Hemolytic-uremic syndrome pathophysiology: Difference between revisions

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{{CMG}}; {{AE}} {{S.G.}}, {{AHS}}
==Overview==
==Overview==
It is understood that hemolytic-uremic syndrome (HUS) is the result of microvascular [[endothelial]] cell damage characterized by [[thrombotic microangiopathy]] ([[TMA]]) in [[renal]] [[glomeruli]], [[gastrointestinal tract]], [[brain]] and [[pancreas]] in all of which the main lesion is the thickening of [[vessel wall]] (mainly in [[Capillary|capillaries]] and [[Arteriole|ar]][[Arteriole|teriol]]<nowiki/>es), microthrombi in [[platelets]] and obstruction of [[vessel]] lumen ( partial or complete). Loss of [[physiological]] resistance to [[thrombus]] formation, complement consumption, [[leukocyte]] [[adhesion]] to damaged [[endothelium]], the abnormal release of von Willibrand Factor ([[vWF]]) and [[Fragmentation (biology)|fragmentation]], and increased vascular shear stress lead to further [[amplification]] of [[microangiopathy]]. Typical/ [[Shiga toxin|Shiga-toxin]]-associated [[Hemolytic-uremic syndrome|hemolytic uremic syndrome]] ([[HUS]]) is usually caused by [[Escherichia coli|E.Coli]] and [[serotype]] O157: H7 is most common while [[congenital]] predisposing conditions like complement factor abnormalities may play a role in recurrent and [[familial]] forms.
==Pathophysiology==
==Pathophysiology==
===Molecular Biology===  
===Pathogenesis===
:*[[Platelet]]-rich thrombi in affected organs (unclear etiology of tissue specificity CD36)
*It is understood that hemolytic-uremic syndrome (HUS) is the result of microvascular [[endothelial cell]] damage characterized by [[thrombotic microangiopathy]] ([[TMA]]) in [[Kidney|renal]] [[glomeruli]], [[gastrointestinal tract]], [[brain]] and [[pancreas]] in all of which the main lesion is the thickening of [[vessel wall]] (mainly in [[capillaries]] and [[arterioles]]), microthrombi in [[Platelet|platelets]] and obstruction of [[vessel]] [[lumen]]( partial or complete).
:*[[vWF]] ([[endothelial]]ly synthesized) -> ULvWf multimers -> shear stress unfolds and causes massive platelet aggregation
*Loss of [[physiological]] resistance to [[thrombus]] formation, [[complement]] consumption, [[leukocyte]] [[adhesion]] to damaged [[endothelium]], the abnormal release of von Willibrand Factor ([[Von Willebrand factor|vWF]]) and [[Fragmentation (cell biology)|fragmentation]], and increased [[vascular]] shear stress lead to further [[amplification]] of [[microangiopathy]].
::*Normally, UlvWf digested by [[metalloprotease]] to “normal” size vWf [[multimers]]
*[[Congenital]] predisposing conditions like [[complement]] factor abnormalities may play a role in recurrent and familial forms.<ref name="pmid11532079">{{cite journal| author=Ruggenenti P, Noris M, Remuzzi G| title=Thrombotic microangiopathy, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura. | journal=Kidney Int | year= 2001 | volume= 60 | issue= 3 | pages= 831-46 | pmid=11532079 | doi=10.1046/j.1523-1755.2001.060003831.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11532079  }} </ref>
::*Familial forms of TTP lack metalloprotease activity
*Typical/ [[Shiga toxin|Shiga-toxin]]-associated [[Hemolytic-uremic syndrome|hemolytic uremic syndrome]] ([[HUS]]) is usually caused by [[E.Coli]].
::*Acquired forms of [[TTP]] have [[IgG]] antibody, which reduce metalloprotease activity during flares
