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Impact of Blood Sampling on Circulating Tissue Inhibitors of Metalloproteinases

Department of Urology, University Hospital Charité, Berlin, Germany

To the Editor: I read with great interest the article by Ruokolainen et al. (1) reporting on the clinical validity of tissue inhibitor of matrix metalloproteinase (MMP)-1 (TIMP-1) in head and neck squamous cell carcinoma. Comparing the preoperative serum TIMP-1 concentrations and the immunohistochemical staining of TIMP-1 in tumor sections, they showed that increased TIMP-1 in both compartments is a suitable indicator in predicting the clinical outcome of these tumor patients. The determination of circulating TIMP-1 as reflection in the tissue could be a promising biomarker to assess the preoperative situation and the follow-up of patients. However, more attention to the interference effect of blood collection on the circulating TIMPs should be given before further studies with more patients as suggested by the authors. The issue whether serum or a special plasma should be used for TIMP determination was discussed in analytic journals (2–4). I recommend considering the possible preanalytic pitfalls in the measurement of circulating TIMPs depending on the blood sample used to improve the interpretation of data in future.

To make the readership aware of that problem, I refer to my own experiments summarized in Fig. 1 (3, 4). Briefly, blood samples from 10 healthy volunteers were simultaneously collected either in plastic tubes supplied with kaolin-coated plastic granulate (S-Monovette tubes 01.1601, Sarstedt, Nümbrecht, Germany) to obtain serum or in devices coated with heparin or EDTA to obtain plasma. The tubes were centrifuged within 30 minutes after venipuncture (1,600 x g, 15 minutes). TIMP-1 and TIMP-2 were measured using ELISA kits from Amersham (Little Chalfont, Buckinghamshire, United Kingdom). The TIMP-1 concentrations were higher in serum than in plasma, probably due to the release of TIMP during the platelet activation. The inhibitory effect of heparin on the determination of TIMP-1 was excluded by recovery studies. In contrast, TIMP-2 values were higher in heparin plasma than in serum or EDTA plasma and increased depending on the heparin concentration (data not shown), probably because of the interaction of heparin with proMMP-2 in the pro-MMP-2/TIMP-2 complex (3).

View larger version (12K): [in this window] [in a new window]   Fig. 1. Effect of blood sampling on the concentration of TIMP-1 and TIMP-2. Columns, mean; bars, SE. a, P < 0.05; b, P < 0.01; c, P < 0.001, (ANOVA, Tukey's multiple comparison test).

References

1. Ruokolainen H, Paakko P, Turpeenniemi-Hujanen T. Tissue inhibitor of matrix metalloproteinase-1 is prognostic in head and neck squamous cell carcinoma: comparison of the circulating and tissue immunoreactive protein. Clin Cancer Res 2005;11:3257–64.[Abstract/Free Full Text]
2. Alby C, Ben AO, Foglietti MJ, et al. Preanalytical aspects regarding the measurement of metalloproteinase-9 and tissue inhibitor or metalloproteinase-1 in blood. Clin Chim Acta 2002;325:183–6.[Medline]
3. Jung K, Laube C, Lein M, et al. Kind of sample as preanalytical determinant of matrix metalloproteinases 2 and 9 (MMP2; MMP9) and tissue inhibitor of metalloproteinase 2 (TIMP2) in blood. Clin Chem 1998;44:1060–2.[Free Full Text]
4. Jung K, Nowak L, Lein M, et al. What kind of specimen should be selected for determining tissue inhibitor of metalloproteinase-1 (TIMP-1) in blood? Clin Chim Acta 1996;254:97–100.[CrossRef][Medline]
5. Meisser A, Cohen M, Bischof P. Concentrations of circulating gelatinases (matrix metalloproteinase-2 and -9) are dependent on the conditions of blood collection. Clin Chem 2005;51:274–6.[Free Full Text]

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