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Latest revision as of 15:28, 26 April 2018

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]

It is a non-inflammatory autoimmune disease, in which antiphospholipid antibodies react against proteins that bind to anionic phospholipids on plasma membranes.
APS can be classified into two types based on the underlying cause.
- Primary APS
- Secondary APS

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: Leptospirosis^[6]^[7] Syphilis Lymes disease Tuberculosis^[8] Leprosy Infective endocarditis Post-streptococcal rheumatic fever Klebsiella infection Viral infections: Hepatitis A,B and C HIV Epstein Barr virus Adenovirus Rubella Parvovirus Cytomegalovirus Varicella Zoster virus Parasitic infections: Visceral leischmaniasis Pneumocysitis jiroveci Malaria	Chlorpromazine Procainamide Hydralazine Quinidine Quinine Phenytoin Alpha interferon Oral contraceptives Amoxicillin Chlorothiazide Propanolol	Tumors of the following organs can cause APS: Lung Colon Breast Cervix Ovary Cancers: Hodgkins lymphoma Non-hodgkins lymphoma Myeloid leukemia Lymphocytic leukemia Primary myelofibrosis Polycythemia vera

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

Antiphospholipid antibody (aPL) affects the coagulation cascade.
They have a procoagulant action on the following proteins and tissue factors in the plasma:
- Protein C
- Annexin V
- Platelets
- Serum proteases
- Toll-like receptors
- Tissue factor, and via impaired fibrinolysis
The cumulative procoagulant effect of these, leads to vascular thrombosis.

Increased vascular tone:

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

Neurological abnormalities such as stroke and transient ischemic attack
Fetal loss
Atherosclerosis

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]

Monocytes, platelets, 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.
In turn, endothelial cells express the following adhesion molecules:
- Intercellular cell adhesion molecule-1
- Vascular cell adhesion molecule-1
- E-selectin
Both endothelial cells and monocytes upregulate the production of tissue factor which activates the coagulation pathway.
Activated 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.
Complement activation play a pivotal role in thrombosis and fetal loss induced by antiphospholipid antibodies.
C3b fragments are deposited in the placentas of patients with antiphospholipid syndrome.

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

Commonly involved organs include the central nervous system (CNS), kidney and distal extremities with acral necrosis. Hypertension is also commonly present, and may be malignant.
- CNS manifestations may be quite heterogeneous, including confusion, focal signs, and/or seizures.
- Acute Respiratory Distress Syndrome (ARDS) may be present
- Adrenal hemorrhage
- Liver and gastrointestinal tract infarctions
- Oliguria and rapidly deteriorating renal function.

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:

A noninflammatory bland thrombosis with no signs of perivascular inflammation or leukocytoclastic vasculitis.
Biopsy samples from affected kidneys demonstrate glomerular and small arterial microthrombi.
Histopathology findings in CAPS shows evidence of multiple small and/or large vessel occlusions.

References

↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ McNeil HP, Chesterman CN, Krilis SA (1991). "Immunology and clinical importance of antiphospholipid antibodies". Adv Immunol. 49: 193–280. PMID 1853785.
↑ 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.
↑ Triplett DA (1998). "Many faces of lupus anticoagulants". Lupus. 7 Suppl 2: S18–22. PMID 9814666.
↑ Bick, RL, et al. Antiphospholipid and thrombosis syndromes. Sem Thromb and Hemostasis 1994;20:3. PMID 8059232
↑ Cervera, R, et al. Clinicopathologic correlations of the antiphospholipid syndrome. Sem Arth and Rheum 1995;24:262. PMID 7740306
↑ Kampe, CE. Clinical syndromes associated with lupus anticoagulants. Sem Thromb and Hemostasis 1994;20:16. PMID 8059230
↑ Asherson, RA. The catastrophic antiphospholipid antibody syndrome. J Rheum 1992:19:508. PMID 1593568
↑ Ruffatti, A, et al. A catastrophic antiphospholipid antibody syndrome: the importance of high levels of warfarin anticoagulation. J Int Med 1994;325:81.PMID8283165
↑ Neuwelt, CM, et al. Catastrophic antiphospholipid syndrome: Response to repeated plasmapheresis. A&R 1997;40:1534. PMID 9259436
↑ Bermas, BL, et al. Prognosis and therapy of antiphospholipid antibody syndrome. UpToDate 1997.
↑ 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.
↑ Shapiro SS (1996). "The lupus anticoagulant/antiphospholipid syndrome". Annu Rev Med. 47: 533–53. doi:10.1146/annurev.med.47.1.533. PMID 8712801.
↑ ^18.0 ^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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.

