On-line version ISSN 1806-4841
An. Bras. Dermatol. vol.80 no.3 Rio de Janeiro May/June 2005
CONTINUING MEDICAL EDUCATION
Jesus Rodriguez SantamariaI; Daniela BadziakII; Michelle Ferreira de BarrosII; Fernando Luiz MandelliIII; Leila Cristina CavalinIV; Maurício Shigueru SatoV
IAssistant Professor of Dermatology
- Departamento de Clínica Médica - UFPR (PR). Master in Dermatology at Escola
Paulista de Medicina - Universidade Federal de São Paulo - Unifesp (SP)
IISecond-year Resident Doctors at Dermatology Service of Universidade Federal do Paraná - UFPR (PR)
IIISecond-year Specializing Doctor at Serviço de Dermatologia - Universidade Federal do Paraná - UFPR (PR)
IVFirst-year Resident Doctor at Dermatology Service of Universidade Federal do Paraná - UFPR (PR)
VFirst-year Specializing Doctor at Dermatology Service of Universidade Federal do Paraná - UFPR (PR)
Antiphospholipid syndrome is an acquired multisystem disorder characterized by recurrent thromboses in the arterial system, venous system, or both. Antiphospholipid syndrome is classified into 2 groups: primary and secondary. Secondary antiphospholipid syndrome is often associated with systemic lupus erythematosus and less frequently with infections, drugs and other diseases. Serologic markers are antiphospholipid antibodies, lupus anticoagulant and anticardiolipin. The primary diagnostic criteria include arterial thrombosis or venous thrombosis and recurrent fetal loss. About 41% of patients with lupus anticoagulant have skin lesions as the first sign of antiphospholipid syndrome. Cutaneous manifestations include livedo reticularis, cutaneous ulceration and livedo vasculitis. The mainstays of prophylaxis and treatment of thrombosis are anticoagulant and antiplatelet agents.
Keywords: Skin manifestations; Antiphospholipid syndrome; Thrombosis
Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by arterial and/or venous thrombosis, fetal death and recurrent miscarriages, and thrombocitopenia, along with elevated titles of atiphospholipid antibodies (APA): lupic anticoagulant and/or cardiolipin. Antiphospholipid syndrome was originally described in patients suffering from systemic lupus erythematosus, and in the past 20 years the involvement of many organs has been described. Cutaneous manifestations are frequent and in 41% of patients they may represent the first manifestation of the syndrome.1 Livedo reticularis and cutaneous ulcerations are the most prevailing dermatological manifestations. Treatment is based on anti-platelet aggregating or aticoagulant drugs.2
The goal of this review is to make readers familiar with historical, epidemiological and etiopathogenic aspects, clinical manifestations, laboratorial diagnosis, differential diagnosis, treatment and prognosis of antiphospholipid syndrome.
The first antiphospholipid antibody (APA), which reacts with bovine heart antigens, was detected in patients with syphilis back in 1906.3 It was later identified as cardiolipin, a mithocondrial phospholipid.4
Conley and Hartmann were the first to describe, in 1952, the presence of circulating anticoagulant in patients with systemic lupus erythematosus (SLE).5
In 1963, Bowie et al.6 noted the relation between systemic anticoagulants in patients with SLE and thromboembolic events.
Feinstein, Rapaport, in 19727 ssuggested the name of "lupic anticoagulant" for this circulating anticoagulant, and Nilsson et al.,8 in 1975, associated it to recurrent spontaneous abortions.
In 1983 Hughes9 described the association between antiphospholipid antibodies and venous and arterial thrombosis.
In 1987 Harris et al.10 Proposed the name antiphospholipid syndrome.
In the beginning of the 1990s, two groups discovered that some anticardiolipin antibodies required the presence of a plasma phospholipid-bound protein (antib2-glucoprotein I) to bind to cardiolipin.11,12
Frequency in the general population is unknown. APAs can be found in 50% of systemic lupus erythematosus (SLE) patients, and in percentages ranging from 1 to 5% of the healthy population, tending to occur more often in the elderly. Recent studies suggest that the occurrence of antiphospholipid syndrome in SLE patients is between 34% and 42%.13 In a study with 100 patients with venous thrombosis and no SLE history, 24% had anticardiolipin antibody, and 4%, lupic anticoagulant.14
Antiphospholipid syndrome can contribute to a increase in the frequency of strokes, especially in young individuals,15 as well as that of myocardial infarction. Valvular cardiac disease can be more aggressive, requiring valve change.16 Recurrent lung embolus or thrombosis may lead to pulmonary hypertension.15
Catastrophic antiphpospholipid syndrome is the most serious manifestation, and is commonly fatal (mortality index of roughly 50%), and is characterized by infarctions in many organs within a period that can vary from days to weeks.17,18
Even though spontaneous fetal loss usually occurs in the second or third trimester of pregnancy, it can occur at any time.19
There is no race predominance in APS.20
There is predominance in females, especially in secondary APS. This is in accordance with the association between APS and SLE and other connective tissue diseases, where there is predominance in females.20
APS commonly occurs in young individuals and middle-aged adults, although it can manifest in children and elderly. There are reports of its occurrence in infants of less than eight months of age.20
Antiphospholipid syndrome is an autoimmune disorder of unknown cause. Association between antiphospholipid antibodies and autoimmune or rheumatic diseases, malignancies, hematological diseases, infections, neurological diseases and drugs has been reported (Chart 1).21
Familial association: APAs are found more often in relatives of individuals with APS. A study showed an incidence of 33%.22
Association with HLA: recent studies have revealed na association between APA and groups of individuals bearing certain HLA genes, including DRw53, DR7 (mainly individuals of hispanic origin) and DR4 (mainly in white individuals).23
An alteration occurs in the homeostasis of blood coagulation. Mechanisms by which APAs interact with the coagulation cascade, thereby producing clinical events, are speculative and have not been totally elucidated yet. Presence of an endothelial lesion, associated to the presence of an APA is a requirement for thrombotic complication.
