Antiphospholipid syndrome pathophysiology: Difference between revisions

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__NOTOC__
__NOTOC__
{{Antiphospholipid syndrome}}
{{Antiphospholipid syndrome}}
{{CMG}}{{AE}}{{FT}}
{{CMG}}; {{AE}}{{FT}}


==Overview==
==Overview==
Antiphospholipid syndrome (APS) is an [[autoimmune disease]] in which [[antiphospholipid antibodies]] ([[anti-cardiolipin antibodies]] and [[lupus anticoagulant]]) react against [[proteins]] that bind to [[anionic]] [[phospholipid]]s on [[plasma membrane]]s. The syndrome can be divided into primary (no underlying disease state) and secondary (in association with an underlying disease state) forms.  
Antiphospholipid syndrome (APS) is an [[autoimmune disease]] in which [[antiphospholipid antibodies]] ([[anti-cardiolipin antibodies]] and [[lupus anticoagulant]]) react against [[proteins]] that bind to [[anionic]] [[phospholipid]]s on [[plasma membrane]]s. This syndrome can be classified into primary (no underlying disease state) and secondary (in association with an underlying disease state) types. The underlying mechanism of APS mediated by the antibodies is mainly mediated via their affect on the coagulation cascade which subsequenlty leads to increased vascular tone of thrombosis. CAPS is a subclass of APS that results in development of a catastrophic illness characterized by progressive, severe arterial and venous thrombosis in multiple organs, often leading to death.


==Pathophysiology==
==Pathophysiology==
The [[pathogenesis]] of antiphospholipid syndrome is as follows:  
The [[pathogenesis]] of antiphospholipid syndrome is as follows:<ref name="pmid27334977">{{cite journal| author=Negrini S, Pappalardo F, Murdaca G, Indiveri F, Puppo F| title=The antiphospholipid syndrome: from pathophysiology to treatment. | journal=Clin Exp Med | year= 2017 | volume= 17 | issue= 3 | pages= 257-267 | pmid=27334977 | doi=10.1007/s10238-016-0430-5 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27334977  }} </ref><ref name="pmid23484830">{{cite journal| author=Giannakopoulos B, Krilis SA| title=The pathogenesis of the antiphospholipid syndrome. | journal=N Engl J Med | year= 2013 | volume= 368 | issue= 11 | pages= 1033-44 | pmid=23484830 | doi=10.1056/NEJMra1112830 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23484830  }} </ref>
 
* It is a non-inflammatory [[autoimmune disease]], in which antiphospholipid [[antibodies]] react against [[proteins]] that bind to [[anionic]] [[phospholipid]]s on [[plasma membrane]]s.  
* It is a non-inflammatory [[autoimmune disease]], in which antiphospholipid [[antibodies]] react against [[proteins]] that bind to [[anionic]] [[phospholipid]]s on [[plasma membrane]]s.  
* APS is divided into two types based on the underlying cause.
* APS can be classified into two types based on the underlying cause.
** Primary APS
** Primary APS
** Secondary APS
** Secondary APS
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=== Secondary APS ===
=== Secondary APS ===
The type of APS which occurs secondary to an underlying disease. The diseases associated with APS are as follows:<ref name="pmid26945023">{{cite journal| author=Taraborelli M, Leuenberger L, Lazzaroni MG, Martinazzi N, Zhang W, Franceschini F et al.| title=The contribution of antiphospholipid antibodies to organ damage in systemic lupus erythematosus. | journal=Lupus | year= 2016 | volume= 25 | issue= 12 | pages= 1365-8 | pmid=26945023 | doi=10.1177/0961203316637431 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26945023  }} </ref><ref name="pmid26821965">{{cite journal| author=Conti F, Ceccarelli F, Perricone C, Leccese I, Massaro L, Pacucci VA et al.| title=The chronic damage in systemic lupus erythematosus is driven by flares, glucocorticoids and antiphospholipid antibodies: results from a monocentric cohort. | journal=Lupus | year= 2016 | volume= 25 | issue= 7 | pages= 719-26 | pmid=26821965 | doi=10.1177/0961203315627199 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26821965  }} </ref><ref name="pmid2110431">{{cite journal| author=Love PE, Santoro SA| title=Antiphospholipid antibodies: anticardiolipin and the lupus anticoagulant in systemic lupus erythematosus (SLE) and in non-SLE disorders. Prevalence and clinical significance. | journal=Ann Intern Med | year= 1990 | volume= 112 | issue= 9 | pages= 682-98 | pmid=2110431 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2110431  }} </ref>
The type of APS which occurs secondary to an underlying disease. The diseases and conditions associated with APS are as follows:<ref name="pmid26945023">{{cite journal| author=Taraborelli M, Leuenberger L, Lazzaroni MG, Martinazzi N, Zhang W, Franceschini F et al.| title=The contribution of antiphospholipid antibodies to organ damage in systemic lupus erythematosus. | journal=Lupus | year= 2016 | volume= 25 | issue= 12 | pages= 1365-8 | pmid=26945023 | doi=10.1177/0961203316637431 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26945023  }} </ref><ref name="pmid26821965">{{cite journal| author=Conti F, Ceccarelli F, Perricone C, Leccese I, Massaro L, Pacucci VA et al.| title=The chronic damage in systemic lupus erythematosus is driven by flares, glucocorticoids and antiphospholipid antibodies: results from a monocentric cohort. | journal=Lupus | year= 2016 | volume= 25 | issue= 7 | pages= 719-26 | pmid=26821965 | doi=10.1177/0961203315627199 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26821965  }} </ref><ref name="pmid2110431">{{cite journal| author=Love PE, Santoro SA| title=Antiphospholipid antibodies: anticardiolipin and the lupus anticoagulant in systemic lupus erythematosus (SLE) and in non-SLE disorders. Prevalence and clinical significance. | journal=Ann Intern Med | year= 1990 | volume= 112 | issue= 9 | pages= 682-98 | pmid=2110431 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2110431  }} </ref>


