Antiphospholipid syndrome: state of the art with emphasis on laboratory evaluation

Antiphospholipid antibodies (aPLs) are associated with arterial and venous thrombosis, recurrent pregnancy loss and thrombocytopenia. Although aPLs have not yet been conclusively shown to be causal in thrombosis and miscarriage, they are useful laboratory markers for the antiphospholipid syndrome (APS). The syndrome can complicate another autoimmune disease, most commonly systemic lupus erythematosus, but more often occurs alone -- primary APS. Identification of the syndrome is clinically important because of the risk of recurrent thrombosis and the need for antithrombotic therapy in many cases. Diagnosis and treatment of APS represent significant challenges, however, owing to the protean clinical manifestations and associations, limitations of currently available laboratory tests for aPLs, and the lack of clear evidence-based guidance on optimal management.     

Clinical significance of different antiphospholipid antibodies in the WAPS (warfarin in the antiphospholipid syndrome) study

To assess the clinical significance of lupus anticoagulants (LAs) and antiphospholipid antibodies (aPLs) toward thrombosis and abortions, we measured them in 112 patients whose samples were available at enrollment in the warfarin in the antiphospholipid syndrome (WAPS) study. Enzyme-linked immunosorbent assay (ELISA) and coagulation test values in the highest and lowest tertiles were compared. When considered separately, IgG antibodies to beta2-glycoprotein I (abeta2GPI) and prothrombin (aPT) were associated with anamnestic arterial and venous thrombosis, respectively, and those to annexin AV (aAnAV) with abortions. IgM antibodies to protein S and the lupus ratio of the dilute prothrombin time were associated with prospective thrombosis. No other association for IgM antibodies was seen. LA-positive patients who carried abeta2GPI antibodies were at risk of anamnestic arterial and total thrombosis and aPT antibodies to that of anamnestic venous and total thrombosis. LA-positive patients who carried IgG abeta2GPI and aAnAV antibodies were at risk for both anamnestic abortion and prospective thrombosis. Overall, these data support the inclusion of abeta2GPI antibodies in and suggest the removal of anticardiolipin antibodies from the laboratory criteria of the antiphospholipid syndrome. They also suggest that the measurement of aPT and aAnAV antibodies is useful in some selected situations and that there is little role for IgM antibody detection.     

Antiphospholipid syndrome

Antiphospholipid syndrome is an autoimmune systemic disorder characterized by arterial, venous, or small vessel thrombosis and/or recurrent early pregnancy loss, fetal loss, or pregnancy morbidity in the setting of documented persistent antiphospholipid antibodies that include the lupus anticoagulant, or moderate-high titer anticardiolipin, or anti-β2Glycoprotein I antibodies. Associated clinical manifestations include livedo reticularis, cutaneous ulcerations, thrombocytopenia, hemolytic anemia, valvular heart disease, and nephropathy. The degree of risk associated with antiphospholipid antibody depends on the characteristics of the antiphospholipid antibody profile and on the presence of additional thrombotic risk factors. Current standard treatment for unprovoked thrombosis is long-term warfarin or other vitamin K antagonist therapy. Treatment to prevent recurrent obstetric complications is low-dose aspirin and prophylactic heparin, usually low-molecular-weight heparin. Optimal treatment for standard therapy failures or for certain nonthrombotic manifestations is uncertain, although nonanticoagulation therapies that address multiple demonstrated mechanisms of disease are being explored.     

Aspirin and antiphospholipid syndrome

INTRODUCTION: Antiphospholipid syndrome is the most frequent cause of acquired thrombophilia. Aspirin may have some indications. CURRENT KONWLEDGE AND KEY POINTS: The usefulness of low doses of aspirin is now well demonstrated in the prevention of obstetric complications associated with antiphospholipid antibodies (especially pregnancy loss). When heparin is combined with low-dose aspirin, the recurrent rate of fetal loss is lower than 30%. In patients with arterial or venous thrombosis, there is a high rate of recurrence during the two first years except if high-dose warfarin was used (i.e., INR > or = 3). The association warfarin-aspirin in secondary prevention of thrombosis may be evaluated in prospective studies. It is not so clear in the literature and in our experience that warfarin is superior to aspirin in stroke recurrence prevention in patients with antiphospholipid antibodies, except in Sneddon's syndrome. There are no guidelines in primary thrombosis prevention in patients with antiphospholipid antibodies. In lupus patients, aspirin may not be sufficient after many years of follow-up in preventing a first episode of thrombosis. Prospective studies may be undertaken. Atherosclerotic patients with antiphospholipid antibodies are particularly exposed to the risk of thrombosis after revascularisation or angioplasty and stent implantation. Aspirin may have a place in those patients but these must be evaluated. FUTUR PROSPECTS AND PROJECTS: Except in prevention of obstetric complications, the usefulness of aspirin in patients with antiphospholipid antibodies must be evaluated in prospective studies.     

