Thrombotic thrombocytopenic purpura classification: Difference between revisions

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{{Thrombotic thrombocytopenic purpura}}
{{Thrombotic thrombocytopenic purpura}}
{{CMG}}
{{CMG}}; {{AE}} {{S.G.}}
==Overview==
==Overview==
== Classification ==
TTP may be classified according to ''[[ADAMTS13]]'' [[gene]] [[Mutation|mutations]] and [[autoantibody]]  against  [[ADAMTS13]] into two subtypes: herditary [[Syndrome|syndromes]], aquired [[Syndrome|syndromes]].
Roughly, there are two forms of TTP: ''idiopathic'' and ''secondary'' TTP. A special case is the inherited deficiency of ADAMTS13, known as the ''Upshaw-Schulman syndrome''.


The differential diagnosis of TTP includes hemolytic-uremic syndrome (HUS; which has neurosymptoms, renal failure, hypertension and fever).  Note that ADAMTS13 activity is normal in HUS.   
==Classification==
TTP may be classified into several subtypes based on ''[[ADAMTS13]]'' [[gene]] [[Mutation|mutations]](herditary [[Syndrome|syndromes]]) and [[autoantibody]] against [[ADAMTS13]](aquired [[Syndrome|syndromes]]):<ref name="pmid26581428">{{cite journal |vauthors=Tersteeg C, Verhenne S, Roose E, Schelpe AS, Deckmyn H, De Meyer SF, Vanhoorelbeke K |title=ADAMTS13 and anti-ADAMTS13 autoantibodies in thrombotic thrombocytopenic purpura - current perspectives and new treatment strategies |journal=Expert Rev Hematol |volume=9 |issue=2 |pages=209–21 |date=2016 |pmid=26581428 |doi=10.1586/17474086.2016.1122515 |url=}}</ref><ref>{{Cite journal
| author = [[Yoshihiro Fujimura]], [[Masanori Matsumoto]], [[Hideo Yagi]], [[Akira Yoshioka]], [[Taei Matsui]] & [[Koiti Titani]]
| title = Von Willebrand factor-cleaving protease and Upshaw-Schulman syndrome
| journal = [[International journal of hematology]]
| volume = 75
| issue = 1
| pages = 25–34
| year = 2002
| month = January
  | pmid = 11843286
}}</ref>


===Idiopathic TTP===
'''1.Hereditary:''' 
The ''[[idiopathic]]'' form of TTP was recently linked to the inhibition of the [[enzyme]] ADAMTS13 by [[antibody|antibodies]], rendering TTP as an [[autoimmune disease]]. [[von Willebrand factor]] (vWF) is a protein that links platelets, [[blood clot]]s, and the blood vessel wall in the process of blood [[coagulation]]. ADAMTS13 is a proteinase responsible for the breakdown of VWF; very large VWF molecules are prone to coagulation.  Without proper cleavage of VWF by ADAMTS13, these unusually large VWF cause coagulation at a higher rate, especially in the part of the circulatory system where VWF is most active due to high shear stress - in the microvascualture, thereby causing thrombi. 
* [[Congenital disorder|Congenital]] TTP
* [[Inherited]] TTP
* [[Familial]] TTP
* Upshaw-Schulman syndrome (USS) is an [[autosomal]] recessive [[disease]] of [[ADAMTS13]] [[gene]] on [[chromosome]] 9q34 .


In idiopathic TTP, severely decreased (<5% of normal) ADAMTS13 activity can be detected in most (80%) patients, and inhibitors are often found in this subgroup (44-56%). The relationship of reduced [[ADAMTS13]] to the pathogenesis of TTP is known as the Furlan-Tsai hypothesis, after the two independent researchers who published their research in the same issue of the [[New England Journal of Medicine]] in 1998.<ref name="pmid9828253">{{cite journal |author=Moake JL |title=Moschcowitz, multimers, and metalloprotease |journal=N. Engl. J. Med. |volume=339 |issue=22 |pages=1629–31 |year=1998 |pmid=9828253 |doi=}}</ref><ref name="pmid9828245">{{cite journal |author=Furlan M, Robles R, Galbusera M, ''et al'' |title=von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome |journal=N. Engl. J. Med. |volume=339 |issue=22 |pages=1578–84 |year=1998 |pmid=9828245 |doi=}}</ref><ref name="pmid9828246">{{cite journal |author=Tsai HM, Lian EC |title=Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura |journal=N. Engl. J. Med. |volume=339 |issue=22 |pages=1585–94 |year=1998 |pmid=9828246 |doi=}}</ref>  This theory is seen as insufficient to explain the etiology of TTP, since many patients with a hereditary lack of [[ADAMTS13]] activity do not manifest clinical symptoms of TTP.
'''2.Acquired'''
* Existence of an [[inhibitory]] [[antibody]] against [[ADAMTS13]] due to the variety of [[Condition|conditions.]]


