Alternative titles; symbols
SNOMEDCT: 373420004; ORPHA: 54057, 93583; DO: 10772;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 9q34.2 | Thrombotic thrombocytopenic purpura, hereditary | 274150 | Autosomal recessive | 3 | ADAMTS13 | 604134 |
A number sign (#) is used with this entry because hereditary thrombotic thrombocytopenic purpura (TTP) is caused by homozygous or compound heterozygous mutation in the ADAMTS13 gene (604134), which encodes the von Willebrand factor (VWF; 613160)-cleaving protease (VWFCP).
See 235400 for a discussion of the hemolytic-uremic syndrome (HUS), which has signs and symptoms similar to those in thrombotic thrombocytopenic purpura.
Hereditary thrombotic thrombocytopenic purpura (TTP), also known as Upshaw-Schulman syndrome (USS), is a rare autosomal recessive thrombotic microangiopathy (TMA). Clinically, acute phases of TTP are defined by microangiopathic mechanical hemolytic anemia, severe thrombocytopenia, and visceral ischemia. Hereditary TTP makes up 5% of TTP cases and is caused mostly by biallelic mutation in the ADAMTS13 gene, or in very rare cases, by monoallelic ADAMTS13 mutation associated with a cluster of single-nucleotide polymorphisms (SNPs); most cases of all TTP (95%) are acquired via an autoimmune mechanism (see 188030). Hereditary TTP is more frequent among child-onset TTP compared with adult-onset TTP, and its clinical presentation is significantly different as a function of its age of onset. Child-onset TTP usually starts in the neonatal period with hematological features and severe jaundice. In contrast, almost all cases of adult-onset hereditary TTP are unmasked during the first pregnancy of a woman whose disease was silent during childhood (summary by Joly et al., 2018).
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 syndrome (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).
Kremer Hovinga and George (2019) reviewed the diagnosis, pathogenesis, and treatment of hereditary thrombotic thrombocytopenic purpura. Precipitants include birth (severe neonatal jaundice), alcohol excess, and especially pregnancy, with early loss and eclampsia in the first or second trimester. Data on long-term outcomes were lacking.
Adult-Onset Hereditary TTP
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.
Joly et al. (2018) reported 22 patients from 20 families with adult-onset congenital TTP from the French registry for thrombotic microangiopathy (TMA). In all patients, TTP was triggered by pregnancy; none had any TMA symptoms at birth, in childhood, or outside of any obstetrical context. BY ELISA, 11 of 20 patients tested had detectable although very low levels of ADAMTS13 antigen (0.034-0.201 microg/ml). ADAMTS13 activity was measurable (between 3 and 10 IU/dL) in 10 of 17 patients tested, and 3 patients recovered a detectable ADAMTS13 activity ranging from 12 to 20 IU/dL in remission phase several years after the inaugural pregnancy-induced acute TTP episode.
Kremer Hovinga and George (2019) noted that adult-onset hereditary TTP is most often precipitated by pregnancy. The authors briefly described 2 patients with adult-onset hereditary TTP, one an 18-year-old man who presented with abdominal pain and vomiting for several days after excessive alcohol intake, and the other a previously healthy 34-year-old woman who presented with sudden vision loss due to serous retinal detachment in the thirteenth week of her first pregnancy.
Hamroun et al. (2020) reported that 5 women with known hereditary TTP (diagnosed in a first complicated pregnancy) were able to have 8 successful pregnancies with weekly monitoring of blood count and administration of plasma if platelet count was less than 150,000. In response, Kremer Hovinga and George (2020) reported that because complications of hTTP had been reported as early as 7 weeks' gestation, they began plasma prophylaxis as soon as pregnancy was confirmed. They began with 10 to 15 ml/kg every 2 weeks initially, and then weekly in the second trimester or sooner, if the woman's platelet count dropped. Their goal was to maintain the woman's platelet count at her normal level, which could be higher than 150,000 per cubic millimeter.
