Investigation of a link between raised levels of pepsinogen in blood as a mediator of in-vitro clot lysis in acid and a cause of abnormal factor XIII screening tests.

: The in-vitro lysis of plasma clots in acetic acid generally indicates a Factor XIII deficiency that is confirmed by quantitative assay. However, there are two rare, poorly understood circumstances whereby clot lysis in acid occurs when factor XIII activity levels are normal: the presence of either an atypical antifactor XIII antibody, or an unknown acid-activated protease. Our centre has identified four patients with in-vitro clot lysis in acetic acid and normal FXIII levels by activity assay. Our aim was to determine whether the cause of this unusual result was an inhibitory antibody or an aspartic acid protease. In each case, we found an inhibitor that was not an IgG but showed characteristics of an acid protease, including that it was neutralized by pepstatin. The four patients had median pepsinogen I levels five-fold to 10-fold higher than the normal median of 89 μg/l. Pepsinogen II was increased by three-fold to six-fold, but from a lower baseline median of 6.5 μg/l. Cathepsin D levels were normal. Clot lysis in the acid test was observed when recombinant human pepsinogen I was added to normal plasma at similarly high concentrations as in patient samples, consistent with a role of an acid protease. Clot lysis also occurred with addition of pepsinogen II, but required four-fold to seven-fold more than in patient samples. Laboratories should be aware that a positive acid clot lysis test can be misleading if pepsinogen levels are raised and should not use this alone to diagnose FXIII deficiency.