Template:WH Template:WS

[pmid27334977-1] 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.

[pmid23484830-2] 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.

[pmid26945023-3] 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.

[pmid26821965-4] 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.

[pmid2110431-5] 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.

[pmid1853785-6] McNeil HP, Chesterman CN, Krilis SA (1991). "Immunology and clinical importance of antiphospholipid antibodies". Adv Immunol. 49: 193–280. PMID 1853785.

[pmid10477458-7] 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.

[pmid9814666-8] 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.

[pmid10365749-16] 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.

[pmid8712801-17] Shapiro SS (1996). "The lupus anticoagulant/antiphospholipid syndrome". Annu Rev Med. 47: 533–53. doi:10.1146/annurev.med.47.1.533. PMID 8712801.

[pmid11159506-18] 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.

[pmid16219103-19] 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.

[pmid19502261-20] 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.

[pmid11127848-21] 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.

[pmid15045126-22] 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.

[pmid15878739-23] 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.

[pmid15026314-24] 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.

[pmid12139749-25] 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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@@ Line 1: / Line 1: @@
 __NOTOC__
 {{Antiphospholipid syndrome}}
-{{CMG}}{{AE}}{{FT}}
+{{CMG}}; {{AE}}{{FT}}
 ==Overview==
-Antiphospholipid syndrome 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. The main target of [[anti-cardiolipin antibodies]] is [[apolipoprotein H]] (commonly referred to as β<sub>2</sub>Glycoprotein 1) and the main target of [[lupus anticoagulant]] is [[prothrombin]].
+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==
-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.
-* APS is divided into two types based on the underlying cause.
+* 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 can be classified into two types based on the underlying cause.
 ** Primary APS
 ** Secondary APS
@@ Line 17: / Line 18: @@
 === 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"
-!Autoimmune diseases
+! align="center" style="background:#4479BA; color: #FFFFFF;" + |Autoimmune diseases
-!Infections
+! align="center" style="background:#4479BA; color: #FFFFFF;" + |Infections
-!Drugs
+! align="center" style="background:#4479BA; color: #FFFFFF;" + |Drugs
-!Malignancy
+! align="center" style="background:#4479BA; color: #FFFFFF;" + |Malignancy
 |-
 |
 * Systemic lupus erythmatosus(SLE)
 |'''Bacterial infections:'''
-* Leptospirosis<ref name="pmid1853785">{{cite journal| author=McNeil HP, Chesterman CN, Krilis SA| title=Immunology and clinical importance of antiphospholipid antibodies. | journal=Adv Immunol | year= 1991 | volume= 49 | issue=  | pages= 193-280 | pmid=1853785 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1853785  }} </ref><ref name="pmid10477458">{{cite journal| author=Safa O, Crippa L, Della Valle P, Sabbadini MG, Viganò D'Angelo S, D'Angelo A| title=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. | journal=Haematologica | year= 1999 | volume= 84 | issue= 9 | pages= 829-38 | pmid=10477458 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10477458  }} </ref>
+* [[Leptospirosis]]<ref name="pmid1853785">{{cite journal| author=McNeil HP, Chesterman CN, Krilis SA| title=Immunology and clinical importance of antiphospholipid antibodies. | journal=Adv Immunol | year= 1991 | volume= 49 | issue=  | pages= 193-280 | pmid=1853785 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1853785  }} </ref><ref name="pmid10477458">{{cite journal| author=Safa O, Crippa L, Della Valle P, Sabbadini MG, Viganò D'Angelo S, D'Angelo A| title=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. | journal=Haematologica | year= 1999 | volume= 84 | issue= 9 | pages= 829-38 | pmid=10477458 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10477458  }} </ref>