Furlan et al. (1997) reported 2 brothers with chronic relapsing TTP who were deficient in the VWF-cleaving protease. In addition to these brothers, Furlan et al. (1998) found complete protease deficiency in 3 sibs: 2 sisters had their first episode of TTP during pregnancy, whereas their protease-deficient brother was asymptomatic for the disorder. Three further unaffected sibs of the family (2 brothers and 1 sister) had normal activity of VWF-cleaving protease. A third family with 2 affected brothers was reported. No consanguinity was established in any of the 3 families Furlan (1999). Autosomal recessive inheritance of the disorder was suggested.
Kremer Hovinga and George (2019) pointed out that the patient's age may help distinguish between acquired and hereditary TTP, with acquired TTP being much less common in young children than in adults. The presence of a functional ADAMTS13 inhibitor or an increased anti-ADAMTS13 immunoglobulin G (IgG) antibody titer argues against the diagnosis of hereditary TTP. An important clue in the diagnosis of hereditary TTP is the persistence of severe ADAMTS13 deficiency in remission. Additionally, patients with hereditary TTP may experience a transient ischemic attack (TIA) without thrombocytopenia or evidence of hemolysis. Thrombocytopenia may not be severe, and patients may present with acute kidney injury. Finally, patients with hereditary TTP recover rapidly after 1 or a few plasma exchanges.
Moake et al. (1982) found unusually large multimers of von Willebrand factor (ULVWFMs) in the plasma of 4 patients, including the girl reported by Schulman et al. (1960), with chronic relapsing thrombotic thrombocytopenic purpura and proposed that these are the 'agglutinative' substances. These unusually large multimers are even larger than the largest multimers of VWF in normal plasma and resemble a subgroup of huge VWF forms secreted by human endothelial cells. After retrograde secretion by endothelial cells, these unusually large multimers become entangled in subepithelial fibrous components, thereby maximizing VWF-mediated adhesion of platelets to subendothelium after vascular damage. Normally, a processing activity in plasma prevents the highly adhesive, unusually large multimers from going far or staying long after being secreted into the bloodstream. Moake (1998) proposed that patients with chronic relapsing thrombotic thrombocytopenic purpura have a defect in the processing of these unusually large multimers that makes them susceptible to periodic relapses.
Furlan et al. (1996) and Tsai (1996) independently reported that a metal-containing proteolytic enzyme (metalloprotease) in normal plasma cleaves the peptide bond between tyrosine at position 842 and methionine at position 843 in monomeric subunits of VWF, thereby degrading the large multimers. This von Willebrand factor-cleaving protease was found by Furlan et al. (1997) to be deficient in 4 patients with chronic relapsing thrombotic thrombocytopenic purpura, 2 of whom were brothers. Because no inhibitor of the enzyme was detected in plasma, the deficiency was ascribed to an abnormality in the production, survival, or function of the protease.
Furlan et al. (1998) studied plasma samples from 30 patients with TTP and 23 patients with the hemolytic-uremic syndrome. Of 24 patients with nonfamilial TTP, 20 had severe and 4 had moderate protease deficiency during an acute event. An inhibitor of VWF found in 20 of the 24 patients (in all 5 plasma samples tested) was shown to be an IgG antibody. Furlan et al. (1998) found that 6 patients with familial TTP lacked VWFCP activity but had no inhibitor, whereas all 10 patients with familial hemolytic-uremic syndrome had normal protease activity. In vitro proteolytic degradation of von Willebrand factor by the protease was studied in 5 patients with familial and 7 patients with nonfamilial hemolytic-uremic syndrome and was found to function normally in all 12 patients. Furlan et al. (1998) concluded that nonfamilial TTP is due to an inhibitor of VWFCP, whereas the familial form is caused by a constitutional deficiency of the protease. Patients with the hemolytic-uremic syndrome do not have a deficiency of VWFCP or a defect in von Willebrand factor that leads to its resistance to protease.
Tsai and Lian (1998) found severe deficiency of von Willebrand factor-cleaving protease in 37 patients with acute thrombotic thrombocytopenic purpura. No deficiency was detected in 16 samples of plasma from patients in remission. Inhibitory activity against the protease was detected in 26 of 39 plasma samples obtained during the acute phase of the disease. The inhibitors were IgG antibodies.
