Atypical reduction of plasma ADAMTS13 activity by a non-IgG-type inhibitor in a patient with hemolytic uremic syndrome caused by Shiga toxin-producing Escherichia coli.

Thrombotic microangiopathies include hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). Measurement of plasma levels of "a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13" (ADAMTS13) activity can distinguish HUS from TTP. Reduced plasma ADAMTS13 activity (< 10% normal range) is atypical for HUS, but not for TTP. However, we detected reduced ADAMTS13 activity in a patient with Shiga toxin-producing Escherichia coli-associated HUS caused by non-IgG anti-ADMTS13 autoantibodies. Furthermore, the patient exhibited possible genetic abnormalities associated with atypical HUS. The patient fully recovered after administration of supportive therapy. To the best of our knowledge, very few cases of STEC-HUS with reduced ADAMTS13 activity have been reported; thus far, none have described the presence of non-IgG anti-ADMTS13 autoantibodies. Therefore, we suggest that anti-ADAMTS13 analyses should be performed in patients diagnosed with STEC-HUS, especially in those who present with prolonged healing or unexpected clinical symptoms.

Influenza-associated thrombotic microangiopathy with unbalanced von Willebrand factor and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 levels in a heterozygous protein S-deficient boy.

Influenza infections often cause pneumonia, but there is limited information on thrombotic microangiopathy (TMA) in these circumstances. We report the case of an 11-year-old boy who developed TMA during the acute phase of H1N1 influenza. Plasma von Willebrand factor (VWF) was elevated, whereas a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) activity was mildly reduced in the absence of ADAMTS13-neutralizing autoantibody, resulting in low ratio of ADAMTS13 to VWF. The patient was treated intensively, including plasma exchange, and he recovered from the TMA. He developed pulmonary embolism (PE), however, after removal of the central venous catheter. The findings suggested that influenza-associated cytokines enhanced the release of unusually large VWF multimers from vascular endothelial cells and promoted the formation of platelet thrombi and TMA. Subsequent analysis further indicated the presence of familial protein S deficiency, and it seemed likely that the PE was more related to this heterozygous protein S defect.

Association between Von Willebrand factor, disintegrin and metalloproteinase with thrombospondin type 1 motif member 13, d-Dimer and cystatin C levels with retinopathy in type 1 diabetes mellitus.

BACKGROUND: We evaluated the association between plasma levels of VWF, ADAMTS13 and d-Dimer, which consist on endothelial dysfunction and hypercoagulability biomarkers, and cystatin C with retinopathy in type 1 diabetic patients. METHODS: Patients were classified according to presence (n=55) or absence (n=70) of retinopathy. Plasma levels of VWF, ADAMTS13, d-Dimer and cystatin C were evaluated by ELISA and ADAMTS13 activity was evaluated by FRET. RESULTS: Plasma levels of VWF (p=0.033), ADAMTS13 activity (p=0.014), d-Dimer (p=0.002) and cystatin C (p<0.001) were elevated in diabetic patients with retinopathy compared to those without this complication. The multivariate logistic regression analysis showed that ADAMTS13 activity (p=0.031) d-Dimer (p=0.015) and cystatin C (p=0.001) remained associated with retinopathy after adjustment for age, diabetes duration, use of statin, use of ACEi or angiotensin antagonist, use of acetylsalicylic acid and glomerular filtration rate. CONCLUSION: ADAMTS13 activity, d-Dimer and cystatin C are associated with retinopathy in type 1 diabetic patients and are promising biomarkers for the diagnosis and monitoring of diabetic retinopathy.

Endpoints in resuscitation.

PURPOSE OF REVIEW: Shock occurs because of a failure to deliver adequate oxygen to meet the metabolic demands of the body resulting in metabolic acidosis, inflammation, and coagulopathy. Resuscitation is the process of treating shock in an attempt to restore normal physiology. Various hemodynamic, metabolic, and regional endpoints have been described to evaluate the degree of shock and guide resuscitation efforts. We will briefly describe these endpoints, and propose damage control resuscitation as an additional endpoint. RECENT FINDINGS: Serum lactate, base deficit, and pH are well established endpoints of resuscitation that provide valuable information when trended over time; however, a single value is inadequate to determine adequacy of resuscitation. Rapid normalization of central venous oxygen concentration has been associated with improved survival, and bedside transthoracic echocardiography can be a reliable assessment of volume status. In hypovolemic/hemorrhagic shock, early hypotensive, or controlled resuscitation strategies have been associated with improved survival, and hemostatic strategies guided by thrombelastography using a balanced transfusion approach result in improved hemostasis. SUMMARY: Numerous endpoints are available; however, no single endpoint is universally applicable. Damage control resuscitation strategies have demonstrated improved survival, hemostasis, and less early death from exsanguination, suggesting that hemorrhage control should be an additional endpoint in resuscitation.