Possible mechanisms by which APAs induce thrombotic events:24,25
1. APAs can bind to platelet membrane phospholipids, resulting in an increase of its adhesion and aggregation.
2. APAs can combine with endothelial cells membrane phospholipids together with antib2-glucoprotein I (b2-GP I) and induce activation of the endothelial cell, thus leading to alteration of expression of adhesion molecules, citocin secretion and prostaciclins metabolism, enhancing platelet adhesion and aggregation.
3. Lesion of the endothelial cell can also lead to a decrease in endothelium-derived relaxing factor, thus enhancing vasospasm and ischemia.
4. In secondary antiphospholipid syndrome, vascular endothelial lesion has already occurred, increasing occlusion/spasm, ischemia/infarction of vessels and alteration in reperfusion.
5. APAs can interfere in the interaction between coagulation proteins C and S, consequently affecting the formation of the coagulation control complex (activated protein C, protein S and factor V).
Possible mechanisms by which APAs can be produced:26-28
2. APAS represent a response to internal membrane antigens (e.g. phosphoserin), which are exposed by cells not cleared from circulation due to overload or clearence system defect.
3. APAs may also be crossed reaction antibodies induced by exogenous antigens of infeccious microorganisms (e.g. viral or bacterial).
CLASSIFICATION AND DIAGNOSTIC CRITERIA
Diagnosis depends on high clinical suspicion and confirmation by laboratory findings. When arterial or venous thrombosis occurs in patients who do not have obvious risk factors for thrombosis, or when thrombotic events are recurrent, APS should be considered.29 However, diagnosis can be difficult owing to a plethora of clinical manifestations and laboratorial difficulties related to detection techniques and result standardization. Moreover, antiphospholipid antibody levels can increase, diminish or occasionally disappear in the course of the disease.30
Due to diagnostic difficulties, classification criteria for the antiphospholipid syndrome have been formulated in a recent consensus (Chart 2).29
Definite diagnosis of APS requires the presence of at least one clinical and one laboratorial criterion, with no interval limits between clinical event and laboratorial finding. Due to lack of worldwide agreement to differentiate low from moderate or high anticardiolipin antibody levels, three definitions are accepted: a) 15 to 20 phospholipid units separate low from moderate anticardiolipin antibody levels; b) two or 2.5 times the average level of anticardiolipin antibody; c) ninety-ninth percentile of anticardiolipin levels of normal population.29
Antiphospholipid syndrome can be classified as primary or secondary. The primary form occurs in the absence of related or base diseases, being more common than the secondary,2 which is characterized by the association with a large spectrum of ilnesses.21
In systemic lupus erythematosus (SLE), antiphospholipid antibodies are present in over one third of patients, although not all of them present the clinical syndrome.2 Clinical features and specific antibodies are similar in both primary and secondary APS, and the clinical course of secondary APS is independent on activity or severity of SLE.31
The most common clinical manifestation of antiphospholipid syndrome is thrombosis, which can affect arterial or venous vessels in any organ. Venous thrombosis, particularly in the lower limbs - probably one of the most common forms of venous thrombosis25 occurs in over 55% of APS patients.32 Other affected sites include renal, retinal and hepatic veins.25 Arterial thrombosis involves the brain in over 50% of the cases, causing transient ischemic attacks (TIA) and strokes; approximately 90% of patients less than 50 years old with TIA are positive for antiphospholipid antibodies.33 Other sites of arterial thrombosis include heart, eyes, kidneys and peripheral arteries.32 In APS, thrombosis episodes can occur in vascular beds infrequently affected by other pro-thrombotic states.
Various obstetrical complications can be associated to APS, including miscarriage (mainly in the end of the first trimester), fetal death (in the second and third trimesters of pregnancy), pre-eclampsia, delayed intrauterine growth and Hellp's syndrome.21 Fetal loss after 10 gestational weeks is a feature of APS bearers, contrary to what is observed in general population, in which miscarriages are more often within the first nine gestational weeks32 and associated to various causes.33
The spectrum of APS clinical manifestations is large; it being able to affect various organs, being characterized by a predominance of thrombotic microangiopathy or ischemia secondary to thromboembolic events34 (Chart 3).
