The classic pentad of TTP includes hemolytic anemia with fragmentation of erythrocytes, thrombocytopenia, diffuse and nonfocal neurologic findings, decreased renal function, and fever. Congenital TTP, also known as Schulman-Upshaw syndrome, is characterized by neonatal onset, response to fresh ... The classic pentad of TTP includes hemolytic anemia with fragmentation of erythrocytes, thrombocytopenia, diffuse and nonfocal neurologic findings, decreased renal function, and fever. Congenital TTP, also known as Schulman-Upshaw syndrome, is characterized by neonatal onset, response to fresh plasma infusion, and frequent relapses (Savasan et al., 2003; Kokame et al., 2002). Acquired TTP, which is usually sporadic, usually occurs in adults and is caused by an IgG inhibitor against the von Willebrand factor-cleaving protease.
Upshaw (1978) described a female with congenital deficiency of a factor in normal plasma that reverses microangiopathic hemolysis and thrombocytopenia, indicating a factor important to platelet and red cell survival. The proband, an only child of unrelated parents, ... Upshaw (1978) described a female with congenital deficiency of a factor in normal plasma that reverses microangiopathic hemolysis and thrombocytopenia, indicating a factor important to platelet and red cell survival. The proband, an only child of unrelated parents, was born with rudimentary right radius and ulna and a lobster claw deformity of the right hand. For the first 12 years of life she had 6 to 10 episodes a year of high fever, petechial rash, severe thrombocytopenia, and severe anemia. She would respond dramatically to blood transfusion, whereas adrenocorticosteroids and splenectomy were of no avail. After age 12, the attacks decreased to 3 or 4 yearly. The same disorder may have been present in the patient of Schulman et al. (1960), an 8-year-old girl who had thrombocytopenia which responded to transfusions of blood or plasma. Deficiency of a stimulating factor that is responsible for megakaryocyte maturation and platelet production was postulated. The family history was negative. The mother's plasma induced normal platelet responses, whereas the father's resulted in submaximal responses. The patient of Schulman et al. (1960) was studied by a number of physicians because she moved from city to city. Splenectomy was of no benefit. In 1965, after a 5-month period of thrombocytopenia during which she did not receive intravenous plasma infusions, she had a complex of symptoms resembling those of glomerulonephritis, which was confirmed by renal biopsy (Abildgaard and Simone, 1967). The symptoms remitted with the reintroduction of plasma therapy. In 1973, the patient had preeclampsia during a pregnancy that resulted in a full-term normal boy. McDonald (1977) also postulated deficiency of a thrombopoietin-like substance in this patient. Plasma saved in 1975 and 1976 from this patient had normal levels of fibronectin (Goodnough et al., 1982). Rennard and Abe (1979) demonstrated deficiency of cold-insoluble globulin (fibronectin) in the patient of Upshaw (1978) but not in 4 other patients with thrombotic thrombocytopenic purpura. Koizumi et al. (1981) described a patient who had thrombocytopenia and microangiopathic hemolytic anemia that seemed to improve with plasma administration. The plasma concentration of fibronectin was normal and intravenous administration of fibronectin was of no benefit. Shinohara et al. (1982) reported the case of a Japanese girl with similar clinical features responsive to plasma infusions. Hemolytic anemia, thrombocytopenia, distorted and fragmented circulating red cells, and megakaryocytosis of the bone marrow were present from the newborn period. They called the condition 'congenital microangiopathic hemolytic anemia' and suggested it was different from thrombotic thrombocytopenic purpura. Of 4 affected sibs (2 male, 2 female) described by Wallace et al. (1975), the disease was fatal in 3. Kirchner et al. (1982) described this disorder in mother and daughter. The daughter's illness, characterized primarily by renal insufficiency was most compatible with adult hemolytic uremic syndrome and the mother's illness, which included neurologic findings and fever, was most compatible with thrombotic thrombocytopenic purpura. Merrill et al. (1985) reported 2 certain cases of thrombotic microangiopathy and 3 possible ones in 2 generations of a North Carolina black family. All affected members presented with acute renal failure and accelerated hypertension. Kinoshita et al. (2001) reported 2 unrelated girls with onset of