-* Syphilis
+* [[Syphilis]]
-* Lymes disease
+* [[Lymes disease]]
-* Tuberculosis<ref name="pmid9814666">{{cite journal| author=Triplett DA| title=Many faces of lupus anticoagulants. | journal=Lupus | year= 1998 | volume= 7 Suppl 2 | issue=  | pages= S18-22 | pmid=9814666 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9814666  }} </ref>
+* [[Tuberculosis]]<ref name="pmid9814666">{{cite journal| author=Triplett DA| title=Many faces of lupus anticoagulants. | journal=Lupus | year= 1998 | volume= 7 Suppl 2 | issue=  | pages= S18-22 | pmid=9814666 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9814666  }} </ref>
-* Leprosy
+* [[Leprosy]]
-* Infective endocarditis
+* [[Infective endocarditis]]
-* Post-Streptococcal rheumatic fever
+* Post-streptococcal rheumatic fever
-* Klebsiella infection
+* [[Klebsiella infection]]
 '''Viral infections:'''
-* Hepatitis A,B and C
+* [[Hepatitis A]],[[Hepatitis B|B]] and [[Hepatitis C|C]]
-* HIV
+* [[HIV]]
-* Ebstein Barr virus
+* [[Epstein Barr virus]]
-* Adenovirus
+* [[Adenovirus]]
-* Rubella
+* [[Rubella]]
-* Parvovirus
+* [[Parvovirus]]
-* Cytomegalovirus
+* [[Cytomegalovirus]]
-* Varicella Zoster virus
+* [[Varicella Zoster|Varicella Zoster virus]]
 '''Parasitic infections:'''
 * Visceral leischmaniasis
-* Pneumocysitis jirovecci
+* [[Pneumocystis jirovecii|Pneumocysitis jiroveci]]
-* Malaria
+* [[Malaria]]
 |
-* Chlorpromazine
+* [[Chlorpromazine]]
-* Procainamide
+* [[Procainamide]]
-* Hydralazine
+* [[Hydralazine]]
-* Quinidine
+* [[Quinidine]]
-* Quinine
+* [[Quinine]]
-* Phenytoin
+* [[Phenytoin]]
-* Alpha interferon
+* [[Alpha interferon]]
-* Oral contraceptives
+* [[Oral contraceptives]]
-* Amoxicillin
+* [[Amoxicillin]]
-* Chlorothiazide
+* [[Chlorothiazide]]
-* Propanolol
+* [[Propanolol]]
 |Tumors of the following organs can cause APS:
-* Lung
+* [[Lung]]
-* Colon
+* [[Colon]]
-* Breast
+* [[Breast]]
-* Cervix
+* [[Cervix]]
-* Ovary
+* [[Ovary]]
 '''Cancers:'''
-* Hodgkins lymphoma
+* [[Hodgkin's lymphoma|Hodgkins lymphoma]]
-* Non-hodgkins lymphoma
+* [[Non-Hodgkin lymphoma|Non-hodgkins lymphoma]]
-* Myeloid leukemia
+* [[Myeloid leukemia]]
-* Lymphocytic leukemia
+* [[Lymphocytic leukemia]]
-* Primary myelofibrosis
+* [[Primary myelofibrosis]]
-* Polycythemia vera
+* [[Polycythemia vera]]
 |}
 === Types of antiphospholipid antibodies ===
-The following antiphospholipid antibodies are found in the plasma of patients:
+The following [[antiphospholipid antibodies]] are found in the [[plasma]] of [[patients]]:
 {| class="wikitable"
-!Antiphospholipid antibodies
+! align="center" style="background:#4479BA; color: #FFFFFF;" + |Antiphospholipid antibodies
-!Percentage
+! align="center" style="background:#4479BA; color: #FFFFFF;" + |Percentage
 |-
-|Anticardiolipin antibody
+|[[Anticardiolipin antibody]]
 |31%
 |-
-|Antilupus antibody
+|[[Lupus anticoagulant]] (LA)
 |23-47%
 |-
-|Beta-2 glycoprotein.
+|[[Anti-β2 glycoprotein I antibody|Anti-beta-2 glycoprotein I]]
 |20%
 |}
 ===Mechanism of action===
-The Lupus anticoagulant antibodies are those that show the closest association with thrombosis, those that target β<sub>2</sub> glycoprotein 1 have a greater association with thrombosis than those that target prothrombin. Anticardiolipin antibodies are associated with thrombosis at moderate to high titres (>40 GPLU or MPLU). Patients with both Lupus anticoagulant antibodies and moderate/high titre anticardiolipin antibodies show a greater risk of thrombosis than with one alone. <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><ref>Khamashta, MT, et al. The management of thrombosis in antiphospholipid antibody syndrome. NEJM 1995;332:993. PMID 7885428</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>