{| class="wikitable"
{| class="wikitable"
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|31%
|31%
|-
|-
|Antilupus antibody
|[[Lupus anticoagulant]] (LA)
|23-47%
|23-47%
|-
|-
|Beta-2 glycoprotein
|[[Anti-β2 glycoprotein I antibody|Anti-beta-2 glycoprotein I]]
|20%
|20%
|}
|}


===Mechanism of action===
===Mechanism of action===
The mechanism by which clinical manifestations occur in APS is mainly mediated by the antibodies which is as follows: <ref>Bick, RL, et al. Antiphospholipid and thrombosis syndromes. Sem Thromb and Hemostasis 1994;20:3. PMID 8059232</ref><ref>Cervera, R, et al. Clinicopathologic correlations of the antiphospholipid syndrome. Sem Arth and Rheum 1995;24:262. PMID 7740306</ref><ref>Kampe, CE. Clinical syndromes associated with lupus anticoagulants. Sem Thromb and Hemostasis 1994;20:16. PMID 8059230</ref><ref>Asherson, RA. The catastrophic antiphospholipid antibody syndrome. J Rheum 1992:19:508. PMID 1593568</ref><ref>Ruffatti, A, et al. A catastrophic antiphospholipid antibody syndrome: the importance of high levels of warfarin anticoagulation. J Int Med 1994;325:81.PMID8283165</ref><ref>Neuwelt, CM, et al. Catastrophic antiphospholipid syndrome: Response to repeated plasmapheresis. A&R 1997;40:1534. PMID 9259436 </ref><ref>Bermas, BL, et al. Prognosis and therapy of antiphospholipid antibody syndrome. UpToDate 1997.</ref>
The mechanism by which clinical manifestations occur in APS is mainly mediated by the [[antibodies]] which is as follows: <ref>Bick, RL, et al. Antiphospholipid and thrombosis syndromes. Sem Thromb and Hemostasis 1994;20:3. PMID 8059232</ref><ref>Cervera, R, et al. Clinicopathologic correlations of the antiphospholipid syndrome. Sem Arth and Rheum 1995;24:262. PMID 7740306</ref><ref>Kampe, CE. Clinical syndromes associated with lupus anticoagulants. Sem Thromb and Hemostasis 1994;20:16. PMID 8059230</ref><ref>Asherson, RA. The catastrophic antiphospholipid antibody syndrome. J Rheum 1992:19:508. PMID 1593568</ref><ref>Ruffatti, A, et al. A catastrophic antiphospholipid antibody syndrome: the importance of high levels of warfarin anticoagulation. J Int Med 1994;325:81.PMID8283165</ref><ref>Neuwelt, CM, et al. Catastrophic antiphospholipid syndrome: Response to repeated plasmapheresis. A&R 1997;40:1534. PMID 9259436 </ref><ref>Bermas, BL, et al. Prognosis and therapy of antiphospholipid antibody syndrome. UpToDate 1997.</ref>


