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| {{DiseaseDisorder infobox | | | __NOTOC__ |
| Name = Antiphospholipid syndrome |
| | {{Antiphospholipid syndrome}} |
| ICD10 = {{ICD10|D|68|8|d|65}} ([[ILDS]] D68.810) |
| | {{CMG}}; {{AE}}{{FT}} |
| ICD9 = |
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| ICDO = |
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| Image = |
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| Caption = |
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| OMIM = 107320 |
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| OMIM_mult = |
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| MedlinePlus = |
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| eMedicineSubj = med |
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| eMedicineTopic = 2923 |
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| DiseasesDB = 775 |
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| MeshID = D016736 |
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| }} | |
| {{SI}} | |
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| {{CMG}} | | {{SK}}Antiphospholipid antibody syndrome; anticardiolipin syndrome; Hughes syndrome; Lupus anticoagulant syndrome |
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| {{Editor Help}}
| | ==[[Antiphospholipid syndrome overview|Overview]]== |
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| == Overview == | | ==[[Antiphospholipid syndrome historical perspective|Historical Perspective]]== |
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| '''Antiphospholipid syndrome''' (APS or APLS) or '''antiphospholipid antibody syndrome''' is a disorder of [[coagulation]], which causes blood clots ([[thrombosis]]) in both [[artery|arteries]] and [[vein]]s, as well as pregnancy-related complications such as [[miscarriage]], [[Premature birth|preterm delivery]], or severe [[preeclampsia]]. The syndrome occurs due to the [[autoimmune disorder|autoimmune]] production of [[antibody|antibodies]] against [[phospholipid]] (aPL), a [[cell membrane]] substance. In particular, the disease is characterised by antibodies against [[cardiolipin]] ([[anti-cardiolipin antibodies]]) and [[Apolipoprotein H|β<sub>2</sub> glycoprotein I]].
| | ==[[Antiphospholipid syndrome classification|Classification]]== |
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| The term "primary antiphospholipid syndrome" is used when APS occurs in the absence of any other related disease. APS is commonly seen in conjunction with other autoimmune diseases; the term "secondary antiphospholipid syndrome" is used when APS coexists with other diseases such as [[systemic lupus erythematosus]] (SLE). In rare cases, APS leads to rapid organ failure due to generalised thrombosis and a high risk of death; this is termed "catastrophic antiphospholipid syndrome".
| | ==[[Antiphospholipid syndrome pathophysiology|Pathophysiology]]== |
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| Antiphospholipid syndrome is sometimes [[eponym|referred to]] as '''Hughes syndrome''' after the [[rheumatology|rheumatologist]] Dr. Graham R.V. Hughes (St. Thomas' Hospital, London, United Kingdom) who worked at the Louise Coote Lupus Unit at St Thomas' Hospital in London.
| | ==[[Antiphospholipid syndrome causes|Causes]]== |
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| == Pathophysiology & Etiology== | | ==[[Differentiating Antiphospholipid syndrome from other diseases|Differentiating Antiphospholipid syndrome from other Diseases]]== |
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| ==Pathogenesis== | | ==[[Antiphospholipid syndrome epidemiology and demographics|Epidemiology and Demographics]]== |
| Antiphospholipid syndrome is an [[autoimmune disease]], in which "antiphospholipid antibodies" (Anticardiolipin antibodies and Lupus anticoagulant) react against proteins that bind to anionic [[phospholipid]]s on [[plasma membrane]]s. Like many [[autoimmune disease]]s, it is more common in women than in men. The exact [[etiology|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 β<sub>2</sub>Glycoprotein 1) and the main target of [[Lupus anticoagulant]] is [[prothrombin]]. Other targets of anti-phospholipid antibodies are protein S, protein C and [[annexin A5]].
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| 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.
| | ==[[Antiphospholipid syndrome risk factors|Risk Factors]]== |
| Anticardiolipin antibodies are associated with thrombosis at moderate to high titres (>40 GPLU or MPLU).