*[[Serotype]] O157: H7 is most commonly seen in the USA and Europe, although other [[Serotype|serotypes]] less commonly associated include O26:H11, O103:H2, O121:H19, O145:NM and O111:NM. Other strains, especially O111:H-serotype is frequently found in other countries as well.
Metalloprotease activity appears normal in HUS
*[[EHEC]] produce several [[virulence factors]] including Shiga-Toxin and that gain access to the blood circulation after damaging the intestinal [[endothelium]] and later affect the target [[Organ (anatomy)|organ]]<nowiki/>s
*[[Pathogen]] is usually transmitted via the [[ingestion]] of undercooked ground meat to the human host.
*Following [[Transmission (medicine)|transmission]]/[[ingestion]], the [[EHEC]] is assumed to bind to the small intestine followed by colonization of [[colon]].<ref name="pmid18974311">{{cite journal| author=Malyukova I, Murray KF, Zhu C, Boedeker E, Kane A, Patterson K et al.| title=Macropinocytosis in Shiga toxin 1 uptake by human intestinal epithelial cells and transcellular transcytosis. | journal=Am J Physiol Gastrointest Liver Physiol | year= 2009 | volume= 296 | issue= 1 | pages= G78-92 | pmid=18974311 | doi=10.1152/ajpgi.90347.2008 | pmc=2636932 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18974311  }}</ref>
*[[EHEC]] interacts with [[intestinal]] [[microflora]] as well as host hormonal response thus leading to the activation of several virulence factors including [[Shiga toxin E. coli|Shiga-Toxin (Stx)]] and others that enable attachment of [[pathogen]] to the [[instestinal]] [[epithelial]] cell and enhancing the mobility of flagella thus leading to induction of [[Shiga toxin E. coli|Stx]] which adheres to the [[endothelium]] of the [[intestine]] and lead to [[ulceration]] and [[hemorrhaging]]<ref name="pmid19318290">{{cite journal| author=Pacheco AR, Sperandio V| title=Inter-kingdom signaling: chemical language between bacteria and host. | journal=Curr Opin Microbiol | year= 2009 | volume= 12 | issue= 2 | pages= 192-8 | pmid=19318290 | doi=10.1016/j.mib.2009.01.006 | pmc=4852728 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19318290  }}</ref><ref>Walker WA. Pediatric Gastrointestinal Disease: Pathophysiology, Diagnosis, Management. 4th ed. Hamilton, Ont.: BC Decker, 2004</ref><ref name="pmid19696934">{{cite journal| author=Hughes DT, Clarke MB, Yamamoto K, Rasko DA, Sperandio V| title=The QseC adrenergic signaling cascade in Enterohemorrhagic E. coli (EHEC). | journal=PLoS Pathog | year= 2009 | volume= 5 | issue= 8 | pages= e1000553 | pmid=19696934 | doi=10.1371/journal.ppat.1000553 | pmc=2726761 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19696934  }}</ref>
*[[Intestinal]] [[epithelial]] damage allows bacterial [[Virulence factor|virulence factors]] to enter the circulation after which Stx in circulation binds to the [[platelet]]<nowiki/>s, [[Neutrophil|neutrophils]], and [[Monocyte|monocytes]] as well as to [[platelet]]-[[monocyte]] and [[platelet]]-[[Neutrophil|neutrophils]] in complexes leading to [[Tissue factor|tissue-factor (TF)]] expressing microparticle release.<ref name="pmid19750223">{{cite journal| author=Ståhl AL, Sartz L, Nelsson A, Békássy ZD, Karpman D| title=Shiga toxin and lipopolysaccharide induce platelet-leukocyte aggregates and tissue factor release, a thrombotic mechanism in hemolytic uremic syndrome. | journal=PLoS One | year= 2009 | volume= 4 | issue= 9 | pages= e6990 | pmid=19750223 | doi=10.1371/journal.pone.0006990 | pmc=2735777 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19750223  }}</ref>
