Abstract:
:Familial bleeding problems are frequently difficult to diagnose because currently used clinical tests cannot identify intracellular molecular defects of platelets. Using platelet proteomics, a comprehensive analytical tool, we diagnosed a family with severe bleeding problems of unknown origin with Quebec Platelet Disorder. Prior to proteomic analysis, we determined platelet counts, presence of glycoprotein (GP) Ib and GPIIb/IIIa, platelet aggregation, dense granule content and release, plasma levels of fibrinogen, Factor XIII and fibrin degradation products in four family members. Abnormalities were detected in platelet aggregation studies, which revealed variably reduced responses to ADP, collagen and epinephrine with concomitantly decreased ATP/serotonin secretion. In addition, D-dimer levels were significantly elevated 72 hours after in vitro thrombin stimulation of platelet-rich plasma. Together with the autosomal dominant inheritance and the delayed onset of bleeding in two of the four patients these results did not support any known platelet disorder. Therefore, the proteome of platelet lysates separated by one-dimensional SDS-PAGE was analysed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Platelet proteomics showed reduced amounts of alpha-granule proteins multimerin, fibrinogen and thrombospondin-1 in patient compared to control samples suggestive of Quebec Platelet Disorder. The diagnosis of Quebec Platelet Disorder was confirmed by urokinase-specific Western blots. Urokinase causes the degradation of alpha-granule proteins in this disorder. Diagnosis of rare bleeding disorders has important implications for prophylactic and acute treatment of bleeding patients. This is the first report using proteomics to identify a familial platelet defect.
journal_name
Plateletsjournal_title
Plateletsauthors
Maurer-Spurej E,Kahr WH,Carter CJ,Pittendreigh C,Cameron M,Cyr TDdoi
10.1080/09537100802010547subject
Has Abstractpub_date
2008-08-01 00:00:00pages
342-51issue
5eissn
0953-7104issn
1369-1635pii
902440883journal_volume
19pub_type
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