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| 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>
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| <ref>Cervera, R, et al. Clinicopathologic correlations of the antiphospholipid syndrome. Sem Arth and Rheum 1995;24:262. PMID 7740306</ref>
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| <ref>Kampe, CE. Clinical syndromes associated with lupus anticoagulants. Sem Thromb and Hemostasis 1994;20:16. PMID 8059230</ref>
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| <ref>Asherson, RA. The catastrophic antiphospholipid antibody syndrome. J Rheum 1992:19:508. PMID 1593568</ref>
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| <ref>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</ref>
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| <ref>Neuwelt, CM, et al. Catastrophic antiphospholipid syndrome: Response to repeated plasmapheresis. A&R 1997;40:1534. PMID 9259436 </ref>
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| <ref>Bermas, BL, et al. Prognosis and therapy of antiphospholipid antibody syndrome. UpToDate 1997.</ref>
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| <ref>Khamashta, MT, et al. The management of thrombosis in antiphospholipid antibody syndrome. NEJM 1995;332:993. PMID 7885428</ref>
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| ==== Usual Antiphospholipid Antibody Syndrome====
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| * Patients with antiphopholipid antibody syndrome and a history of clot have a recurrence rate as high as 0.2 events per year.
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| * 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).
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| * The target of both antibodies may be phospholipid bound to a cofactor.
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| *:* ''Beta2-glycoprotein-I'' is likely the cofactor in patients with anti-cardiolipin antibodies, and may also be important in patients with a lupus anticoagulant.
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| *:* ''Prothrombin'' is an important cofactor in patients with lupus anticoagulant.
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| * ''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.
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| * The vascular disease of the antiphospholipid antibody syndrome is not due to [[vasculitis]]. The characteristic histopathologic finding is thrombotic microangiopathy.
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| * Anticardiolipin antibody
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| *:* 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).
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| *:* 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.
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| * Lupus Anticoagulant
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| *:* 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).
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| *:* Lupus anticoagulant is also directed against the phospholipid membrane, and requires the cofactor prothrombin.
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| ==== Catastrophic Antiphospholipid Antibody Syndrome ==== | | ==[[Antiphospholipid syndrome natural history, complications and prognosis|Natural History, Complications and Prognosis]]== |
| * 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.
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| * Though specific diagnostic criteria have not been established, some have suggested that criteria include documented thrombosis in 3 or more organs.
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| *:* 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.
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| *:*:* CNS manifestations may be quite heterogeneous, including [[confusion]], focal signs, and/or [[seizures]].
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| *:*:* [[Acute Respiratory Distress Syndrome]] ([[ARDS]]) may be present
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| *:*:* Signficant cardiac necrosis has been described
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| *:*:* [[Adrenal hemorrhage]] has been described
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| *:*:* Liver and gastrointestinal tract infarctions have been described
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| *:*:* [[Oliguria]] and rapidly deteriorating renal function may be observed.
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| *:* Histopathology shows evidence of multiple small and/or large vessel occlusions.
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| * Frequently no specific etiology is identifiable, and patients present quite suddenly without any obvious precipiting factors.
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| ==Diagnosis== | | ==Diagnosis== |
| Antiphospholipid syndrome is tested for in the [[laboratory]] using both liquid phase coagulation assays ([[lupus anticoagulant]]) and solid phase [[ELISA]] assays ([[anti-cardiolipin antibodies]]). | | [[Antiphospholipid syndrome history and symptoms|History and Symptoms]] | [[Antiphospholipid syndrome physical examination|Physical Examination]] | [[Antiphospholipid syndrome laboratory findings|Laboratory Findings]] | [[Antiphospholipid syndrome CT|CT]] | [[Antiphospholipid syndrome MRI|MRI]] | [[Antiphospholipid syndrome echocardiography or ultrasound|Echocardiography or Ultrasound]] | [[Antiphospholipid syndrome other imaging findings|Other Imaging Findings]] | [[Antiphospholipid syndrome other diagnostic studies|Other Diagnostic Studies]] |
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| Genetic thrombophilia is part of the differential diagnosis of APS and can coexist in some APS patients. Thus genetic thrombophilia screening can consist of:
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| * Further studies for [[Factor V Leiden]] variant and the [[thrombin|prothrombin mutation]], [[Factor VIII]] levels, [[MTHFR]] mutation.