'''Vascular thrombosis'''
'''Vascular thrombosis'''
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=== Role of Antiphospholipid Antibodies: ===
=== Role of Antiphospholipid Antibodies: ===
These antibodies have the following mechanism of action:<ref name="pmid10365749">{{cite journal| author=Merrill JT, Zhang HW, Shen C, Butman BT, Jeffries EP, Lahita RG et al.| title=Enhancement of protein S anticoagulant function by beta2-glycoprotein I, a major target antigen of antiphospholipid antibodies: beta2-glycoprotein I interferes with binding of protein S to its plasma inhibitor, C4b-binding protein. | journal=Thromb Haemost | year= 1999 | volume= 81 | issue= 5 | pages= 748-57 | pmid=10365749 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10365749  }} </ref><ref name="pmid8712801">{{cite journal| author=Shapiro SS| title=The lupus anticoagulant/antiphospholipid syndrome. | journal=Annu Rev Med | year= 1996 | volume= 47 | issue=  | pages= 533-53 | pmid=8712801 | doi=10.1146/annurev.med.47.1.533 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8712801  }} </ref><ref name="pmid11159506">{{cite journal| author=Male C, Mitchell L, Julian J, Vegh P, Joshua P, Adams M et al.| title=Acquired activated protein C resistance is associated with lupus anticoagulants and thrombotic events in pediatric patients with systemic lupus erythematosus. | journal=Blood | year= 2001 | volume= 97 | issue= 4 | pages= 844-9 | pmid=11159506 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11159506  }} </ref><ref name="pmid11159506">{{cite journal| author=Male C, Mitchell L, Julian J, Vegh P, Joshua P, Adams M et al.| title=Acquired activated protein C resistance is associated with lupus anticoagulants and thrombotic events in pediatric patients with systemic lupus erythematosus. | journal=Blood | year= 2001 | volume= 97 | issue= 4 | pages= 844-9 | pmid=11159506 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11159506  }} </ref>
These antibodies have the following mechanism of action:<ref name="pmid10365749">{{cite journal| author=Merrill JT, Zhang HW, Shen C, Butman BT, Jeffries EP, Lahita RG et al.| title=Enhancement of protein S anticoagulant function by beta2-glycoprotein I, a major target antigen of antiphospholipid antibodies: beta2-glycoprotein I interferes with binding of protein S to its plasma inhibitor, C4b-binding protein. | journal=Thromb Haemost | year= 1999 | volume= 81 | issue= 5 | pages= 748-57 | pmid=10365749 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10365749  }} </ref><ref name="pmid8712801">{{cite journal| author=Shapiro SS| title=The lupus anticoagulant/antiphospholipid syndrome. | journal=Annu Rev Med | year= 1996 | volume= 47 | issue=  | pages= 533-53 | pmid=8712801 | doi=10.1146/annurev.med.47.1.533 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8712801  }} </ref><ref name="pmid11159506">{{cite journal| author=Male C, Mitchell L, Julian J, Vegh P, Joshua P, Adams M et al.| title=Acquired activated protein C resistance is associated with lupus anticoagulants and thrombotic events in pediatric patients with systemic lupus erythematosus. | journal=Blood | year= 2001 | volume= 97 | issue= 4 | pages= 844-9 | pmid=11159506 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11159506  }} </ref><ref name="pmid11159506">{{cite journal| author=Male C, Mitchell L, Julian J, Vegh P, Joshua P, Adams M et al.| title=Acquired activated protein C resistance is associated with lupus anticoagulants and thrombotic events in pediatric patients with systemic lupus erythematosus. | journal=Blood | year= 2001 | volume= 97 | issue= 4 | pages= 844-9 | pmid=11159506 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11159506  }} </ref>
* Beta2-glycoprotein-I enhances the anticoagulant function of protein S by interfering its binding to its inhibitor C4b binding protein.
* [[Anti-β2 glycoprotein I antibody|Anti-beta-2 glycoprotein I antibody]] enhances the anticoagulant function of [[protein S]] by interfering its binding to its inhibitor C4b binding protein.
* They bind negatively charged [[Phospholipid|phospholipids]] and inhibit contact activation of the clotting cascade and platelet activation.
* They bind negatively charged [[Phospholipid|phospholipids]] and inhibit contact activation of the clotting cascade and [[platelet]] activation.
* Another mechanism by which antiphospholipid antibodies create a prothrombotic state is by developing acquired activated protein C resistance.
* Another mechanism by which antiphospholipid antibodies create a prothrombotic state is by developing acquired activated [[protein C]] resistance.