Cutaneous manifestations are generally explained by vascular occlusion and represent a landmark for diagnosis and for the need for extensive systemic investigation, since in 41% of patients suffering from APS they constitute the first sign of the disease.2,35
Livedo reticularis (Figure 1) and cutaneous ulcerations are the most frequent dermatological lesions,30 the former being characterized by purpuric and mottled vascular lesions, with location, extension, infiltration and regularity of different patterns, and which can be physiological or related to numerous conditions, such as SLE and other immunological conditions, infectious diseases and cholesterol embolization.2 The association between APS and moderate to severe livedo reticularis is significant,2 and lesions are usually disseminated, infiltrated and have irregular pattern.30
Sneddon's syndrome, characterized by extensive livedo reticularis and strokes,30,36,37 can be associated to APS, and the state of hypercoagulability justifies these features;30 nevertheless, the absence of antiphospholipid antibodies has been described.2
Cutaneous ulcerations normally appear in the extremities, even though they can occur in other areas, leaving atrophic scars.30 There are four distinct types of ulcerations: 1. small, painful leg ulcerations, of livedoid vasculitis; 2. large ulcerations similar to those of gangrenous pioderma; 3. Delos type ulcerations; 4. periungueal ulcerations.38
Other cutaneous manifestations of APS are thrombophlebites, more common in patients with primary APS when compared to controls,21 sharpned subungueal hemorrhages (multiple lesions in different fingers warn the occurrence of thrombotic events) and a variety of lesions resembling vasculitis, including purpuras, echimoses, painful nodules and erythematous maculae.30 Cutaneous gangrene has been reported in 19% of APS patients,2 and disseminated superficial cutaneous necrosis occurs in 3% of the patients, being the latter characterized by sudden onset painful purpuric lesions in the limbs, head and buttocks.30
The association between Degos' disease (malignant atrophic papulosis), anetodermia, progressive systemic sclerosis (PSS), discoid lupus erythematosus (DLE) and T-cell lymphoma and antiphosholipid syndrome is debated. Patients with apparent Degos' disease and positive for antiphospholipid antibodies are speculated to have APS with livedoid vasculitic lesions, resembling malignant atrophic papulosis. Anetodermia could develop due to dermal ischemia and a consequent degeneration of elastic fibers. In PSS, elevated titles of anticardiolipin antibody are found in 33% of patients. These antibodies are proposed to modulate platelet function, resulting in tissue fibrosis and vascular injury. Rarely, DLE lesions can be associated with APS, with no clinical or laboratorial evidence of SLE. In T-cell lymphoma, neoplastic clones are suggested to be able to induce B-cell proliferation with the production of antiphospholipid antibodies.2
Antiphospholipid antibodies form a familily of autoantibodies that exhibit a great spectrum of specific targets, all of them recognizing various combinations of phospholipids, phospholipid-bound plasmatic proteins or both.34 They can be IgG, and/or IgM, or, less often, IgA.39 Even though these antibodies have not yet been conclusively evidenced as a cause of thrombosis and abortions, they are useful laboratorial markers of APS.40 The most common antiphospholipid antibodies subgroups are lupic anticoagulant antibody, anticardiolipin antibody and antib2-glucoprotein I antibody. Recent works have described antibodies such as antiprothrombin; however, furher work is still needed for the establishment of its clinical relevance.41
Anticardiolipin antibodies are currently detected by an ELISA-type standardized test, which measures immunological reactivity to phospholipids or to b2-glucoprotein phospholipids-bound proteins.42 Results are expressed quantitatively:33
a. weakly positive if IgG varies between 5 and 15 GPL (IgG phospholipid) or if IgM is lower than 6 MPL (IgM phospholipid);
b. moderately positive if IgG varies between 15 and 80 GPL, and IgM between 6 and 50 MPL; and
c. strongly positive if IgG is over 80 GPL and IgM ove 50 MPL.
High IgG levels are seemingly more clinically relevant in terms of predicting the occurrence of thromboses, thrombocitopenia and recurrent miscarriages. Many cases of low or moderate levels of anticardiolipin antibodies have proven to be transient, able to result in occasional interoccurring infections. This is why it is important to repeat the test after six or eight weeks after an initial positive result. Persistence of anticardiolipin antibody in he serum is a necessary criterion for establishing APS.2
Antib2-glucoprotein antibodies are also detected by immunoassay technique (ELISA).43,44 Presence of antib2-glucoprotein IgG has a high specificity for APS; however, it has low sensitivity, thus its detection should be associated to that of antiardiolipin antibodies.29 Although its positivity is not currently included in the criteria for APS, antib2-glucoprotein antibodies are also related to thromboses and other APS manifestations.34
Lupic anticoagulant antibodies are directed against phospholipid-bound proteins, such as b2-glucoprotein I or prothrombin, and are detected by tests that assess phospholipid-dependent coagulation.45 Due to their heterogenous nature, performing more than one assay becomes necessary for a correct diagnosis. There are different methods to detect a lengthening of clotting time (Chart 4).34 The most frequently used are aPTT (activated partial thromboplastin time), KCT (Kaolin clotting time) and dRVVT (dilute Russel's Viper Venom Time). aPTT was previously used as a screening test for lupic anticoagulant antibody,2 but its sensitivity in APS patients is approximately 30% to 40%. Therefore, many patients with APS have a normal aPTT. KCT is a good screening test for lupic anticoagulant, though the technique is difficult and has complicating factors. dRVVT (based on snake poison) is the most sensitive,29 thus being the prefered method for the detection of lupic anticoagulant antibody. A more complete screening demands a combination of all of these tests.2
