What is antiphospholipid syndrome?


Author: Succeeder    

The lupus anticoagulant (LA) test is an important part of the laboratory test for antiphospholipid antibodies and has been recommended for use in a variety of clinical situations, such as the laboratory diagnosis of antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE), the risk assessment of venous thromboembolism (VTE), and the explanation of unexplained prolonged activated partial thromboplastin time (APTT). This article will help you get familiar with what antiphospholipid syndrome (APS) is.

Antiphospholipid syndrome (APS) is an autoimmune disease with recurrent vascular thrombotic events, recurrent spontaneous abortion, thrombocytopenia, etc. as the main clinical manifestations, accompanied by persistent medium and high titer positive antiphospholipid antibody spectrum (aPLs). It is usually divided into primary APS and secondary APS, the latter of which is mostly secondary to connective tissue diseases such as systemic lupus erythematosus (SLE) and Sjögren's syndrome. The clinical manifestations of APS are complex and diverse, and all systems of the body can be affected, with the most prominent manifestation being vascular thrombosis. The pathogenesis of APS is that circulating aPL binds to cell surface phospholipids and phospholipid-binding proteins, activating endothelial cells, PLTs and wBc, leading to vascular thrombotic events and obstetric complications, and promoting the occurrence of other autoimmune and inflammatory complications. Although aPL is pathogenic, thrombosis only occurs occasionally, indicating that short-term "secondary strikes" such as infection, inflammation, surgery, pregnancy and other triggering factors are essential in the process of thrombosis.

In fact, APS is not uncommon. Studies have shown that 25% of patients with unexplained stroke under the age of 45 are aPLs positive, 14% of patients with recurrent venous thrombosis events are aPLs positive, and 15% to 20% of female patients with recurrent pregnancy loss are aPLs positive. Due to the lack of understanding of this type of disease by clinicians, the average delayed diagnosis time of APS is about 2.9 years. APS is usually more common in women, with a female: male ratio of 9:1, and is more common in young and middle-aged people, but 12.7% of patients are >50 years old.

1-CLINICAL MANIFESTATIONS OF APS

1.Thrombotic events

The clinical manifestations of vascular thrombosis in APS depend on the type, location and size of the affected blood vessels, and can be manifested as single or multiple blood vessels involved. Venous thromboembolism (VTE) is more common in APS, most commonly in the deep veins of the lower extremities. It can also affect the intracranial venous sinuses, retina, subclavian, liver, kidneys, and superior and inferior vena cava. APS arterial thrombosis (AT) is most common in intracranial arteries, and can also affect the renal arteries, coronary arteries, mesenteric arteries, etc. In addition, APS patients may also have microvascular thrombosis in the skin, eyes, heart, lungs, kidneys and other organs. Meta-analysis found that lupus anticoagulant (LA) positivity has a greater risk of thromboembolism than antiphospholipid antibodies (acL); clinical studies have shown that APS patients with positive aPL [i.e., LA, aCL, glycoprotein I antibodies (αβGPI) positivity] show a high risk of thrombosis, including a thrombosis rate of 44.2% within 10 years.

2.Pathological pregnancy

The pathophysiology of obstetric manifestations of APS is equally complex and may vary according to the stage of pregnancy, resulting in the heterogeneity of observed clinical features. Inflammation, complement activation, and placental thrombosis are all considered to be pathogenic factors of obstetric APS. Pathological pregnancy caused by APS is one of the few causes that can be prevented and treated, and proper management can effectively improve pregnancy outcomes. A meta-analysis published in 2009 found that the presence of LA and aCL was significantly associated with fetal death at >10 weeks of gestation; a recent systematic review and meta-analysis also found that LA positivity was closely associated with fetal death. In patients known to have APS, the risk of fetal death is still as high as 10% to 12% even with standard treatment of heparin and low-dose aspirin. For APS patients with severe symptoms of preeclampsia or placental insufficiency, the presence of LA and aCL is significantly associated with preeclampsia; recurrent early miscarriage (<10 weeks of gestation) is an obstetric complication that often considers the possibility of APS.

2-CLINICAL MANIFESTATIONS OUTSIDE THE STANDARD

1.Thrombocytopenia

Thrombocytopenia is one of the common clinical manifestations of APS patients, with an incidence of 20%~53%. Usually, SLE secondary APS is more prone to thrombocytopenia than primary APS. The degree of thrombocytopenia in APS patients is often mild or moderate. Possible pathogenesis includes aPLs directly binding to platelets to activate and aggregate platelets, consumption of thrombotic microangiopathy, consumption of large amounts of thrombosis, increased retention in the spleen, and adverse reactions related to anticoagulant drugs represented by heparin. Because thrombocytopenia may increase the risk of bleeding, clinicians have some concerns about the use of antithrombotic therapy in APS patients with thrombocytopenia, and even mistakenly believe that APS thrombocytopenia can reduce the risk of recurrence of thrombotic events in patients. In fact, on the contrary, studies have shown that the risk of recurrence of thrombotic events in APS patients with thrombocytopenia is significantly increased, so it should be treated more actively.

