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Upshaw-Schulman syndrome(TTP)

MedGen UID:
224783
Concept ID:
C1268935
Disease or Syndrome
Synonyms: Congenital thrombotic thrombocytopenic purpura; Familial Thrombotic Thrombocytopenia Purpura; THROMBOTIC THROMBOCYTOPENIC PURPURA, HEREDITARY; TTP
SNOMED CT: Upshaw-Schulman syndrome (373420004); Familial thrombotic thrombocytopenic purpura / hemolytic uremic syndrome (373420004); Familial TTP/HUS (373420004); Congenital ADAMTS-13 deficiency (373420004)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): ADAMTS13 (9q34.2)
 
Monarch Initiative: MONDO:0010122
OMIM®: 274150
Orphanet: ORPHA93583

Definition

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). [from OMIM]

Additional description

From MedlinePlus Genetics
Thrombotic thrombocytopenic purpura is a rare disorder that causes blood clots (thrombi) to form in small blood vessels throughout the body. These clots can cause serious medical problems if they block vessels and restrict blood flow to organs such as the brain, kidneys, and heart. Complications resulting from these clots can include neurological problems (such as personality changes, headaches, confusion, and slurred speech), fever, abnormal kidney function, abdominal pain, and heart problems.

Blood clots normally form to stop blood loss at the sites of blood vessel injury. In people with thrombotic thrombocytopenic purpura, clots develop even in the absence of apparent injury. Blood clots are formed from clumps of cells called platelets that circulate in the blood and assist with clotting. Because a large number of platelets are used to make clots in people with thrombotic thrombocytopenic purpura, fewer platelets are available in the bloodstream. A reduced level of circulating platelets is known as thrombocytopenia. Thrombocytopenia can lead to small areas of bleeding just under the surface of the skin, resulting in purplish spots called purpura.

This disorder also causes red blood cells to break down (undergo hemolysis) prematurely. As blood squeezes past clots within blood vessels, red blood cells can break apart. A condition called hemolytic anemia occurs when red blood cells are destroyed faster than the body can replace them. This type of anemia leads to paleness, yellowing of the eyes and skin (jaundice), fatigue, shortness of breath, and a rapid heart rate.

There are two major forms of thrombotic thrombocytopenic purpura, an acquired (noninherited) form and a familial (inherited) form. The acquired form usually appears in late childhood or adulthood. Affected individuals may have a single episode of signs and symptoms, or, more commonly, they may experience multiple recurrences over time. The familial form of this disorder is much rarer and typically appears in infancy or early childhood, although it can appear later in life. In people with the familial form, signs and symptoms often recur on a regular basis and may return during times of stress, such as during illness or pregnancy.  https://medlineplus.gov/genetics/condition/thrombotic-thrombocytopenic-purpura

