|Year : 2013 | Volume
| Issue : 2 | Page : 68-73
ADAMTS-13 contents in therapeutic plasma products
Samy B.M. El-Hady1, Manal H. Farahat1, Eman Almasry2
1 Department of Clinical Pathology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
2 Department of Biochemistry, Faculty of Medicine, AlMenia University, Almenia, Egypt
|Date of Submission||18-Dec-2012|
|Date of Acceptance||11-Feb-2013|
|Date of Web Publication||20-Jun-2014|
Samy B.M. El-Hady
Department of Clinical Pathology, Faculty of Medicine, Zagazig University, Zagazig
Source of Support: None, Conflict of Interest: None
ADAMTS-13 is a zinc-containing metalloprotease enzyme that cleaves the von Willebrand factor (VWF). In human beings, changes in ADAMTS-13 levels have been observed in a number of diseases. The determination of ADAMTS-13 levels and those of its substrate will help to elucidate therapeutic strategies including ADAMTS-13 supplementation for these diseases. Successful treatment has been reported with both fresh-frozen plasma and cryoprecipitate poor plasma (CPP) as replacement fluids. This study aimed to investigate ADAMTS-13 and some coagulation factors in the different plasma products commonly used to increase ADAMTS-13 levels.
Materials and methods
A total of 180 U of whole blood (WB) were collected from healthy young male blood donors, their ages ranging from 20 to 32 years. Sixty donors were of blood type O+, 50 were A+, 50 were B+, and 20 were AB+. All blood donors included in this study underwent tests for assessment of their liver and kidney functions, and they were declared free from any disease. Plasma from the blood samples was extracted either on the day of collection (the platelet-rich plasma method) or after an overnight hold of WB (the Buffy coat method). Factor VIII (FVIII) activity was measured and levels of fibrinogen, VWF, and human ADAMTS-13 in plasma were quantitatively determined.
There was no difference in the mean concentrations of ADAMTS-13 in plasma products obtained using the two different methods. Blood group O showed a higher concentration compared with other ABO blood groups. The concentration of ADAMTS-13 was higher in cryoprecipitate than in plasma and CPP. The mean values of FVIII activity were lower in many plasma and cryoprecipitate units prepared by overnight holding of WB for close to 24 h. In addition, the mean values of FVIII activities and VWF levels were lower in plasma and cryoprecipitate units prepared from blood group O compared with those prepared from other ABO blood groups. No differences were detected in the mean values of fibrinogen and VWF in the plasma products when different methods were used for preparation.
The observation that the concentration of ADAMTS-13 is higher in cryoprecipitate than in plasma and CPP suggests that cryoprecipitate may be a reasonable source of ADAMTS-13 in clinical settings when volume is an issue. In addition, in our study, the use of cryoprecipitate from blood group O in clinical settings yielded higher concentrations of ADAMTS-13 with less VWF. Although the use of cryoprecipitate instead of plasma or CPP could potentially double the amount of ADAMTS-13 infused, further studies from multiple centers are needed to validate the results.
Keywords: ADAMTS-13, cryoprecipitate poor plasma, cryoprecipitate, frozen plasma
|How to cite this article:|
El-Hady SB, Farahat MH, Almasry E. ADAMTS-13 contents in therapeutic plasma products. Egypt J Haematol 2013;38:68-73
| Introduction|| |
ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), also known as von Willebrand factor (VWF) cleaving protease, is a zinc-containing metalloprotease enzyme that cleaves VWF, a large protein involved in blood clotting. It is secreted in blood and degrades large VWF multimers, decreasing their activity 1. The binding of ADAMTS-13 to Lys-plasminogen may have an important role in localizing these two proteases at sites of thrombus formation or vascular injury where the fibrinolytic system is activated 2. Further, ADAMTS-13 is cleaved by plasmin in plasma 3. In human beings, changes in ADAMTS-13 levels have been observed in a number of diseases. For example, both plasma ADAMTS-13 activity and antigen levels decrease with increasing severity of liver cirrhosis. An imbalance between decreasing ADAMTS-13 levels and increasing levels of its substrate may be a predisposing factor for platelet thrombi formation in patients with advanced liver cirrhosis 4. Decreased ADAMTS-13 activity may be involved not only in sinusoidal microcirculatory disturbances but also in subsequent progression of liver injuries, eventually leading to multiorgan failure 5. High levels of fully functional VWF and a temporary ADAMTS-13 deficiency occur during liver transplantation and these changes contribute to postoperative thrombotic complications 6. In addition, plasma ADAMTS-13 activity has been seen to significantly decrease after hepatectomy because of ischemic injury, together with liver mass reduction, reflecting a postoperative liver dysfunction 7. Data suggest a potential role of kidney dysfunction in ADAMTS-13 synthesis or metabolism. The imbalance between