Antiphospholipid-thrombosis syndromes

Antiphospholipid antibodies are strongly associated with thrombosis and appear to be the most common of the acquired blood protein defects causing thrombosis. Based upon our experience, approximately 25% of patients with unexplained venous thrombosis, approximately 60% of patients with cerebrovascular thrombosis, approximately 37% of patients with transient ischemic attacks, approximately 18% with premature coronary artery thrombosis and approximately 60% of patients with recurrent fetal loss (recurrent miscarriage syndrome) harbor antiphospholipid antibodies. Although the precise mechanism(s) whereby antiphospholipid antibodies alter hemostasis to induce a hypercoagulable state remain unclear, several theories have been advanced. Since the aPTT is unreliable in patients with lupus anticoagulant and is not usually prolonged in patients with anticardiolipin antibodies, definitive tests, ELISA for IgG, IgA and IgM anticardiolipin antibodies and the dilute Russel's viper venom time (followed by cephalin correction for confirmation) for lupus anticoagulant should be immediately ordered when suspecting the antiphospholipid syndrome in individuals with otherwise unexplained thrombotic or thromboembolic events or recurrent fetal loss. However, if one strongly suspects antiphospholipid thrombosis syndrome clinically and assays for lupus anticoagulants and anticardiolipin antibodies are negative, specific assays for all three idiotypes of phosphatidylserine, phosphatidylethanolamine, phosphatidylcholine, phosphatidylinositol and phosphatidylglycerol are available and should be considered. These may clearly be indicated for difficult diagnostic cases of fetal wastage syndrome, and cerebrovascular events, but their significance in other types of thrombosis, particularly venous, remains unclear at present. Since about 65% of patients with antiphospholipid antibodies will fail warfarin therapy (rethrombose), it is important to define this common defect and institute appropriate antithrombotic therapy for appropriate time periods.     

Antiphospholipid antibodies and thrombosis

Antiphospholipid antibodies are associated with arterial and venous thrombosis, recurrent pregnancy loss, and thrombocytopenia. Although the antibodies have not been conclusively shown to be causal in thrombosis and miscarriage, they are useful laboratory markers for the antiphospholipid syndrome. The identification of the syndrome is clinically important because of the risk of recurrent thrombosis and the need for antithrombotic therapy in many cases. Diagnosis and treatment of antiphospholipid syndrome is difficult, however, because of the protean clinical manifestations and associations, limitations of existing laboratory tests for antiphospholipid antibodies, and the absence of evidence-based guidance on best management.     

Cerebral blood flow and glucose metabolism in multi-infarct-dementia related to primary antiphospholipid antibody syndrome

The primary antiphospholipid antibody syndrome (PAPS) has been described in patients with a history of fetal loss, thrombocytopenia and arterial or venous thrombosis. In PAPS, a prothrombotic state is mediated by antiphospholipid antibodies (aPLs) leading to disseminated thromboembolic vascular occlusion. Today, the presence of aPLs in the serum is considered as a distinct risk factor for recurrent stroke in young adults. Some PAPS patients develop a multi-infarct-syndrome with a stepwise decline of higher cortical functions. We report on a 55-year-old man suffering from progressive dementia and PAPS, in whom cerebral glucose metabolism and blood flow were examined by positron emission tomography (PET). Cerebral atrophy and moderate signs of leukaraiosis were detected in magnetic resonance imaging (MRI), whereas the PET scans showed a considerable diffuse impairment of cortical glucose metabolism combined with a reduced cerebral perfusion in the arterial border zones. These findings indicate that PAPS-associated vascular dementia is accompanied by a cortical neuronal loss, presumably caused by a small-vessel disease with immune-mediated intravascular thrombosis. This case shows that pathological findings in PAPS are congruent to cerebral changes of metabolism and blood flow in systemic lupus erythematosus (SLE).     

Primary antiphospholipid syndrome presented with portal vein thrombosis]

Antiphospholipid Antibody Syndrome (APS) is defined by arterial and venous thrombosis, recurrent spontaneous abortions and thrombocytopenia associated with persistence of antiphospholipid antibodies. Thrombosis may involve virtually all arterial or venous sites, but deep vein thrombosis of the lower limbs are the most common; however, unusual thrombi that involve the portal vein have been described. We report females with documented portal vein thrombosis and primary APS. The treatment of these patients is difficult because of the risk of bleeding and the recurrent thrombosis if they don't receive appropriate long-term anticoagulant therapy.     

