Thrombotic thrombocytopenic purpura causes: Difference between revisions

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{{Thrombotic thrombocytopenic purpura}}
{{Thrombotic thrombocytopenic purpura}}
{{CMG}}
{{CMG}} {{AE}} {{S.G.}}
==Overview==
==Overview==
TTP may be caused by decreasing function or amount of [[von Willebrand factor]]([[Von Willebrand factor|vWF]]) cleaving [[protease]] [[ADAMTS13]] .
==Causes==
==Causes==
ADAMTS13 is a zinc-requiring and calcium-requiring 190,000 Dalton glycosylated protein that is encoded on chromosome 9q34.  It is a disintegrin and a metalloprotease with 8 thrombospondin 1-like domains composed of an aminoterminal metalloprotease followed by a disintegrin domain; a thrombospondin 1-like domain; a cysteine-rich domain and an adjacent spacer portion; seven additional thrombospondin 1-like domains and 2 other different types of domains that resemble each other at the carboxyl-terminal end of the molecule.  It cleaves a tyrosine 1605-1606 methionine peptide bond of VWF.  This protease is #13 in a family of 19 distinct ADAMTS-type metalloprotease enzymes.  It is produced predominantly in endothelial cells for slow, constitutive release into the circulation.  Endothelial cells can be stimulated to secrete long VWF strings by inflammatory cytokines (TNF, IL8 & IL6, shiga toxins or estrogen).  ADAMTS13 is inhibited by EDTA and therefore functional assays of the enzyme are usually performed using plasma anticoagulated with citrate (a weaker divalent cation binder than EDTA). 
Decrease function or amount of [[von Willebrand factor]] cleaving [[protease]] [[ADAMTS13]] causes TTP.
 
TTP, as with other [[microangiopathic hemolytic anemia]]s (MAHAs), is caused by a spontaneous [[aggregation]] of [[platelet]]s and activation of [[coagulation]] in the small [[blood vessel]]s. When stimulated, endothelial cells secrete the ultra-large VWF multimers in long strips that remain anchored to the cell membrane.  The long VWF multimeric strings are EXTREMELY "sticky" to the glycoprotein Iba components of platelet GPIb-IX-V surface receptors.  The initial adherence of platelets via the GPIb receptors to the long VWF strings and the subsequent coherence of additional platelets to each other (aggregation) via activated GPIIb/IIIa receptors produces potentially occlusive platelet thrombi.  Platelets are consumed in the coagulation process, and bind [[fibrin]], the end product of the coagulation pathway. These platelet-fibrin complexes form microthrombi which circulate in the vasculature and cause shearing of [[red blood cell]]s, resulting in [[hemolysis]].
 
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. 
 
===Idiopathic TTP===
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. 


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.
'''Hereditary:''' [[Insertion|Insertions]], [[Deletion (genetics)|deletions]], [[Missense mutation|missense]], [[Nonsense mutation|nonsense]] point [[Mutation|mutations]] and [[splice]] site [[Mutation|mutations]] <ref>{{Cite journal
| author = [[Y. Fujimura]], [[M. Matsumoto]], [[A. Isonishi]], [[H. Yagi]], [[K. Kokame]], [[K. Soejima]], [[M. Murata]] & [[T. Miyata]]
| title = Natural history of Upshaw-Schulman syndrome based on ADAMTS13 gene analysis in Japan
| journal = [[Journal of thrombosis and haemostasis : JTH]]
| volume = 9 Suppl 1
| pages = 283–301
| year = 2011
| month = July
| doi = 10.1111/j.1538-7836.2011.04341.x
| pmid = 21781265
}}</ref><ref>{{Cite journal
| author = [[Luca A. Lotta]], [[Haifeng M. Wu]], [[Ian J. Mackie]], [[Marina Noris]], [[Agnes Veyradier]], [[Marie A. Scully]], [[Giuseppe Remuzzi]], [[Paul Coppo]], [[Ri Liesner]], [[Roberta Donadelli]], [[Chantal Loirat]], [[Richard A. Gibbs]], [[April Horne]], [[Shangbin Yang]], [[Isabella Garagiola]], [[Khaled M. Musallam]] & [[Flora Peyvandi]]
| title = Residual plasmatic activity of ADAMTS13 is correlated with phenotype severity in congenital thrombotic thrombocytopenic purpura
| journal = [[Blood]]
| volume = 120
| issue = 2
| pages = 440–448
| year = 2012
| month = July
| doi = 10.1182/blood-2012-01-403113
| pmid = 22529288
}}</ref> of both [[Allele|alleles]] of [[ADAMTS13]] [[Gene|genes]] on [[chromosome]] 9q34  cause decrease in the amount or [[Activity (chemistry)|activity]] of the enzyme.


