Are You Confident of the Diagnosis?
What you should be alert for in the history
In an international cohort of 1000 patients with a mean age of 34 at onset of antiphospholipid antibody syndrome (APS), thrombotic events in arteries, veins or small vessels in any organ were the most common presenting events: deep venous thrombosis (32%), stroke (13%), superficial venous thrombosis (9%), pulmonary embolus (9%), transient ischemic attack (7%), and myocardial infarction (3%). There are other historical findings which should prompt consideration of this syndrome at presentation: thrombocytopenia (22%), livedo reticularis (20%), and fetal loss and premature births (10%).
In the prediagnosis phase of this series additional conditions were increased in frequency: migraine (20%), epilepsy (7%) or amaurosis fugax (5%), cardiac valve thickening or dysfunction (12%), and hemolytic anemia (10%). In addition to migraine and epilepsy, some neurologic problems not commonly thought of in relation to APS, but for which evidence suggests a causal relationship, include acute dizziness, vertigo and balance problems, tinnitus, memory loss, and peripheral neuropathy.
Characteristic findings on physical examination
APS cutaneous involvement can produce many types of lesions, and some may mimic other cutaneous disorders. Livedo reticularis or racemosa is the most common. It is a presenting sign in 17- 40% of patients, and up to 70% of SLE patients with APS; prevalence 16-25%.While this is not specific for APS, livedo that does not disappear with warming, or is asymmetric and patchy should spark consideration of this diagnosis. Some patients may present with or evolve into Sneddon syndrome phenotype.
Retiform purpura (Figure 1) (purpura which is branching, or shows branching at the margins) strongly suggests microvascular occlusion and should prompt consideration of APS, as well as other occlusive syndromes and some lesions of Wegeners granulomatosis, microscopic polyangiitis, or benign cutaneous periarteritis nodosa.
Cutaneous ulcerations/vasculopathy, including:
atrophie blanche/livedoid vasculopathy-like lesions
malignant atrophic papulosis (Degos)-like lesions
post deep venous thrombosis stasis with ulceration
chilblains-like distal cyanosis
pyoderma gangrenosum-like ulcers
cholesterol embolus-like proximal livedo with distal focal retiform purpura
superficial thrombophlebitis migrans
focal necrotic lesions, sometimes bullous
subungual splinter hemorrhages
rarely, thrombocytopenic petechiae
erythematous macules or papules
Behçet-like pustules, nodules
painful skin nodules
Catastrophic APS (CAPS) is a rare (1%) but very serious presentation of APS, which results in multiorgan dysfunction from vascular occlusion and frequently involves skin, sometimes extensively (Figure 2). It is triggered by infection in roughly 50% of cases and, given the sometimes extensive retiform purpura, may be mistaken for disseminated intravascular coagulation (DIC) or purpura fulminans. This is especially true if he partial thromboplastin time (PTT) is prolonged, due to lupus anticoagulant activity. Unlike DIC, the prothrombin time is rarely prolonged during the onset and early stages of catastrophic APS.
Expected results of diagnostic studies
In 1998, diagnostic criteria were proposed in Sapporo, Japan, and these were revised in Sydney, Australia in 2005, and remain the standard for inclusion of patients in studies. The presence of at least one clinical and one laboratory criterion from the following list is required:
Vascular thrombosis: one or more venous, arterial, or small vessel thrombotic events in any tissue or organ (excluding superficial vein thrombosis).
Pregnancy morbidity: one or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation; one or more premature births of a morphologically normal neonate before the 34th week of gestation because of eclampsia, severe preeclampsia, or placental insufficiency; three or more consecutive spontaneous abortions before the 10th week of gestation (in the absence of parental chromosomal causes and maternal anatomic or hormonal abnormality
Lupus anticoagulant (LA) present in plasma on two or more occasions at least 12 weeks apart (measured in accordance with guidelines of the International Society on Thrombosis and Haemostasis)
Anti-cardiolipin antibodies (aCL-Abs), IgG or IgM, present in serum or plasma on two or more occasions at least 12 weeks apart (medium or high titer, >40 GPL IgG phospholipid or >40 MPL IgM phospholipid units, or >99th percentile, measured by a standardized enzyme-linked immunosorbent assay [ELISA].