In spite of the frequent concordance between lupic anticoagulant antibody and anticardiolipin or antib2-glucoprotein, these antibodies are not identical. Some lupic anticoagulant antibodies react with phospholipids other than cardiolipin and with other proteins besides antib2-glucoprotein, whereas some anticardiolipins and antib2-glucoprotein antibody do not have activity against lupic anticoagulant.34 Cooccurrence of both anticardiolipin and lupic anticoagulant antibodies in a same patient ranges between 50% and 75%.21 Several antipospholipid antibodies assays should be used for laboratorial diagnosis of APS, since the patient can be negative according to one test and positive according to another.34
Generally, lupic anticoagulant antibodies are more specific for APS, albeit anticardiolipin antibodies are more sensitive. APS specificity of anticardiolipin antibody increases with title increase and is higher for IgG than for the IgM isotype.34
In studies of the association between the presence of antiphospholipid antibodies and the risk for thrombosis, lupic anticoagulant was concluded to be a clear risk factor for thrombosis, regardeless of type or site of affection, presence of SLE or of the methods used for detection. Conversely, anticardiolipin antibody and antib2-glucoprotein antibody are possible risk factors for thrombosis in a few selected situations. Measurement of antiprothrombin antibodies, on the other hand, have not been, to date, helpful in the definition of thrombosis risk, due to the lack of data proving their clinical association with APS.39
Skin biopsy is usually necessary for a differential diagnosis. Absence of vasculitis and the finding of non-inflammatory thrombosis of small dermal and hipodermal arteries and veins are the characteristic cutaneous lesions of antiphospholipid syndrome.34
Differential diagnosis of the antiphospholipid syndrome should be made with patients presenting thromboembolic disorders, infections, vasculidites and increased KPTT (Kaolim partial thromboplastin time).29
Antiphospholipid syndrome is one of the many disorders that present a hypercoagulable state, in which thromboembolic phenomena can happen in both arterial and venous territory.46 Differential diagnosis should be made with diseases and predisposing factors for thromboembolism, such as clotting factors deffects, clot lysis, metabolic defects, platelet alterations, stasis (immobilization, surgery), hyperviscosity, vessel wall defect, use of oral contraceptives, estrogen therapy, pregnancy, puerperium, neoplasia, diabetes, hypertension, cigarrette smoking, hyperlipidemia.34
Contrary to other predisposing diseases, which can be identified by means of laboratory exams, APS can display as single alteration the presence of antiphospholipid antibodies. Diagnosis may not be suspected in patients that present symptoms of slow and gradual evolution, potentially leading to idle ischemia and progressive functional loss of an organ.34
When high levels of antiphospholipid antibodies are detected, the possibility of an infectious cause should be considered. These antibodies are frequently seen in patients with syphilis, Lyme's disease, HIV-1, Micoplasma infections, malaria and viral infections such as hepatites C, adenovirus, rubella, varicella and mumps.29 Diagnosis will be made clear with specific tests for the suspected infection.
The majority of APS patients has altered clotting screening tests, arterial or venous thrombosis and recurrent abortions. When vascular occlusion occurs in the presence of a known autoimmune disease, e.g. SLE, the possibility of vasculiditis should be considered.47 Particularly in patients with catastrophic APS, multisystem vascular occlusion can simulate a disseminated vasculiditis, such as thrombotic thrombocitopenic purpura (TTP) and disseminated intravascular coagulation (DIVC).48 In TTP, the finding of microangiopathic hemolytic anemia (squizocytes) associated with fever, neural and renal alterations, albeit with normal coagulation tests is common. On the other hand, in DIVC, the patient usually has a base disease, which evolves with complex coagulopathy and with formation of fibrin degradation products and increased KPTT.
Increased KPTT as an isolated laboratory finding can occur in acquired or hereditary deficiencies of clotting factors VIII, IX, XI and XII. It can also occur secondarily to the presence of an inhibiting factor, which can be a specific factor itself (e.g. an antibody against factor VIII) or a non-specific one (e.g. heparin or lupic anticoagulant). For this reason, KPTT is considered as a good screening test to assess inhibitors such as lupic anticoagulant.49 In order to differentiate between deficiency of a factor and presence of an inhibitor, normal plasma should be used. In APA, there is a failure in the correction of KPTT even after the infusion of normal plasma. The finding of antiphospholipid antibodies help to confirm the diagnosis. In the presence of specific inhibiting factors, such as antifactor VIII antibody, KPTT is increased due to a reduction of the clotting factor's levels. After mixing normal plasma in the proportion of 1:1, an immediate correction of its values occurs; however, KPTT might increase again within one or two hours under a temperature of 37ºC.29 Inhibitory effects of fibrin degradation products in DIVC can also prolong KPTT. Moreover, depending on the reactant system used, heparin effects (therapeutic or contamination) can also be detected through KPTT prolonging, even in concentrations which are considered low, like 0,05U/ml.29
A very frequent skin color alteration found in patients with APS can occur phisiologically (cutis marmorata), idiopathically, congenitally or being part of collagen disases (PAN, dermatomiositis, SLE), chronic infections (syphilis, tuberculosis), intravascular obstruction (embolus, thrombocitemia, crioglobulinemia), vessel wall disease (artherosclerosis), lymphomas and by drugs (amantadine, quinine).
