Platelets and the antiphospholipid syndrome

The antiphospholipid syndrome is a non-inflammatory autoimmune disease characterised by the presence of antiphospholipid antibodies in the plasma of patients with venous or arterial thrombosis or recurrent complications of pregnancy. The strong relation between the presence of antibodies against anionic phospholipids and thrombo-embolic complications is well established, but how the presence of antiphospholipid antibodies results in the observed clinical manifestations remains a mystery. Experimental observations suggest that an altered regulation of platelet function can cause the thrombotic complications observed in the antiphospholipid syndrome. In this review, we will discuss the evidence that the platelet is an important player in the pathogenesis of the antiphospholipid syndrome.     

Autoimmune-mediated atherothrombosis

Autoimmune vascular inflammation and oxidative stress (lipid peroxidation) are common in systemic autoimmune diseases and contribute to the oxidative modification of low-density lipoprotein (oxLDL) and oxLDL/beta2GPI complex formation. Circulating oxLDL/beta2GPI complexes have been detected in patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). The presence of antibodies to oxLDL/beta2GPI complexes indicates that these complexes are immunogenic, and the coexistence of complexes and antibodies has pointed to an active proatherogenic role in the development of autoimmune vascular complications. Immunohistochemical staining of atherosclerotic lesions suggest that these complexes are formed in the arterial wall and released into circulation. The in vitro macrophage uptake of oxLDL/beta2GPI complexes was significantly increased in the presence of antiphospholipid antibodies, either beta2GPI-dependent anticardiolipin or anti-beta2GPI antibodies, suggesting that macrophage Fcgamma receptors are involved in lipid intracellular influx and foam cell formation. These findings provide an explanation for the accelerated development of atherosclerosis seen in SLE and APS. The presence of circulating oxLDL/beta2GPI complexes and IgG antibodies to these complexes indicate significant vascular injury and oxidative stress as well as an active role in autoimmune-mediated atherothrombosis.     

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.     

Auto-immune hepatitis and antiphospholipids

INTRODUCTION: Only few series have reported the association of autoimmune hepatitis with antiphospholipid antibodies. The aim of our study is to investigate the frequency of these antibodies in a series of autoimmune hepatitis and to search for a correlation with clinical, biological or histological characteristics. MATERIAL AND METHODS: Antiphospholipid were investigated in 24 patients with well defined autoimmune hepatitis. Characteristics were compared between antiphopholipids positive and negative patients. Characteristics of our patients were also compared toward cases collected in a literature review. RESULTS: The frequency of antiphospholipid antibodies is of 70.8% in our series. Four patients had a well defined antiphospholid syndrome. Seven patients had a systemic lupus erythematosus in the antiphospholipid group whereas none in the antiphospholipid negative group. The frequency of the different antiphopholipid antibodies was: IgG ACL (52.9%), IgM APE (52.9%), ACC (43.7%), IgG Abeta2GP1 (41.2%). We found no correlation between hypergammaglobulinemia and the presence or the isotype of antiphospholipid antibodies. Clinical presentation and outcome as biological and histological parameters were similar in both groups. CONCLUSION: Our study report a high frequency of antiphospholipids antibodies in autoimmune hepatitis patients. However we found no clinical, biological or histological correlation with the presence of antiphospholipids. Further longitudinal studies on larger cohorts should clarify the association between antiphospholipid antibodies and autoimmune hepatitis and potential therapeutic issues.     

Diagnosis of antiphospholipid syndrome

Antiphospholipid syndrome is a multisystem autoimmune disease, characterized by recurrent vascular thrombosis and/or pregnancy losses in the presence of persistently positive antiphospholipid antibodies. In clinical practice, testing for anticardiolipin antibodies and lupus anticoagulant is mandatory for the laboratory diagnosis of antiphospholipid syndrome. Identification of patients with antiphospholipid syndrome is important, as prophylactic anticoagulant therapy may prevent thrombosis from recurring, and treatment during pregnancy can improve fetal and maternal outcome.     

Antiphospholipid antibodies and stroke in Down syndrome

Two patients with Down syndrome and the primary antiphospholipid antibody are described. One patient had a vasculopathy similar to that previously described as Moyamoya. Down syndrome is characterized by immune defects including a tendency to autoimmune phenomena. This report extends the scope of these observations and particularly draws out the potential role of antiphospholipid antibodies. Indeed antiphospholipid antibodies may well explain the well-known association of Down syndrome and stroke.     

