title: Plasma of patients with Upshaw-Schulman syndrome, a congenital deficiency of von Willebrand factor-cleaving protease activity, enhances the aggregation of normal platelets under high shear stress.
abstract: Upshaw-Schulman syndrome (USS) is an autosomal recessive disorder characterized by repeated episodes of chronic thrombocytopenia and microangiopathic haemolytic anaemia (MAHA) that responds dramatically to infusions of fresh frozen plasma (FFP). Recent studies have provided consistent evidence that USS is a congenital deficiency of plasma von Willebrand factor-cleaving protease (VWF-CPase) activity and, therefore, unusually large VWF multimers (UL-VWFMs) are present in the plasma. However, the molecular mechanism of the clinical symptoms of USS is not well understood. We studied the relationship between UL-VWFMs and thrombocytopenia in two USS patients by analysing platelet aggregation using a mixture of the patient's plasma and normal washed platelets under high shear stress. Our results clearly showed a remarkably enhanced high shear stress-induced platelet aggregation (H-SIPA) by the patient's plasma. At 24 h after FFP infusion (approximately equal to 10 ml/kg body weight), the enhanced H-SIPA became almost completely normalized but, 2 d later, it began to return to the preinfusion level. These results were in accordance with the change in VWFM patterns. The specific effects of enhanced H-SIPA on VWF, platelet glycoprotein Ib and endogenous ADP released from platelets upon stimulation were confirmed using reagents that specifically inhibit their respective functions. Our present results clearly indicate that thrombocytopenia in USS patients is caused by a combination of the presence of UL-VWFMs, platelets and high shear stress generated in the microcirculation.
authors.affiliation: Department of Blood Transfusion Medicine, Nara Medical University, 840 Shijyo-cho, Kashihara, Nara 634-8522, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Yagi
authors.forename: M
authors.initials: M
authors.lastname: Konno
authors.forename: S
authors.initials: S
authors.lastname: Kinoshita
authors.forename: M
authors.initials: M
authors.lastname: Matsumoto
authors.forename: H
authors.initials: H
authors.lastname: Ishizashi
authors.forename: T
authors.initials: T
authors.lastname: Matsui
authors.forename: K
authors.initials: K
authors.lastname: Titani
authors.forename: Y
authors.initials: Y
authors.lastname: Fujimura
mesh_terms: D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; D000293:Adolescent; D000743:Anemia, Hemolytic / Q000097:blood* / Q000628:therapy; D005260:Female; D006801:Humans; D008666:Metalloendopeptidases / Q000032:analysis / Q000172:deficiency*; D010949:Plasma; D010974:Platelet Aggregation; D010976:Platelet Count; D013314:Stress, Mechanical; D013577:Syndrome; D013921:Thrombocytopenia / Q000097:blood* / Q000628:therapy; D014841:von Willebrand Factor / Q000032:analysis
chemical_list: D014841:von Willebrand Factor; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human