Within common APS dermatological manifestations, cutaneous ulcerations should be dicerned from ulcers of vascular origin (artirial, venous, small, medium and large-caliber vasculiditis and lymphatic), neuropathic origin (diabetes, hansebiasis, tabes dorsalis and syringomielia), metabolic origin (goou, Gaucher's disease), hematological origin (sickle cell anemia, spherocitosis, talassemia, leukemia), traumatic (pressure), cold, radiodermitis, burns, factitious, neoplastic origin (basocellular and scamocellular carcinomas, sarcomas, lymphomas and metastasis), infectious (bacterial, fungic and protozoan), paniculitis and gangrenous pioderma.
In cutaneous gangrene and necrosis which occur in APS, antiphospholipid antibodies can be associated with other pathogenic circulating factors, such as crioglobulins, hepatitis antibodies or antiendothelial antibodies.2
Patients with SLA and antilupic antibodies may present ulcerations that leave scars with china-like atrophic centers when involute, mimmicking Degos' disease. This latter syndrome is a rare entity, with leality of 50%, and in which antiphospolipid antibodies are negative.2
Primary profilaxis, prevention of recurrent thrombosis, treatment of acute thrombosis and handling during pregnancy should all be considered for the treatment of APS.
Patients who are positive for antibodies but have no history of thrombosis are not candidates for profilatic treatment with drugs.2 Nevertheless, risk factors for thrombosis, e.g. hypertension, smoking, hypercholesterolemia, contraceptive use and prolonged immobilization should be eliminated.50
Profilatic use of aspirin in low doses is useful for prevention of thrombosis in women with recurrent miscarriages, but it does not prevent deep venous thrombosis in men with APS.29,34,50 In SLE and secondary APS, hydroxicloroquine has shown protecting effect against thromboses, not to mention reduction of cholesterol levels and glicemia.2,29,34
Patients who undergo surgery and need to be immobilized for long periods of time require profilatic heparinization, and in APS sometimes doses should be higher than usual, namely, 25,000 to 40,000U/day, due to resistance to anticoagulants effects.2
Treatment of obstetrical complications
Presence of antiphospholipid antibodies increases risk of miscarriages during the fetal period (over 10 gestational weeks) and of premature labor due to uteroplacentary failure.2,34 Treatment has evolved, thus decreasing the number of these complications (Chart 5).
Use of prednisone, at the daily dose of 40mg, has decreased incidence of spontaneous abortion, but increased the number of preterm labors and maternal morbidity,32,51,52 including diabetes, hypertension and sepsis.32 Although intravenous immunoglobulins can be used for the treatment of a few autoimmune diseases during pregnancy, randomized studies have not demonstrated benefit in comparison to heparin treatment in APS.34,51,52
Many prospective studies have demonstrated that treatment with a combination of heparin and low-dose aspirin are more effective in preventing spontaneous abortions in patients with APS than aspirin alone,2,29,32,34,40,51,52 hence, this should be initiated as soon as pregnancy is confirmed.34,40 Aspirin dose should be of 81mg/day; however, heparin dosing is still a controversial issue.2,29,32,34,51,52 Some authors recommend doses of 5,000 SC every 12 hours, in the absence of a history of previous thromboses,32,52 while others recommend doses which vary according to pregnancy stage and previous history of thrombosis.32,51
Non-fractioned heparin can be replaced by low molecular weight heparin, with the advantage of daily administration, in addition to reducing the risks of low platelet counts and osteoporosis induced by non-fractioned heparin.29,32,34,40 The low molecular weight heparins used in pregnancy are enoxaparin 40mg/day and dalteparin 5,000U/day.29
Incidental finding of antiphospholipid antibodies during pregnancy with no previous clinical history of its complications does not require treatment.29
Patients using warfarin for previous thrombosis should have their treatments substituted with heparin in the course of pregnancy, due to the latter's teratogenic effects.2,32
Catastrophic antiphospholipid syndrome
This rare manifestation of APS, characterized by generalized vascular occlusion, often resulting in death, might not respond to isolated anticoagulant therapy. Treatment is made with a combination of anticoagulation, steroids, and plasmapheresis or intravenous immunoglobulin.2,29,32,34,50 The use of fibrinolytic agents has no proven benefit.
Treatment after primary thrombotic event
There is no evidence that acute treatment of thrombosis secondary to APS should be any different from treatment of acute thrombosis due to other causes.20 Initial therapy is made with non-fractioned or low molecular weight heparin, followed by warfarin.32,51 Since patients with APS and thrombosis are at high risk for recurrent thromboembolism episodes, prolonged, perhaps life-long oral anticoagulation therapy is a guarantee for the prevention of new episodes.29 The most widely used oral anticoagulant is warfarin. Studies show still variable resultes concerning intensity of anticoagulant treatment.32,40,50,51 Whereas some indicate a lower risk for new episodes of thrombosis with an intensive warfarin treatment, maitaining INR > 3,2,29,53,54 other studies, including a prospective one,55 show that INR can be maintained between 2 and 3 in control, with recurrence indices similar to patients with INR > 3, albeit with lower bleeding risk.34,55,56
Cutaneous manifestations in general respond to the treatment of base disease. There are studies which report cure of chronic ulcerations caused by livedoid vasculiditis after the use of fibrinolytic agents.2
EVOLUTION, PROGNOSIS AND COMPLICATIONS
Clinical manifestations of APS are quite heterogenous, which determines a highly variable evolution.57,58
Even though the association between clinical manifestations and presence of antiphospholipid antibody is more evident in primary APS, there is no difference in evolution of primary or secondary forms.34
There is little consistent data in the literature concerning prognosis and clinical evolution of patients. A few recent studies suggest three forms of evolution:59
1. isolated or associated clinical manifestation in a single episode (e.g. livedo reticularis and livedo reticularis + cerebral ischemia);
2. recurrent episodes: APS frequently occurs with recurrence of its clinical manifestations, mainly thrombotic events.57,60,61 Anticardiolipin antibodies titles greater than 40, associated with a previous thrombosis episode, are independent risk factors for a new thrombosis episode. Patients with SLE and who are positive for anticardiolipin antibodies have a higher predisposition to recurrent thrombotic events. Average time between the first and the second event is three years. The severity of the initial clinical manifestation and the presence of antib2-GPI antibody in the first episode of the disease suggest a worse prognosis, since average time for the second event is reduced to less than 12 months;57,62
3. catastrophic antiphospholipid syndrome (CAS) or Asherson's syndrome: is an uncommon variant of APS, predominantly characterized by small vessel obstructive disease, affecting at least three different organs in a period varying from days to weeks. It manifests clinically as three distinct forms:48
a. einitial event of APS;
b. primary evolution of APS: most common form;
c. secondary evolution of APS (commonly associated with SLE).