Anti-beta-2-glycoprotein I (b2GPI) antibody (IgG or IgM) present in serum or plasma on two or more occasions at least 12 weeks apart (in titer >99th percentile, measured by a standardized ELISA)
The revised Sapporo (Sydney) Criteria remain the standard for confirmation. The requirement for serologic positivity 12 weeks after the first test at the time of presentation was included to minimize the antibodies that might be triggered by the occlusive event, rather than be causative. This 12-week requirement obviously means that at time of presentation of a new case, no patient would have a confirmed diagnosis. Each patient must be considered as a possible or probable case of APS, based on the best clinical and laboratory correlation possible, since treatment must be chosen at the time of diagnosis, not 12 weeks later.
Careful attention to excluding other possible diagnoses is therefore paramount. Retiform purpura with minimal inflammation prompt consideration of the many other causes of cutaneous microvascular occlusion (especially heparin or Coumadin necrosis, cholesterol embolus, early purpura fulminans, or cryoprotein-related occlusion). APS may also mimic atrophie blanche/livedoid vasculopathy and malignant atrophic papulosis lesions in the occlusion differential.
Certain vasculitides can produce lesions which suggest microvascular occlusion, including those of APS, especially Wegeners granulomatosis (WG), microscopic polyangiitis (MPA), and benign cutaneous periarteritis nodosa (BCPAN). The number and distribution of lesions are usually helpful in suggesting the presence of one of these vasculitides when lesions are sparse, as well as the involvement of upper respiratory tract, lung, joints, nerves, and kidney. ANCA testing is usually positive in WG and MPA, but not in BCPAN.
Idiopathic livedo reticularis with cerebrovascular accidents, or Sneddon syndrome, can be caused by APS, and therefore APS-antibody testing in such patients is essential. It is important to remember that false positive non-specific tests for syphilis (phospholipid-based) may be seen in patients as part of APS.
Who is at Risk for Developing this Disease?
In the general population, antiphospholipid antibodies (aPL-abs) range from 1-10%, increasing above this range in the elderly. Most of these patients will never have a thrombotic episode, with the risk of thrombotic events in asymptomatic individuals less than 3% per year. Antibody testing is of little help in identifying a group at higher risk.
In patients with SLE, the incidence ranges from 30-40%, and lupus patients appear more likely to develop thrombosis when positive for aPL-abs. In asymptomatic patients with aPL-abs, thrombotic events run up to 3% per year. In unselected women, the screening found 3-5% positivity, whereas in women with recurrent fetal losses the incidence of positivity has varied from 5% to 60%, depending on type of aPL-abs screening used.
What is the Cause of the Disease?
Antiphospholipid antibodies are most often idiopathic, but may also be associated with autoimmune diseases (especially lupus), or triggered by some cancers, especially hematologic malignancies, certain infections (see annotated reference), and selected medications (chlorpromazine, phenytoin, hydralazine, procainamide, Fansidar, quinidine, interferon, and cocaine). Most aPL from medications are IgM type, low level, and unassociated with thrombosis.
Pathologic antibodies appear to bind to both phospholipid and to a protein antigen bound with the phospholipid; antibodies that bind to phospholipid alone seldom, if ever, induce thrombosis. Protein targets reported in pathologic aPL-abs include beta2-glycoprotein I, prothrombin, coagulation cascade proteins (factors VII, XI, XII), protein C/S complex, annexin A5, coagulation, proteins of the fibrinolytic system and of the kininogen-bradykinin pathway, and others.
The mechanisms by which aPL-abs cause thrombotic events, whether arterial, venous, or microvascular, are not certain.
Plasma beta2-glycoprotein I has an affinity for anionic membrane phospholipids, and binds tightly to membranes when antibodies which recognize b2GPI and phospholipid are present. These bindings, among other effects, interrupt the annexin 5 coating on endothelium, and this disruption seems to expose phospholipid which can be an initiation site for coagulation. Endothelial cells also increase expression of adhesion molecules, and both endothelial cells and monocytes upregulate the production of tissue factor, a procoagulant molecule.