Specificity of antinuclear and antiphospholipid antibodies in sera of patients with autoimmune lymphoproliferative disease (ALD)

OBJECTIVE: A human lymphoproliferative syndrome characterized by a defect of the Fas-mediated apoptosis pathway in the absence of a fas gene mutation (Autoimmune Lymphoproliferative Disease) has recently been described and characterized by autoimmune phenomena. The aim of this study was to investigate the presence of antinuclear and antiphospholipid antibodies and to define their specificity in 5 pediatric patients with this syndrome. METHODS: Antinuclear antibodies were investigated by Western Blot and IIF performed under standard as well as apoptotic conditions. The fine specificity of antiphospholipid antibodies was dissected by an ELISA for anti-beta 2-glycoprotein I, anti-prothrombin, anti-annexin V and anti-protein S antibodies, and by immunostaining on thin layer chromatography plates for antiphospholipid molecule antibodies. RESULTS: This study showed that the autoantibodies found in these patients targeted a broad spectrum of nuclear antigens which undergo redistribution from the nucleus to the cytoplasm and plasma membrane during the course of the apoptotic process. This reactivity does not comprise known specificities such as anti-extractable nuclear antigens or anti-dsDNA. Antiphospholipid antibodies were also found in these sera. A further characterization of the antiphospholipid antibodies showed the presence of a heterogeneous response with antibodies directed to negatively-charged phospholipids and antibodies targeting coagulation-related proteins (beta 2-GPI, prothrombin, annexin V) which are considered relevant antigens in the antiphospholipid syndrome. CONCLUSIONS: These results suggest that lack of tolerance due to a defect of Fas-mediated apoptosis allows the survival of B and T clones involved in the antinuclear and antiphospholipid immune responses.     

Atherosclerosis in autoimmune diseases

Lipid peroxidation occurs frequently in patients with systemic autoimmune diseases and contributes to autoimmune vascular inflammation. Oxidized low-density lipoprotein (oxLDL) interacts with β2-glycoprotein I (β2GPI), forming oxLDL/β2GPI complexes. Circulating oxLDL/β2GPI complexes and autoantibodies to these complexes have been demonstrated in patients with systemic lupus erythematosus and antiphospholipid syndrome. These findings suggest an immunogenic nature of the complexes and an active proatherogenic role in autoimmunity. Biochemical characterization of the complexes and immunohistochemical studies of atherosclerotic lesions suggest that most of the complexes originate in the arterial wall and are released into circulation. The in vitro macrophage uptake of oxLDL/β2GPI complexes increased significantly in the presence of antiphospholipid antibodies (anti-β2GPI), suggesting that macrophage Fcγ receptors are involved in the lipid intracellular inflthat leads to foam cell formation. These findings provide an immunologic explanation for the accelerated development of atherosclerosis seen in systemic lupus erythematosus and antiphospholipid syndrome.     

Autoimmune hepatitis associated with coagulation disorders and immunethyreopathy

We present the case of a 42-year-old female patient with the diagnoses of autoimmune hepatitis type I and autoimmune thyroiditis. Furthermore this patient had an unusual combination of coagulation disorders with homozygous Factor V Leiden mutation (APC resistance) and presence of antiphospholipid antibodies, leading to deep vein thromboses and miscarriages. Only few cases with the combination of autoimmune hepatitis and antiphospholipid antibodies have been described and almost all of them had become symptomatic with the antiphospholipid syndrome. As both autoimmune phenomenons furthermore share similar HLA-patterns, their coincidence is probably not as uncommon as the limited number of case reports suggests. Therefore attention in patients with autoimmune hepatitis should be focused on thrombophilia.     

Hughes (antiphospholipid) syndrome. Clinical features

Hughes (antiphospholipid) syndrome is a noninflammatory autoimmune disease. The most critical pathologic process is thrombosis, which results in most of the clinical features suffered by these patients. Recurrent thrombosis together with an adverse pregnancy history and the presence of antiphospholipid antibodies defines the syndrome.     

Autoimmune hepatitis associated with the antiphospholipid syndrome

The antiphospholipid syndrome has rarely been described in patients with autoimmune hepatitis. Two cases with type I autoimmune hepatitis and antiphospholipid syndrome are presented. The first case is that of a 53-year-old Caucasian female with a history of arterial thrombosis and fetal loss who was submitted to clinical and laboratory testing due to persistent transaminasaemia and was found to have autoimmune hepatitis. Antiphospholipid antibodies (anticardiolipin antibodies and lupus anticoagulant) were positive. The second case is that of a 31-year-old Caucasian woman with a history of autoimmune hepatitis who was submitted to laboratory testing due to a second-trimester fetal death, revealing an increased activated partial thromboplastin time and positive antiphospholipid antibodies. In conclusion, secondary antiphospholipid syndrome may accompany autoimmune hepatitis.     