*Aggregates are formed between [[monocyte]] and [[Platelet|platelets]] and also between [[Neutrophil|neutrophils]] and [[Platelet|platelets]]. [[Shiga toxin E. coli|Stx]] can also bind to the blood cells via G3b<nowiki/> receptors in addition to other [[glycolipid]] receptors where as [[lipopolysaccharide]] or LPS binds via [[TLR4|TLR-4]] or Toll like receptor, which is in complex with CD62 on [[Platelet|platelets]].<ref name="pmid16514062">{{cite journal| author=Ståhl AL, Svensson M, Mörgelin M, Svanborg C, Tarr PI, Mooney JC et al.| title=Lipopolysaccharide from enterohemorrhagic Escherichia coli binds to platelets through TLR4 and CD62 and is detected on circulating platelets in patients with hemolytic uremic syndrome. | journal=Blood | year= 2006 | volume= 108 | issue= 1 | pages= 167-76 | pmid=16514062 | doi=10.1182/blood-2005-08-3219 | pmc=1895830 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16514062  }}</ref>
*[[Platelet]] activation lead to prothrombotic state and microthrombi lead to [[thrombocytopenia]]. In presence of a circulation with high resistance <nowiki/>like [[renal]] microcirculations, these effects are enhanced. Other G3b expressing organs like including brain can also be affected.
*Stx induces cell death by inhibiting the [[protein]] [[synthesis]] or by [[apoptosis]].<ref name="pmid14638419">{{cite journal| author=Cherla RP, Lee SY, Tesh VL| title=Shiga toxins and apoptosis. | journal=FEMS Microbiol Lett | year= 2003 | volume= 228 | issue= 2 | pages= 159-66 | pmid=14638419 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14638419  }}</ref>
*[[Neutrophil|Neutrophils]], [[Monocyte|monocytes]] and [[IgM]]-producing [[B lymphocytes]] show resistance to [[cytotoxic]] effects of [[shiga toxin]]. In [[macrophage]]-like THP-1 cells, both [[Apoptosis|apoptotic]] and cell survival signaling pathways were activated after they were exposed to Shiga toxin-1, hence, most [[leukocytes]] being exposed to [[Shiga toxin]] will not undergo cell death, allowing the toxin to circulate bound to their [[cell membrane]].<ref name="pmid18625912">{{cite journal| author=Brigotti M, Carnicelli D, Ravanelli E, Barbieri S, Ricci F, Bontadini A et al.| title=Interactions between Shiga toxins and human polymorphonuclear leukocytes. | journal=J Leukoc Biol | year= 2008 | volume= 84 | issue= 4 | pages= 1019-27 | pmid=18625912 | doi=10.1189/jlb.0308157 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18625912  }}</ref>
*[[Endothelium|Endothelial]] cell damage of [[glomerular capillaries]] is the main feature in the pathogenesis of [[HUS]].
*[[Shiga toxin E. coli|Stx]] exerts [[cytotoxic]] and [[apoptotic]] effects on [[glomerular]] endothelial and [[epithelial cells]]<ref>Pijpers AH, van Setten PA, van den Heuvel LP, et al. Verocytotoxin-induced
apoptosis of human microvascular endothelial cells. J Am Soc Nephrol 2001;12:767-
778</ref><ref name="pmid10844605">{{cite journal| author=Hughes AK, Stricklett PK, Schmid D, Kohan DE| title=Cytotoxic effect of Shiga toxin-1 on human glomerular epithelial cells. | journal=Kidney Int | year= 2000 | volume= 57 | issue= 6 | pages= 2350-9 | pmid=10844605 | doi=10.1046/j.1523-1755.2000.00095.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10844605  }}</ref>.
*The [[pathogenesis]] in [[complement]] mediated or atypical [[HUS]] may include [[complement]] mediated [[platelet activation]] and [[endothelial]] damage and usually have low [[complement]] levels.
 