-==== Usual Antiphospholipid Antibody Syndrome====
-Antiphospholipid syndrome (APS) is characterized by the presence of two major components:
-*The plasma should have at least one type of autoantibody known as an antiphospholipid antibody (aPL)
+'''Vascular thrombosis'''
+*[[Antiphospholipid antibody]] (aPL) affects the [[coagulation cascade]].
+*They have a procoagulant action on the following [[proteins]] and [[Tissue factor|tissue factors]] in the [[plasma]]:
+** [[Protein C]]
+** Annexin V
+**[[Platelets]]
+**[[Serum]] proteases
+** [[Toll-like receptors]]
+**[[Tissue factor]], and via impaired [[fibrinolysis]]
+* The cumulative procoagulant effect of these, leads to [[vascular]] [[thrombosis]].
-*The presence of at least one of the following clinical manifestations:
+'''Increased vascular tone:'''
-**Venous thrombosis
-**Arterial thrombosis
-**Pregnancy morbidity
+Another effect of aPL is increased [[vascular]] tone which subsequently results in the following manifestations:
+* [[Neurological]] abnormalities such as stroke and [[transient ischemic attack]]
+* [[Fetal]] loss
+* [[Atherosclerosis]]
+=== 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>
+* [[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.
+* 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:<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>
+*  [[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 I antibody|anti-β2-glycoprotein-1]] activate endothelial cells and [[Monocyte|monocytes]].
+* In turn, [[Endothelium|endothelial cells]] express the following [[adhesion]] molecules:
+** [[Intercellular adhesion molecule|Intercellular cell adhesion molecule-1]]
+** Vascular cell adhesion molecule-1
+** [[E-selectin]]
+* Both endothelial cells and monocytes upregulate the production of tissue factor which activates the coagulation pathway.
+* Activated [[Platelet|platelets]] increase expression of [[glycoprotein IIb/IIIa]] and synthesis of [[thromboxane A2]].
+* [[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.
+* [[C3b]] fragments are deposited in the [[placenta]]<nowiki/>s of patients with antiphospholipid syndrome.
-* Patients with antiphopholipid antibody syndrome and a history of clot have a recurrence rate as high as 0.2 events per year.
+===Microparticles===
-* There is an association between the antiphospholipid syndrome and systemic rheumatic disease, though overall more patients do not have systemic rheumatic disease than do.  The most common association is with [[SLE]] (termed secondary anti-phospholipid antibody syndrome, and occurs in about 10-40% of [[SLE]] patients).  There is also association with cancer, [[leukemia]], idiopathic/[[immune thrombocytopenic purpura]] ([[ITP]]), [[human immunodeficiency virus]] ([[HIV]]), [[rheumatoid arthritis]] ([[RA]]), [[Sjogren’s]], [[Behcet’s]], and some drugs ([[chlorpromazine]], [[dilantin]], [[hydralazine]], [[quinidine]], [[procainamide]], [[interferon]], [[pyrimethamine]], etc).
+*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>
-* The target of both antibodies may be phospholipid bound to a cofactor.
+*These are cell surface fragments released from the damaged, [[Apoptosis|apoptotic]] and dying cells.
-*:* ''Beta2-glycoprotein-I'' is likely the cofactor in patients with anti-cardiolipin antibodies, and may also be important in patients with a lupus anticoagulant.
+*They lead to cell activation and subsequently lead to a prothrombotic state in the plasma.
-*:* ''Prothrombin'' is an important cofactor in patients with lupus anticoagulant.