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| * Levels of [[protein C]], free and total [[protein S]], [[Factor VIII]], [[antithrombin]], [[plasminogen]], [[tissue plasminogen activator]] (TPA) and [[plasminogen activator inhibitor-1]] (PAI-1)
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| The testing of antibodies to the possible individual targets of aPL such as [[Apolipoprotein H|β<sub>2</sub> Glycoprotein 1]] and antiphosphatidyl serine is currently under debate as testing for anticardiolipin appears to be currently sensitive and specific for diagnosis of APS even though [[cardiolipin]] is not considered an [[in vivo]] target for antiphospholipid antibodies.
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| ==Signs and symptoms==
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| The presence of ''antiphospholipid antibodies'' (aPL) in the absence of blood clots or pregnancy-related complications does not indicate APS (see below for the diagnosis of APS).
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| Antiphosphilipid syndrome can cause ([[artery|arterial]]/[[vein|venous]]) [[blood clot]]s (in any organ system) or [[pregnancy]]-related complications (especially [[miscarriage]] in the second or third [[trimester]]). In APS patients, the most common venous event is [[deep vein thrombosis]] of the lower extremities (blood clot of the deep veins of the legs) and the most common arterial event is [[stroke]].
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| Other common findings, although not part of the APS Classification Criteria, are [[thrombocytopenia]] (low [[platelet]] count), heart valve disease, and [[livedo reticularis]] (a [[skin]] condition). Some patients report [[headache]]s and [[migraine]]s. Antiphospholipid syndrome can rarely mimic [[multiple sclerosis]] with an estimated 10% of patients misdiagnosed.
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| Very few patients with primary APS go on to develop [[SLE]].
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| === Usual Antiphospholipid Antibody Syndrome===
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| * Associated sign and symptoms may include:
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| *:* Major Features:
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| *:*:* Venous thrombosis
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| *:*:* Arterial thrombosis
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| *:*:* Thrombocytopenia
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| *:*:* Recurrent fetal loss
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| *:* Minor Features:
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| *:*:* Migraine
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| *:*:* Livedo reticularis
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| *:*:* Endocardial valvular vegetations
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| *:*:* Transverse myelopathy
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| *:*:* Chorea
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| *:*:* Leg ulcers
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| * Other signs and symptoms include:
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| *:* [[Myocardial Infarction]]
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| *:* Stroke
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| *:* Pulmonary embolism
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| *:* Amaurosis fugax
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| *:* Retinal infarct
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| *:* Other visceral infarct
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| *:* Peripheral or deep venous occlusion
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| *:* Raynaud’s syndrome
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| *:* Pulmonary hypertension
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| *:* Avascular necrosis
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| *:* Recurrent fetal loss (especially in the 2nd or 3rd trimester)
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| *:* Pre-eclampsia
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| *:* Adrenal insufficiency
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| *:* Coomb’s positive hemolysis
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| *:* Sudden multi-systemic occlusion (the Catastropic antiphospholipid-antibody syndrome).
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| ===Lupus anticoagulant===
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| This is tested for by using a minimum of two coagulation tests that are phospholipid sensitive this is due to the heterogeneous nature of the [[lupus anticoagulant]] antibodies. The patient on initial screening will typically have been found to have a prolonged [[APTT]] that does not correct in an 80:20 mixture with normal human [[Blood plasma|plasma]] (50:50 mixes with normal plasma are insensitive to all but the highest antibody levels). The APTT (plus 80:20 mix), [[dilute Russell's viper venom time]] (DRVVT), the kaolin clotting time (KCT), dilute thromboplastin time (TDT/DTT) or [[Prothrombin time]] (using a lupus sensitive [[thromboplastin]]) are the principal tests used for the detection of [[lupus anticoagulant]]. These tests must be carried out on a minimum of two occasions at least 6 weeks apart and be positive on each occasion demonstrating persistent positivity to allow a diagnosis of antiphospholipid syndrome. This is to prevent patients with transient positive tests (due to infection etc) being diagnosed as positive.