Platelet a disintegrin and metallopeptidase 10 expression correlates with clock drawing test scores in Alzheimer's disease.

OBJECTIVE: Earlier studies have demonstrated that a disintegrin and metallopeptidase 10 (ADAM10) levels are reduced in Alzheimer's disease (AD) patients compared with healthy subjects. The objective of this study was to evaluate whether platelet ADAM10 levels correlates with the clock drawing test (CDT) scores, which is a simple and a reliable measure of visuospatial ability and executive function in AD patients. METHODS: Thirty elderly patients with probable AD and 25 healthy patients forming the control group, matched by age, gender, and educational level, were evaluated. Platelet proteins were analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis, and ADAM10 was identified by western blotting. The Spearman's correlation coefficient between ADAM10 and CDT was obtained for each group. The areas under the curves were used to compare the receiver operating characteristic curves. RESULTS: The CDT scores and platelet ADAM10 expression were significantly different between patients with AD and controls and also along the disease's progression. In AD patients, there was a positive correlation between ADAM10 expression and CDT scores. Among non-AD subjects, no correlation was found. The combination of ADAM10 and CDT was significantly better to confirm the AD diagnosis than the AUCs of ADAM10 and CDT separately. CONCLUSIONS: The association of blood-based biomarkers, such as ADAM10, and cognitive tests may be helpful for a more reliable AD diagnosis.

[Second trimester screening for trisomy 21 using ADAM12-S as a maternal serum marker].

OBJECTIVE: To investigate the value of a disintegrin and metalloproteinase 12 secreting form (ADAM12-S) as a maternal serum marker in second trimester screening for trisomy 21 (Down syndrome, DS), and to develop an appropriate prenatal DS screening protocol. METHODS: Serum samples were collected from 53 pregnant women carrying a trisomy 21 fetus and 621 pregnant women with matched gestational age and weight carrying a healthy fetus. ADAM12-S concentrations were determined with a time-resolved fluorescence immunoassay (TRFIA). Curve fitting by weighted regression and other statistical methods were conducted, and the model was optimized for prenatal trisomy 21 screening program in second trimester. ADAM12-S alone or in combination with other two- or three-combination test was selected as a serum marker for prenatal second-trimester screening of trisomy 21 by calculation of detection rate (DR) and false positive rate (FPR). RESULTS: By comparison, the median multiple of the median (MoM) value of ADAM12-S in DS pregnancy group was higher than that of the control group (P< 0.01). When FPR = 5%, the DR of ADAM12-S was 28.3%, and the positive and negative likelihood ratios were 5.66 and 0.75, respectively. The DR of three-combination test of ADAM12-S, alpha-fetoprotein (AFP) and free beta subunit of human chorionic gonadotropin (ß-HCG) has increased to 52.80% from 39.62% of the conventional two-combination test (AFP and free ß-HCG). For women with a risk between 1/300 and 1/1000 by two-combination test for DS, the DR has increased from 39.62% to 47.12%, but FPR only increased by 0.8% after adding ADAM12-S as a maternal serum marker. CONCLUSION: Considering the increased DR of pregnancies with a risk between 1/300 and 1/1000 in second trimester, ADAM12-S may provide a feasible maternal serum maker when combined with AFP and free ß-HCG. The cost-effectiveness ratio is reasonable.

A disintegrin and metalloprotease protein-12 as a novel marker for the diagnosis of ectopic pregnancy.

