Antiphospholipid Syndrome
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Antiphospholipid Syndrome
Antiphospholipid syndrome
(APS) is an autoimmune disorder of unknown cause. It is also
called as Antiphospholipid antibody syndrome or Hughes
syndrome. It is characterized by recurrent thrombosis, pregnancy wastage and/or thrombocytopenia, associated with increased
antibody levels against membrane phospholipids (anticardiolipin antibody [ACA], antiphosphatidylserine) or plasma proteins, beta-2 glycoprotein I (apolipoprotein or lupus
anticoagulant [LA]). In 1983, Dr. Graham Hughes described the association between antiphospholipid antibodies and
arterial as well as venous thrombosis.
APS, an autoimmune phenomenon, is of two types.
- Primary APS which is not associated any definable disease.
- Secondary APS which is associated with an underlying autoimmune disorder, e.g. systemic lupus erythematosus (SLE).
Frequency
The exact prevalence is not known, but estimated to be around 2-4% in the general population. Among APL patients about 50% have primary APL. It is worth to note that aPL antibodies occur in 5% of healthy individuals. Recent evidences indicate that about 35-40% of people afflicted with SLE are affected by APS, thus young-to-middle-aged adult females, African Americans and Hispanics are more affected.
Antiphospholipid antibody
There are two major antiphospholipid (aPL ) antibody types, used to screen for the syndrome and/or predict risk of arterial thrombosis.
Anticardiolipin antibodies
Both IgG ACA and IgM ACA may carry a risk.
Lupus anticoagulant (LA)
dilute Russell viper venom time (dRVVT) is a sensitive assay to screen and confirm. A prolonged dRVVT may be better a predictor of arterial thrombosis.
In patients with the APS syndrome, ACA occurs about five times more often than LA.
Pathophysiology
Though the earlier mentioned antibodies are clinically linked to APS, their involvement in the pathogenesis of the syndrome is not clear.
In APL the body produces antibodies against various molecules of its own that, under normal circumstances, it would not. These molecules (e.g. phospholipids) play a role in the clotting process.
Principally due to a series of events, a state of hypercoagulability occurs with a tendency for recurrent thrombosis venous or arterial thrombosis. This in turn affects many organs/systems like peripheral veins, pulmonary blood vessels, central nervous system, blood cells (thrombocytopenia, hemolytic anemia), and in females also lead to obstetric complications like eclampsia and pregnancy loss.
There are many proposed mechanisms, like defective programmed cell death (apoptosis) – exposure of membrane phospholipids which bind various coagulation proteins to form phospholipid-protein complex which are then attacked by the autoantibodies.
Activation of platelets and vascular endothelium enhances adherence of platelets and monocytes to the inner surface of blood vessels (endothelium). Antibodies are produced against coagulation factors, including prothrombin, protein C, and protein S. Activation of complement causes pregnancy loss. Antibodies against low-density lipoprotein (LDL) predispose to atherosclerosis and myocardial infarction.
Blood vessels (veins or arteries) of almost any organ/system is affected which include, leg (veins), brain, lungs, heart, eyes, skin, bones, kidneys, and endocrine glands especially adrenals. This leads to hemorrhage or infarction depending upon the type of the vessel and organ involved. Among the venous system, leg veins and among the arterial system, cerebral arteries are more commonly affected.
Clinical features
One or more clinical episodes of arterial, venous thrombosis occur in any or many of the organs mentioned earlier.
The clinical features are varied.
Limbs
thrombophlebitis, venous thrombosis, leg swelling, ulcers, gangrene in limbs, painful purpura.
CNS
Non-thrombotic neurologic symptoms: migraine headache, chorea, seizures, transverse myelitis, Guillain-Barré syndrome, dementia; and thrombotic symptoms due to cerebrovascular accident (CVA) especially in a younger individual or in those with risk factors
Heart
murmurs of aortic or mitral insufficiency, cardiac valvular vegetations, symptoms of myocardial ischemia/infarction
Hematologic abnormalities: thrombocytopenia or hemolytic anemia
Skin
Livedo reticularis (lattice like discolored skin) is seen in over 3/4th of patients with aPL antibodies.
