ABSTRACT
Congenital thrombotic thrombocytopenic purpura (TTP), also known as Upshaw-Schulman syndrome, is associated with an inherited deficiency of ADAMTS13, a von Willebrand factor-cleaving protease. It is a rare, life-threatening disorder characterized by thrombocytopenia, hemolytic anemia, neurological symptoms, renal dysfunction, and fever resulting from formation of platelet thrombi within the microvasculature. Patients have initial episodes mainly during infancy or early childhood, and are conventionally treated with fresh frozen plasma. However, a more appropriate approach based on recombinant ADAMTS13 is slated to begin shortly. Mutations throughout the ADAMTS13 have been identified in congenital TTP patients. The prevalence of this entity is probably underestimated because it is often not suspected, the clinical course is usually heterogeneous and most of the symptoms are common to other diseases. The present review summarizes our current knowledge about Upshaw-Schulman syndrome.
Subject(s)
ADAM Proteins/deficiency , ADAM Proteins/genetics , Genetic Testing/methods , Plasma , Polymorphism, Single Nucleotide/genetics , Purpura, Thrombotic Thrombocytopenic/congenital , Purpura, Thrombotic Thrombocytopenic/diagnosis , ADAMTS13 Protein , Genetic Predisposition to Disease/genetics , Humans , Purpura, Thrombotic Thrombocytopenic/therapySubject(s)
ADAM Proteins/genetics , Codon, Nonsense , Frameshift Mutation , Purpura, Thrombotic Thrombocytopenic/genetics , ADAM Proteins/biosynthesis , ADAM Proteins/chemistry , ADAM Proteins/deficiency , ADAMTS13 Protein , Diagnostic Errors , Female , Genotype , HEK293 Cells , Heterozygote , Humans , Infant , Male , Mutation, Missense , Pedigree , Protein Stability , Purpura, Thrombocytopenic, Idiopathic/diagnosis , Purpura, Thrombotic Thrombocytopenic/diagnosis , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Sequence Deletion , TransfectionABSTRACT
BACKGROUND: Mutation C1149R in the von Willebrand factor (VWF) gene has been thought to cause autosomal dominant severe type 1 von Willebrand disease (VWD). DESIGN AND METHODS: Eight patients from three unrelated families with this mutation were included in the present study who had distinct VWF abnormalities, not described in earlier studies. RESULTS: The patients showed notably low levels of VWF antigen (VWF:Ag), VWF ristocetin cofactor activity (VWF:RCo), VWF collagen binding (VWF:CB), and a reduced ristocetin-induced platelet aggregation (RIPA). VWF:RCo/VWF:Ag and VWF:CB/VWF:Ag ratios were lower than 0.7. At basal conditions, all the VWF multimers were decreased in plasma, with a clearly lower relative proportion of the high molecular weight VWF multimers (HMWM). In high-resolution agarose gels, a large decrease in the relative proportions of the satellite bands was seen. The patients had a brief good response to desmopressin (DDAVP) administration, but the released VWF half-life was shorter than normal, indicating an accelerated clearance of their VWF. Platelet VWF was abnormal. CONCLUSIONS: We conclude from the results obtained in these patients for plasma phenotypic data that this mutation should be classified as a VWD type 2A (IIE). DDAVP therapy may be somewhat helpful for this mutation, at least for mild to moderate bleeding. These data provide evidence that for VWD classification factors other than basal VWF, such as DDAVP response and platelet VWF, should be considered.