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. 
'''Acquried:'''
* '''Diseases:''' [[Lupus]], [[cancer]], [[Human Immunodeficiency Virus (HIV)|HIV]], and [[Infection|infections]]([[influenza]])<ref name="FujimuraMatsumoto2011">{{cite journal|last1=Fujimura|first1=Y.|last2=Matsumoto|first2=M.|last3=Isonishi|first3=A.|last4=Yagi|first4=H.|last5=Kokame|first5=K.|last6=Soejima|first6=K.|last7=Murata|first7=M.|last8=Miyata|first8=T.|title=Natural history of Upshaw-Schulman syndrome based on ADAMTS13 gene analysis in Japan|journal=Journal of Thrombosis and Haemostasis|volume=9|year=2011|pages=283–301|issn=15387933|doi=10.1111/j.1538-7836.2011.04341.x}}</ref>
* '''Conditions:''' [[Pregnancy]], [[surgery]], [[blood]] and [[marrow]] [[stem cell]] [[transplant]]


===Secondary TTP===
* '''Drugs:''' [[Mitomycin]], [[Cyclosporine|cyclosporin A]], [[cisplatin]], [[bleomycin]], [[quinine]], [[ticlopidine]], [[clopidogrel]], [[estrogen]], [[HRT]]
''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]]
[[ADAMTS13]] is a [[zinc]] and [[calcium]] requiring 190,000 Dalton [[Glycosylation|glycosylated]] [[protein]] that is encoded on [[chromosome]] 9q34.  It is a [[disintegrin]] and a [[Metalloproteinase|metalloprotease]] with 8 [[thrombospondin]] 1-like domains composed of an aminoterminal [[Metalloproteinase|metalloprotease]] followed by a [[disintegrin]] [[Domain (biology)|domain]]; a [[thrombospondin]] 1-like domain; a cysteine-rich domain and an adjacent spacer portion; seven additional thrombospondin 1-like domains and 2 other different types of domains that resemble each other at the carboxyl-terminal end of the molecule. It cleaves a tyrosine 1605-1606 methionine peptide bond of VWF.  This [[protease]] is 13 in a family of 19 distinct ADAMTS-type [[Metalloproteinase|metalloprotease]] [[enzymes]].  It is produced predominantly in [[Endothelium|endothelial]] [[Cell (biology)|cells]] for slow, constitutive release into the circulation.  [[Endothelial]] [[Cell (biology)|cells]] can be [[Stimulated emission|stimulated]] to secrete long [[Von Willebrand factor|vWF]] strings by [[Inflammation|inflammatory]] [[Cytokine|cytokines]] ([[Tumor necrosis factors|TNF]], [[Interleukin 8 receptor, alpha|IL8]] & [[Interleukin-6 receptor|IL6]], [[Shiga-like toxin|shiga toxins]] or [[estrogen]]).  [[ADAMTS13]] is inhibited by [[EDTA]] and therefore functional assays of the enzyme are usually performed using plasma [[Anticoagulant|anticoagulated]] with [[citrate]] (a weaker divalent cation binder than [[EDTA]]). 
* [[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.
TTP, as with other [[microangiopathic hemolytic anemia]]s (MAHAs), is caused by a spontaneous [[aggregation]] of [[platelet]]s and activation of [[coagulation]] in the small [[blood vessel]]s. When [[Stimulated emission|stimulated]], [[endothelial]] [[Cell (biology)|cells]] [[secrete]] the ultra-large [[Von Willebrand factor|VWF]] [[Multimeric protein|multimers]] in long strips that remain anchored to the [[Cell (biology)|cell]] [[membrane]]. The long [[Von Willebrand factor|VWF]] [[Multimeric protein|multimeric]] strings are sticky to the [[glycoprotein]] Iba components of [[platelet]] GPIb-IX-V surface [[Receptor (biochemistry)|receptor]]<nowiki/>s.  The initial adherence of [[Platelet|platelets]] via the [[Glycoprotein Ib|GPIb]] receptors to the long [[Von Willebrand factor|vWF]] strings and the subsequent coherence of additional [[Platelet|platelets]] to each other ([[aggregation]]) via activated [[Glycoprotein IIb/IIIa|GPIIb/IIIa]] [[Receptor (biochemistry)|receptors]] produces potentially occlusive [[platelet]] [[Thrombus|thrombi]].  [[Platelet|Platelets]] are consumed in the [[coagulation]] process, and bind [[fibrin]], the end [[Product (biology)|product]] of the [[coagulation]] pathway. These [[platelet]] [[fibrin]] complexes form microthrombi which circulate in the [[vasculature]] and cause shearing of [[red blood cell]]s, resulting in [[hemolysis]].
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==
{{reflist|2}}
{{reflist|2}}

Latest revision as of 15:32, 28 September 2018

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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 caused by decreasing function or amount of von Willebrand factor(vWF) cleaving protease ADAMTS13 .