==Genetics==
 
[[Mutation]]<nowiki/>s in the genes associated with atypical HUS can cause uncontrolled complement system activation which attacks [[endothelial]] cells leading to inflammation and [[thrombi]] formation and may lead to [[kidney injury]] and [[renal failure]]. Examples include:<ref name="pmid24594571">{{cite journal| author=Frémeaux-Bacchi V| title=[Pathophysiology of atypical hemolytic uremic syndrome. Ten years of progress, from laboratory to patient]. | journal=Biol Aujourdhui | year= 2013 | volume= 207 | issue= 4 | pages= 231-40 | pmid=24594571 | doi=10.1051/jbio/2013027 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24594571  }}</ref><ref name="pmid18594873">{{cite journal| author=Loirat C, Noris M, Fremeaux-Bacchi V| title=Complement and the atypical hemolytic uremic syndrome in children. | journal=Pediatr Nephrol | year= 2008 | volume= 23 | issue= 11 | pages= 1957-72 | pmid=18594873 | doi=10.1007/s00467-008-0872-4 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18594873  }}</ref><ref>{{Cite journal
| author = [[Jessica Caprioli]], [[Marina Noris]], [[Simona Brioschi]], [[Gaia Pianetti]], [[Federica Castelletti]], [[Paola Bettinaglio]], [[Caterina Mele]], [[Elena Bresin]], [[Linda Cassis]], [[Sara Gamba]], [[Francesca Porrati]], [[Sara Bucchioni]], [[Giuseppe Monteferrante]], [[Celia J. Fang]], [[M. K. Liszewski]], [[David Kavanagh]], [[John P. Atkinson]] & [[Giuseppe Remuzzi]]
| title = Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome
| journal = [[Blood]]
| volume = 108
| issue = 4
| pages = 1267–1279
| year = 2006
| month = August
| doi = 10.1182/blood-2005-10-007252
| pmid = 16621965
}}</ref>
* [[Complement]] [[factor H]] (CFH) [[mutation]]/ [[factor H]] [[deficiency]] ([[autosomal dominant]])
* [[Membrane]] co-factor protein [[deficiency]] (MCP; [[CD46]])
* [[Factor B]] overactivity ([[Complement]] [[Factor B]] [[mutation]])
* [[Diacylglycerol kinase]] epsilon [[gene]] [[mutations]]
* [[Factor I]] (IF) [[mutation]]
Other genetic conditions predisposing to atypical [[HUS]] include:
* [[Mutations]] in the [[MMACHC]] ([[methyl]] [[malonic aciduria]] and [[homocystinuria]] type C) [[gene]]<ref name="pmid27324188">{{cite journal| author=Adrovic A, Canpolat N, Caliskan S, Sever L, Kıykım E, Agbas A et al.| title=Cobalamin C defect-hemolytic uremic syndrome caused by new mutation in MMACHC. | journal=Pediatr Int | year= 2016 | volume= 58 | issue= 8 | pages= 763-5 | pmid=27324188 | doi=10.1111/ped.12953 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27324188  }}</ref>
* [[Genetic]] [[disorders]] of [[ADAMTS13]]<ref name="pmid23847193">{{cite journal| author=Feng S, Eyler SJ, Zhang Y, Maga T, Nester CM, Kroll MH et al.| title=Partial ADAMTS13 deficiency in atypical hemolytic uremic syndrome. | journal=Blood | year= 2013 | volume= 122 | issue= 8 | pages= 1487-93 | pmid=23847193 | doi=10.1182/blood-2013-03-492421 | pmc=3750341 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23847193  }}</ref>
 
==Associated Conditions==
Conditions associated with HUS include:
* [[Malignancy]], [[cancer]] [[chemotherapy]] and [[ionizing radiation]]
* [[Calcineurin]] inhibitors and [[transplantation]]
* [[Pregnancy]], [[HELLP syndrome]], and [[oral contraceptive pill]]
* [[Systemic lupus erythematosus]] and [[antiphospholipid antibody syndrome]]
* [[Glomerulopathy]]
 
==Gross Pathology==
On gross pathology, [feature2], and [feature3] are characteristic findings of HUS.
 
==Microscopic Pathology==
On microscopic [[Histopathological|histopathologica]]<nowiki/>l analysis finding of [[Hemolytic-uremic syndrome|HUS]].
 