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| Distinguishing a lupus antibody from a specific coagulation factor inhibitor (eg: [[Factor VIII]]). This is normally achieved by differentiating the effects of a lupus anticoagulant on factor assays from the effects of a specific coagulation factor antibody.
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| The lupus anticoagulant will inhibit all the contact activation pathway antibodies ([[Factor VIII]], [[Factor IX]], [[Factor XI]] and [[Factor XII]]). Lupus anticoagulant will also rarely cause a factor assay to give a result lower than 35 iudl (35%) where as a specific factor antibody will rarely give a result higher than 10iudl (10%).
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| Monitoring IV anticoagulant therapy by the APTR is compromised due to the effects of the lupus anticoagulant and in these situations is generally best performed using a chromogenic assay based on the inhibition of [[Factor Xa]] by [[Antithrombin]] in the presence of [[Heparin]].
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| ===Anticardiolipin antibodies===
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| These can be detected using an [[ELISA|enzyme-linked immunosorbent assay]] (ELISA) [[immunology|immunological test]], which screens for the presence of β<sub>2</sub>glycoprotein 1 dependent anticardiolipin antibodies (ACA).
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| A [[Thrombocytopenia|Low platelet count]] and positivity for antibodies against β<sub>2</sub>-glycoprotein 1 or [[phosphatidylserine]] may also be observed in a positive diagnosis.
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| ==Diagnostic Criteria==
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| The diagnosis of APS is made in case of a clinical event (vascular thrombosis or pregnancy event) '''and''' repeated positive tests of aPL performed 12 weeks apart (repeat aPL testing is necessary due to the naturally occurring presence of transient low levels of aPL following infections).
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| The Updated Sapporo APS Classification Criteria are commonly used for APS diagnosis.<ref>Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4:295-306)</ref> Based on these criteria, APS diagnosis requires:
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| * a) ''Vascular Thrombosis'' (blood clots) in any organ or tissue '''or''' ''Pregnancy Event'' (one or more miscarriages after 10th week of gestation, three or more miscarriages before 10th week of gestation, or one or more premature births before 34th week of gestation due to [[eclampsia]]) '''and'''
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| * b) ''Persistenly (12 weeks apart) Positive aPL'' (lupus anticoagulant test, moderate-to-high titer anticardiolipin antibodies, or moderate-to-high titer β<sub>2</sub>-glycoprotein-I antibodies).
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| The International Consensus Statement is commonly used for Catastrophic APS diagnosis.<ref>{{cite journal |author=Asherson RA, Cervera R, de Groot PG, ''et al'' |title=Catastrophic antiphospholipid syndrome: international consensus statement on classification criteria and treatment guidelines |journal=Lupus |volume=12 |issue=7 |pages=530-4 |year=2003 |pmid=12892393 |doi=}}</ref> Based on this statement, Definite CAPS diagnosis requires:
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| * a) Vascular Thrombosis in three or more organs or tissues '''and'''
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| * b) Development of manifestations simultaneously or in less than a week '''and''
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| * c) Evidence of small vessel thrombosis in at least one organ or tissue '''and'''
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| * d) Laboratory confirmation of the presence of aPL.
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| Some serological tests for syphilis may be positive in aPL-positive patients (aPL bind to the lipids in the test and make it come out positive) although the more specific tests for syphilis that use recombinant antigens will be negative.
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| == Differential Diagnosis ==
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| * [[Hemolytic uremic syndrome]]-[[Thrombotic thrombocytopenic purpura]] (HUS-TTP)
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| * [[Disseminated Intravascular Coagulation]] (DIC)
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| * [[Vasculitis]]
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| * [[Embolic disease]]
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| * [[Cryoglobinemia]]
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| * [[Calciphylaxis]]
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| ==Treatment== | | ==Treatment== |
| The cornerstone of therapy for symptomatic antiphospholipid syndrome hinges on platelet inhibition with or without [[anticoagulation]]. Platelet inhibition is often achieved with [[aspirin]], while [[warfarin]] and [[heparin]] are the mainstays of anticoagulation. Generally there is no indication for primary prophylaxis. Immunosuppression, the use of [[intravenous immunoglobulin]], and [[plasmapheresis]] have also been used with modest success.