Tati et al. (2013) demonstrated deposition of complement C3 (120700) and C5b (120900)-C9 (120940) in renal cortex of 2 TTP patients using immunofluorescence microscopy and immunohistochemical analysis, respectively. Flow cytometric analysis showed that plasma from TTP patients contained significantly higher levels of complement-coated endothelial particles than control plasma. Histamine-stimulated glomerular endothelial cells exposed to patient platelet-rich plasma or patient platelet-poor plasma combined with normal platelets induced C3 deposition, via the alternative pathway, on VWF platelet strings and on endothelial cells in an in vitro perfusion system under shear conditions. No complement was detected when cells were exposed to control plasma or to patient plasma treated with EDTA or that had been heat-inactivated. Tati et al. (2013) concluded that the microvascular process induced by ADAMTS13 deficiency triggers complement activation on platelets and endothelium and may contribute to thrombotic microangiopathy.
In the 2 patients with USS reported by Kinoshita et al. (2001), Yagi et al. (2001) studied the relationship between ULVWFMs and thrombocytopenia by analyzing platelet aggregation using a mixture of the patients' plasma and normal washed platelets under high shear stress. There was a remarkably enhanced high shear stress-induced platelet aggregation by the patients' plasma, which was almost completely normalized by administration of fresh frozen plasma. The results indicated that thrombocytopenia in USS patients is caused by a combination of the presence of ULVWFMs, platelets, and high shear stress generated in the microcirculation.
Vesely et al. (2003) stated that initial management of patients with TTP is difficult because of lack of specific diagnostic criteria, high mortality without plasma exchange treatment, and risks of plasma exchange. They performed a prospective study of ADAMTS13 activity in 142 consecutive patients, making measurements before beginning plasma exchange treatment. Severe ADAMTS13 deficiency, defined in this study as ADAMTS13 activity levels less than 5% of normal, was found in 18 (13%) of the 142 patients; it occurred only among pregnant/postpartum (2 of 10) and idiopathic (16 of 48) patients. Among the 48 patients with idiopathic TTP, the presenting features and clinical outcomes of the 16 who had severe ADAMTS13 deficiency were variable and not distinct from the 32 who did not have severe ADAMTS13 deficiency. Patients at all levels of ADAMTS13 activity apparently responded to plasma exchange treatment.
In a review, Kremer Hovinga and George (2019) noted that plasma infusions were used to treat acute episodes and chronically in patients with recurrent symptoms. They also discussed the institution of at-home recombinant human ADAMTS13 to treat this condition.
Joly et al. (2018) stated that while their child-onset USS patients exhibited a severe disease characterized by a 47% rate of ischemic sequelae and a high frequency of relapses requiring efficient prophylactic plasma therapy in 82% of cases, their adult-onset patients (who were exclusively pregnancy-induced) had no relapse and no requirement for plasma prophylaxis outside of an obstetrical context.
Scully et al. (2024) conducted a phase 3, open-label, crossover trial in which adult and child congenital TTP patients were randomly assigned in a 1:1 ratio to two 6-month periods of prophylaxis with recombinant ADAMTS13 (40 IU/kg of body weight, administered intravenously) or standard therapy, followed by the alternate treatment; thereafter, all patients received recombinant ADAMTS13 for an additional 6 months. The trigger for this interim analysis was trial completion by at least 30 patients. The primary outcome was acute TTP events. Manifestations of TTP, safety, and pharmacokinetics were assessed. Patients who had an acute TTP event could receive on-demand treatment. A total of 48 patients underwent randomization; 32 completed the trial. No acute TTP event occurred during prophylaxis with recombinant ADAMTS13, whereas 1 patient had an acute TTP event during prophylaxis with standard therapy (mean annualized event rate, 0.05). Thrombocytopenia was the most frequent TTP manifestation (annualized event rate, 0.74 with recombinant ADAMTS13 and 1.73 with standard therapy). Adverse events occurred in 71% of the patients with recombinant ADAMTS13 and in 84% with standard therapy. Adverse events that were considered by investigators to be related to the trial drug occurred in 9% of the patients with recombinant ADAMTS13 and in 48% with standard therapy. Trial-drug interruption or discontinuation due to adverse events occurred in no patients with recombinant ADAMTS13 and in 8 patients with standard therapy. No neutralizing antibodies developed during recombinant ADAMTS13 treatment. The mean maximum ADAMTS13 activity after recombinant ADAMTS13 treatment was 101%, as compared with 19% after standard therapy. The authors concluded that during prophylaxis with recombinant ADAMTS13 in patients with congenital TTP, ADAMTS13 activity reached approximately 100% of normal levels, adverse events were generally mild or moderate in severity, and TTP events and manifestations were rare.