Clinical features

From HPO
Hemolytic-uremic syndrome
MedGen UID:
42403
Concept ID:
C0019061
Disease or Syndrome
A thrombotic microangiopathy with presence of non-immune, intravascular hemolytic anemia, thrombocytopenia and acute kidney injury. A vicious cycle of complement activation, endothelial cell damage, platelet activation, and thrombosis is the hallmark of the disease.
Proteinuria
MedGen UID:
10976
Concept ID:
C0033687
Finding
Increased levels of protein in the urine.
Abnormal renal physiology
MedGen UID:
508816
Concept ID:
C0151746
Pathologic Function
An abnormal functionality of the kidney.
Microscopic hematuria
MedGen UID:
65997
Concept ID:
C0239937
Finding
Microscopic hematuria detected by dipstick or microscopic examination of the urine.
Transient ischemic attack
MedGen UID:
853
Concept ID:
C0007787
Disease or Syndrome
A brief attack (from a few minutes to an hour) of cerebral dysfunction of vascular origin, with no persistent neurological deficit.
Myocardial infarction
MedGen UID:
10150
Concept ID:
C0027051
Disease or Syndrome
Necrosis of the myocardium caused by an obstruction of the blood supply to the heart and often associated with chest pain, shortness of breath, palpitations, and anxiety as well as characteristic EKG findings and elevation of serum markers including creatine kinase-MB fraction and troponin.
Stroke disorder
MedGen UID:
52522
Concept ID:
C0038454
Disease or Syndrome
Sudden impairment of blood flow to a part of the brain due to occlusion or rupture of an artery to the brain.
Jaundice
MedGen UID:
43987
Concept ID:
C0022346
Sign or Symptom
Yellow pigmentation of the skin due to bilirubin, which in turn is the result of increased bilirubin concentration in the bloodstream.
Prolonged neonatal jaundice
MedGen UID:
347108
Concept ID:
C1859236
Finding
Neonatal jaundice refers to a yellowing of the skin and other tissues of a newborn infant as a result of increased concentrations of bilirubin in the blood. Neonatal jaundice affects over half of all newborns to some extent in the first week of life. Prolonged neonatal jaundice is said to be present if the jaundice persists for longer than 14 days in term infants and 21 days in preterm infants.
Confusion
MedGen UID:
3587
Concept ID:
C0009676
Mental or Behavioral Dysfunction
Lack of clarity and coherence of thought, perception, understanding, or action.
Tremor
MedGen UID:
21635
Concept ID:
C0040822
Sign or Symptom
An unintentional, oscillating to-and-fro muscle movement about a joint axis.
Thrombocytopenia
MedGen UID:
52737
Concept ID:
C0040034
Disease or Syndrome
A reduction in the number of circulating thrombocytes.
Reticulocytosis
MedGen UID:
60089
Concept ID:
C0206160
Finding
An elevation in the number of reticulocytes (immature erythrocytes) in the peripheral blood circulation.
Microangiopathic hemolytic anemia
MedGen UID:
65120
Concept ID:
C0221021
Disease or Syndrome
Acquired anemia due to destruction of red blood cells by physical trauma such as FIBRIN strands in the blood vessels, artificial heart valve, AORTIC COARCTATION. I can also be associated with hematologic diseases such as DISSEMINATED INTRAVASCULAR COAGULATION; HEMOLYTIC-UREMIC SYNDROME; and THROMBOTIC THROMBOCYTOPENIC PURPURA.
Schistocytosis
MedGen UID:
576247
Concept ID:
C0344386
Laboratory or Test Result
The presence of an abnormal number of fragmented red blood cells (schistocytes) in the blood.
Respiratory distress
MedGen UID:
96907
Concept ID:
C0476273
Sign or Symptom
Respiratory distress is objectively observable as the physical or emotional consequences from the experience of dyspnea. The physical presentation of respiratory distress is generally referred to as labored breathing, while the sensation of respiratory distress is called shortness of breath or dyspnea.
Fever
MedGen UID:
5169
Concept ID:
C0015967
Sign or Symptom
Body temperature elevated above the normal range.
Increased blood urea nitrogen
MedGen UID:
760252
Concept ID:
C0151539
Finding
An increased amount of nitrogen in the form of urea in the blood.
Elevated circulating creatinine concentration
MedGen UID:
148579
Concept ID:
C0700225
Finding
An increased amount of creatinine in the blood.
Increased circulating lactate concentration
MedGen UID:
332209
Concept ID:
C1836440
Finding
Abnormally increased level of blood lactate (2-hydroxypropanoic acid). Lactate is produced from pyruvate by lactate dehydrogenase during normal metabolism. The terms lactate and lactic acid are often used interchangeably but lactate (the component measured in blood) is strictly a weak base whereas lactic acid is the corresponding acid. Lactic acidosis is often used clinically to describe elevated lactate but should be reserved for cases where there is a corresponding acidosis (pH below 7.35).

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVUpshaw-Schulman syndrome
Follow this link to review classifications for Upshaw-Schulman syndrome in Orphanet.

