ABSTRACT
Thrombotic thrombocytopenic purpura (TTP) is a life-threatening systemic illness of abrupt onset and unknown cause. Proteolysis of the blood-clotting protein von Willebrand factor (VWF) observed in normal plasma is decreased in TTP patients. However, the identity of the responsible protease and its role in the pathophysiology of TTP remain unknown. We performed genome-wide linkage analysis in four pedigrees of humans with congenital TTP and mapped the responsible genetic locus to chromosome 9q34. A predicted gene in the identified interval corresponds to a segment of a much larger transcript, identifying a new member of the ADAMTS family of zinc metalloproteinase genes (ADAMTS13). Analysis of patients' genomic DNA identified 12 mutations in the ADAMTS13 gene, accounting for 14 of the 15 disease alleles studied. We show that deficiency of ADAMTS13 is the molecular mechanism responsible for TTP, and suggest that physiologic proteolysis of VWF and/or other ADAMTS13 substrates is required for normal vascular homeostasis.
Subject(s)
Metalloendopeptidases/genetics , Mutation , Purpura, Thrombotic Thrombocytopenic/genetics , von Willebrand Factor/metabolism , Chromosome Mapping , Chromosomes, Human, Pair 9 , DNA Mutational Analysis , Female , Humans , Male , Metalloendopeptidases/blood , Metalloendopeptidases/physiology , Molecular Sequence Data , Multigene Family , Pedigree , Physical Chromosome Mapping , Purpura, Thrombotic Thrombocytopenic/congenital , Purpura, Thrombotic Thrombocytopenic/enzymologyABSTRACT
We present three cases of thrombotic thrombocytopenic purpura (TTP) and one case of the hemolytic-uremic syndrome (HUS) occurring during pregnancy. All patients and their offspring survived, and none of the infants had TTP or HUS. Plasma manipulations (exchange and infusions) were the effective therapeutic measures in all patients. The most significant complication of therapy was posttransfusion hepatitis, which occurred in three patients, and from which recovery was complete.
Subject(s)
Blood Transfusion , Pregnancy Complications, Hematologic/therapy , Purpura, Thrombotic Thrombocytopenic/therapy , Adult , Erythrocyte Transfusion , Exchange Transfusion, Whole Blood , Female , Hemolytic-Uremic Syndrome/complications , Hepatitis/etiology , Humans , Infant, Newborn , Infant, Premature , Plasma Exchange , Pregnancy , Transfusion ReactionABSTRACT
We have described six new patients accounting for seven episodes of agranulocytosis due to procainamide. Six episodes involved the slow-release oral preparation. With continued use of this convenient antiarrhythmic agent, it is important that physicians be alert to the possibility of agranulocytosis in febrile patients receiving procainamide. If agranulocytosis occurs, procainamide should be discontinued promptly and the fever should be treated aggressively with combination broad spectrum antibiotics.