OBJECTIVE: To evaluate the performance of a novel biomarker, a disintegrin and metalloprotease-12 (ADAM-12), to differentiate an ectopic pregnancy (EP) from normal intrauterine pregnancies (IUPs). DESIGN: Case-control study. SETTING: Three urban academic centers. PATIENT(S): Women who were seen in the emergency department with pain or bleeding in the first trimester of pregnancy. INTERVENTION(S): Sera from women with diagnosed EP or IUP were evaluated via proteomics and an ADAM-12 dissociation-enhanced lanthanide fluoroimmunoassay. MAIN OUTCOME MEASURE(S): Differences between groups, area under the receiver operating curve, sensitivity, and specificity. RESULT(S): Via a proteomics evaluation, we found a statistically significant decrease in ADAM-12 in the sera of patients with EP, which we confirmed in a larger group of 199 patients (median IUP 18.6 ng/mL versus median EP 2.5 ng/mL with good discrimination between the groups as assessed by receiver operating characteristics [area under the curve = 0.82]). At a low cut-point, the sensitivity was 70% and specificity 84%, but, at a higher cut-point optimizing sensitivity, the ADAM-12 test demonstrated a sensitivity of 97%. CONCLUSION(S): ADAM-12 is a promising marker for the diagnosis of EP in women with symptoms in the first trimester, validating the proteomics findings. Further studies in additional patient populations and in combination with other biomarkers are needed.

[Correlation of a disintegrin and metalloprotease 12 level in maternal serum during the first trimester with pregnancy outcome].

OBJECTIVE: To explore the relationship between pregnant outcomes and the maternal serum level of a disintegrin and metalloprotease 12 (ADAM 12) in the first trimester. METHODS: From July 2007 to January 2008, the serum levels of ADAM 12 of 511 women in their first trimester (6 - 13 gestational weeks), who attended the clinics at Peking Union Medical College Hospital, were tested by Time-Resolved Fluorescence Immunoassay (TR-FIA), and the results and pregnant outcomes were analyzed. RESULTS: (1) The median levels of ADAM 12 at 6, 7, 8, 9, 10, 11, 12, 13 weeks of gestation were 14.63 microg/L, 35.08 microg/L, 88.90 microg/L, 186.51 microg/L, 370.62 microg/L, 537.71 microg/L, 632.55 microg/L, and 769.42 microg/L, respectively, showing a linear increase with the gestational age (r =0. 992, P < 0.01). (2) Among the 511 pregnancies, 427 were normal singleton term pregnancies and 84 had adverse perinatal outcomes. Twenty-seven miscarriages (5.3%, 27/511) and 5 ectopic pregnancies were reported and the Multiple of Medians (MOM) of them were 0.24 and 0.32, respectively, which was significantly lower than the normal singleton pregnancies (1.01, P < 0.05). However, the serum level of ADAM 12 in 5 women with placenta previa (MOM = 1.45) was significantly higher than the normal ones (P < 0.05). No significant correlation was found between the fetal birth weight and maternal serum level of ADAM 12 in the first trimester (r = -0.15, P < 0.05). (3) Thirteen cases with chromosomal abnormalities was identified out of 97 cases who received fetal karyotyping, including 3 Down's syndrome and 2 Turner syndrome, and the MOM of ADAM 12 in these 13 cases (0.34) was significantly different from those normal singleton pregnancies (P < 0.05). MoMs of ADAM 12 in 10 euchromosome aneupolyhaploids cases (0.29)were lower than the normal ones (P < 0.05). CONCLUSION: The maternal serum level of ADAM 12 in the first-trimester is a potential marker for aneupolyhaploid screening and early fetal loss prediction, and is suggested to be tested at 9-12 gestational weeks as part of prenatal screening.

First-trimester maternal serum a disintegrin and metalloprotease 12 (ADAM12) and adverse pregnancy outcome.