===Cellular mechanism===
===Cellular mechanism===
The underlying cellualar mechanism involved in the pathogenesis of APS in as follows:<ref name="pmid16219103">{{cite journal| author=Morel O, Jesel L, Freyssinet JM, Toti F| title=Elevated levels of procoagulant microparticles in a patient with myocardial infarction, antiphospholipid antibodies and multifocal cardiac thrombosis. | journal=Thromb J | year= 2005 | volume= 3 | issue=  | pages= 15 | pmid=16219103 | doi=10.1186/1477-9560-3-15 | pmc=1266401 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16219103  }} </ref><ref name="pmid19502261">{{cite journal| author=Pericleous C, Giles I, Rahman A| title=Are endothelial microparticles potential markers of vascular dysfunction in the antiphospholipid syndrome? | journal=Lupus | year= 2009 | volume= 18 | issue= 8 | pages= 671-5 | pmid=19502261 | doi=10.1177/0961203309103062 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19502261  }} </ref><ref name="pmid11127848">{{cite journal| author=Williams FM, Parmar K, Hughes GR, Hunt BJ| title=Systemic endothelial cell markers in primary antiphospholipid syndrome. | journal=Thromb Haemost | year= 2000 | volume= 84 | issue= 5 | pages= 742-6 | pmid=11127848 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11127848  }} </ref>
The underlying cellular mechanism involved in the pathogenesis of APS in as follows:<ref name="pmid16219103">{{cite journal| author=Morel O, Jesel L, Freyssinet JM, Toti F| title=Elevated levels of procoagulant microparticles in a patient with myocardial infarction, antiphospholipid antibodies and multifocal cardiac thrombosis. | journal=Thromb J | year= 2005 | volume= 3 | issue=  | pages= 15 | pmid=16219103 | doi=10.1186/1477-9560-3-15 | pmc=1266401 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16219103  }} </ref><ref name="pmid19502261">{{cite journal| author=Pericleous C, Giles I, Rahman A| title=Are endothelial microparticles potential markers of vascular dysfunction in the antiphospholipid syndrome? | journal=Lupus | year= 2009 | volume= 18 | issue= 8 | pages= 671-5 | pmid=19502261 | doi=10.1177/0961203309103062 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19502261  }} </ref><ref name="pmid11127848">{{cite journal| author=Williams FM, Parmar K, Hughes GR, Hunt BJ| title=Systemic endothelial cell markers in primary antiphospholipid syndrome. | journal=Thromb Haemost | year= 2000 | volume= 84 | issue= 5 | pages= 742-6 | pmid=11127848 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11127848  }} </ref>
*  Monocytes, platelets, endothelial cells and complement play an important role in induction of thrombosis and fetal death in antiphospholipid syndrome.
*  [[Monocyte|Monocytes]], [[Platelet|platelets]], [[Endothelium|endothelial]] cells and complement play an important role in induction of [[thrombosis]] and fetal death in antiphospholipid syndrome.
* APS antibodies such as anti-β2-glycoprotein-1 activate endothelial cells and monocytes.
* APS antibodies such as [[Anti-β2 glycoprotein I antibody|anti-β2-glycoprotein-1]] activate endothelial cells and [[Monocyte|monocytes]].
* In turn, endothelial cells express the following adhesion molecules:
* In turn, [[Endothelium|endothelial cells]] express the following [[adhesion]] molecules:
** Intercellular cell adhesion molecule-1
** [[Intercellular adhesion molecule|Intercellular cell adhesion molecule-1]]
** Vascular cell adhesion molecule-1
** Vascular cell adhesion molecule-1
** E-selectin
** [[E-selectin]]
* Both endothelial cells and monocytes upregulate the production of tissue factor which activates the coagulation pathway.  
* Both endothelial cells and monocytes upregulate the production of tissue factor which activates the coagulation pathway.  
* Activated platelets increase expression of glycoprotein 2b-3a and synthesis of thromboxane A2.  
* Activated [[Platelet|platelets]] increase expression of [[glycoprotein IIb/IIIa]] and synthesis of [[thromboxane A2]].  
* Nuclear factor κB (NFκB) and p38 mitogen-activated protein kinase (p38 MAPK) are important mediators of these three processes.
* [[NF-kB|Nuclear factor κB]] ([[NF-κB|NFκB]]) and [[P38 mitogen-activated protein kinases|p38 mitogen-activated protein kinase]] (p38 MAPK) are important mediators of these three processes.
* Complement activation play a pivotal role in thrombosis and fetal loss induced by antiphospholipid antibodies.
* [[Complement]] activation play a pivotal role in thrombosis and fetal loss induced by antiphospholipid antibodies.
* C4d and C3b fragments are deposited in the placentas of patients with antiphospholipid syndrome.
* [[C3b]] fragments are deposited in the [[placenta]]<nowiki/>s of patients with antiphospholipid syndrome.


