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A modified thrombin generation test for the measurement of factor VIII concentrates.
J Thromb Haemost. 2003 May; 1(5):1005-11.JT

Abstract

It has been well documented that there is an uncertainty over the true factor (F)VIII level in postinfusion samples due to assay discrepancies. The thrombin generation test (TGT) was used as a potentially more physiological approach to assess and compare FVIII concentrates. FVIII concentrates were added to artificial FVIII-deficient plasma. Thrombin generation was initiated by the addition of FIXa (14 nm), phospholipid and CaCl2. Thrombin was measured by subsampling into fibrinogen, and curves quantified as area under the curve (AUC) and time taken to half-maximum (t(1/2)max). Addition of one plasma-derived concentrate to as little as 0.005 IU mL-1 gave a normal AUC, but prolonged t(1/2)max. Increasing FVIII to 1 IU mL-1 had little effect on AUC, but did reduce the t(1/2)max to 64 s (normal 114 s). A range of plasma-derived and recombinant concentrates were tested at 1 IU mL-1; results were similar, except the B-domain deleted concentrate, which had the most rapid initial rate of thrombin generation (t(1/2)max 48 s, P < 0.05). Two hemophilic plasmas (< 0.01 IU mL-1) produced large amounts of thrombin (AUC 65% and 69%), although t(1/2)max was prolonged. Addition of a FVIII antibody abolished thrombin generation, indicating that these plasmas contained low levels of FVIII. Decreasing the FIXa concentration (0.2 nm) minimized thrombin generation in hemophilic plasma but not in normal plasma. These results indicate that FVIII < 0.01 IU mL-1 can generate significant quantities of thrombin depending upon the amount of FIXa present. The TGT could prove useful for patient monitoring in gene therapy and prophylaxis.

Authors+Show Affiliations

Haemophilia Centre and Haemostasis Unit, Royal Free Hospital, Pond Street, London, UK.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Evaluation Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12871369

Citation

McIntosh, J H., et al. "A Modified Thrombin Generation Test for the Measurement of Factor VIII Concentrates." Journal of Thrombosis and Haemostasis : JTH, vol. 1, no. 5, 2003, pp. 1005-11.
McIntosh JH, Owens D, Lee CA, et al. A modified thrombin generation test for the measurement of factor VIII concentrates. J Thromb Haemost. 2003;1(5):1005-11.
McIntosh, J. H., Owens, D., Lee, C. A., Raut, S., & Barrowcliffe, T. W. (2003). A modified thrombin generation test for the measurement of factor VIII concentrates. Journal of Thrombosis and Haemostasis : JTH, 1(5), 1005-11.
McIntosh JH, et al. A Modified Thrombin Generation Test for the Measurement of Factor VIII Concentrates. J Thromb Haemost. 2003;1(5):1005-11. PubMed PMID: 12871369.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A modified thrombin generation test for the measurement of factor VIII concentrates. AU - McIntosh,J H, AU - Owens,D, AU - Lee,C A, AU - Raut,S, AU - Barrowcliffe,T W, PY - 2003/7/23/pubmed PY - 2004/1/17/medline PY - 2003/7/23/entrez SP - 1005 EP - 11 JF - Journal of thrombosis and haemostasis : JTH JO - J Thromb Haemost VL - 1 IS - 5 N2 - It has been well documented that there is an uncertainty over the true factor (F)VIII level in postinfusion samples due to assay discrepancies. The thrombin generation test (TGT) was used as a potentially more physiological approach to assess and compare FVIII concentrates. FVIII concentrates were added to artificial FVIII-deficient plasma. Thrombin generation was initiated by the addition of FIXa (14 nm), phospholipid and CaCl2. Thrombin was measured by subsampling into fibrinogen, and curves quantified as area under the curve (AUC) and time taken to half-maximum (t(1/2)max). Addition of one plasma-derived concentrate to as little as 0.005 IU mL-1 gave a normal AUC, but prolonged t(1/2)max. Increasing FVIII to 1 IU mL-1 had little effect on AUC, but did reduce the t(1/2)max to 64 s (normal 114 s). A range of plasma-derived and recombinant concentrates were tested at 1 IU mL-1; results were similar, except the B-domain deleted concentrate, which had the most rapid initial rate of thrombin generation (t(1/2)max 48 s, P < 0.05). Two hemophilic plasmas (< 0.01 IU mL-1) produced large amounts of thrombin (AUC 65% and 69%), although t(1/2)max was prolonged. Addition of a FVIII antibody abolished thrombin generation, indicating that these plasmas contained low levels of FVIII. Decreasing the FIXa concentration (0.2 nm) minimized thrombin generation in hemophilic plasma but not in normal plasma. These results indicate that FVIII < 0.01 IU mL-1 can generate significant quantities of thrombin depending upon the amount of FIXa present. The TGT could prove useful for patient monitoring in gene therapy and prophylaxis. SN - 1538-7933 UR - https://www.unboundmedicine.com/medline/citation/12871369/A_modified_thrombin_generation_test_for_the_measurement_of_factor_VIII_concentrates_ L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&amp;sid=nlm:pubmed&amp;issn=1538-7933&amp;date=2003&amp;volume=1&amp;issue=5&amp;spage=1005 DB - PRIME DP - Unbound Medicine ER -