Professional guidelines

PubMed

Sakai K, Fujimura Y, Nagata Y, Higasa S, Moriyama M, Isonishi A, Konno M, Kajiwara M, Ogawa Y, Kaburagi S, Hara T, Kokame K, Miyata T, Hatakeyama K, Matsumoto M
J Thromb Haemost 2020 Nov;18(11):2929-2941. Epub 2020 Oct 15 doi: 10.1111/jth.15064. PMID: 33433066
Kremer Hovinga JA, Lämmle B
Hematology Am Soc Hematol Educ Program 2012;2012:610-6. doi: 10.1182/asheducation-2012.1.610. PMID: 23233642
Coppo P, Veyradier A
Presse Med 2012 Mar;41(3 Pt 2):e163-76. Epub 2012 Jan 21 doi: 10.1016/j.lpm.2011.10.024. PMID: 22265954

Recent clinical studies

Etiology

Nusrat S, Beg K, Khan O, Sinha A, George J
Genes (Basel) 2023 Oct 18;14(10) doi: 10.3390/genes14101956. PMID: 37895305Free PMC Article
Tsuda M, Shiratsuchi M, Nakashima Y, Ikeda M, Muta H, Narazaki T, Masuda T, Kimura D, Takamatsu A, Matsumoto M, Fujimura Y, Kokame K, Matsushima T, Ogawa Y
Transfus Apher Sci 2018 Dec;57(6):790-792. Epub 2018 Nov 16 doi: 10.1016/j.transci.2018.10.023. PMID: 30471945
Hassenpflug WA, Obser T, Bode J, Oyen F, Budde U, Schneppenheim S, Schneppenheim R, Brehm MA
Thromb Haemost 2018 Apr;118(4):709-722. Epub 2018 Mar 19 doi: 10.1055/s-0038-1637749. PMID: 29554699
Kremer Hovinga JA, Coppo P, Lämmle B, Moake JL, Miyata T, Vanhoorelbeke K
Nat Rev Dis Primers 2017 Apr 6;3:17020. doi: 10.1038/nrdp.2017.20. PMID: 28382967
Coppo P, Veyradier A
Presse Med 2012 Mar;41(3 Pt 2):e163-76. Epub 2012 Jan 21 doi: 10.1016/j.lpm.2011.10.024. PMID: 22265954

Diagnosis

Nusrat S, Beg K, Khan O, Sinha A, George J
Genes (Basel) 2023 Oct 18;14(10) doi: 10.3390/genes14101956. PMID: 37895305Free PMC Article
Tsuda M, Shiratsuchi M, Nakashima Y, Ikeda M, Muta H, Narazaki T, Masuda T, Kimura D, Takamatsu A, Matsumoto M, Fujimura Y, Kokame K, Matsushima T, Ogawa Y
Transfus Apher Sci 2018 Dec;57(6):790-792. Epub 2018 Nov 16 doi: 10.1016/j.transci.2018.10.023. PMID: 30471945
Kremer Hovinga JA, Coppo P, Lämmle B, Moake JL, Miyata T, Vanhoorelbeke K
Nat Rev Dis Primers 2017 Apr 6;3:17020. doi: 10.1038/nrdp.2017.20. PMID: 28382967
Ahmad R, Natiq M, Aziz M
J Coll Physicians Surg Pak 2015 Oct;25 Suppl 2:S97-9. doi: 10.2015/JCPSP.S9799. PMID: 26522217
Pérez-Rodríguez A, Lourés E, Rodríguez-Trillo Á, Costa-Pinto J, García-Rivero A, Batlle-López A, Batlle J, López-Fernández MF
Thromb Res 2014 Dec;134(6):1171-5. Epub 2014 Sep 10 doi: 10.1016/j.thromres.2014.09.004. PMID: 25242241