Levy et al. (2001) used the plasma levels of VWF-cleaving protease as a phenotypic trait for linkage analysis. They analyzed DNA from affected individuals and other informative family members using 382 polymorphic microsatellite markers. A lod score of 5.63 at theta of 0.0 was obtained for marker D9S164 on 9q34 using a codominant model. Multipoint analysis for D9S164 and 4 flanking markers yielded a maximum lod score of 7.37 at marker D9S164.
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).
Of 22 patients with adult-onset congenital TTP studied by Joly et al. (2018), all with pregnancy-triggered disease, 18 (82%) carried the arg1060-to-trp (R1060W) mutation (604134.0025), 3 in homozygosity and 15 in heterozygosity.
Van Dorland et al. (2019) presented data on 123 patients enrolled in the International Hereditary Thrombotic Thrombocytopenic Purpura Registry between 2006 (the start of the study) through the end of 2017. Disease onset ranged from birth to 70 years of age. All patients were considered biallelic for mutated ADAMTS13; a table listed 47 homozygotes and 76 compound heterozygotes, but in the text it was stated that in 1 patient, whose phenotype was confirmed by a plasma infusion trial, only 1 mutation could be found. The most frequent mutation was c.4143_4144dupA (604134.0023), present on 60 of 246 alleles, followed by R1060W (604134.0025) on 13 of 246 alleles.
Moschcowitz (1924) described the abrupt onset of petechiae and pallor, followed rapidly by paralysis, coma, and death, in a 16-year-old girl. At autopsy, terminal arterioles and capillaries were occluded by hyaline thrombi, later determined to consist mostly of platelet without perivascular inflammation or endothelial desquamation. Moschcowitz (1924) suspected a 'powerful poison which had both agglutinative and hemolytic properties' as the cause of this disorder, now known as thrombotic thrombocytopenic purpura.
Abildgaard, C. F., Simone, J. V. Thrombopoiesis. Semin. Hemat. 4: 424-452, 1967. [PubMed: 4864988]
Fujimura, Y., Matsumoto, M., Kokame, K., Isonishi, A., Soejima, K., Akiyama, N., Tomiyama, J., Natori, K., Kuranishi, Y., Imamura, Y., Inoue, N., Higasa, S., Seike, M., Kozuka, T., Hara, M., Wada, H., Murata, M., Ikeda, Y., Miyata, T., George, J. N. Pregnancy-induced thrombocytopenia and TTP, and the risk of fetal death, in Upshaw-Schulman syndrome: a series of 15 pregnancies in 9 genotyped patients. Brit. J. Haemat. 144: 742-754, 2008. [PubMed: 19055667] [Full Text: https://doi.org/10.1111/j.1365-2141.2008.07515.x]
Furlan, M., Lammle, B. Aetiology and pathogenesis of thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome: the role of von Willebrand factor-cleaving protease. Best Pract. Res. Clin. Haemat. 14: 437-454, 2001. [PubMed: 11686108] [Full Text: https://doi.org/10.1053/beha.2001.0142]
Furlan, M., Robles, R., Galbusera, M., Remuzzi, G., Kyrle, P. A., Brenner, B., Krause, M., Scharrer, I., Aumann, V., Mittler, U., Solenthaler, M., Lammle, B. Von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. New Eng. J. Med. 339: 1578-1584, 1998. [PubMed: 9828245] [Full Text: https://doi.org/10.1056/NEJM199811263392202]
Furlan, M., Robles, R., Lammle, B. Partial purification and characterization of a protease from human plasma cleaving von Willebrand factor to fragments produced by in vivo proteolysis. Blood 87: 4223-4234, 1996. [PubMed: 8639781]
Furlan, M., Robles, R., Solenthaler, M., Wassmer, M., Sandoz, P., Lammle, B. Deficient activity of von Willebrand factor-cleaving protease in chronic relapsing thrombotic thrombocytopenic purpura. Blood 89: 3097-3103, 1997. [PubMed: 9129011]
Furlan, M. Personal Communication. Bern, Switzerland 1/5/1999.