The reason why some patients develop thromboembolic events in large vessels and others in small vessels is still unknown. Notwithstanding the fact that 45% of the patients do not have a well defined triggering factor, it is postulated that infections, trauma, coagulopathies, use of medication, neoplasias, pregnancy and acutization of SLE might be involved as triggers of this syndrome.48
The kidney is the most affected organ, followed by the lung, CNS, heart and skin (55% to 66%). The most commom dermatological manifestations are livedo reticularis, skin necrosis and purpura.34
The mortality rate is 50% and death is due to multiple organ dysfunction.34,48,59
Prognosis of patients suffering from APS is quite variable and depends on different factors:
1. severity of initial clinical manifestation: the kind of initial clinical manifestatin affects both the frequency and type of a subsequent event. If the clinical picture is associated with high anticardiolipin antibody titles (over 40); if there are two associated clinical manifestation (e.g. livedo reticularis and venous thrombosis) or hemolytic anemia as the initial manifestation, prognosis is worse;57,59
2. previous disease history: A previous thrombotic episode increases the probability of a new event;60
3. high antibody levels: presence of antib2-GPI in the initial picture increases the probability of complications in over 50%;
4. proper therapy: the use of anticoagulants decreases the probability of serious events by about 78 to 91%;34,57,60
5. neoplasias: neoplasia prevalence during APS evolution ranges from 17 to 20%.60
The Antiphospholipid Syndrome is a multisystem disorder associated with a variety of circulating antibodies, the targets of which are different phospholipid complexes. The main clinical manifestations are fetal loss and arterial and/or venous thrombotic complications, which may manifest as cutaneous lesions. It is important for the dermatologist to recognize cutaneous signs associated to this syndrome, thus collaborating for its early diagnosis and treatment. q
1. Marai I, Zandman-Goddard G, Schoenfeld Y. The systemic nature of antiphospholipid syndrome. Scand J Rheumatol. 2004; 33: 365-72. [ Links ]
2. Gibson GE, Su WP, Pittelkow MR. Antiphospholipid syndrome and the skin. J Am Acad Dermatol. 1997; 36:970-82. [ Links ]
3. Wassermann A, Neisser A, Bruck C. Eine serodiagnostichereaktion bey syphilis. Deuts Che Méd Wochenschr. 1906; 32: 745-2. [ Links ]
4. Pangborn MC. A new serologically active phospholipid from beef heart. Proc Soc Exp Biol Méd. 1941; 48: 484-6. [ Links ]
5. Conley CL, Hartmann RC. A hemorrhagic disorder caused by circulating anticoagulant in patients with disseminated lupus erythematosus. J Clin Invest. 1952; 31:621-2. [ Links ]
6. Bowie EJW, Thompson JH, Pascuzzi CA, Owen CA. Thrombosis in systemic lupus erythematosus despite circulating antibodies. J Lab Clin Méd. 1963; 62: 416-30. [ Links ]
7. Feinstein DI, Rapaport SI. Acquired Inhibitors of blood coagulation. Prog Hemost Thromb. 1972; 1: 75-95. [ Links ]
8. Nilsson IM, Astedt B, Hedner U, Berezine D. Intrauterine death and circulating anticoagulant "antithromboplastin". Acta Méd Scand. 1975; 197:153-9. [ Links ]
9. Hughes GR. The anticardiolipin syndrome. Clin Exp Rheumatol. 1985; 3:285-6. [ Links ]
10. Harris EM, Hughes GR, Gharavi AE. Antiphospholipid antibodies: an elderly statesman dons new garments. J Rheumatol. 1987; 13: S208-13. [ Links ]
11. Galli M, Comfurius P, Maassen C, Hemker HC, de Baets MH, van Breda-Vriesman PJ, et al. Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor. Lancet. 1990; 335: 1544-7. [ Links ]
12. McNeil HP, Simpson RJ, Chesterman CN, Krilis AS. Anti-phospholipid antibodies are direct against a complex antigen that includes a lipid-binding inhibitor of coagulation: beta-2-glycoprotein I (apolipoprotein H). Proc Natl Acad Sci USA. 1990; 87: 4120-4. [ Links ]
13. Galli M, Luciani D, Bertolini G, Barbui T. Lupus anticoagulants are stronger risk factors for thrombosis then anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature. Blood. 2003; 101: 1827-32. [ Links ]