2.CAPS is a rare, life-threatening disease characterized by multiple (≥3) vascular embolisms in a small number of APS patients within a short period of time (≤7 days), usually with high titers, affecting small blood vessels, and histopathological confirmation of thrombosis in small blood vessels. APL positivity persists within 12 weeks, causing multiple organ failure and risk of death, known as catastrophic antiphospholipid syndrome. Its incidence is about 1.0%, but the mortality rate is as high as 50%~70%, often due to stroke, encephalopathy, hemorrhage, infection, etc. Its possible pathogenesis is the formation of thrombotic storm and inflammatory storm in a short period of time.

3-LABORATORY EXAMINATION

aPLs is a general term for a group of autoantibodies with phospholipids and/or phospholipid-binding proteins as target antigens. aPLs are mainly found in patients with autoimmune diseases such as APS, SLE, and Sjögren's syndrome. They are the most characteristic laboratory markers of APS and the main risk predictors of thrombotic events and pathological pregnancy in APS patients. Among them, lupus anticoagulant (LA), anticardiolipin antibodies (aCL), and anti-β-glycoprotein I (αβGPⅠ) antibodies, as laboratory indicators in the APS classification standard, have been widely used in clinical practice and have become one of the most common autoantibody tests in clinical laboratories.

Compared with aCL and anti-βGPⅠ antibodies, LA has a stronger correlation with thrombosis and pathological pregnancy. LA has a higher risk of thrombosis than acL. And it is closely related to miscarriage in pregnancy >10 weeks. In short, persistently positive LA is the most effective single predictor of thrombotic risk and pregnancy morbidity.

LA is a functional test that determines whether the body has LA based on the fact that LA can prolong the coagulation time of different phospholipid-dependent pathways in vitro. The detection methods of LA include:

1.Screening test: including diluted viper venom time (dRVVT), activated partial thromboplastin time (APTT), silica coagulation time method, giant snake coagulation time and snake vein enzyme time. At present, the international aPLs detection guidelines such as the International Society on Thrombosis and Haemostasis (ISTH) and the Clinical Laboratory Standards Institute (CLSI) recommend that LA be detected by two different coagulation pathways. Among them, dRVVT and APTT are the most commonly used detection methods internationally. Usually dRVVT is used as the first method of choice, and the more sensitive APTT (low phospholipids or silica as an activator) is used as the second method.

2.Mixing test: Patient plasma is mixed with healthy plasma (1:1) to confirm that the prolonged coagulation time is not due to a lack of coagulation factors.

3.Confirmation test: The concentration or composition of phospholipids is changed to confirm the presence of LA.

It is worth noting that the ideal sample for LA should be collected from patients who have not received anticoagulant therapy, because patients treated with warfarin, heparin, and new oral anticoagulants (such as rivaroxaban) may have false-positive LA test results; therefore, the LA test results of patients receiving anticoagulant therapy should be interpreted with caution. In addition, LA testing should also be interpreted with caution in the acute clinical setting, because acute elevations in C-reactive protein levels can also interfere with the test results.

4-SUMMARY

APS is an autoimmune disease with recurrent vascular thrombotic events, recurrent spontaneous abortion, thrombocytopenia, etc. as the main clinical manifestations, accompanied by persistent medium and high titers of aPLs.

APS is one of the few treatable causes of pathological pregnancy. Proper management of APS can effectively improve pregnancy outcomes.

In clinical work, APS should also include patients with aPLs-related clinical manifestations such as livedo reticularis, thrombocytopenia, and heart valve disease, as well as those who meet the clinical classification criteria and have persistent low titers of aPLs. Such patients also have the risk of thrombotic events and pathological pregnancy.

The treatment goals of APS mainly include preventing thrombosis and avoiding pregnancy failure.

References

[1] Zhao Jiuliang, Shen Haili, Chai Kexia, et al. Diagnosis and treatment guidelines for antiphospholipid syndrome[J]. Chinese Journal of Internal Medicine

[2] Bu Jin, Liu Yuhong. Advances in the diagnosis and treatment of antiphospholipid syndrome[J]. Journal of Clinical Internal Medicine

[3] BSH GUIDELINE Guidelines on the investigation and management of antiphospholipid syndrome.

[4] Thrombosis and Hemostasis Committee of Chinese Society of Research Hospitals. Consensus on the standardization of lupus anticoagulant detection and reporting[J].