Antiphospholipid syndrome pathophysiology: Difference between revisions

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===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 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>
==== Usual Antiphospholipid Antibody Syndrome====  
==== Usual Antiphospholipid Antibody Syndrome====  

Revision as of 14:23, 26 March 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 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. 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 β2Glycoprotein 1) and the main target of lupus anticoagulant is prothrombin.

Pathophysiology

The pathogenesis of antiphospholipid syndrome is as follows:

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

Primary APS

The type of APS which has no other associated condition.

Secondary APS

The type of APS which occurs secondary to an underlying disease. The diseases associated with APS are as follows:[1][2][3]

Autoimmune diseases Infections Drugs Malignancy
  • Systemic lupus erythmatosus(SLE)
 Bacterial infections:
  • Leptospirosis[4][5]
  • Syphilis
  • Lymes disease
  • Tuberculosis[6]
  • Leprosy
  • Infective endocarditis
  • Post-Streptococcal rheumatic fever
  • Klebsiella infection

Viral infections:

  • Hepatitis A,B and C
  • HIV
  • Ebstein Barr virus
  • Adenovirus
  • Rubella
  • Parvovirus
  • Cytomegalovirus
  • Varicella Zoster virus

Parasitic infections:

  • Visceral leischmaniasis
  • Pneumocysitis jirovecci
  • 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%
Antilupus antibody 23-47%
Beta-2 glycoprotein. 20%

Mechanism of action

The Lupus anticoagulant antibodies are those that show the closest association with thrombosis, those that target β2 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. [7][8][9][10][11][12][13][14]

Usual Antiphospholipid Antibody Syndrome

  • Patients with antiphopholipid antibody syndrome and a history of clot have a recurrence rate as high as 0.2 events per year.
  • 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).
  • The target of both antibodies may be phospholipid bound to a cofactor.
    • Beta2-glycoprotein-I is likely the cofactor in patients with anti-cardiolipin antibodies, and may also be important in patients with a lupus anticoagulant.
    • 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

  • 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.
  • Though specific diagnostic criteria have not been established, some have suggested that criteria include documented thrombosis in 3 or more organs.
    • 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.
    • Histopathology shows evidence of multiple small and/or large vessel occlusions.
  • Frequently no specific etiology is identifiable, and patients present quite suddenly without any obvious precipiting factors.

Genetic association

Antiphospholipid antibody syndrome is associated with the following genetic mutations:

  • Factor V Leiden
  • Prothrombin gene mutation
  • Activated protein C resistance

References

  1. ↑ 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.
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ McNeil HP, Chesterman CN, Krilis SA (1991). "Immunology and clinical importance of antiphospholipid antibodies". Adv Immunol. 49: 193–280. PMID 1853785.
  5. ↑ 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.
  6. ↑ Triplett DA (1998). "Many faces of lupus anticoagulants". Lupus. 7 Suppl 2: S18–22. PMID 9814666.
  7. ↑ Bick, RL, et al. Antiphospholipid and thrombosis syndromes. Sem Thromb and Hemostasis 1994;20:3. PMID 8059232
  8. ↑ Cervera, R, et al. Clinicopathologic correlations of the antiphospholipid syndrome. Sem Arth and Rheum 1995;24:262. PMID 7740306
  9. ↑ Kampe, CE. Clinical syndromes associated with lupus anticoagulants. Sem Thromb and Hemostasis 1994;20:16. PMID 8059230
  10. ↑ Asherson, RA. The catastrophic antiphospholipid antibody syndrome. J Rheum 1992:19:508. PMID 1593568
  11. ↑ Ruffatti, A, et al. A catastrophic antiphospholipid antibody syndrome: the importance of high levels of warfarin anticoagulation. J Int Med 1994;325:81.PMID8283165
  12. ↑ Neuwelt, CM, et al. Catastrophic antiphospholipid syndrome: Response to repeated plasmapheresis. A&R 1997;40:1534. PMID 9259436
  13. ↑ Bermas, BL, et al. Prognosis and therapy of antiphospholipid antibody syndrome. UpToDate 1997.
  14. ↑ Khamashta, MT, et al. The management of thrombosis in antiphospholipid antibody syndrome. NEJM 1995;332:993. PMID 7885428

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