Antiphospholipid syndrome (APS) is caused by anti-phospholipid-antibody (APA) and is a syndrome characterized by recurrent arterial or venous thrombosis, habitual abortion, thrombocytopenia with persistent positive anticardiolipin or lupus anticoagulant tests. It is a syndrome characterized by recurrent arterial or venous thrombosis, miscarriage, thrombocytopenia with persistent positive anticardiolipin or lupus anticoagulant tests. During pregnancy, some patients also present with reticular cyanosis, heart valve redundancy, calf ulcers, migraine, transverse myelopathy, chorea, and hemolytic anemia. The disorder can be secondary to SLE or other autoimmune diseases, but can also occur alone (primary antiphospholipid syndrome).
I. Clinical manifestations
(A) Main symptoms
1. Thrombosis The most prominent manifestation in antiphospholipid syndrome is thrombosis, which is characterized by.
①Thrombosis can occur in all large, medium, small and micro arteries;
②Thrombosis can occur at a single site or at multiple sites simultaneously.
(3) Repeated thrombosis is a characteristic feature, and thrombosis often occurs intermittently. Strokes or transient ischemic attacks are the most common manifestations of arterial thrombosis, and strokes in APL-positive patients are often multifocal and recurrent, with middle cerebral artery occlusion being the most common site. Cerebral ischemia may have no clinical manifestations and cognitive impairment as the first manifestation. Occlusion of a major limb artery may lead to limb necrosis leading to amputation or eventually gangrene of the limb. Arterial occlusion can also lead to monocular blindness, myocardial, intestinal and adrenal infarction, etc. Venous thrombosis in APS is dominated by deep vein thrombosis, especially lower extremity deep vein thrombosis and pulmonary embolism are the most common.
2. Fetal pregnancy loss is mainly manifested as habitual abortion and intrauterine fetal death. It can occur at any stage of pregnancy, and is most common in the fourth to ninth month of pregnancy. The risk of miscarriage and intrauterine death increases with the increase of APL titers. The main causes of miscarriage or stillbirth are thinning of the placental trophoblast, marked reduction of the villi vessels, placental vascular thrombosis and placental infarction, resulting in placental insufficiency and fetal growth retardation.
3, thrombocytopenia APL binds to platelet membrane phospholipids, activates and promotes platelet aggregation, and is increased by phagocytosis and destruction when passing through the monocyte-phagocyte system, resulting in thrombocytopenia. The main manifestation is petechiae ecchymosis of the skin.
4. Skin manifestations: reticular cyanosis and chronic skin ulcers are the most common skin manifestations of APS. Other skin manifestations include superficial thrombophlebitis, skin gangrene, extremity necrosis, vascular inflammatory lesions (spots or nodules) and debris-like bleeding under the nails.
(II) Secondary symptoms
1. Thrombosis.
(1) Neurological manifestations In addition to stroke and TIA are common, it may also manifest as chorea, the first attack may appear during pregnancy or puerperium, others are epilepsy, acute ischemic encephalopathy, transverse myelitis, Guillain-Barré syndrome or anterior spinal artery occlusion, in addition migraine is more common in APL-positive patients.
(2) Cardiac manifestations: heart valve damage mainly involves mitral and aortic valves, there are two types including thrombotic redundancy, and abnormal valve function with incomplete valve closure or stenosis, the latter is more common; intra-cardiac thrombus is mainly seen in the left atrial thrombus, right atrial thrombus is occasionally seen; coronary artery occlusion can reach myocardial infarction; cardiomyopathy, when there is acute extensive intra-myocardial micro-artery thrombosis can lead to massive myocardial When there is acute extensive intra-myocardial micro-artery thrombosis can lead to massive myocardial necrosis, manifesting as congestive heart failure; chronic local myocardial ischemia can lead to abnormal ventricular function; abnormalities in the blood vessels supplying cardiac conduction can lead to conduction block and other heart rate disorders.
(3) Pulmonary manifestations: mainly pulmonary embolism and pulmonary infarction, other symptoms include pulmonary hypertension, pulmonary artery thrombosis, alveolar hemorrhage.
(4) Abdominal manifestations: kidney is one of the main target organs of APS, and renal damage includes renal artery occlusion, renal vein thrombosis, renal infarction and renal thrombotic microangiopathy; adrenal vein thrombosis can lead to swelling of the gland and reduced arterial blood supply, resulting in Addison’s disease and hyperalgesia; liver involvement is manifested by Bu-plus syndrome, nodular regenerative hyperplasia, liver infarction and elevated liver enzymes Intestinal involvement includes mesenteric ischemia, focal segmental small bowel ischemia and colonic ischemia, which can lead to colic, intestinal hemorrhage and intestinal infarction.