Endocrine
unexplained adrenal insufficiency
Respiratory: tachypnea due to pulmonary embolism, pulmonary hypertension.
Obstetric
recurrent miscarriages or premature births consequent to severe placental insufficiency occur because of severe preeclampsia/eclampsia.
Others
vascular necrosis of bone, ascites, generalized edema (renal vein thrombosis), retinal vein thrombosis (fundus examination).
Investigations
Investigation is called for, if there is a history of deep vein thrombosis (DVT) and in conditions like, pulmonary embolism, acute coronary syndrome, myocardial infarction, transient ischemia, recurrent miscarriages and other suspected clinical features listed earlier.
Laboratory tests
ACL antibodies – higher the titer, more the probability. Both IgG and IgM rise, but IgG aCL is an independent risk factor for thrombotic events. A previous history of thrombosis and an IgG ACA >40 U/mL are considered as two independent risk factors for arterial thrombosis.
Anti–beta-2 glycoprotein I antibodies
It is to be noted that the concentration of antibodies do not have a direct correlation with the extent of thrombosis.
Activated partial thromboplastin time (aPTT) - is prolonged LA tests such as dRVVT – prolonged and serves as a screening as well as confirmatory test. It is a better test to predict arterial thrombosis.
Serologic test for syphilis (false positive VDRL) CBC (thrombocytopenia, hemolytic anemia) ESR (elevated)
Imaging studies
- to confirm thrombotic event
CT Chest (pulmonary embolism) CT Abdomen (Budd-Chiari syndrome) Doppler ultrasound to detect DVT Two-dimensional echocardiography – to detect valve thickening, vegetations, aortic or mitral insufficiency.
Histopathologic studies
Skin, kidney or other involved sites (if possible) reveal thrombosis with no signs of perivascular inflammation.
Causes
The exact etiology of APS is not known. However the following are implicated.
Genetic and familial predisposition. Autoimmune diseases that are frequently associated with APS include - SLE, Sjögren syndrome, rheumatoid arthritis, autoimmune thrombocytopenic purpura, autoimmune hemolytic anemia, psoriasis, systemic sclerosis, polymyalgia rheumatica or giant cell arteritis, Behçet syndrome.
Infections Syphilis, hepatitis C, HIV, malaria, bacterial septicemia Drugs Antiarrhythmics – hydralazine, procainamide, quinidine, propranolol Antiepileptic - phenytoin Antipsychotic - chlorpromazine Chemotherapeutics – amoxicillin, interferon alfa
Treatment
Eliminate risk factors - oral contraceptives, smoking, hypertension, prolonged immobilization.
Individualize management according to the clinical status and thrombotic events. Intravenous or subcutaneous unfractionated or low–molecular-weight heparin [LMWH])
Warfarin (not in pregnancy) is given for recurrent thrombosis. In APS patients anticoagulants are usually given for 3-6 months and in some cases lifelong (oral anticoagulant like warfarin).
Hydroxychloroquine – SLE Low-dose aspirin or clopidogrel (if intolerance to aspirin). Corticosteroids – to reduce morbidity, and fetal prematurity. In severe cases - plasmapheresis, corticosteroids, cyclophosphamide, and intravenous immunoglobulin are used. Surgery- placement of an inferior vena cava filter in patients with recurrent DVT.
Aspirin may be given as a preventive drug in APL even if there is no known thrombosis related problems.
Complications
Permanent functional disability may occur due to: CVA, MI, pulmonary hypertension, renal failure. Death occurs in severe cases.
Mortality/Morbidity
Morbidity and mortality rates associated with the catastrophic aPL syndrome are high. A positive ANA is associated with increased risk of stroke or transient ischemic attack (TIA). Also infarction of organs results in increased frequency of myocardial infarction (MI), valvular heart disease, pulmonary embolism, pulmonary hypertension, intrauterine growth retardation and fetal death.
Prognosis
Most patients with primary APS lead normal life with drugs and appropriate lifestyle modifications. Significant morbidity or early mortality occurs in some who have thrombotic events despite treatment. In secondary APS – the picture is similar but additional risks due to the underlying cause remains. With aspirin and heparin, prognosis is good in aPL antibody positive women with H/O recurrent miscarriages.
Author
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