Gasser, C., Gautier, E., Steck, A., Siebenmann, R. E., Oechslin, R. Hamolytisch-uramische syndrome: Bilaterale Nierenrindennekrosen bei akuten erworbenen hamolytischen Anamien. Schweiz. Med. Wochenschr. 85: 905-909, 1955. [PubMed: 13274004]
Goodnough, L. T., Saito, H., Ratnoff, O. D. Fibronectin levels in congenital thrombocytopenia: Schulman's syndrome. (Letter) New Eng. J. Med. 306: 938-939, 1982. [PubMed: 7062977] [Full Text: https://doi.org/10.1056/NEJM198204153061516]
Hamroun, A., Prouteau, C., Provot, F. Hereditary thrombotic thrombocytopenic purpura. New Eng. J. Med. 382: 392-393, 2020. [PubMed: 31971691] [Full Text: https://doi.org/10.1056/NEJMc1915670]
Joly, B. S., Boisseau, P., Roose, E., Stepanian, A., Biebuyck, N., Hogan, J., Provot, F., Delmas, Y., Garrec, C., Vanhoorelbeke, K., Coppo, P., Veyradier, A. ADAMTS13 gene mutations influence ADAMTS13 conformation and disease age-onset in the French cohort of Upshaw-Schulman syndrome. Thromb. Haemost. 118: 1902-1917, 2018. [PubMed: 30312976] [Full Text: https://doi.org/10.1055/s-0038-1673686]
Karmali, M. A., Petric, M., Lim, C., Fleming, P. C., Arbus, G. S., Lior, H. The association between idiopathic hemolytic uremic syndrome and infection by verotoxin-producing Escherichia coli. J. Infect. Dis. 151: 775-782, 1985. [PubMed: 3886804] [Full Text: https://doi.org/10.1093/infdis/151.5.775]
Kinoshita, S., Yoshioka, A., Park, Y. D., Ishizashi, H., Konno, M., Funado, M., Matsui, T., Titani, K., Yagi, H., Matsumoto, M., Fujimura, Y. Upshaw-Schulman syndrome revisited: a concept of congenital thrombotic thrombocytopenic purpura. Int. J. Hemat. 74: 101-108, 2001. [PubMed: 11530798] [Full Text: https://doi.org/10.1007/BF02982558]
Kirchner, K. A., Smith, R. M., Gockerman, J. P., Luke, R. G. Hereditary thrombotic thrombocytopenic purpura: microangiopathic hemolytic anemia, thrombocytopenia, and renal insufficiency occurring in consecutive generations. Nephron 30: 28-30, 1982. [PubMed: 7201082] [Full Text: https://doi.org/10.1159/000182427]
Koizumi, S., Miura, M., Yamagami, M., Horita, N., Taniguchi, N., Migita, S. Upshaw-Schulman syndrome and fibronectin (cold-soluble globulin). New Eng. J. Med. 305: 1284-1285, 1981. [PubMed: 7290149] [Full Text: https://doi.org/10.1056/nejm198111193052116]
Kokame, K., Matsumoto, M., Soejima, K., Yagi, H., Ishizashi, H., Funato, M., Tamai, H., Konno, M., Kamide, K., Kawano, Y., Miyata, T., Fujimura, Y. Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity. Proc. Nat. Acad. Sci. 99: 11902-11907, 2002. [PubMed: 12181489] [Full Text: https://doi.org/10.1073/pnas.172277399]
