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 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 as follows: [7][8][9][10][11][12][13]
Vascular thrombosis
- Antiphospholipid antibody (aPL) effects upon pathways of coagulation.
- 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
- 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.
- 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.