ADAMTS-13 and VWF levels in hemodialysis patients contributes to the hypercoagulability state 8,9. Findings reveal that ADAMTS-13 and VWF are causally involved in myocardial ischemia/reperfusion injury 10. Helena et al. 11 concluded that both high VWF and low ADAMTS-13 plasma levels increase the risk of ischemic stroke and myocardial infarction. Further, there is a functional role for the antithrombotic enzyme ADAMTS-13 in reducing excessive vascular inflammation and plaque formation during early atherosclerosis, likely through the proteolytic cleavage of ultralarge VWF multimers, thereby inhibiting platelet deposition and inflammation 12,13. ADAMTS-13 may have a critical role in the central nervous system, particularly after neuronal injuries 14. ADAMTS-13 deficiency was detected in thrombotic thrombocytopenic purpura (TTP) 15,16. Severe ADAMTS-13 deficiency due to circulating anti-ADAMTS-13 autoantibodies, inhibiting ADAMTS-13 enzymatic activity or increasing ADAMTS-13 clearance, defines a subset of patients with idiopathic TTP 17. Defects in protein secretion and catalytic activity are the main mechanisms responsible for the deficiency of ADAMTS-13 in congenital TTP patients 18. Kremer Hovinga et al. 19 demonstrated that a lower level of initial plasma ADAMTS-13 activity is associated with higher risk of relapse in patients with TTP. Further, patients with a low plasma ADAMTS-13 activity and high-titer levels of inhibitors appear to have a lower survival rate. Yang and colleagues 20,21 suggested the need for clinical testing of plasma ADAMTS-13 activity and inhibitors during the course of therapy and follow-up of TTP and acute liver disease patients, respectively. In addition, the determination of levels of ADAMTS-13 and its substrate will help us to elucidate additional therapeutic strategies including ADAMTS-13 supplementation for these diseases 21. It is known that therapeutic plasma exchange therapy in TTP reduces the mortality rate to ∼20%, presumably because of the removal of the patient’s inhibitory autoantibody and replacement of ADAMTS-13 activity derived from the infused plasma products; daily administration of therapeutic plasma exchange therapy over several weeks is often necessary to achieve disease remission 22. Successful treatment has been reported with both fresh-frozen plasma (FFP) and reduced plasma cryoprecipitate [also known as cryosupernatant or cryoprecipitate poor plasma (CPP)] as replacement fluids 23,24. However, It has been questioned as to whether one product may be more effective than the other 24. This study aimed to investigate ADAMTS-13 and some coagulation factors in the different plasma products commonly used to increase ADAMTS-13 levels.
| Materials and methods|| |
A total of 180 U of whole blood (WB) were collected from healthy young male blood donors, their ages ranging from 20 to 32 years. Sixty donors were of blood type O+, 50 were A+, 50 were B+, and 20 were AB+. All blood donors included in this study underwent tests for assessment of their liver and kidney functions and were declared free from any disease.
Plasma from the blood samples was either extracted on the day of collection [the platelet-rich plasma (PRP) method; FFP] or after an overnight hold of WB (the Buffy coat method; FP-24).
In the Buffy coat method, 90 U of plasma (30 from O+ donors, 25 from A+ donors, 25 from B+ donors, and 10 from AB+ donors) were extracted and stored only after an overnight hold of the WB. Blood was collected using a MacoPharma bag system (Leukoflex LCR5; LQT System, Lille, France). The WB was cooled after storage in a refrigerator at 1–6°C. The following day, the WB was subjected to ‘hard-spin’ centrifugation. The plasma was extracted from the top and, simultaneously, red blood cells were extracted from the bottom of the bag, leaving the platelet-containing ‘Buffy coat’ in the central pouch. The plasma samples were frozen by placing them in a freezer at −80°C between 22 and 24 h of collection.
In the PRP method, 90 U of plasma (30 from O+ donors, 25 from A+ donors, 25 from B+ donors, and 10 from AB+ donors) were extracted on the day of collection (1–8 h after collection) using a MacoPharma bag system (Leukoflex LCR5, LQE/LQF System). In this method, units were not actively cooled after collection. Briefly, PRP was obtained from the WB by ‘soft-spin’ centrifugation and then was subjected to ‘hard-spin’ centrifugation. The plasma was extracted from the top of the bag and was frozen by placing it in a freezer at −80°C.
Samples of plasma obtained using both methods were taken and stored at −80°C for coagulation factor testing.
Cryoprecipitate and cryoprecipitate poor plasma preparation
Plasma units were thawed at 1–6°C and subjected to centrifugation. The cryoprecipitate was resuspended in 20 ml of plasma, and samples of the resuspended cryoprecipitate and CPP were stored at −80°C for coagulation factor testing.
Coagulation factor analysis
A coagulation analyzer Sysmex CA-1500 (Siemens, Sysmex America Inc., White Parkway, Mundelein, USA) was used for determination of FVIII activities and levels of fibrinogen and VWF in plasma.