Kremer Hovinga, J. A., George, J. N. Hereditary thrombotic thrombocytopenic purpura. New Eng. J. Med. 381: 1653-1662, 2019. [PubMed: 31644845] [Full Text: https://doi.org/10.1056/NEJMra1813013]
Kremer Hovinga, J. A., George, J. N. Hereditary thrombotic thrombocytopenic purpura. New Eng. J. Med. 382: 394 only, 2020. [PubMed: 31971693] [Full Text: https://doi.org/10.1056/NEJMc1915670]
Levy, G. G., Nichols, W. C., Lian, E. C., Foroud, T., McClintick, J. N., McGee, B. M., Yang, A. Y., Slemieniak, D. R., Stark, K. R., Gruppo, R., Sarode, R., Shurin, S. B., Chandrasekaran, V., Stabler, S. P., Sabio, H., Bouhassira, E. E., Upshaw, J. D., Jr., Ginsburg, D., Tsai, H.-M. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature 413: 488-494, 2001. [PubMed: 11586351] [Full Text: https://doi.org/10.1038/35097008]
Marcus, A. J. Moschcowitz revisited. (Editorial) New Eng. J. Med. 307: 1447-1448, 1982. [PubMed: 6813741] [Full Text: https://doi.org/10.1056/NEJM198212023072311]
Matsumoto, M., Kokame, K., Soejima, K., Miura, M., Hayashi, S., Fujii, Y., Iwai, A., Ito, E., Tsuji, Y., Takeda-Shitaka, M., Iwadate, M., Umeyama, H., Yagi, H., Ishizashi, H., Banno, F., Nakagaki, T., Miyata, T., Fujimura, Y. Molecular characterization of ADAMTS13 gene mutations in Japanese patients with Upshaw-Schulman syndrome. Blood 103: 1305-1310, 2004. [PubMed: 14563640] [Full Text: https://doi.org/10.1182/blood-2003-06-1796]
McDonald, T. P. Demonstration of thrombopoietin production after plasma infusion in a patient with congenital thrombopoietin deficiency. Thromb. Haemost. 37: 577-579, 1977. [PubMed: 578039]
Merrill, R. H., Knupp, C. L., Jennette, J. C. Familial thrombotic microangiopathy. Quart. J. Med. 57: 749-759, 1985. [PubMed: 4080959]
Moake, J. L., Rudy, C. K., Troll, J. H., Weinstein, M. J., Colannino, N. M., Azocar, J., Seder, R. H., Hong, S. L., Deykin, D. Unusually large plasma factor VIII:von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura. New Eng. J. Med. 307: 1432-1435, 1982. [PubMed: 6813740] [Full Text: https://doi.org/10.1056/NEJM198212023072306]
Moake, J. L. Moschcowitz, multimers, and metalloprotease. (Editorial) New Eng. J. Med. 339: 1629-1631, 1998. [PubMed: 9828253] [Full Text: https://doi.org/10.1056/NEJM199811263392210]
Moake, J. L. Thrombotic microangiopathies. New Eng. J. Med. 347: 589-600, 2002. [PubMed: 12192020] [Full Text: https://doi.org/10.1056/NEJMra020528]
Moschcowitz, E. Hyaline thrombosis of the terminal arterioles and capillaries: a hitherto undescribed disease. Proc. N.Y. Path. Soc. 24: 21-24, 1924.
Moschcowitz, E. An acute febrile pleiochromic anemia with hyaline thrombosis of the terminal arterioles and capillaries: an undescribed disease. Arch. Intern. Med. 36: 89-93, 1925. Note: Reprinted in Am. J. Med. 13: 567-569, 1952.