OBJECTIVE: To examine the possible association of maternal serum a disintegrin and metalloprotease (ADAM12) in the first trimester of pregnancy and subsequent development of preeclampsia, delivery of small for gestational age (SGA) neonates, and spontaneous preterm delivery. METHODS: The maternal serum concentration of ADAM12 at 11 0/7 to 13 6/7 weeks was measured in 128 cases of preeclampsia, 88 cases of gestational hypertension, 296 cases with SGA neonates, 58 cases of spontaneous preterm delivery, and 570 controls. Regression analysis was used to determine which of the maternal factors and fetal crown rump length were significant predictors of ADAM12 in the control group, and from the regression model the value in each case and control was expressed as a multiple of median (MoM). The levels of ADAM12 MoM were compared in cases and controls. RESULTS: In the control group the concentration of ADAM12 increased with fetal crown rump length, decreased with maternal weight and was higher in African-American than in white women. There was a significant association between ADAM12 and pregnancy-associated plasma protein A (r=0.417, P<.001) and between each metabolite and birth weight percentile (r=0.176, P<.001 and r=0.109, P=.009). In the SGA group, the median ADAM12 concentration (0.848 MoM) was lower (P<.001), but in pregnancies complicated by preeclampsia (0.954 MoM), gestational hypertension (1.013 MoM), and spontaneous preterm delivery (1.048 MoM) the levels were not significantly different from controls (1.011 MoM). CONCLUSION: There is a good correlation between the maternal serum ADAM12 and pregnancy-associated plasma protein A concentration. Measurement of ADAM12 does not provide useful prediction of SGA, preeclampsia, or spontaneous preterm delivery. LEVEL OF EVIDENCE: II.

ADAM 12 as a first-trimester maternal serum marker in screening for Down syndrome.

BACKGROUND: A Disintegrin And Metalloprotease 12 (ADAM 12) is a glycoprotein synthesised by placenta and it has been shown to be a potential first-trimester maternal serum marker for Down syndrome (DS) in two small series. Here we analyse further, the potential of ADAM 12 as a marker for DS in a large collection of first-trimester serum samples. MATERIALS AND METHODS: The concentration of ADAM 12 was determined in 10-14-week pregnancy sera from 218 DS pregnancies and 389 gestational age-matched control pregnancies, which had been collected as part of routine prospective first-trimester screening programs (DS = 105) or as part of previous research studies (DS = 113). ADAM 12 was measured using a semi-automated time resolved immunofluorometric assay and median values for normal pregnancies were established by polynomial regression. These medians were then used to determine population distribution parameters for DS and normal pregnancy groups. Correlation with previously established PAPP-A and free beta-hCG multiple of the medians (MoMs) and delta nuchal translucency (NT) were determined and used to model the performance of first-trimester screening with ADAM 12 in combination with other first-trimester markers at various time periods across the first trimester. The benefits of a contingent testing model incorporating early measurement of PAPP-A and ADAM 12 were also explored. RESULTS: The maternal serum concentration of ADAM 12 was significantly reduced (p = 0.0049) with an overall median MoM of 0.79 in the DS cases and a log(10) MoM SD of 0.3734 in the DS cases and 0.3353 in the controls. There was a significant correlation of ADAM 12 MoM in DS cases with gestational age (r = 0.375) and the median MoM increased from 0.50 at 10-11 weeks to 1.38 at 13 weeks. ADAM 12 was correlated with maternal weight (r(controls) = 0.283), PAPP-A (r(controls) = 0.324, r(DS) = 0.251) but less so with free beta-hCG (r(controls) = 0.062, r(DS) = 0.049) and delta NT (r(controls) = 0.110, r(DS) = 0.151). ADAM 12 was significantly (p = 0.026) lower in smokers (0.87 vs 1.00) and elevated in Afro-Caribbean women compared to Caucasian women (1.34 vs 1.00). Population modelling using parameters from this and an earlier study showed that a combination of ADAM 12 and PAPP-A measured at 8-9 weeks and combined with NT and free beta-hCG measured at 12 weeks could achieve a detection rate of 97% at a 5% false-positive rate or 89% at a 1% false-positive rate. PAPP-A and ADAM 12 alone at 8-9 weeks could identify 91% of cases at a 5% false-positive rate. Using this as part of a contingent-screening model to select an intermediate risk group of women for NT and free beta-hCG at 11-12 weeks would enable the detection of 92% of cases with a 1% false-positive rate at a cost of providing NT and free beta-hCG for 6% of women with 94% of women having completed screening by the 10th week of pregnancy. CONCLUSION: ADAM 12 in early first trimester is a very efficient marker of DS. In combination with existing markers, it offers enhanced screening efficiency in a two-stage sequential first-trimester screening program or in a contingent-screening model, which may have benefits in health economies where universal access to high quality ultrasound is difficult. More data on early first-trimester cases with DS are required to establish more secure population parameters by which to assess further the validity of these models.

Maternal serum ADAM12 levels in Down and Edwards' syndrome pregnancies at 9-12 weeks' gestation.