| | [[Antiphospholipid syndrome medical therapy|Medical Therapy]] | [[Antiphospholipid syndrome surgery|Surgery]] | [[Antiphospholipid syndrome primary prevention|Primary Prevention]] | [[Antiphospholipid syndrome secondary prevention|Secondary Prevention]] |
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| ===Anticoagulation===
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| When anticoagulation with warfarin is pursued, some authors recommend a goal INR of 3.0-4.0.<ref>{{cite journal |author=Horton JD, Bushwick BM |title=Warfarin therapy: evolving strategies in anticoagulation |journal=American family physician |volume=59 |issue=3 |pages=635-646 |year=1999 |pmid=10029789 |doi=}}</ref> However, the current standard of care targets a therapeutic INR of 2.0-3.0 following initial venous thromboembolism, and an INR >3.0 for an arterial event or venous thrombosis refractory to anticoagulation.<ref name="pmid18050167">{{cite journal |author=Ruiz-Irastorza G, Hunt BJ, Khamashta MA |title=A systematic review of secondary thromboprophylaxis in patients with antiphospholipid antibodies |journal=Arthritis and Rheumatism |volume=57 |issue=8 |pages=1487–95 |year=2007 |month=December |pmid=18050167 |doi=10.1002/art.23109 |url=http://dx.doi.org/10.1002/art.23109}}</ref> Khamashta et al in a study of 147 patients with usual antiphopholipid antibody syndrome showed a low rate of recurrent thrombosis in patients with INR >3, with a risk of 7.1% bleeding complications per patient year (a third of which were serious).
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| ====Anticoagulation in pregnancy==== | | ==Case Studies== |
| {{main|Anticoagulation in pregnancy}}
| | [[Antiphospholipid syndrome case study one|Case #1]] |
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| During pregnancy, [[low molecular weight heparin]] and low-dose [[aspirin]] are used to avoid warfarin's teratogenicity. Women with recurrent miscarriage are often advised to take aspirin and to start low molecular weight heparin treatment after missing a menstrual cycle.
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| ===Platelet inhibition===
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| Aspirin is frequently added to a regimen of chronic anticoagulation, particularly when patients experience recurrent thrombosis despite therapeutic aticoagulation. However data demonstrating additive benefit are lacking.
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| ===Immunosuppression===
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| It is not clear that immunosuppression is beneficial, particularly in patients who do not have an underlying autoimmune process. Nevertheless, immunosuppression is often tried in patients who have failed usual anticoagulation. Steroids, for example [[prednisone]] 1 mg/kg (or equivalent), has been used with moderate success. Pulse solumedrol IV 1 g/d for 3 days is an alternative regimen. [[Cyclophosphamide]], either oral or pulse IV, has demonstrated modest utility.
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| Other, more desperate interventions include [[intravenous immunoglobulin]] and [[plasmapheresis]]. The latter has been shown via case reports to have efficacy in patients who have failed other interventions.
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| ===Treatment of catastrophic disease===
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| Optimal treatment has not been clearly defined in this condition. We are limited to data from small case report studies. These patients often display a fulminant course with rapid multiorgan system failure, so multiple interventions are often desperately tried in hopes that the patient might respond to something and survive.
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| ==References==
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| {{reflist|2}}
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| ==Bibliography==
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| * Triona Holden. "Positive Options for Antiphospholipid Antibody Syndrome" ISBN 0-89793-409-1.
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| * Kay Thackray. ''Sticky Blood''. ISBN 1-898030-77-4. A personal account of dealing with the condition.
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| ==External links==
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| *[http://www.apsfa.org APS Foundation of America, Inc.]
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| *[http://www.hughes-syndrome.org Hughes Syndrome Foundation]
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| {{Autoantibodies}} | | {{Autoantibodies}} |
| {{Hematology}} | | {{Hematology}} |
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| [[de:Anti-Phospholipid-Syndrom]]
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