-* ''Beta2-glycoprotein-I'' usually binds negatively charged phospholipids and inhibits contact activation of the clotting cascade and platelet activation.  In this syndrome, anitphospholipid antibodies may facilitate thrombosis by inhibiting the anticoagulant effects of beta2-glycoprotein-I.  In the future, a test for antibodies to beta2-glycoprotein-I may be used clinically.
-* The vascular disease of the antiphospholipid antibody syndrome is not due to [[vasculitis]].  The characteristic histopathologic finding is thrombotic microangiopathy.
-* Anticardiolipin antibody
-*:* The antibody is directed against ''beta2-glycoprotein-I'' and cardiolipin, a phospholipid component of cell membranes, also used as an antigen in the assay for syphilis (why [[syphilis]] elicits an antibody response to cardiolipin is not clear).
-*:* Patients with anticardiolipin antibody are more likely to have ''arterial clots'' than those with lupus anticoagulant.  These patients are also at increased risk for early coronary artery bypass graft (CABG) graft occlusion, precocious coronary artery disease (CAD), and valvular heart disease.
-* Lupus Anticoagulant
-*:* Lupus anticoagulant is a misnomer: it’s actually a pro-coagulant in vivo, and is often seen in patients without lupus.  It usually (not always) elevates the lab reading of the partial thromboplastin time (PTT).
-*:* Lupus anticoagulant is also directed against the phospholipid membrane, and requires the cofactor prothrombin.
-==== Catastrophic Antiphospholipid Antibody Syndrome ====
+== Catastrophic Antiphospholipid Antibody Syndrome (CAPS) ==
-* A subset of patients with antiphospholipid antibody syndrome develop 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.
-* Though specific diagnostic criteria have not been established, some have suggested that criteria include documented thrombosis in 3 or more organs.
+* Classification criteria for CAPS is as follows:
-*:* Commonly involved organs include the central nervous system (CNS), kidney and distal extremities with [[acral necrosis]].  Hypertension is also commonly present, and may be malignant.
+{| class="wikitable"
-*:*:* CNS manifestations may be quite heterogeneous, including [[confusion]], focal signs, and/or [[seizures]].
+! align="center" style="background:#4479BA; color: #FFFFFF; colspan=" 4 " |Classification criteria for CAPS
-*:*:* [[Acute Respiratory Distress Syndrome]] ([[ARDS]]) may be present
+|-
-*:*:* Signficant cardiac necrosis has been described
+|'''Criteria'''
-*:*:* [[Adrenal hemorrhage]] has been described
+|-
-*:*:* Liver and gastrointestinal tract infarctions have been described
+|
-*:*:* [[Oliguria]] and rapidly deteriorating renal function may be observed.
+{| class="wikitable"
-*:* Histopathology shows evidence of multiple small and/or large vessel occlusions.
+|1. Evidence of involvement of three or more organs, systems, and/or tissues
-* Frequently no specific etiology is identifiable, and patients present quite suddenly without any obvious precipiting factors.
+|-
+|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|lupus]] anticoagulant, [[Anti-cardiolipin antibodies|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
+|}
+:* Commonly involved organs include the central nervous system (CNS), kidney and distal extremities with [[acral necrosis]].  Hypertension is also commonly present, and may be malignant.
+:*:* CNS manifestations may be quite heterogeneous, including [[confusion]], focal signs, and/or [[seizures]].
+:*:* [[Acute Respiratory Distress Syndrome]] ([[ARDS]]) may be present
+:*:* [[Adrenal hemorrhage]]
+:*:* Liver and gastrointestinal tract infarctions
+:*:* [[Oliguria]] and rapidly deteriorating renal function.
 ==Genetic association==
-Antiphospholipid antibody syndrome is associated with the following genetic mutations:
+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==
+==Microscopic Pathology Findings==
+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.
+* 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.
 ==References==