 
*Granular (muddy brown) casts
 
*Characteristic fibrin thrombi in glomerular and interstitial capillaries
*Slough into [[tubular]] [[lumen]]
 
<nowiki/>[[File:Acute thrombotic microangiopathy - pas - high mag.jpg|300px|thumb|none| High magnification microscopy of HUS Source:By Nephron [CC BY-SA 3.0  (https://creativecommons.org/licenses/by-sa/3.0) or GFDL (http://www.gnu.org/copyleft/fdl.html)], from Wikimedia Commons]]


:*In HUS, and in cases of TTP without decreased metalloprotease activity, other etiologies of platelet activation have been proposed:
::*Endothelial injury (esp. drug induced)
::*Toxins (i.e. Shiga toxin)
::*PAI – 1
::*Other genetic factors ([[Factor H]], [[Factor I]] deficiencies, [[complement]] derangements).
==References==
==References==
{{reflist|2}}
{{Reflist|2}}
 
{{WH}}
{{WH}}
{{WS}}
{{WS}}
[[Category:Disease]]
 
[[Category:Nephrology]]
[[Category:Nephrology]]
[[Category:Hematology]]
[[Category:Hematology]]
[[Category:Mature chapter]]
[[Category:Syndromes]]

Latest revision as of 23:26, 19 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], Anila Hussain, MD [3]

Overview

It is understood that hemolytic-uremic syndrome (HUS) is the result of microvascular endothelial cell damage characterized by thrombotic microangiopathy (TMA) in renal glomeruli, gastrointestinal tract, brain and pancreas in all of which the main lesion is the thickening of vessel wall (mainly in capillaries and arterioles), microthrombi in platelets and obstruction of vessel lumen ( partial or complete). Loss of physiological resistance to thrombus formation, complement consumption, leukocyte adhesion to damaged endothelium, the abnormal release of von Willibrand Factor (vWF) and fragmentation, and increased vascular shear stress lead to further amplification of microangiopathy. Typical/ Shiga-toxin-associated hemolytic uremic syndrome (HUS) is usually caused by E.Coli and serotype O157: H7 is most common while congenital predisposing conditions like complement factor abnormalities may play a role in recurrent and familial forms.


Pathophysiology

Pathogenesis

Genetics

Mutations in the genes associated with atypical HUS can cause uncontrolled complement system activation which attacks endothelial cells leading to inflammation and thrombi formation and may lead to kidney injury and renal failure. Examples include:[12][13][14]

Other genetic conditions predisposing to atypical HUS include:

Associated Conditions

Conditions associated with HUS include:

Gross Pathology

On gross pathology, [feature2], and [feature3] are characteristic findings of HUS.

Microscopic Pathology

On microscopic histopathological analysis finding of HUS.


  • Granular (muddy brown) casts
  • Characteristic fibrin thrombi in glomerular and interstitial capillaries
  • Slough into tubular lumen
High magnification microscopy of HUS Source:By Nephron [CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0) or GFDL (http://www.gnu.org/copyleft/fdl.html)], from Wikimedia Commons