Therapy

Chrisentery-Singleton T, Boggio LN, Carcao MD, Ibrahimi S, Khan O, Mahajerin A, Rajasekhar A, Sharma V, Steele M, Torres M, Rodino FJ, Carpenter SL
Haemophilia 2023 Nov;29(6):1638-1645. Epub 2023 Oct 19 doi: 10.1111/hae.14891. PMID: 37855744
Kremer Hovinga JA, Coppo P, Lämmle B, Moake JL, Miyata T, Vanhoorelbeke K
Nat Rev Dis Primers 2017 Apr 6;3:17020. doi: 10.1038/nrdp.2017.20. PMID: 28382967
Joly BS, Stepanian A, Leblanc T, Hajage D, Chambost H, Harambat J, Fouyssac F, Guigonis V, Leverger G, Ulinski T, Kwon T, Loirat C, Coppo P, Veyradier A; French Reference Center for Thrombotic Microangiopathies
Lancet Haematol 2016 Nov;3(11):e537-e546. Epub 2016 Oct 3 doi: 10.1016/S2352-3026(16)30125-9. PMID: 27720178
Steele M, Chen HH, Steele J, Chan AK, Lau KK
Zhongguo Dang Dai Er Ke Za Zhi 2012 Nov;14(11):803-10. PMID: 23146723
Coppo P, Veyradier A
Presse Med 2012 Mar;41(3 Pt 2):e163-76. Epub 2012 Jan 21 doi: 10.1016/j.lpm.2011.10.024. PMID: 22265954

Prognosis

Woods AI, Paiva J, Dos Santos C, Alberto MF, Sánchez-Luceros A
Semin Thromb Hemost 2023 Apr;49(3):284-294. Epub 2022 Nov 11 doi: 10.1055/s-0042-1758059. PMID: 36368692
Hassenpflug WA, Obser T, Bode J, Oyen F, Budde U, Schneppenheim S, Schneppenheim R, Brehm MA
Thromb Haemost 2018 Apr;118(4):709-722. Epub 2018 Mar 19 doi: 10.1055/s-0038-1637749. PMID: 29554699
Pérez-Rodríguez A, Lourés E, Rodríguez-Trillo Á, Costa-Pinto J, García-Rivero A, Batlle-López A, Batlle J, López-Fernández MF
Thromb Res 2014 Dec;134(6):1171-5. Epub 2014 Sep 10 doi: 10.1016/j.thromres.2014.09.004. PMID: 25242241
Hassenpflug WA, Budde U, Schneppenheim S, Schneppenheim R
Semin Thromb Hemost 2014 Jun;40(4):487-92. Epub 2014 May 11 doi: 10.1055/s-0034-1376152. PMID: 24816970
Fujimura Y, Matsumoto M, Yagi H, Yoshioka A, Matsui T, Titani K
Int J Hematol 2002 Jan;75(1):25-34. doi: 10.1007/BF02981975. PMID: 11843286

Clinical prediction guides

Letzer A, Lehmann K, Mess C, König G, Obser T, Peine S, Schneppenheim S, Budde U, Schneider SW, Schneppenheim R, Brehm MA
PLoS One 2020;15(5):e0232637. Epub 2020 May 4 doi: 10.1371/journal.pone.0232637. PMID: 32365113Free PMC Article
Hassenpflug WA, Obser T, Bode J, Oyen F, Budde U, Schneppenheim S, Schneppenheim R, Brehm MA
Thromb Haemost 2018 Apr;118(4):709-722. Epub 2018 Mar 19 doi: 10.1055/s-0038-1637749. PMID: 29554699
von Krogh AS, Quist-Paulsen P, Waage A, Langseth ØO, Thorstensen K, Brudevold R, Tjønnfjord GE, Largiadèr CR, Lämmle B, Kremer Hovinga JA
J Thromb Haemost 2016 Jan;14(1):73-82. Epub 2016 Jan 8 doi: 10.1111/jth.13186. PMID: 26566785
Bennett M, Chubar Y, Gavish I, Aviv A, Stemer G, Chap-Marshak D
Clin Appl Thromb Hemost 2014 Apr;20(3):296-303. Epub 2013 Jul 19 doi: 10.1177/1076029613495309. PMID: 23872162
Fujimura Y, Matsumoto M, Yagi H, Yoshioka A, Matsui T, Titani K
Int J Hematol 2002 Jan;75(1):25-34. doi: 10.1007/BF02981975. PMID: 11843286

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