symptoms of USS at ages 4 years and 11 months, respectively. One of the girls developed a right hemiparesis caused by thrombotic occlusion of the left internal carotid artery at the age of 11 years. Both girls had received fresh frozen plasma infusion every 2 weeks. Levy et al. (2001) studied 4 pedigrees with TTP. All patients presented at birth, except for 2 who experienced their first episode of TTP at ages 4 and 8 years; however, both of these individuals had sibs with disease onset as neonates. All patients had a chronic relapsing course and responded to plasma infusion. Activity of von Willebrand factor-cleaving protease (VWFCP) (see PATHOGENESIS) was measured in the plasma of 7 affected individuals and was found to be 2 to 7% of normal; none of the patients tested positive for inhibitors. Plasma levels of the protease in the parents of the affected individuals were 0.51 to 0.68 units/ml, consistent with a heterozygous carrier state. Levels for at-risk sibs of the patients and parents fell into a bimodal distribution, with one peak consistent with carriers and the other indistinguishable from the normal distribution. Moake (2002) reviewed thrombotic microangiopathies. Familial TTP is associated with plasma levels of ADAMTS13 activity less than 5% of normal. The disease usually presents in infancy or childhood but sometimes is not evident until much later (Furlan and Lammle, 2001). Autoantibodies against ADAMTS13 are found in some cases of acquired idiopathic TTP. There is an association with the drug ticlopidine. Upshaw-Schulman (USS) was originally reported as a disease complex with repeated episodes of thrombocytopenia and hemolytic anemia that quickly responded to infusions of fresh frozen plasma. Clinical signs often develop in the patients during the newborn period or early infancy. Indeed, the earliest and most frequently encountered clinical manifestation is severe hyperbilirubinemia with negative Coombs test soon after birth, which requires exchange blood transfusions. Pediatric hematologists had long been more familiar with this disease than general physicians, and a variety of alternative designations were given to the disease, such as chronic relapsing TTP, congenital microangiopathic hemolytic anemia (MAHA), and familial TTP/HUS, the last because the features of thrombotic thrombocytopenic purpura were almost indistinguishable from those of hemolytic-uremic syndrome (235400) (Matsumoto et al., 2004). - Pregnancy Fujimura et al. (2008) reported 9 Japanese women from 6 families with genetically confirmed USS who were diagnosed with the disorder during their first pregnancy. Six of the 9 had episodes of thrombocytopenia during childhood misdiagnosed as autoimmune idiopathic thrombocytopenic purpura (AITP; 188030). Thrombocytopenia occurred during the second to third trimesters in each of their 15 pregnancies, often followed by TTP. Of 15 pregnancies, 8 babies were stillborn or died soon after birth, and the remaining 7 were all premature except 1, who was born naturally following plasma infusions to the mother that had started at 8 weeks' gestation. All women had severely deficient ADAMTS13 activity. Fujimura et al. (2008) emphasized the importance of measuring ADAMTS13 activity in the evaluation of thrombocytopenia during childhood and pregnancy.
By analysis of genomic DNA from patients with familial TTP, Levy et al. (2001) identified 12 mutations in the ADAMTS13 gene (604134.0001-604134.0012), accounting for 14 of the 15 disease alleles studied. Levy et al. (2001) demonstrated that deficiency ... By analysis of genomic DNA from patients with familial TTP, Levy et al. (2001) identified 12 mutations in the ADAMTS13 gene (604134.0001-604134.0012), accounting for 14 of the 15 disease alleles studied. Levy et al. (2001) demonstrated that deficiency of ADAMTS13 is the molecular mechanism responsible for thrombotic thrombocytopenic purpura and suggested that physiologic proteolysis of von Willebrand factor and/or other ADAMTS13 substrates is required for normal vascular homeostasis. In 2 Japanese families with Upshaw-Schulman syndrome, characterized by congenital TTP with neonatal onset and frequent relapses, Kokame et al. (2002) reported 4 novel mutations in the ADAMTS13 gene (604134.0013-604134.0016). Activity of von Willebrand factor-cleaving protease was less than 3% of normal in all probands; VWFCP activity in heterozygous parents ranged from 30 to 60%. In a patient with USS and severely reduced levels of VWFCP activity, Savasan et al. (2003) identified a homozygous mutation in the ADAMTS13 gene (604134.0017).