Antiphospholipid antibiodies: a critical review of the literature

PURPOSE OF REVIEW: The antiphospholipid antibody syndrome is defined by the presence of antiphospholipid antibodies in patients with recurrent venous or arterial thromboembolism or pregnancy morbidity. Antithrombotic therapies are the mainstay of treatment to reduce the risk of recurrent thromboembolism that characterizes this condition. RECENT FINDINGS: Limitations in the laboratory testing for antiphospholipid antibodies and changes in the diagnostic criteria for antiphospholipid antibody syndrome are important to recognize as they will affect the type of patients enrolled in the clinical trials evaluating antiphospholipid antibody syndrome therapies. In this review, we discuss the laboratory testing and diagnostic criteria for antiphospholipid antibody syndrome, and examine the evidence supporting the optimal antithrombotic management of patients with antiphospholipid antibodies. Studies addressing the management of patients with antiphospholipid antibodies and venous thromboembolism, and antiphospholipid antibodies and ischemic stroke, will be critically reviewed. SUMMARY: Clinical trials and observational studies have evaluated the optimal type, intensity and duration of anticoagulant therapy in patients with antiphospholipid antibodies. Critical evaluation of these studies is required to assess the generalizability of the results and how these results may be applicable to individual patients.     

Current insight into diagnostics and pathophysiology of the antiphospolipid syndrome

The diagnosis of the antiphospholipid syndrome, a non-inflammatory autoimmune disease characterized by thrombosis or pregnancy morbidity in the presence of antiphospholipid antibodies, depends greatly upon laboratory diagnostics. The diagnostic value of all available assays to detect antiphospholipid antibodies and the anticardiolipin assay in particular, is a matter of ongoing debate. Although the presence of lupus anticoagulant correlates best with thrombosis, accurate determination is not always possible due to anticoagulant treatment. Data on the predictive value of alternatives such as the anti-beta2-glycoprotein I and the anti-prothrombin antibody assay are insufficient and prospective cohort studies are needed. Determining antiphospholipid antibody profiles seems to increase diagnostic specificity. Substantial progress has been made in unravelling the pathophysiological mechanisms underlying the antiphospholipid syndrome. Several cellular receptors for antibody-beta2-glycoprotein I complexes have been identified and their roles in cellular activation are being investigated. In vivo data should provide more insight into the importance of the interaction with individual receptors.     

Mesenteric vein thrombosis triggered by blunt abdominal trauma in a patient with the primary antiphospholipid syndrome

The antiphospholipid syndrome is defined by the presence of autoimmune antiphospholipid antibodies in serum together with venous, arterial or small-vessel thrombosis and/or morbidity with pregnancy. Superior mesenteric vein thrombosis represents a rare complication associated with this syndrome; triggering events such as surgical procedures, drug administration and anticoagulation withdrawal have been reported. We describe a case of superior mesenteric vein thrombosis triggered by blunt abdominal trauma in a 47-year-old man with the primary antiphospholipid syndrome. It confirms a previous report describing a patient suffering from the catastrophic antiphospholipid syndrome after a fall. This provides evidence, previously unreported, for the possible role of trauma as a precipitating factor leading to thrombosis, even in cases of 'simple' antiphospholipid syndromes. Our patient required extensive small-bowel resection but could be discharged after complete recovery.     

beta2-glycoprotein I-dependent lupus anticoagulant highly correlates with thrombosis in the antiphospholipid syndrome

The antiphospholipid syndrome is characterized by the presence of antiphospholipid antibodies in plasma of patients with thromboembolic complications. A major problem in defining the syndrome is that serologic assays to detect antiphospholipid antibodies have a low specificity. We recently published a method that specifically detects lupus anticoagulant (LAC) caused by anti-beta(2)-glycoprotein I antibodies. Here, we studied the clinical relevance of detecting beta(2)-glycoprotein I-dependent LAC. Plasma samples were collected from 198 patients with autoimmune diseases. In those samples with a positive partial thromboplastin time-lupus anticoagulant (PTT-LA), a modified activated partial thromboplastin time (aPTT)-based LAC test was performed with cardiolipin as confirming agent. Twenty-five of 58 patients with an aPTT-based LAC were dependent on the presence of anti-beta(2)-glycoprotein I antibodies. Presence of beta(2)-glycoprotein I-dependent LAC was almost completely associated with a history of thromboembolic complications (odds ratio, 42.3; 95% confidence interval, 194.3-9.9). An increased frequency of thrombosis was not found in 33 patients with LAC independent of anti-beta(2)-glycoprotein I antibodies (odds ratio, 1.6; 95% confidence interval, 3.9-0.8). The use of an LAC assay with cardiolipin as confirming agent strongly improves the detection of patients at risk of thrombosis. Our findings suggest that anti-beta(2)-glycoprotein I antibodies with LAC activity are antibodies that are responsible for the thromboembolic complications in the antiphospholipid syndrome.     