A systematic review of secondary thromboprophylaxis in patients with antiphospholipid antibodies

OBJECTIVE: To systematically review the efficacy and safety data of different therapeutic approaches in patients with antiphospholipid antibodies (aPL) and thrombosis. METHODS: The Medline database and references from selected reports and review articles were used. Randomized controlled trials, prospective and retrospective cohort studies, and subgroup analysis (n > 15) that focused on the secondary thromboprophylaxis in patients with aPL were selected. RESULTS: Sixteen studies were selected. Patients with venous events and a single test for aPL showed a low recurrence rate while receiving oral anticoagulation at a target international normalized ratio (INR) of 2.0-3.0. Patients with stroke and a single positive aPL test had no increased risk compared with those without aPL. Recurrence rates in patients with definite antiphospholipid syndrome (APS) and previous venous thromboembolism were lower than in patients with arterial and/or recurrent events, both with and without therapy. Only 3.8% of recurrent events occurred at an actual INR >3.0. Mortality due to recurrent thrombosis was higher than mortality due to bleeding (18 patients versus 1 patient reported). CONCLUSION: For patients with definite APS, we recommend prolonged warfarin therapy at a target INR of 2.0-3.0 in APS patients with first venous events and >3.0 for those with recurrent and/or arterial events. For patients with venous thromboembolism or stroke and a single positive aPL test, we recommend further testing to determine if they have a persisting antibody. If they do not, the same therapy as for the general population should be used (warfarin at a target INR of 2.0-3.0 and low-dose aspirin, respectively).     

The systemic nature of the antiphospholipid syndrome

Antiphospholipid syndrome (APS, Hughes' syndrome) is a systemic autoimmune disorder characterized by arterial and/or venous thrombosis and recurrent foetal loss, accompanied by mild to moderate thrombocytopaenia and elevated titres of antiphospholipid antibodies (aPLs): lupus anticoagulant (LAC) and/or anticardiolipin (aCL) antibodies. APS was defined originally in 1983 in systemic lupus erythematosus (SLE) patients, but later it was found that APS can be primary or secondary to other autoimmune diseases or malignancy. During the past 20 years many organs have been reported to be involved in this syndrome and the clinical manifestations are seen in every medical field. Moreover, many aPLs have been found in APS besides aCLs and LACs, which bind to the autoantigen beta-2-glycoprotein I (beta2GPI). Treatment for APS, based on antiplatelet and anticoagulation drugs, is dependent on various parameters, including whether SLE is also present, classical vs non-classical manifestations of the diseases, women with APS based on pregnancy morbidity, the presence of elevated aCL antibody titres in the absence of clinical manifestations, and catastrophic APS.     

Oral anticoagulant therapy in subjects with congenital or acquired thrombophilia

Thrombophilia testing is now commonplace. However, testing for heritable thrombophilia does not predict outcome in response to oral anticoagulant therapy. At present there is no conclusive evidence that recurrence on treatment with warfarin with a target International Normalized Ratio of 2.5 is greater in patients with laboratory evidence of heritable thrombophilia compared with those without. Similarly, there is no conclusive evidence that patients with laboratory evidence of heritable thrombophilia are more likely to suffer an earlier recurrence once treatment is stopped. Therefore, the management of patients with familial thrombotic disease and patients with laboratory evidence of heritable thrombophilia should be influenced by their personal and family history rather than the results of laboratory investigations. There is no doubt that the relative risk of thrombosis is increased in affected family members of thrombosis-prone families but this translates to a relatively low absolute risk per year, and long-term primary prophylaxis with oral anticoagulant therapy is not justified in the majority. Evidence of antiphospholipid syndrome is associated with an increased risk of recurrent venous thromboembolism, but there is still uncertainty as to the optimal intensity and duration of oral anticoagulant therapy after an episode of arterial or venous thrombosis in patients with detectable antiphospholipid activity.     

Hypertension due to renal artery occlusion in a patient with antiphospholipid syndrome

We report an unusual case of renovascular hypertension in a 16-year-old boy with primary antiphospholipid syndrome (PAPS), admitted to our clinic for severe drug-resistant hypertension and hypokalemia. Hormonal investigation revealed secondary aldosteronism and positive captopril test for renovascular disease. Aortography confirmed the occlusion of the left renal artery. After nephrectomy, normalization of blood pressure and secondary aldosteronism occurred. Presently the patient remains in good health, receiving warfarin anticoagulant therapy. PAPS is defined by the presence of antiphospholipid antibodies and recurrent thrombosis. Arterial thrombosis (29%) appears to be less prevalent than venous thrombosis. Thrombotic microangiopathy of the kidney is frequently observed but renal artery occlusion, as seen in our patient, is unusual.     