References

  1. ↑ Ruggenenti P, Noris M, Remuzzi G (2001). "Thrombotic microangiopathy, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura". Kidney Int. 60 (3): 831–46. doi:10.1046/j.1523-1755.2001.060003831.x. PMID 11532079.
  2. ↑ Malyukova I, Murray KF, Zhu C, Boedeker E, Kane A, Patterson K; et al. (2009). "Macropinocytosis in Shiga toxin 1 uptake by human intestinal epithelial cells and transcellular transcytosis". Am J Physiol Gastrointest Liver Physiol. 296 (1): G78–92. doi:10.1152/ajpgi.90347.2008. PMC 2636932. PMID 18974311.
  3. ↑ Pacheco AR, Sperandio V (2009). "Inter-kingdom signaling: chemical language between bacteria and host". Curr Opin Microbiol. 12 (2): 192–8. doi:10.1016/j.mib.2009.01.006. PMC 4852728. PMID 19318290.
  4. ↑ Walker WA. Pediatric Gastrointestinal Disease: Pathophysiology, Diagnosis, Management. 4th ed. Hamilton, Ont.: BC Decker, 2004
  5. ↑ Hughes DT, Clarke MB, Yamamoto K, Rasko DA, Sperandio V (2009). "The QseC adrenergic signaling cascade in Enterohemorrhagic E. coli (EHEC)". PLoS Pathog. 5 (8): e1000553. doi:10.1371/journal.ppat.1000553. PMC 2726761. PMID 19696934.
  6. ↑ Ståhl AL, Sartz L, Nelsson A, Békássy ZD, Karpman D (2009). "Shiga toxin and lipopolysaccharide induce platelet-leukocyte aggregates and tissue factor release, a thrombotic mechanism in hemolytic uremic syndrome". PLoS One. 4 (9): e6990. doi:10.1371/journal.pone.0006990. PMC 2735777. PMID 19750223.
  7. ↑ Ståhl AL, Svensson M, Mörgelin M, Svanborg C, Tarr PI, Mooney JC; et al. (2006). "Lipopolysaccharide from enterohemorrhagic Escherichia coli binds to platelets through TLR4 and CD62 and is detected on circulating platelets in patients with hemolytic uremic syndrome". Blood. 108 (1): 167–76. doi:10.1182/blood-2005-08-3219. PMC 1895830. PMID 16514062.
  8. ↑ Cherla RP, Lee SY, Tesh VL (2003). "Shiga toxins and apoptosis". FEMS Microbiol Lett. 228 (2): 159–66. PMID 14638419.
  9. ↑ Brigotti M, Carnicelli D, Ravanelli E, Barbieri S, Ricci F, Bontadini A; et al. (2008). "Interactions between Shiga toxins and human polymorphonuclear leukocytes". J Leukoc Biol. 84 (4): 1019–27. doi:10.1189/jlb.0308157. PMID 18625912.
  10. ↑ Pijpers AH, van Setten PA, van den Heuvel LP, et al. Verocytotoxin-induced apoptosis of human microvascular endothelial cells. J Am Soc Nephrol 2001;12:767- 778
  11. ↑ Hughes AK, Stricklett PK, Schmid D, Kohan DE (2000). "Cytotoxic effect of Shiga toxin-1 on human glomerular epithelial cells". Kidney Int. 57 (6): 2350–9. doi:10.1046/j.1523-1755.2000.00095.x. PMID 10844605.
  12. ↑ Frémeaux-Bacchi V (2013). "[Pathophysiology of atypical hemolytic uremic syndrome. Ten years of progress, from laboratory to patient]". Biol Aujourdhui. 207 (4): 231–40. doi:10.1051/jbio/2013027. PMID 24594571.
  13. ↑ Loirat C, Noris M, Fremeaux-Bacchi V (2008). "Complement and the atypical hemolytic uremic syndrome in children". Pediatr Nephrol. 23 (11): 1957–72. doi:10.1007/s00467-008-0872-4. PMID 18594873.
  14. ↑ Jessica Caprioli, Marina Noris, Simona Brioschi, Gaia Pianetti, Federica Castelletti, Paola Bettinaglio, Caterina Mele, Elena Bresin, Linda Cassis, Sara Gamba, Francesca Porrati, Sara Bucchioni, Giuseppe Monteferrante, Celia J. Fang, M. K. Liszewski, David Kavanagh, John P. Atkinson & Giuseppe Remuzzi (2006). "Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome". Blood. 108 (4): 1267–1279. doi:10.1182/blood-2005-10-007252. PMID 16621965. Unknown parameter |month= ignored (help)
  15. ↑ Adrovic A, Canpolat N, Caliskan S, Sever L, Kıykım E, Agbas A; et al. (2016). "Cobalamin C defect-hemolytic uremic syndrome caused by new mutation in MMACHC". Pediatr Int. 58 (8): 763–5. doi:10.1111/ped.12953. PMID 27324188.
  16. ↑ Feng S, Eyler SJ, Zhang Y, Maga T, Nester CM, Kroll MH; et al. (2013). "Partial ADAMTS13 deficiency in atypical hemolytic uremic syndrome". Blood. 122 (8): 1487–93. doi:10.1182/blood-2013-03-492421. PMC 3750341. PMID 23847193.

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