Antiphospholipid syndrome pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Pathophysiology
Pathogenesis
Antiphospholipid syndrome is an autoimmune disease, in which "antiphospholipid antibodies" (Anticardiolipin antibodies and Lupus anticoagulant) react against proteins that bind to anionic phospholipids on plasma membranes. Like many autoimmune diseases, it is more common in women than in men. The exact cause is not known, but activation of the system of coagulation is evident. Clinically important antiphospholipid antibodies (those that arise as a result of the autoimmune process) are associated with thrombosis and vascular disease. 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. Other targets of anti-phospholipid antibodies are protein S, protein C and annexin A5.
The Lupus anticoagulant antibodies are those that show the closest association with thrombosis, those that target β2glycoprotein 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. [1] [2] [3] [4] [5] [6] [7] [8]
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.
- 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.
References
- ↑ 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. PMID 8283165
- ↑ 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.
- ↑ Khamashta, MT, et al. The management of thrombosis in antiphospholipid antibody syndrome. NEJM 1995;332:993. PMID 7885428