===Microparticles===
===Microparticles===
*Microparticles are found in the plasma of patients with APS in elevated levels.<ref name="pmid15045126">{{cite journal| author=Dignat-George F, Camoin-Jau L, Sabatier F, Arnoux D, Anfosso F, Bardin N et al.| title=Endothelial microparticles: a potential contribution to the thrombotic complications of the antiphospholipid syndrome. | journal=Thromb Haemost | year= 2004 | volume= 91 | issue= 4 | pages= 667-73 | pmid=15045126 | doi=10.1160/TH03-07-0487 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15045126  }} </ref><ref name="pmid15878739">{{cite journal| author=Ambrozic A, Bozic B, Kveder T, Majhenc J, Arrigler V, Svetina S et al.| title=Budding, vesiculation and permeabilization of phospholipid membranes-evidence for a feasible physiologic role of beta2-glycoprotein I and pathogenic actions of anti-beta2-glycoprotein I antibodies. | journal=Biochim Biophys Acta | year= 2005 | volume= 1740 | issue= 1 | pages= 38-44 | pmid=15878739 | doi=10.1016/j.bbadis.2005.02.009 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15878739  }} </ref>
*Microparticles are found in the plasma of patients with APS in elevated levels.<ref name="pmid15045126">{{cite journal| author=Dignat-George F, Camoin-Jau L, Sabatier F, Arnoux D, Anfosso F, Bardin N et al.| title=Endothelial microparticles: a potential contribution to the thrombotic complications of the antiphospholipid syndrome. | journal=Thromb Haemost | year= 2004 | volume= 91 | issue= 4 | pages= 667-73 | pmid=15045126 | doi=10.1160/TH03-07-0487 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15045126  }} </ref><ref name="pmid15878739">{{cite journal| author=Ambrozic A, Bozic B, Kveder T, Majhenc J, Arrigler V, Svetina S et al.| title=Budding, vesiculation and permeabilization of phospholipid membranes-evidence for a feasible physiologic role of beta2-glycoprotein I and pathogenic actions of anti-beta2-glycoprotein I antibodies. | journal=Biochim Biophys Acta | year= 2005 | volume= 1740 | issue= 1 | pages= 38-44 | pmid=15878739 | doi=10.1016/j.bbadis.2005.02.009 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15878739  }} </ref>
*These are cell surface fragments released from the damaged, apoptotic and dying cells.
*These are cell surface fragments released from the damaged, [[Apoptosis|apoptotic]] and dying cells.
*They lead to cell activation and subsequently lead to a prothrombotic state in the plasma.
*They lead to cell activation and subsequently lead to a prothrombotic state in the plasma.


== Catastrophic Antiphospholipid Antibody Syndrome (CAPS): ==
== Catastrophic Antiphospholipid Antibody Syndrome (CAPS) ==
* CAPS is a subclass of APS that results in development of a catastrophic illness characterized by progressive, severe arterial and venous thrombosis in multiple organs, often leading to death.
* CAPS is a subclass of APS that results in development of a catastrophic illness characterized by progressive, severe arterial and venous thrombosis in multiple organs, often leading to death.
* Classification criteria for CAPS is as follows:
* Classification criteria for CAPS is as follows:
Line 153: Line 154:
|2. Development of manifestations simultaneously or in less than a week
|2. Development of manifestations simultaneously or in less than a week
|-
|-
|3. Confirmation by histopathology of small vessel occlusion in at least one organ or tissue
|3. Confirmation by [[histopathology]] of small vessel occlusion in at least one organ or tissue
|-
|-
|4. Laboratory confirmation of the presence of antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibodies, and/or anti-beta2-glycoprotein I antibodies)
|4. Laboratory confirmation of the presence of antiphospholipid antibodies ([[Lupus anticoagulant|lupus]] anticoagulant, [[Anti-cardiolipin antibodies|anticardiolipin]] antibodies, and/or anti-beta2-glycoprotein I antibodies)
|}
|}
|-
|-
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:*:* Liver and gastrointestinal tract infarctions  
:*:* Liver and gastrointestinal tract infarctions  
:*:* [[Oliguria]] and rapidly deteriorating renal function.
:*:* [[Oliguria]] and rapidly deteriorating renal function.
==Genetic association==
==Genetic association==
Antiphospholipid antibody syndrome is associated with the following genetic mutations:<ref name="pmid15026314">{{cite journal| author=Brouwer JL, Bijl M, Veeger NJ, Kluin-Nelemans HC, van der Meer J| title=The contribution of inherited and acquired thrombophilic defects, alone or combined with antiphospholipid antibodies, to venous and arterial thromboembolism in patients with systemic lupus erythematosus. | journal=Blood | year= 2004 | volume= 104 | issue= 1 | pages= 143-8 | pmid=15026314 | doi=10.1182/blood-2003-11-4085 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15026314  }} </ref>
Antiphospholipid antibody syndrome is associated with the following genetic mutations:<ref name="pmid15026314">{{cite journal| author=Brouwer JL, Bijl M, Veeger NJ, Kluin-Nelemans HC, van der Meer J| title=The contribution of inherited and acquired thrombophilic defects, alone or combined with antiphospholipid antibodies, to venous and arterial thromboembolism in patients with systemic lupus erythematosus. | journal=Blood | year= 2004 | volume= 104 | issue= 1 | pages= 143-8 | pmid=15026314 | doi=10.1182/blood-2003-11-4085 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15026314 }} </ref><ref name="pmid12139749">{{cite journal| author=Nojima J, Kuratsune H, Suehisa E, Kawasaki T, Machii T, Kitani T et al.| title=Acquired activated protein C resistance is associated with the co-existence of anti-prothrombin antibodies and lupus anticoagulant activity in patients with systemic lupus erythematosus. | journal=Br J Haematol | year= 2002 | volume= 118 | issue= 2 | pages= 577-83 | pmid=12139749 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12139749 }} </ref>
*Factor V Leiden
*[[Factor V Leiden]]
*Prothrombin gene mutation
*[[Prothrombin gene mutation G20210A|Prothrombin gene mutation]]
*Activated protein C resistance
*[[Activated protein C resistance|Activated protein C]] resistance