The Management of Stroke in Antiphospholipid Syndrome

Ischemic stroke is one of the most common complications of the antiphospholipid syndrome (APS). Because of the relative lack of definitive prospective studies, there is still some debate as to whether the persistent presence of antiphospholipid antibodies (aPLs) increases the risk of recurrent stroke. There is more evidence for aPLs as a risk factor for first stroke. The mechanisms of ischemic stroke are considered to be thrombotic and embolic. APS patients with thrombotic stroke frequently have other, often conventional vascular risk factors. Transesophageal echocardiogram is strongly recommended in APS patients with ischemic stroke because of the high yield of valvular abnormalities. The appropriate management of thrombosis in patients with APS is still controversial because of limited randomized clinical trial data. This review discusses the current evidence for antithrombotic therapy in patients who are aPL positive but do not fulfill criteria for APS, and in APS patients. Alternative and emerging therapies including low molecular weight heparin, new oral anticoagulants (including direct thrombin inhibitors), hydroxychloroquine, statins, and rituximab, are also addressed.     

Complete resolution of a mitral valve vegetation with anticoagulation in seronegative antiphospholipid syndrome

Antiphospholipid syndrome (APS) is a disorder characterized by recurrent venous or arterial thrombosis and/or fetal loss; involvement of cardiac valves is also seen. A seronegative variant has been described previously. We report a case of a woman with recurrent pregnancy loss, prior strokes, and a negative workup for known antiphospholipid antibodies. During her current pregnancy, she presented with acute stroke and mitral valve vegetation. Her workup for antiphospholipid syndrome and other thrombophilias remained negative even after the stroke. Her mitral valve vegetation resolved completely with aspirin, heparin, and warfarin. We believe this to be the first report of complete resolution of valvular vegetation with antiplatelet and anticoagulant therapy alone in a patient with seronegative antiphospholipid syndrome. Moreover, this appears to be the first report of stroke associated with this condition.     

Management of thrombosis in antiphospholipid antibody syndrome

Antiphospholipid antibody positive patients are at risk for venous and arterial thrombosis. The risk of recurrent thromboembolism is high. Although the standard of care is high-intensity warfarin after a thromboembolic event, some studies indicate that this degree of anticoagulation is not needed. There is an urgent need of clinical trials to address management of thrombosis in antiphospholipid syndrome.     

Antiphospholipid thrombosis: clinical course after the first thrombotic event in 70 patients.

OBJECTIVE: To determine the clinical course and influence of antithrombotic therapy in patients with lupus anticoagulant or anticardiolipin antibodies, or both, after the first thromboembolic event. DESIGN: Retrospective survey of consecutive patients treated according to their physician's best judgment. SETTING: Secondary and tertiary referral practice. PATIENTS: Seventy patients (48 women [69%]) with a mean age (+/- SD) of 45.5 +/- 17.3 years. The antiphospholipid syndrome was primary in 51 patients (73%) and secondary to systemic lupus erythematosus in 14 patients (20%) and to chronic idiopathic thrombocytopenic purpura in 5 patients (7%). MEASUREMENTS: Site of initial and recurrent thrombotic events (venous or arterial), as well as kind (aspiring, heparin, or warfarin) and intensity of anticoagulation. RESULTS: Total follow-up after the first thrombotic event was 361.0 patient-years (mean [+/- SD], 5.2 +/- 5.6 years per patient). Thirty-seven patients (53%) had 54 recurrent events, with 2 patients experiencing fatal events. Arterial events were followed by arterial events, and venous events by venous events, in 49 of 54 instances (91%). Recurrence rates during "no treatment;" aspirin therapy; or low-, intermediate-, or high-intensity warfarin therapy (international normalized ratios [INRs] less than or equal to 1.9, 2.0 to 2.9, and greater than or equal to 3.0, respectively, or rabbit brain thromboplastin prothrombin time ratios of approximately less than 1.3, 1.3 to 1.5, and greater than 1.5, respectively) were 0.19, 0.32, 0.57, 0.07 (P = 0.12), and 0.00 (P less than 0.001) per patient-year. The follow-up periods for the five types of therapy were 161.2, 37.8, 11.3, 40.9, and 110.2 patient-years, respectively. The highest INR coincident with thrombosis was 2.6. Five warfarin-treated patients had five significant bleeding events (0.031 per patient-year). CONCLUSIONS: Recurrent thrombosis is a potentially serious problem for patients with lupus anticoagulant or anticardiolipin antibodies or both. The site of the first event (arterial or venous) tended to predict the site of subsequent events. Intermediate- to high-intensity warfarin therapy may confer better antithrombotic protection than low- to intermediate-intensity warfarin therapy or aspirin therapy. Further studies are needed to define more precisely the rethrombosis rate and optimal type, intensity, and duration of antithrombotic therapy.     