14. Fessler BJ. Thrombotic syndromes and auto immunes diseases. Rheum Dis Clin North Am. 1997; 23:461-79. [ Links ]
15. Zanon E, Saggiorato G, Ramon R. Anti-prothrombin antibodies as a potential risk factor of recurrent venous thromboembolism. Thromb Haemost. 2004; 91: 255-8. [ Links ]
16. Hojnik M, George J, Ziporen L, Shoenfeld Y. Heart valve involvement (Libman-Sacks endocarditis) in the antiphospholipid syndrome. Circulation. 1996; 93: 1579-87. [ Links ]
17. Asherson RA, Cervera R, Piette JC, Shoenfeld Y, Espinosa G, Petri MA, et al. Catastrophic antiphospholipid syndrome: clues to the pathogenesis from a series of 80 patients. Medicine (Baltimore). 2001; 80: 355-77. [ Links ]
18. Ruiz-Irastorza G, Egurbide MV, Aguirre C. High impact of antiphospholipid syndrome on irreversible organ damage and survival of patients with systemic lupus erythematosus. Arch Intern Med. 2004; 164: 77-82 [ Links ]
19. Derksen RH, Khamashta MA, Branch DW. Management of the obstetric antiphospholipid syndrome. Arthritis Rheum. 2004; 50: 1028-39. [ Links ]
20. Cervera R, Piette JC, Fornt J. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum. 2002; 46: 1019-27. [ Links ]
21. Nahass GT. Antiphospholipid antibodies and the antiphospholipid antibody syndrome. J Am Acad Dermatol. 1997; 36: 149-71. [ Links ]
22. Goldberg SN, Conti-Kelly AM, Greco T. A family study of anticardiolipin antibodies and associated clinical conditions. Am J Med. 1995; 99: 473-9. [ Links ]
23. Sebastiani GD, Galeazzi M, Morozzi G, Marcolongo R. The immunogenetics of the antiphospholipid syndrome, anticardiolipin antibodies, and lupus anticoagulant. Semin Arthritis Rheum. 1996; 25: 414-20. [ Links ]
24. McNeil HP, Chesterman CN, Krilis AS. Immunology and clinical importance of antiphospholipid antibodies. Adv Immunol. 1991; 49: 193-280. [ Links ]
25. Petri M. Pathogenesis and treatment of the antiphospholipid antibody syndrome. Med Clin North Am. 1997; 81: 151-77. [ Links ]
26. Salmon JE, Girrardi G. The role of complement in the antiphospholipid syndrome. Curr Dir Autoimmun. 2004; 7: 133-48. [ Links ]
27. Simantov R, LaSala JM, Lo SK, Gharavi AE, Sammaritano LR, Salmon JE, et al. Activation of cultured vascular endothelial cells by antiphospholipid antibodies. J Clin Invest. 1995; 96: 2211-9. [ Links ]
28. Carmo-Pereira S, Bertolaccini ML, Escudero-Contreras A. Value of IgA anticariolipin and anti-beta 2-glycoprotein I antibody testing in patients with pregnancy morbidity. Ann Rheum Dis. 2003; 62: 540-3. [ Links ]
29. Gezer S. Antiphospholipid Syndrome. Dis Mon. 2003; 49: 696-741. [ Links ]
30. Cuadrado MJ, Hughes GRV. Hughes (antiphospholipid) syndrome. Clinical features. Rheum Dis Clin North. Am 2001; 27: 507-24. [ Links ]
31. Amigo MC, Khamashta MA. Antiphospholipid (Hughes) syndrome in systemic lupus erythematosus. Rheum Dis Clin North Am. 2000; 26: 331-48. [ Links ]
32. Hanly JG. Antiphospholipid syndrome. An overview. CMAJ. 2003; 168: 1675-82. [ Links ]
33. Mulinari-Brenner FA, Pizzol ASD, Manfrinato LC, Santamaria JR, Gemelli JJ. An Bras Dermatol. 2000; 75: 219-24. [ Links ]
34. Levine JS, Branch DW, Rauch J. The antiphospholipid syndrome. N Engl J Med. 2002; 346: 752-63. [ Links ]
35. Diógenes MJN, Diógenes PCN, Carneiro RMM, et al. Cutaneous manifestations associated with antiphospholipid antibodies. Int J Dermatol. 2004; 43:632-7. [ Links ]
36. Alegre VA, Winkelmann RK, Gastineau DA. Cutaneous thrombosis, cerebrovascular thrombosis and lupus anticoagulant- the Sneddon syndrome. Report of 10 cases. Int J Dermatol. 1990; 29: 45-9. [ Links ]
37. Levine SR, Langer SL, Albers JW, Welch KMA. Sneddon's syndrome: an antiphospholipid antibody syndrome?. Neurology. 1988; 38: 798-800. [ Links ]
38. Gantcheva M. Dermatologic aspects of antiphospholipid syndrome. Int J Dermatol. 1998; 37: 173-80. [ Links ]
39. Galli M. Antiphospholipid syndrome: association between laboratory tests and clinical practice. Pathophysiol Haemost Thromb. 2004; 33: 249-55. [ Links ]
40. Greaves M. Antiphospholipid antibodies and thrombosis. Lancet. 1999; 353: 1348-53. [ Links ]