==Gross Pathology Findings==
==Gross Pathology Findings==
==Microscopic Pathology Findings==
==Microscopic Pathology Findings==
The histologic findings seen in APS are as follows:
Histologic studies of skin or other involved tissues reveal the following:
Histologic studies of skin or other involved tissues reveal the following:
* A noninflammatory bland [[thrombosis]] with no signs of [[Perivascular cell|perivascular]] inflammation or [[Leukocytoclastic vasculitis|leukocytoclastic]] vasculitis.
* A noninflammatory bland [[thrombosis]] with no signs of [[Perivascular cell|perivascular]] inflammation or [[Leukocytoclastic vasculitis|leukocytoclastic]] vasculitis.
* Biopsy samples from affected [[Kidney|kidneys]] demonstrate [[Glomerulus|glomerular]] and small arterial microthrombi.
* Biopsy samples from affected [[Kidney|kidneys]] demonstrate [[Glomerulus|glomerular]] and small arterial microthrombi.
* Histopathology findings in CAPS shows evidence of multiple small and/or large vessel occlusions.
* [[Histopathology]] findings in CAPS shows evidence of multiple small and/or large vessel occlusions.


==References==
==References==

Latest revision as of 15:28, 26 April 2018

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

Overview

Antiphospholipid syndrome (APS) is an autoimmune disease in which antiphospholipid antibodies (anti-cardiolipin antibodies and lupus anticoagulant) react against proteins that bind to anionic phospholipids on plasma membranes. This syndrome can be classified into primary (no underlying disease state) and secondary (in association with an underlying disease state) types. The underlying mechanism of APS mediated by the antibodies is mainly mediated via their affect on the coagulation cascade which subsequenlty leads to increased vascular tone of thrombosis. CAPS is a subclass of APS that results in development of a catastrophic illness characterized by progressive, severe arterial and venous thrombosis in multiple organs, often leading to death.

Pathophysiology

The pathogenesis of antiphospholipid syndrome is as follows:[1][2]

Primary APS

This type of APS has no other associated condition.

Secondary APS

The type of APS which occurs secondary to an underlying disease. The diseases and conditions associated with APS are as follows:[3][4][5]

Autoimmune diseases Infections Drugs Malignancy
  • Systemic lupus erythmatosus(SLE)
 Bacterial infections:

Viral infections:

Parasitic infections:

Tumors of the following organs can cause APS:

Cancers:

Types of antiphospholipid antibodies

The following antiphospholipid antibodies are found in the plasma of patients:

Antiphospholipid antibodies Percentage
Anticardiolipin antibody 31%
Lupus anticoagulant (LA) 23-47%
Anti-beta-2 glycoprotein I 20%

Mechanism of action

The mechanism by which clinical manifestations occur in APS is mainly mediated by the antibodies which is as follows: [9][10][11][12][13][14][15]

Vascular thrombosis

Increased vascular tone:

Another effect of aPL is increased vascular tone which subsequently results in the following manifestations:

Role of Antiphospholipid Antibodies:

These antibodies have the following mechanism of action:[16][17][18][18]

  • Anti-beta-2 glycoprotein I antibody enhances the anticoagulant function of protein S by interfering its binding to its inhibitor C4b binding protein.
  • They bind negatively charged phospholipids and inhibit contact activation of the clotting cascade and platelet activation.
  • Another mechanism by which antiphospholipid antibodies create a prothrombotic state is by developing acquired activated protein C resistance.