(5) Ocular manifestations: retinal small vessel occlusion can lead to retinal ischemia and infarction, and cardiovascular proliferation can cause secondary vitreous hemorrhage, retinal detachment or glaucoma.
(6) Large vessels: thrombosis can occur in the superior and inferior vena cava, manifesting as superior vena cava syndrome and inferior vena cava syndrome. The aorta can also be involved, and when the acute iliac artery is occluded, the clinical manifestations are decreased skin temperature, pallor, cyanosis and weakened dorsalis pedis artery pulsation in the affected lower limbs.
2, hemolytic anemia: mostly autoimmune hemolytic anemia can be manifested as anemia, jaundice, splenomegaly.
Hypertension: when the kidneys are involved, it can be manifested as malignant hypertension, and APS patients with gestational hypertension are also combined with gestational hypertension during pregnancy, and the onset is early and severe.
(C) Physical signs
1. Petechiae of the skin, reticular bruises and chronic skin ulcers are the most common skin manifestations of APS in patients with mild disease. Other skin manifestations include superficial thrombophlebitis, skin gangrene, extremity necrosis, vascular inflammatory lesions (spots or nodules), and debris-like bleeding under the nails.
In acute iliac artery occlusion, the clinical manifestations are decreased skin temperature, pallor, cyanosis and decreased dorsalis pedis artery pulsation in the affected lower extremities. Patients with hemolytic anemia may present with anemic appearance, jaundice, and splenomegaly; those with heart valve damage may present with signs of congestive heart failure.
(IV) Analysis of misdiagnosis
1, pregnancy failure Habitual abortion and intrauterine death are mainly due to immune factors, genetic factors, endocrine factors, uterine malformations and diseases. 5%-15% of women with recurrent pregnancy failure and 0.5%-2% of women with normal pregnancy are positive for APL. Genetic deficiencies of protein C, protein S or antithrombin III, severe hyperemesis and diabetes mellitus may also cause pregnancy complications and stillbirth. When there are no other possible causes, pregnancy failure occurs in the fourth to ninth month, with high titers of APL before pregnancy and repeatedly after delivery, and placental pathology suggesting vascular lesions and infarction, pregnancy failure is most likely due to APL. A single miscarriage before 10 weeks of gestation in a woman with a positive low-titer APL is most likely due to fetal chromosomal abnormalities, infection, and maternal hormonal or reproductive system structural abnormalities. The cause of miscarriage is clarified by history, physical examination, pelvic examination, maternal and fetal ultrasound, and chromosomal analysis if necessary.
2, venous thrombosis In patients with recurrent venous thromboembolic disease, 14% have APL. for those with unexplained venous thrombosis, the following factors or diseases should also be considered: factor V Leiden mutation (activated protein C resistance), poor fibrinogenemia; abnormal fibrinolysis; nephrotic syndrome; true erythrocytosis; Behçet’s syndrome; paroxysmal sleep Hemoglobinuria and oral contraceptives, etc.
3, arterial occlusion For arterial occlusion, hyperlipidemia, diabetes mellitus, hypertension, vasculitis, hyperhomocysteinemia, thrombo-occlusive vasculitis and lenient cell disease should be considered.
4. Positive antiphospholipid antibodies APL is necessary for the diagnosis of APS. Persistent positive high titers of β2GP1-dependent IgG-type antiphospholipid antibodies and clinical manifestations of tuberculosis can confirm the diagnosis of APS. However, APL can be detected in the serum of normal subjects and patients with other diseases, when APL is not to thrombosis. The positive rate of low-titer ACL in normal human plasma ranges from 2% to 6.5%, and the positive rate of moderate-to-high-titer ACL or LA is about 0.2%.The positive rate of APL increases with age. Infection-induced APL is usually a transient positive. Transient and low-titer APL cannot be used as a basis for diagnosis.
Auxiliary tests
(A) Primary tests
1.Anti-cardiolipin antibody (ACL) The current standardized test is the enzyme-linked immunosorbent assay (ELISA) method. sustained medium to high titers of IgG/IgM type ACL are closely associated with thrombosis, and IgG type ACL is associated with mid- to late-stage miscarriage. ACL is divided into two categories, one is non-β2-GP1-dependent antibodies, mostly seen in infectious diseases; the other is β2-GP1-dependent antibodies, mostly seen in autoimmune diseases. are mostly seen in autoimmune diseases. ACL detected by ELISA has a high sensitivity but relatively low specificity for the diagnosis of APS, and is often used for screening tests.