Domain 1 of beta2-glycoprotein I is an epitope exposed only when b2GPI undergoes conformational change, especially when binding to phospholipid. Antibodies to domain 1 of b2GPI are much more closely associated with risk of thrombosis than are other types of b2GPI antibodies.
Antibodies to the protein targets listed previously may enhance coagulation similarly by exposing phospholipid for coagulation activation or by activation endothelial cells (enhancing coagulation), but some may interfere with protein C activation (inhibiting natural anticoagulation), with tissue factor pathway inhibitor (thereby blocking early inhibition of coagulation activation), with plasmin (inhibiting fibrinolysis).
aPL-abs effects on platelets include increase in GPIIb-IIa expression and in thromboxane A2 synthesis, stimulating platelet aggregation. The complement system may also be activated by aPL-abs.
Fetal loss mechanisms are also poorly understood. b2GPI or antiphospholipid antibodies could affect placentation by binding to anionic phospholipids during trophoblast differentiation, interfere with annexin A5 (placental anticoagulant protein), or by complement activation leading to fetal damage.
Systemic Implications and Complications
The systemic disorders, etiologic factors, work-up, and management are highlighted in other sections. Given that APS was not recognized as a syndrome until the 1980s, there is much to learn about all aspects of this syndrome.
The main systemic complications are thrombotic events in arteries, veins or small vessels in any organ. Deep venous thrombosis (32%), stroke(13%), superficial venous thrombosis (9%), pulmonary embolus (9%),transient ischemic attack (7%), and myocardial infarction (3%) are the most common complications.
-control of underlying vascular risk factors
-acetylsalicylic acid (ASA)
Optimal Therapeutic Approach for this Disease
Whether asymptomatic patients with aPL-abs benefit from primary prophylaxis is not known, but strict control of other vascular risk factors should be considered (eg, tobacco, estrogens, control of chronic inflammation). The risk of thrombosis in healthy individuals positive for aPL-abs is less than 1% per year up to 3% per year.
There is no proven benefit of ASA use (81mg, once daily) in such individuals though it is often recommended, and there is not enough risk of thrombosis to merit consideration of other therapies. In patients with SLE and aPL-abs antibodies, the risk of thrombosis is higher, and evidence suggests that hydroxychloroquine appears to offer some protection against thrombosis, possibly in combination with low dose aspirin.
Acute venous or arterial thrombotic events should be treated initially the same way they would be treated in patients without aPL-abs. Oral anticoagulant therapy (typically warfarin) prevents recurrent venous and possibly some arterial events, with a target INR between 2 and 3. Some recommend that patients with APS and arterial events be maintained at a target INR between 3 and 4.
In a prospective cohort study of patients with aPL-abs and a first episode of ischemic stroke, long-term ASA and oral anticoagulant (INR 1.4-2.8) were equally effective in reducing the risk of recurrence.
Current clinical practice guidelines support the use of prophylactic heparin with low-dose ASA to reduce future pregnancy losses in women with previous fetal loss due to APS.
In patients with APS, the optimal duration of oral anticoagulant therapy after a first episode of venous thromboembolism is not known. Given a high rate of recurrence if therapy is stopped, most experts recommend indefinite oral anticoagulation.
In patients with SLE and aPL-abs, hydroxychloroquine therapy is supported by some studies. Whether low-dose ASA confers additional protection in this setting is not known, nor is the optimal duration or dosing of hydroxychloroquine prophylaxis.
Unusual Clinical Scenarios to Consider in Patient Management
Treatment of minor to moderate skin disease without prior history of extra-cutaneous thrombosis is unclear. In instances of painful cutaneous ulceration, the risk of anticoagulation may be warranted to alleviate symptoms. In nonulcerative/necrotic disease, there is no clearly effective therapy.
The role of hydroxychloroquine in such lesions is unclear, though its use as a therapeutic trial, at least in SLE patients, seems reasonable. Treatment of CAPS is not standardized, due to lack of evidence for treatment of this rare condition. Precipitating factors, primarily infections, should be recognized and treated.
Anticoagulant therapy, usually heparin, is the primary treatment for these patients to inhibit further clotting. High-dose corticosteroids have been used and are often recommended as adjuncts to reduce the inflammatory exacerbation of coagulation., and cyclophosphamide has been suggested in the context of SLE flare. Plasma exchange, IVIg, and rituximab have also been recommended to remove or inhibit aPL-abs.