Catastrophic antiphospholipid syndrome: remission following leg amputation in 2 cases

OBJECTIVE: The antiphospholipid syndrome is characterized by venous and arterial thrombotic events that are often recurrent, thrombocytopenia, recurrent fetal loss, and elevated titers of antiphospholipid antibodies. A subtype of patients with a particularly overwhelming clinical picture has been termed catastrophic antiphospholipid syndrome (CAPS). In this report, we present 2 patients who exhibited a similar multisystem disorder associated with gangrenous changes in the lower extremities. METHODS: Two patients with CAPS are presented, highlighting the impact of this disorder on the patients and the response to various therapeutic modalities. RESULTS: Both patients had pulmonary, cardiac, cutaneous, and neurologic findings consistent with CAPS. In addition, they had large purulent leg ulcers associated with livedo reticularis. Amputation of the legs in each case induced remission of the systemic illness. CONCLUSIONS: We believe that infection plays a significant role in the pathogenesis and amplification of the antiphospholipid syndrome. In certain patients, this association probably is mediated via immune mechanisms, which also enhance the genesis of atherosclerosis. After the foci of infection (suppurative leg ulcers) were removed, the underlying illness improved. These case studies provide an opportunity to study the interrelationship between several confounding factors that converge and lead to the development of this autoimmune condition.     

A maternal death due to the intracerebral hemorrhage caused by antiphospholipid syndrome: a case report

Clinical Rheumatology - Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by the presence of antiphospholipid antibodies in patients with arterial or venous thrombosis...     

Antiphospholipid syndrome during pegylated interferon alpha-2a therapy for chronic hepatitis C

A great variety of autoimmune side effects have been reported during interferon alpha therapy. The presence of anticardiolipin antibodies during interferon alpha therapy in chronic hepatitis C has also been reported. There are no reports on the occurrence of antiphospholipid syndrome in patients with chronic hepatitis C while on pegylated interferon alpha therapy. We report a case of a 46-year-old man who developed antiphospholipid syndrome 12 weeks after starting pegylated interferon alpha plus ribavirin for chronic hepatitis C. The clinical presentation of antiphospholipid syndrome was primary adrenal insufficiency secondary to bilateral adrenal haematoma and subclavian vein thrombosis. A pathogenic role of pegylated interferon alpha as a trigger factor for antiphospholipid syndrome development is suggested.     

SLE, atherosclerosis and cardiovascular disease

Atherosclerosis is an inflammatory disease and the major cause of cardiovascular disease (CVD) in general. Atherosclerotic plaques are characterized by the presence of activated immune competent cells, but antigens and underlying mechanisms causing this immune activation are not well defined. During recent years and with improved treatment of acute disease manifestations, it has become clear that the risk of CVD is very high in a prototypic autoimmune disease, systemic lupus erythematosus (SLE). SLE-related CVD and atherosclerosis are important clinical problems but may in addition also shed light on how immune reactions are related to premature atherosclerosis and atherothrombosis. A combination of traditional and nontraditional risk factors, including dyslipidaemia (and to a varying degree hypertension, diabetes and smoking), inflammation, antiphospholipid antibodies (aPL) and lipid oxidation are related to CVD in SLE. Premature atherosclerosis in some form leading to atherothrombosis is likely to be a major underlying mechanism, though distinctive features if any, of SLE-related atherosclerosis when compared with 'normal' atherosclerosis are not clear. One interesting possibility is that factors such as inflammation or aPL make atherosclerotic lesions in autoimmune disease more prone to rupture than in 'normal' atherosclerosis. Whether premature atherosclerosis is a general feature of SLE or only affects a subgroup of patients remains to be demonstrated. Treatment of SLE patients should also include a close monitoring of traditional risk factors for CVD. In addition, attention should also be paid to nontraditional risk factors such as inflammation and SLE-related factors such as aPL. Hopefully novel therapeutic principles will be developed that target the causes of the inflammation and immune reactions present in atherosclerotic lesions.     

Primary versus secondary antiphospholipid syndrome: Is this lupus or not?

Antiphospholipid syndrome is a hypercoaguable state characterized by recurrent venous and/or arterial thrombosis and/or pregnancy complications of fetal loss, pre-eclampsia, or eclampsia in the presence of antiphospholipid antibodies. It was first described in the setting of systemic lupus erythematosus and subsequently recognized to also exist as an independent condition and in conjunction with a variety of other autoimmune, infectious, and malignant illnesses. These diseases have been called primary antiphospholipid syndrome and secondary antiphospholipid syndrome. However, the two conditions can have significant overlapping features. This paper reviews the similarities and the differences between the two conditions.