Rennard, S., Abe, S. Decreased cold-insoluble globulin in congenital thrombocytopenia (Upshaw-Schulman syndrome). (Letter) New Eng. J. Med. 300: 368 only, 1979. [PubMed: 759902] [Full Text: https://doi.org/10.1056/NEJM197902153000718]
Savasan, S., Lee, S.-K., Ginsburg, D., Tsai, H.-M. ADAMTS13 gene mutation in congenital thrombotic thrombocytopenic purpura with previously reported normal VWF cleaving protease activity. Blood 101: 4449-4451, 2003. [PubMed: 12576319] [Full Text: https://doi.org/10.1182/blood-2002-12-3796]
Schulman, I., Pierce, M., Lukens, A., Currimbhoy, Z. Studies on thrombopoiesis. I. A factor in normal human plasma required for platelet production; chronic thrombocytopenia due to its deficiency. Blood 16: 943-957, 1960. [PubMed: 14443744]
Scully, M., Antun, A., Cataland, S. R., Coppo, P., Dossier, C., Biebuyck, N., Hassenpflug, W. A., Kentouche, K., Knobl, P., Kremer Hovinga, J. A., Lopez-Fernandez, M. F., Matsumoto, M., and 12 others. Recombinant ADAMTS13 in congenital thrombotic thrombocytopenic purpura. New Eng. J. Med. 390: 1584-1596, 2024. [PubMed: 38692292] [Full Text: https://doi.org/10.1056/NEJMoa2314793]
Shinohara, T., Miyamura, S., Suzuki, E., Kobayashi, K. Congenital microangiopathic hemolytic anemia: report of a Japanese girl. Europ. J. Pediat. 138: 191-193, 1982. [PubMed: 7094941] [Full Text: https://doi.org/10.1007/BF00441153]
Tati, R., Kristoffersson, A.-C., Stahl, A., Rebetz, J., Wang, L., Licht, C., Motto, D., Karpman, D. Complement activation associated with ADAMTS13 deficiency in human and murine thrombotic microangiopathy. J. Immun. 191: 2184-2193, 2013. Note: Erratum: J. Immun. 192: 1990 only, 2014. [PubMed: 23878316] [Full Text: https://doi.org/10.4049/jimmunol.1301221]
Tsai, H.-M., Lian, E. C.-Y. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. New Eng. J. Med. 339: 1585-1594, 1998. [PubMed: 9828246] [Full Text: https://doi.org/10.1056/NEJM199811263392203]
Tsai, H.-M. Physiologic cleavage of von Willebrand factor by a plasma protease is dependent on its conformation and requires calcium ion. Blood 87: 4235-4244, 1996. [PubMed: 8639782]
Upshaw, J. D. Congenital deficiency of a factor in normal plasma that reverses microangiopathic hemolysis and thrombocytopenia. New Eng. J. Med. 298: 1350-1352, 1978. [PubMed: 651994] [Full Text: https://doi.org/10.1056/NEJM197806152982407]
van Dorland, H. A., Taleghani, M. M., Sakai, K., Friedman, K. D., George, J. N., Hrachovinova, I., Knobl, P. N., von Krogh, A. S., Schneppenheim, R., Aebi-Huber, I., Butikofer, L., Largiader, C. R., and 11 others. The International Hereditary Thrombotic Thrombocytopenic Purpura registry: key findings at enrollment until 2017. Haematologica 104: 2107-2116, 2019. [PubMed: 30792199] [Full Text: https://doi.org/10.3324/haematol.2019.216796]
Vesely, S. K., George, J. N., Lammle, B., Studt, J.-D., Alberio, L., El-Harake, M. A., Raskob, G. E. ADAMTS13 activity in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: relation to presenting features and clinical outcomes in a prospective cohort of 142 patients. Blood 102: 60-68, 2003. [PubMed: 12637323] [Full Text: https://doi.org/10.1182/blood-2003-01-0193]
Waage, A., Siegel, J., Thorstensen, K., Lamvik, J. Thrombotic thrombocytopenic purpura in 2 siblings: defective platelet function and plasma factor deficiency occurring simultaneously. Scand. J. Haemat. 36: 55-57, 1986. [PubMed: 3952464] [Full Text: https://doi.org/10.1111/j.1600-0609.1986.tb02649.x]
Wallace, D. C., Lovric, A., Clubb, J. S., Carseldine, D. B. Thrombotic thrombocytopenic purpura in four siblings. Am. J. Med. 58: 724-734, 1975. [PubMed: 1168994] [Full Text: https://doi.org/10.1016/0002-9343(75)90510-0]
Watson, C. G., Cooper, W. M. Thrombotic thrombocytopenic purpura: concomitant occurrence in husband and wife. JAMA 215: 1821-1822, 1971. [PubMed: 5107722] [Full Text: https://doi.org/10.1001/jama.215.11.1821]
Yagi, H., Konno, M., Kinoshita, S., Matsumoto, M., Ishizashi, H., Matsui, T., Titani, K., Fujimura, Y. 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. Brit. J. Haemat. 115: 991-997, 2001. [PubMed: 11843838] [Full Text: https://doi.org/10.1046/j.1365-2141.2001.03222.x]