaving protease (ADAMTS13) in thrombocytopenic disorders: a severely deficient activity is specific for thrombotic thrombocytopenic purpura

Blood ◽  
2002 ◽  
Vol 100 (2) ◽  
pp. 710-713 ◽  
Author(s):  
Valentina Bianchi ◽  
Rodolfo Robles ◽  
Lorenzo Alberio ◽  
Miha Furlan ◽  
Bernhard Lämmle
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Von Willebrand Factor ◽  
Adamts13 Activity ◽  
Thrombocytopenic Purpura ◽  
Heparin Induced Thrombocytopenia ◽  
Severe Deficiency ◽  
Uremic Syndrome ◽  
Adamts13 Deficiency ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract A severe deficiency in von Willebrand factor–cleaving protease (ADAMTS13) activity (&lt; 5% that in normal plasma) has been observed in most patients with a diagnosis of thrombotic thrombocytopenic purpura (TTP) but not in those with a diagnosis of hemolytic uremic syndrome. However, ADAMTS13 deficiency has been claimed not to be specific for TTP, since it was observed in various thrombocytopenic and other conditions. We studied 68 patients with thrombocytopenia due to severe sepsis or septic shock (n = 17), heparin-induced thrombocytopenia (n = 16), idiopathic thrombocytopenic purpura (n = 10), or other hematologic (n = 15) or miscellaneous conditions (n = 10). Twelve of the 68 patients had subnormal levels of ADAMTS13 activity (≤ 30%), but none had less than 10%. Thus, the study showed that ADAMTS13 activity is decreased in a substantial proportion of patients with thrombocytopenia of various causes. A severe deficiency of ADAMTS13 (&lt; 5%), identified in more than 120 patients during 1996 to 2001 in our laboratory, is specific for a thrombotic microangiopathy commonly labeled TTP.

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