Catastrophic antiphospholipid syndrome associated with malignancies (case report and review of the literature)

We describe a 58-year old female patient with rapid development of arterial and venous thromboembolisms, including deep vein thrombosis (DVT) in the lower limbs, recurrent cerebral infarctions and bilateral pulmonary emboli. Her laboratory data on admission showed positive anticardiolipin antibody of IgG isotype (IgG aCL) and positive anti-beta2 glycoprotein-I antibody of IgG isotype (IgG abeta2-GPI), and decreased protein C activity and protein S antigen. Systemic examinations revealed the presence of an ovarian cancer. Surgical resection was attempted, but her cancer infiltrated the pelvic wall and could not be resected. Despite treatment with unfractionated heparin followed by warfarin, she died due to recurrent episodes of cerebral infarction. This case was considered as probable catastrophic antiphospholipid syndrome (CAPS), which might be associated with ovarian cancer. Known as Trousseau's syndrome, arterial and, more commonly, venous thrombosis is a frequent complication of cancer and sometimes a harbinger of occult cancer. Our case indicates that there is an overlap between antiphospholipid syndrome (APS) and Trousseau's syndrome. It is important to bear in mind that a thrombotic event associated with cancer can be the first manifestation of CAPS.     

Renal involvement in primary antiphospholipid syndrome and its response to immunosuppressive therapy

Antiphospholipid syndrome (APS) is the association between antiphospholipid antibodies, venous and arterial thrombosis and pregnancy morbidity. Although the kidney may be affected in APS, the treatment of renal involvement is yet to be elucidated. This report describes the clinical and laboratory features of four patients with primary APS nephropathy, and the beneficial effect of immunosuppressive therapy accompanied by warfarin and angiotensin-converting enzyme inhibitor. We also briefly discuss the possible mechanisms of the beneficial effects of immunosuppressives on primary APS nephropathy.     

Cardiovascular events in patients with antiphospholipid antibodies: Strategies of prevention

Antiphospholipid antibodies are a heterogeneous group of auto-antibodies against phospholipids-binding proteins. The antiphospholipid syndrome is an autoimmune disorder characterized by the clinical association of antiphospholipid antibodies with a condition of hypercoagulability that can affect any blood vessel. Involvement of larger vessels, such as arteries or veins, manifests in the form of thrombosis or thromboembolism, whereas involvement of small vessels manifests as thrombotic micro-angiopathy. The antiphospholipid syndrome is also characterized by the presence of recurrent fetal loss. Patients who are persistently positive for antiphospholipid tests, and who have an arterial thrombosis or venous thrombosis history, are at increased risk of recurrence. Oral anticoagulant therapy is the mainstay of treatment for the thrombotic manifestations of the syndrome. Therapy with anticoagulant drugs should be long-term.On the other hand, although the thromboembolic potential of antiphospholipid antibodies has been well documented, there is still no general consensus on the prophylactic treatment of antiphospholipid antibodies carriers who have never developed vascular/obstetric manifestations. The effect of primary prophylaxis in antiphospholipid antibodies positive individuals is not well known and no evidence-based recommendations exist for thrombosis prevention in these individuals. However, the presence of risk factors for thrombosis increases the risk of first event of antiphospholipid antibodies positive patients.In conclusion, there is still much to learn on primary prophylaxis of asymptomatic antiphospholipid antibodies carriers. Hopefully, evidence-based guidelines will be available in the future.     

Management of Obstetric Antiphospholipid Syndrome

Recurrent early miscarriages (excluding chromosomal anomalies), late fetal loss, and maternal thrombosis are characteristic of obstetric antiphospholipid syndrome (APS). Obstetric complications such as preeclampsia, fetal growth restriction, premature delivery, and fetal death also occur in higher frequency in APS patients than in the general population. A high-risk obstetric center is needed for proper evaluation of and intervention with pregnant women with APS. Association with lupus carries additional risk of thrombosis when antiphospholipid antibodies (aPLs) are present. Gestational results with live births are improved to about 80% when antithrombotic therapy is used, but failure in 20% to 30% of the cases despite correct treatment with low-dose aspirin with or without heparin reveals new pathways for pregnancy loss in APS and unmet needs. At the moment, there is no recommendation to investigate patients with infertility for the presence of aPLs.