41. Amengual O, Atsumi T, Koike T. Antiprothrombin antibodies and the diagnosis of antiphospholipid syndrome. Clin Immun. 2004; 112: 144-9. [ Links ]
42. Myers B, Gould J. The place of beta 2 glycoprotein 1 in the assessment of antiphospholipid syndrome. Blood Coagul Fibrinolysis. 2003; 14: 1-2. [ Links ]
43. Reddel SW, Krilis AS. Testing for and clinical significance of anticardiolipin antibodies. Clin Diagn Lab Immunol. 1999; 6: 775-82. [ Links ]
44. Obermoser G, Bitterlich W, Kunz F, Sepp NT. Clinical significance of anticardiolipin and anti-beta 2-glycoprotein antibodies. Int Arch Allergy Immunol. 2004; 135: 148-53. [ Links ]
45. Alving BM. Diagnosis and management of patients with the antiphospholipid syndrome. J Thromb Thromboly. 2001; 12: 89-93. [ Links ]
46. Rodgers GM. Thrombosis and antithrombotic therapy. In Lee GR, Foersten J, Kukens J, et al. Editors. Wintrobe Clinical Hematology. Baltimore: Williams & Wilkins; 1999. p.1781-820. [ Links ]
47. Golan TD. Lupus vasculitis: differential diagnosis with antiphospholipid syndrome. Curr Rheumatol Rep. 2002; 4: 18-24. [ Links ]
48. Asherson RA. The catastrophic antiphospholipid (Asherson's syndrome) in 2004- a review. Autoimmune Rev. 2005; 4: 48-54. [ Links ]
49. Alving BM, Barr CF, Tang DB. Correlation between lupus anticoagulants and anticardiolipin antibodies in patients with prolongated activated partial thrombo plastin times. Am J Méd. 1990; 88: 112-6. [ Links ]
50. Loskshin MD, Erkan D. Treatment of the antiphospholipid syndrome. N Engl J Med. 2003; 349: 1133-8. [ Links ]
51. Luzzana C, Gerosa M, Riboldi P, Meroni PL. Update on the antiphospholipid syndrome. J Nephrol. 2002; 15: 342-8. [ Links ]
52. Lassere M, Empson M. Treatment of antiphospholipid syndrome in pregnants-a systematic review of randomized therapeutic trial. Thrombosis Research. 2004; 114: 419-26. [ Links ]
53. Goldhaber SZ. Pulmonary embolism. N Engl J Med. 2005; 339: 93-102. [ Links ]
54. Khamashta MA, Cuadrado MJ, Mujic F, Taub NA, Hunt BJ, Hughes GR. The management of thrombosis in the antiphospholipid-antibody syndrome. N Engl J Med. 1995; 332 : 993-7. [ Links ]
55. Crowther MA, Ginsberg JS, Julian J, Math. M, Denburg J, Hirsh J, et al. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med. 2003; 349:1133-8. [ Links ]
56. Crowther M, Wisloff F. Evidence based treatment of the antiphospholipid syn drome. Optimal anticoagulant therapy for thrombosis. Thrombosis Research. 2005; 115: 3-8. [ Links ]
57. Tektonidou MG, Ioannidis JP, Boki KA, Vlachoyiannopoulos PG, Moutsopoulos HM. Prognostic factors and clustering of serious clinical outcomes in antiphospholipid syndrome. Q J Med. 2000; 93: 525-30. [ Links ]
58. Buhler-Singer S, von Hintzenstern J, Fartasch M, Hornstein OP. Anticardiolipin syndrome with only skin envolvement. Hautzart. 1994; 45: 394-7. [ Links ]
59. Piette WW. Antiphospholipid antibody syndrome: the problems and the promise. Br J Dermatol. 2000; 142: 1080. [ Links ]
60. Finazzi G, Brancaccio V, Moia M, Ciaverella N, Mazzucconi MG, Schinco PC, et al. Natural history and risk factors for thrombosis in 360 patients with antiphospholipid antibodies: a four year prospective study from the italian register. Am J Med. 1996; 100: 530-6. [ Links ]
61. Rosove MH, Petronella MC. Antiphospholipid thrombosis: clinical course after the first thrombotic event in 70 patients. Ann Int Med. 1992; 117: 303-8. [ Links ]
62. Camps Garcia MT, Gutierrez Rueda A, Guil Garcia M, Perello-Gonzalez Moreno I, Garcia Portales R, Belmonte Lopez A, et al. Clinical and analytical manifestations of primary antiphospholipid antibody syndrome. An Med Interna. 1993;10:576-82. [ Links ]
Jesus Rodriguez Santamaria
Rua General Aristides Athayde Junior, 1039 - Bigorrilho
80710-520 Curitiba PR
Tel.: (41) 3233-7479 / Fax: (41) 3233-7479
Received on May 05, 2005.
Approved by the Editorial Council and accepted for publication on May 19, 2005.
* Work done at Dermatology Service of the Hospital de Clínicas de Curitiba - Departamento de Clínica Médica da Universidade Federal do Paraná - UFPR (PR) - Brazil.