Determination of FVIII activity: the assay involves measurement of the clotting time, in the presence of cephalin and activator, of a system in which all the factors are present and in excess, except FVIII, which is derived from the sample being tested.
Quantitative determination of the VWF antigen: the assay is based on the change in turbidity of the microparticle suspension, which is measured by photometry. A suspension of latex microparticles, coated by covalent bonding with antibodies specific for VWF, is mixed with the test plasma. An antigen–antibody reaction takes place, leading to agglutination of the latex microparticles, which induces an increase in turbidity of the reaction medium. This increase in turbidity is reflected by an increase in absorbance, the latter being measured photometrically. The increase in absorbance is a function of the VWF level present in the test sample.
Quantitative determination of fibrinogen levels
In the presence of an excess of thrombin, the clotting time of diluted plasma has a direct bearing on the level of plasma fibrinogen.
The level of human ADAMTS-13 in plasma was measured quantitatively using a commercially available Quantikine ELISA kit (R&D Systems Europe, Ltd., Abingdon Science Park, Abingdon, UK).
This assay uses the quantitative sandwich enzyme immunoassay technique. A monoclonal antibody specific to ADAMTS-13 is precoated onto a microplate. Standards and samples are pipetted into the wells and any ADAMTS-13 present is bound by the immobilized antibody. After washing away any unbound substance, an enzyme-linked polyclonal antibody specific to ADAMTS-13 is added into the wells. After a wash to remove any unbound antibody–enzyme reagent, a substrate solution is added into the wells and color develops in proportion to the amount of ADAMTS-13 bound in the initial step. The color development is stopped and the intensity of the color is measured at 450 nm.
Results are expressed as mean±SD and are analyzed statistically using analysis of variance. The least significant difference was assessed to test the difference between the different studied groups. Correlation analysis was carried out using Pearson’s correlation test. P-values below 0.05 were considered significant. Data were tabulated statistically and analyzed using SPSS version 20.0 for Windows (SPSS Inc., Chicago, Illinois, USA).
| Results|| |
[Table 1] and [Figure 1] and [Figure 2] show that there is no difference in the mean concentrations of ADAMTS-13 in plasma products when the two different methods were used for preparation. Blood group O showed a higher concentration compared with other ABO blood groups.
|Figure 1: ADAMTS-13 levels in the different products from blood group O.|
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|Figure 2: ADAMTS-13 levels in FFP (PRP) from the different blood groups. FFP, fresh-frozen plasma; PRP, platelet-rich plasma.|
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The mean values of FVIII activities were lower in many plasma and cryoprecipitate units prepared by overnight WB holding for nearly 24 h. Further, the mean values of FVIII activities were lower in the plasma and cryoprecipitate units prepared from blood group O compared with those prepared from other ABO blood groups [Table 2].
[Table 3] and [Table 4] show no differences between the mean values of fibrinogen and VWF levels in the plasma products on using different methods for preparation. Plasma and cryoprecipitate of blood group O show lower levels of VWF compared with those of other ABO blood groups.
|Table 3: Von Willebrand factor levels (%) in the different plasma products|
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[Table 1], [Table 2], [Table 3] and [Table 4] show that the concentrations of ADAMTS-13, VWF, and fibrinogen and FVIII activity are higher in cryoprecipitate than in plasma and CPP. In addition, these levels and activity are higher in plasma than in CPP.
| Discussion|| |
Under physiological conditions, ultralarge VWF (UL-VWF) multimers are cleaved by ADAMTS-13 into smaller, less-reactive VWF multimers 25. Higher levels of plasma ADAMTS-13 activity and antigen were indicators of risk for hepatocellular carcinoma development in chronic liver disease and may be useful in the prediction of hepatocarcinogenesis 26. ADAMTS-13 activity is deficient in many diseases, resulting in the presence of UL-VWF multimers in the circulation, which form high-strength bonds with the Gp Ib-IX-V receptor complex on platelets 27, leading to the formation of VWF-rich thrombi in the microvasculature of many organs as well as consumptive thrombocytopenia 28. Successful treatment has been reported with both FFP and CPP as replacement fluids 23,24. FFP infusion as ADAMTS-13 replacement therapy may improve both liver dysfunction and thrombocytopenia in liver transplant patients. Uemura et al. 29 are particularly interested in conducting clinical trials with recombinant ADAMTS-13 preparations not only in patients with advanced liver cirrhosis but also in patients with hepatic veno-occlusive disease and liver transplantations. Their results have shown that exogenous ADAMTS-13 can efficiently cleave both UL-VWF that pre-exists in the circulation and the newly produced molecules at the endothelial cell surface. From this point of view, this study was intended to study ADAMTS-13 and some coagulation factors in the different plasma products commonly used to increase ADAMTS-13 levels in different diseases.