Causes

Decrease function or amount of von Willebrand factor cleaving protease ADAMTS13 causes TTP.

Hereditary: Insertions, deletions, missense, nonsense point mutations and splice site mutations [1][2] of both alleles of ADAMTS13 genes on chromosome 9q34 cause decrease in the amount or activity of the enzyme.

Acquried:

ADAMTS13 is a zinc and calcium requiring 190,000 Dalton glycosylated protein that is encoded on chromosome 9q34. It is a disintegrin and a metalloprotease with 8 thrombospondin 1-like domains composed of an aminoterminal metalloprotease followed by a disintegrin domain; a thrombospondin 1-like domain; a cysteine-rich domain and an adjacent spacer portion; seven additional thrombospondin 1-like domains and 2 other different types of domains that resemble each other at the carboxyl-terminal end of the molecule. It cleaves a tyrosine 1605-1606 methionine peptide bond of VWF. This protease is 13 in a family of 19 distinct ADAMTS-type metalloprotease enzymes. It is produced predominantly in endothelial cells for slow, constitutive release into the circulation. Endothelial cells can be stimulated to secrete long vWF strings by inflammatory cytokines (TNF, IL8 & IL6, shiga toxins or estrogen). ADAMTS13 is inhibited by EDTA and therefore functional assays of the enzyme are usually performed using plasma anticoagulated with citrate (a weaker divalent cation binder than EDTA).

TTP, as with other microangiopathic hemolytic anemias (MAHAs), is caused by a spontaneous aggregation of platelets and activation of coagulation in the small blood vessels. When stimulated, endothelial cells secrete the ultra-large VWF multimers in long strips that remain anchored to the cell membrane. The long VWF multimeric strings are sticky to the glycoprotein Iba components of platelet GPIb-IX-V surface receptors. The initial adherence of platelets via the GPIb receptors to the long vWF strings and the subsequent coherence of additional platelets to each other (aggregation) via activated GPIIb/IIIa receptors produces potentially occlusive platelet thrombi. Platelets are consumed in the coagulation process, and bind fibrin, the end product of the coagulation pathway. These platelet fibrin complexes form microthrombi which circulate in the vasculature and cause shearing of red blood cells, resulting in hemolysis.

References

  1. ↑ Y. Fujimura, M. Matsumoto, A. Isonishi, H. Yagi, K. Kokame, K. Soejima, M. Murata & T. Miyata (2011). "Natural history of Upshaw-Schulman syndrome based on ADAMTS13 gene analysis in Japan". Journal of thrombosis and haemostasis : JTH. 9 Suppl 1: 283–301. doi:10.1111/j.1538-7836.2011.04341.x. PMID 21781265. Unknown parameter |month= ignored (help)
  2. ↑ Luca A. Lotta, Haifeng M. Wu, Ian J. Mackie, Marina Noris, Agnes Veyradier, Marie A. Scully, Giuseppe Remuzzi, Paul Coppo, Ri Liesner, Roberta Donadelli, Chantal Loirat, Richard A. Gibbs, April Horne, Shangbin Yang, Isabella Garagiola, Khaled M. Musallam & Flora Peyvandi (2012). "Residual plasmatic activity of ADAMTS13 is correlated with phenotype severity in congenital thrombotic thrombocytopenic purpura". Blood. 120 (2): 440–448. doi:10.1182/blood-2012-01-403113. PMID 22529288. Unknown parameter |month= ignored (help)
  3. ↑ Fujimura, Y.; Matsumoto, M.; Isonishi, A.; Yagi, H.; Kokame, K.; Soejima, K.; Murata, M.; Miyata, T. (2011). "Natural history of Upshaw-Schulman syndrome based on ADAMTS13 gene analysis in Japan". Journal of Thrombosis and Haemostasis. 9: 283–301. doi:10.1111/j.1538-7836.2011.04341.x. ISSN 1538-7933.

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