BACKGROUND: Maternal serum ADAM12 is reduced, on average, in early first-trimester Down and Edwards' syndrome pregnancies but the extent of reduction declines with gestation. Here we study levels at 9-12 weeks when the marker might be used concurrently with other established markers. METHODS: Samples from 16 Down and 2 Edwards' syndrome cases were retrieved from storage and tested together with 313 unaffected singleton pregnancies using a semi-automated time-resolved immuno-fluorometric assay. Results were expressed in multiples of the gestation-specific median (MoM) based on regression. RESULTS: The median in Down syndrome was 0.94 MoM with a 10th-90th centile range of 0.22-1.63 MoM compared with 1.00 and 0.33-2.24 MoM in unaffected controls (P = 0.21, one-side Wilcoxon Rank Sum Test). The two Edwards' syndrome cases had values 0.31 and 2.17 MoM. CONCLUSIONS: ADAM12 cannot be used concurrently with other markers in the late first trimester. However, it does have the potential to be used earlier in pregnancy either concurrently with other early markers or in a sequential or contingent protocol. More data will be required to reliably predict the performance of either approach.

Reduction of the disintegrin and metalloprotease ADAM12 in preeclampsia.

OBJECTIVES: The secreted form of ADAM12 is a metalloprotease that may be involved in placental and fetal growth. We examined whether the concentration of ADAM12 in first-trimester maternal serum could be used as a marker for preeclampsia. METHODS: We developed a semiautomated, time-resolved, immunofluorometric assay for the quantification of ADAM12 in serum. The assay detected ADAM12 in a range of 78-1248 microg/L. Serum samples derived from women in the first trimester of a normal pregnancy (n = 324) and from women who later developed preeclampsia during pregnancy (n = 160) were obtained from the First Trimester Copenhagen Study. ADAM12 levels were assayed in these serum samples. Serum levels of ADAM12 were converted to multiples of the median (MoM) after log-linear regression of concentration versus gestational age. RESULTS: Serum ADAM12 levels in women who developed preeclampsia during pregnancy had a mean log MoM of -0.066, which was significantly lower than the mean log MoM of -0.001 for ADAM12 levels observed in serum samples from women with normal pregnancy (P = .008). The mean log MoM was even lower in serum derived from preeclamptic women whose infant's weight at birth was less than 2,500 g (n = 27, mean log MoM of -0.120, P = .053). CONCLUSION: The maternal serum levels of ADAM12 are significantly lower during the first trimester in women who later develop preeclampsia during pregnancy when compared with levels in women with normal pregnancies. Because the secreted form of ADAM12 cleaves insulin-like growth factor binding protein (IGFBP)-3 and IGFBP-5, the IGF axis may play a role in preeclampsia. ADAM12 may be a useful early marker for preeclampsia. LEVEL OF EVIDENCE: II-2.

ADAM12: a novel first-trimester maternal serum marker for Down syndrome.

OBJECTIVES: The concentration of bioavailable insulin-like growth factor (IGF) I and II is important to foetal growth. It is regulated by insulin-like growth factor binding proteins (IGFBP) 1 through 6. Proteolytic cleavage of IGFBP-3 takes place in human pregnancy serum; accordingly, IGFBP-3 serum levels decrease markedly during pregnancy. ADAM12 (A disintegrin and metalloprotease) is an IGFBP-3 and IGFBP-5 protease and is present in human pregnancy serum. The goal of this study was to determine whether ADAM12 concentration in maternal serum is a useful indicator of foetal health. METHODS: We developed an enzyme-linked immunosorbent assay (ELISA) for the quantification of ADAM12 in serum. The assay range was 42 to 667 micro g/L. Recombinant ADAM12 was used as the standard for calibration. RESULTS: We found that ADAM12 was highly stable in serum. Serum concentration increased from 180 micro g/L at week 8 of pregnancy to 670 micro g/L at 16 weeks, and reached 12 000 micro g/L at term. In 18 first-trimester Down syndrome pregnancies, the concentration of ADAM12 was decreased, thus the median multiple of mean (MoM) value was 0.14 (0.01-0.76). A detection rate for foetal Down syndrome of 82% for a screen-positive rate of 3.2% and a 1:400 risk cut-off was found by Monte Carlo estimation using ADAM12 and maternal age as screening markers. CONCLUSION: ADAM12 is a promising marker for Down syndrome.