Antiphospholipid syndrome pathophysiology
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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. The syndrome can be divided into primary (no underlying disease state) and secondary (in association with an underlying disease state) forms.
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
This type of APS 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 |
|---|---|---|---|
|
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% |
| Antilupus antibody | 23-47% |
| Beta-2 glycoprotein | 20% |
Mechanism of action
The mechanism by which clinical manifestations occur in APS is mainly mediated by the antibodies which is as follows: [7][8][9][10][11][12][13]
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
Beta2-glycoprotein-I:
These antibodies have the following mechanism of action:[14][15][16][16]
- Beta2-glycoprotein-I 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
- 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 2b-3a 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.
- C4d and 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.[17][18]
- 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 | |||||||
| |||||||
- 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
- Signficant cardiac necrosis has been described
- Adrenal hemorrhage has been described
- Liver and gastrointestinal tract infarctions have been described
- Oliguria and rapidly deteriorating renal function may be observed.
- Histopathology shows evidence of multiple small and/or large vessel occlusions.
- 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.
- 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
Gross 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:
- A noninflammatory bland thrombosis with no signs of perivascular inflammation or leukocytoclastic vasculitis.
- Biopsy samples from affected kidneys demonstrate glomerular and small arterial microthrombi.
References
- ↑ 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.
- ↑ 16.0 16.1 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.
- ↑ 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.