Congenital or acquired ADAMTS13 deficiency causes TTP; acute TTP in adults is usually due to an acquired atuoantibody to ADAMTS13. However, as stated before, cases of plasma exchange-responsive acute TTP have been reported in patients who have no evidence of an autoantibody to ADAMTS13 and patients with congenital ADAMTS13 deficiency may not manifest TTP until adulthood.  Autoantibodies against ADAMTS13 present in a majority of patients with idiopathic TTP and, additionally, ticlopidine and clopidogrel associated TTP.  Severe deficiency of ADAMTS13 activity (<5%) is a specific feature of TTP.  Normal levels of ADAMTS13 do NOT rule out the diagnosis of TTP.  Normally there is only a slight increase in D-dimers, FDP and thrombin-antithrombin complexes in acute TTP.  Secondary DIC may arise due to prolonged tissue ischemia and is an ominous prognostic sign. 
===Secondary TTP===
''Secondary TTP'' is diagnosed when the patient's history mentions one of the known features associated with TTP. It comprises about 40% of all cases of TTP. Predisposing factors are:
* [[Cancer]]
* [[Bone marrow transplantation]]; (TBI is a risk factor). 
* [[Pregnancy]]; rare.
* [[Medication]] use:
** Platelet aggregation inhibitors ([[ticlopidine]] and [[clopidogrel]])
** Immunosuppressants ([[cyclosporine]], [[mitomycin]], [[tacrolimus]]/FK506, [[interferon|interferon-α]])
* [[HIV-1]] infection
The mechanism of ''secondary'' TTP is poorly understood, as ADAMTS13 activity is generally not as depressed as in idiopathic TTP, and inhibitors cannot be detected. The probable etiology may involve, at least in some cases, endothelial damage.
A small fraction of patients treated for arterial thrombosis with the platelet P2Y12 adenosine diphosphate receptor inhibiting thienopyridine drugs ticopidine (Ticlid) or clopidogrel (Plavix) develop TTP within a few weeks after the initiation of treatment.  Autoantibodies that inhibit plasma ADAMTS13 have been demonstrated in a few patients with Ticlid-associated or Plavix-associated TTP, indicating a possible immune dysregulation induced by these similar thienpyridine compounds.  Ticlodipine-associated TTP may respond to drug withdrawal and plasma exchange whereas TTP-like syndromes occuring after transplantation (often in associated with cyclosporine or FK506) are less likely to be responsive to plasma exchange treatment. 
===Upshaw-Schulman syndrome===
A hereditary form of TTP is called the ''Upshaw-Schulman syndrome''; this is generally due to inherited deficiency of ADAMTS13 (frameshift and point mutations). Patients with this inherited ADAMTS13 deficiency have a surprisingly mild phenotype, but develop TTP in clinical situations with increased [[von Willebrand factor]] levels, e.g. infection. Reportedly, 5-10% of all TTP cases are due to Upshaw-Schulman syndrome.
==References==
==References==
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{{Reflist|2}}
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[[Category:Disease]]
[[Category:Autoimmune diseases]]
[[Category:Hematology]]
[[Category:Rare diseases]]
[[Category:Dermatology]]

Latest revision as of 12:02, 14 March 2019

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sogand Goudarzi, MD [2]

Overview

TTP may be classified according to ADAMTS13 gene mutations and autoantibody against ADAMTS13 into two subtypes: herditary syndromes, aquired syndromes.

Classification

TTP may be classified into several subtypes based on ADAMTS13 gene mutations(herditary syndromes) and autoantibody against ADAMTS13(aquired syndromes):[1][2]

1.Hereditary:

2.Acquired

References

  1. ↑ Tersteeg C, Verhenne S, Roose E, Schelpe AS, Deckmyn H, De Meyer SF, Vanhoorelbeke K (2016). "ADAMTS13 and anti-ADAMTS13 autoantibodies in thrombotic thrombocytopenic purpura - current perspectives and new treatment strategies". Expert Rev Hematol. 9 (2): 209–21. doi:10.1586/17474086.2016.1122515. PMID 26581428.
  2. ↑ Yoshihiro Fujimura, Masanori Matsumoto, Hideo Yagi, Akira Yoshioka, Taei Matsui & Koiti Titani (2002). "Von Willebrand factor-cleaving protease and Upshaw-Schulman syndrome". International journal of hematology. 75 (1): 25–34. PMID 11843286. Unknown parameter |month= ignored (help)

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