Cellular mechanism

The underlying cellular mechanism involved in the pathogenesis of APS in as follows:[19][20][21]

Microparticles

  • Microparticles are found in the plasma of patients with APS in elevated levels.[22][23]
  • These are cell surface fragments released from the damaged, apoptotic and dying cells.
  • They lead to cell activation and subsequently lead to a prothrombotic state in the plasma.

Catastrophic Antiphospholipid Antibody Syndrome (CAPS)

  • CAPS is a subclass of APS that results in development of a catastrophic illness characterized by progressive, severe arterial and venous thrombosis in multiple organs, often leading to death.
  • Classification criteria for CAPS is as follows:
Classification criteria for CAPS
Criteria
1. Evidence of involvement of three or more organs, systems, and/or tissues
2. Development of manifestations simultaneously or in less than a week
3. Confirmation by histopathology of small vessel occlusion in at least one organ or tissue
4. Laboratory confirmation of the presence of antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibodies, and/or anti-beta2-glycoprotein I antibodies)
Classification
Definite CAPS
  • Requires all four criteria
Probable CAPS
  • All four criteria, except for only two organs, systems, and/or sites of tissue involvement or
  • All four criteria, except for the laboratory confirmation at least six weeks apart due to the early death of a patient never tested for aPL before the catastrophic APS or
  • Criteria 1, 2, and 4 above or
  • 1, 3, and 4 and the development of a third event in more than a week but less than a month, despite anticoagulation

Genetic association

Antiphospholipid antibody syndrome is associated with the following genetic mutations:[24][25]

Gross Pathology Findings

Microscopic Pathology Findings

Histologic studies of skin or other involved tissues reveal the following:

References

  1. ↑ Negrini S, Pappalardo F, Murdaca G, Indiveri F, Puppo F (2017). "The antiphospholipid syndrome: from pathophysiology to treatment". Clin Exp Med. 17 (3): 257–267. doi:10.1007/s10238-016-0430-5. PMID 27334977.
  2. ↑ Giannakopoulos B, Krilis SA (2013). "The pathogenesis of the antiphospholipid syndrome". N Engl J Med. 368 (11): 1033–44. doi:10.1056/NEJMra1112830. PMID 23484830.
  3. ↑ Taraborelli M, Leuenberger L, Lazzaroni MG, Martinazzi N, Zhang W, Franceschini F; et al. (2016). "The contribution of antiphospholipid antibodies to organ damage in systemic lupus erythematosus". Lupus. 25 (12): 1365–8. doi:10.1177/0961203316637431. PMID 26945023.
  4. ↑ Conti F, Ceccarelli F, Perricone C, Leccese I, Massaro L, Pacucci VA; et al. (2016). "The chronic damage in systemic lupus erythematosus is driven by flares, glucocorticoids and antiphospholipid antibodies: results from a monocentric cohort". Lupus. 25 (7): 719–26. doi:10.1177/0961203315627199. PMID 26821965.
  5. ↑ Love PE, Santoro SA (1990). "Antiphospholipid antibodies: anticardiolipin and the lupus anticoagulant in systemic lupus erythematosus (SLE) and in non-SLE disorders. Prevalence and clinical significance". Ann Intern Med. 112 (9): 682–98. PMID 2110431.
  6. ↑ McNeil HP, Chesterman CN, Krilis SA (1991). "Immunology and clinical importance of antiphospholipid antibodies". Adv Immunol. 49: 193–280. PMID 1853785.
  7. ↑ Safa O, Crippa L, Della Valle P, Sabbadini MG, Viganò D'Angelo S, D'Angelo A (1999). "IgG reactivity to phospholipid-bound beta(2)-glycoprotein I is the main determinant of the fraction of lupus anticoagulant activity quenched by addition of hexagonal (II) phase phospholipid in patients with the clinical suspicion of antiphospholipid-antibody syndrome". Haematologica. 84 (9): 829–38. PMID 10477458.
  8. ↑ Triplett DA (1998). "Many faces of lupus anticoagulants". Lupus. 7 Suppl 2: S18–22. PMID 9814666.
  9. ↑ Bick, RL, et al. Antiphospholipid and thrombosis syndromes. Sem Thromb and Hemostasis 1994;20:3. PMID 8059232
  10. ↑ Cervera, R, et al. Clinicopathologic correlations of the antiphospholipid syndrome. Sem Arth and Rheum 1995;24:262. PMID 7740306
  11. ↑ Kampe, CE. Clinical syndromes associated with lupus anticoagulants. Sem Thromb and Hemostasis 1994;20:16. PMID 8059230
  12. ↑ Asherson, RA. The catastrophic antiphospholipid antibody syndrome. J Rheum 1992:19:508. PMID 1593568
  13. ↑ Ruffatti, A, et al. A catastrophic antiphospholipid antibody syndrome: the importance of high levels of warfarin anticoagulation. J Int Med 1994;325:81.PMID8283165
  14. ↑ Neuwelt, CM, et al. Catastrophic antiphospholipid syndrome: Response to repeated plasmapheresis. A&R 1997;40:1534. PMID 9259436
  15. ↑ Bermas, BL, et al. Prognosis and therapy of antiphospholipid antibody syndrome. UpToDate 1997.
  16. ↑ Merrill JT, Zhang HW, Shen C, Butman BT, Jeffries EP, Lahita RG; et al. (1999). "Enhancement of protein S anticoagulant function by beta2-glycoprotein I, a major target antigen of antiphospholipid antibodies: beta2-glycoprotein I interferes with binding of protein S to its plasma inhibitor, C4b-binding protein". Thromb Haemost. 81 (5): 748–57. PMID 10365749.
  17. ↑ Shapiro SS (1996). "The lupus anticoagulant/antiphospholipid syndrome". Annu Rev Med. 47: 533–53. doi:10.1146/annurev.med.47.1.533. PMID 8712801.
  18. ↑ 18.0 18.1 Male C, Mitchell L, Julian J, Vegh P, Joshua P, Adams M; et al. (2001). "Acquired activated protein C resistance is associated with lupus anticoagulants and thrombotic events in pediatric patients with systemic lupus erythematosus". Blood. 97 (4): 844–9. PMID 11159506.
  19. ↑ Morel O, Jesel L, Freyssinet JM, Toti F (2005). "Elevated levels of procoagulant microparticles in a patient with myocardial infarction, antiphospholipid antibodies and multifocal cardiac thrombosis". Thromb J. 3: 15. doi:10.1186/1477-9560-3-15. PMC 1266401. PMID 16219103.
  20. ↑ Pericleous C, Giles I, Rahman A (2009). "Are endothelial microparticles potential markers of vascular dysfunction in the antiphospholipid syndrome?". Lupus. 18 (8): 671–5. doi:10.1177/0961203309103062. PMID 19502261.
  21. ↑ Williams FM, Parmar K, Hughes GR, Hunt BJ (2000). "Systemic endothelial cell markers in primary antiphospholipid syndrome". Thromb Haemost. 84 (5): 742–6. PMID 11127848.
  22. ↑ Dignat-George F, Camoin-Jau L, Sabatier F, Arnoux D, Anfosso F, Bardin N; et al. (2004). "Endothelial microparticles: a potential contribution to the thrombotic complications of the antiphospholipid syndrome". Thromb Haemost. 91 (4): 667–73. doi:10.1160/TH03-07-0487. PMID 15045126.
  23. ↑ Ambrozic A, Bozic B, Kveder T, Majhenc J, Arrigler V, Svetina S; et al. (2005). "Budding, vesiculation and permeabilization of phospholipid membranes-evidence for a feasible physiologic role of beta2-glycoprotein I and pathogenic actions of anti-beta2-glycoprotein I antibodies". Biochim Biophys Acta. 1740 (1): 38–44. doi:10.1016/j.bbadis.2005.02.009. PMID 15878739.
  24. ↑ Brouwer JL, Bijl M, Veeger NJ, Kluin-Nelemans HC, van der Meer J (2004). "The contribution of inherited and acquired thrombophilic defects, alone or combined with antiphospholipid antibodies, to venous and arterial thromboembolism in patients with systemic lupus erythematosus". Blood. 104 (1): 143–8. doi:10.1182/blood-2003-11-4085. PMID 15026314.
  25. ↑ Nojima J, Kuratsune H, Suehisa E, Kawasaki T, Machii T, Kitani T; et al. (2002). "Acquired activated protein C resistance is associated with the co-existence of anti-prothrombin antibodies and lupus anticoagulant activity in patients with systemic lupus erythematosus". Br J Haematol. 118 (2): 577–83. PMID 12139749.

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