In this study, we found that there is no difference in the mean concentrations of ADAMTS-13 in plasma products when the two different methods were used for preparation of plasma. ADAMTS-13 remains stable in products prepared by holding WB overnight. Our results are in line with those of Serrano et al. 30 and Rock et al. 31, who found that ADAMTS-13 activity remains stable in plasma at room temperature for 48 h with little loss. Similarly, the results of Erik et al. 32 show that ADAMTS-13 activity is stable in FFP and CPP over 5 days of storage at 1–6°C. Yarranton et al. 33 reported similar results of stable ADAMTS-13 activity in all plasma products after overnight storage at room temperature. Our findings show significant differences between plasma products and cryoprecipitate; data suggest that ADAMTS-13 is concentrated in cryoprecipitate. This result agrees with that of Erik et al. 32 according to whom the ADAMTS-13 concentration in cryoprecipitate was approximately double that in FFP and CPP. In addition, our results show that ADAMTS-13 concentration in plasma is higher than that in CPP. These findings disagree with those of Erik et al. 32 who found that ADAMTS-13 activity did not differ between FFP and CPP. Mannucci et al. 34 observed a 10% higher ADAMTS-13 activity in plasma from blood group O compared with that from groups A, B, and AB. Our results similarly revealed that the mean ADAMTS-13 level in plasma products from blood group O was higher than that from other groups. Mannucci et al. 34 suggest that the higher ADAMTS-13 activity observed in group O donors is related to the lower VWF levels associated with individuals of that blood type. Similarly, Rios et al. 8 found a decrease in ADAMTS-13 levels in donors of non-O blood groups compared with those of blood group O. In contrast, Erik et al. 32 found that the difference in mean ADAMTS-13 activity between the FFP of group O and that of group A did not reach significance.
In our study, holding blood at 1–6°C overnight resulted in a reduction in FVIII activities. This reduction was statistically significant in some plasma and cryoprecipitate units. This result is in agreement with that of Cardigan et al. 35, who found that holding blood at 4°C overnight resulted in a more than 20% loss of FVIII. In addition, Serrano et al. 30 found that FVIII activity was noticeably lower with the overnight WB holding for nearly 24 h. Similarly, Thibault et al. 36 found that cryoprecipitate produced after an overnight hold of the WB also had reduced coagulation FVIII activity compared with that produced from plasma frozen within 8 h of collection. Similar results have been reported previously in studies comparing overnight holding of WB with plasma frozen within 8 h of collection 37.
Our results did not show any significant difference in VWF levels when plasma was prepared using the two different methods. This result agrees with that of Serrano and colleagues who reported that VWF activity appeared to be well preserved 24 h after donation 30, 35, 38.
Our data show that the mean values of FVIII activities and VWF levels were lower in plasma and cryoprecipitate units prepared from blood group O compared with that prepared from other ABO blood groups. This finding agrees with that of Rios et al. 8, who found an increase in FVIII activity and VWF levels in individuals of non-O blood groups when compared with those with blood group O. Their data confirmed that the ABO blood group is an important risk factor for increased procoagulant factors in plasma, such as FVIII and VWF. Cardigan et al. 35 reported that the levels of VWF are lower in group O donors, whereas Mannucci et al. 34 have shown that the levels of VWF are higher in group O donors.
Our findings have shown that fibrinogen is stable in WB stored at 1–6°C for 24 h. This result disagrees with that in the study by Cardigan et al.35, who found modest reductions in levels of fibrinogen in plasma prepared from overnight WB holding compared with plasma frozen within 8 h of donation. It is surprising that Serrano et al. 30 found that fibrinogen levels were higher in the plasma samples prepared from WB holding at 4°C overnight.
It is important to note that in our study all cryoprecipitate units tested met the quality standard requirements; fibrinogen levels met the requirement of 150 mg/U or more in 75% or more of the units tested and FVIII activity met the requirement of 80 IU/U or more in 75% or more of the units tested. Our study suggests that holding WB overnight before processing does not have a negative effect on the quality of plasma or cryoprecipitate for transfusion, as assessed using standard quality control measures. In addition, there was no significant difference in the ADAMTS-13 content of plasma prepared within 8 h after donation and that prepared 24 h after donation, suggesting that these plasma products should be equally effective at restoring ADAMTS-13 activity. The observation that the concentration of ADAMTS-13 is higher in cryoprecipitate than in plasma and CPP would suggest that cryoprecipitate may be a reasonable source of ADAMTS-13 in clinical settings when volume is an issue. In addition, in our study, the use of group O cryoprecipitate in clinical settings yields more ADAMTS-13 with less VWF. Although the use of cryoprecipitate instead of plasma and CPP could potentially double the amount of ADAMTS-13 infused, further studies from multiple centers are needed to validate the results.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]