What is the Evidence?
Donadini, MP, Crowther, M. “Antiphospholipid syndrome: a challenging hypercoagulable state with systemic manifestations”. Hematol-Oncol. vol. 24. 2010. pp. 669-76. (Recent concise review and update of this syndrome. Many of the clinical statistics were cited from this review.)
Ruiz-Irastorza, G, Crowther, M, Branch, W, Khamashta, MA. “Antiphospholipid syndrome”. Lancet. vol. 376. 2010. pp. 1498-1509. (Along with the first listed reference, a key source for this chapter, especially with respect to treatment recommendations.)
Frances, C. “Dermatological manifestations of Hughes' antiphospholipid antibody syndrome”. Lupus. vol. 19. 2010. pp. 1071-77. (Current review of cutaneous manifestations.)
Weinstein, S, Piette, W. “Cutaneous manifestations of antiphospholipid antibody syndrome”. Hematol Oncol Clinics N Am. vol. 22. 2008. pp. 67-77. (Relatively recent review of cutaneous findings.)
Hughes, GRV. “Antiphospholipid syndrome (Hughes syndrome): 10 clinical topics”. Lupus. vol. 19. 2010. pp. 343-346. (Brief overview of 10 clinical topics which broaden the concept of APS.)
Urbanus, RT, DeGroot, PG. “Antiphospholipid antibodies–we are not quite there yet”. Blood Reviews. vol. 25. 2011. pp. 97-106. (Nice overview of antibody association with complications of APS, as well as review of methods for testing for these antibodies.)
Bas da Laat, DeGroot, PG. “Autoantibodies directed against domain I of beta2-glycoprotein I”. Curr Rheumatol Rep. vol. 13. 2011. pp. 70-76. (Discussion of the molecular interactions of b2GPI with antibodies and with phospholipids, allowing better understanding of the possible pathophysiology of the procoagulant effect.)
Rand, JH, Wu, XX, Quinn, AS, Ashton, AW, Chen, PP, Hathcock, JJ, Andree, HAM, Taatjes, DJ. “Hydroxychloroquine protects the annexin A5 anticoagulant shield from disruption by antiphospholipid antibodies: evidence for a novel effect for an old antimalarial drug”. Blood. vol. 115. 2010. pp. 2292-99. (Novel investigation of a mechanism of thrombosis prophylaxis mechanism of this drug.)
Petri, M. “Use of hydroxychloroquine to prevent thrombosis in systemic lupus erythematosus and in antiphospholipid antibody-positive patients”. Curr Rheumatol Rep. vol. 13. 2011. pp. 77-80. (Review of lupus cohort data in support of clinical use of this drug for thrombosis prophylaxis in SLE.)
Cervera, R. “Catastrophic antiphospholipid syndrome (CAPS): update from the 'CAPS Registry'”. Lupus. vol. 19. 2010. pp. 412-8. (Current overview of this rare but deadly complication.)
Baker, WF, Bick, RL. “The clinical spectrum of antiphospholipid syndrome”. Hematol Oncol Clin N Am. vol. 22. 2008. pp. 33-52. (Overview of APS, with details on drug-related antibodies.)
Pham, C, Shen, YM. “Antiphospholipid antibodies and malignancy”. Hematol Oncol Clin N Am. vol. 22. 2008. pp. 121-130. (Details concurrence of malignancies with antibodies, with discussion of possible pathophysiology.)
Amin, NM. “Antiphospholipid syndromes in infectious diseases”. Hematol Oncol Clin N Am. vol. 22. 2008. pp. 131-144. (Discusses antibodies associated with 11 viral infections (especially parvovirus B19, hepatitis C, HIV, varicella), gram-positive bacteria (Streptococcus pyogenes, Staphylococcus aureus), gram-negative (Salmonella typhi, Klebsiella pneumoniae, Shigella dysenteriae, Helicobacter pylori), spirochetes (Treponema pallidum, Borrelia burgdorferi, Leptospira), atypical mycobacteria, Mycobacterium tuberculosis and leprae, rickettsiae (Coxiella burnetti), and parasites (Leishmania, toxoplasma, malaria).
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