2. Lupus anticoagulant (LA) LA is an IgG or IgM type immunoglobulin that can prolong the duration of phospholipid-dependent coagulation test in vitro. Therefore, the detection of LA is a functional test with activated prothrombin time (APPT),, white clay agglutination time (KCT) and Russell’s snake venom coagulation test (RVVT). The KCT and RVVT are more sensitive, and LA has a high specificity for the diagnosis of APS.
3. anti-nuclear, anti-DNA and anti-ENA antibodies PAPS patients can have positive ANA and anti-ds-DNA antibodies. IgG-like antibodies to SS-A antibodies can cause neonatal lupus syndrome (NLE) after entering the fetus through the placenta, and the antibody positivity rate is 90%; binding to the fetal heart conduction system can cause congenital heart block, and pregnant women should be routinely tested for anti-SS-A and anti-SS-B antibodies. SS-A and anti-SS-B antibodies should be routinely tested in pregnant women.
4. Routine examination Blood test may include thrombocytopenia, decreased red blood cell count, increased plasma free hemoglobin, increased free bilirubin, occasionally decreased neutrophils, decreased blood complement, and increased sedimentation. Urinalysis may include proteinuria, increased urinary bilirubin, and cellular tubularity.
(II) Secondary examinations
1.Imaging examination Imaging examination
(1)Ultrasound Vascular Doppler ultrasound helps to diagnose peripheral arterial thrombosis; M-mode ultrasound and cross-sectional ultrasound help to detect heart valve structure and redundancy; B ultrasound can also monitor placental function and fetal condition in mid and late pregnancy.
(2) Angiography Arteriovenous angiography can show the site of obstruction and is the gold standard for the diagnosis of intravascular thrombosis.
(3) Computed tomography (CT) CT of the head is of great diagnostic value for cerebral infarction; CT of the chest is useful for the diagnosis of pulmonary embolism.
(4) Magnetic resonance imaging (MRI) cranial MRI is of greater value than CT for the diagnosis of cerebral infarction.
(5) Nuclear examination Radionuclide lung ventilation/perfusion (V/Q) imaging is meaningful for the diagnosis of pulmonary embolism.
2. Histopathological examination Biopsy of skin, kidney or other tissues shows non-inflammatory vascular occlusion, i.e. the vascular lesion is thrombotic and inflammatory phenomenon is not obvious.
(C) Examination precautions
1. Because APL is heterogeneous, polyclonal and multispecific, LA and ACL are not identical. About 80% of LA-positive patients have ACL at the same time, and 20% of ACL-positive patients are also positive for LA. When APS is clinically suspected, LA and ACL should be tested simultaneously.
2. Autoimmune APL targets the target antigen β2-GP1, which binds to phospholipids through β2-GP1. Infection-related APL can be induced by spirochetes (such as leptospira and syphilis spirochetes) and HIV, and is not associated with thrombosis and pregnancy loss, and cannot be used to diagnose APS.
III. Treatment points
(I) Treatment principles
Early prevention of thrombosis, monitoring of fetal growth and development and intrauterine status during pregnancy, timely detection of signs and symptoms of pre-eclampsia and thrombophilia.
(II) Specific treatment methods
The main therapeutic drugs for this disease are aspirin, heparin and adrenocorticotropic hormone, etc.
1.Aspirin can inhibit platelet aggregation and reduce the activity of prostaglandin synthetase, thus having the effect of anti-thrombosis and relieving vasospasm. It can be used for pregnant women with positive APA and previous history of fetal growth restriction and intrauterine fetal death.
Low-dose aspirin 50mg-75mg/d should be continued after 12 weeks of gestation until discontinued before 35 weeks of gestation. Note: There is a risk of fetal precocious heart disease before 12 weeks of gestation. The drug can pass through the placenta and there is a risk of neonatal hemorrhage when administered before delivery.
At present, the international treatment plan is advocated: heparin or low-molecular heparin combined with aspirin treatment, heparin (low-molecular heparin dose: 5000U/d) dose: 10000-15000U/d, every 12 hours, two separate administration. Monitor coagulation function during dosing to keep the APTT value 1.5 times the average value of a normal person. The dosage of aspirin is 50mg~75mg/d.
2.Heparin is mainly used for people with a history of thromboembolic disease or those with poor effect of aspirin alone, 7000~10000U per drip or subcutaneous injection every 12 hours, with antithrombotic and circulatory effects.
Note: Long-term use of heparin can lead to osteoporosis, thrombocytopenia, induced bleeding and other adverse reactions.
3.Adrenocorticotropic hormone can be applied alone or in combination when the above treatment is not effective. It can inhibit antibody production and antigen-antibody reaction, and reduce platelet destruction.
Generally use small dose 5mg/d, can be combined with aspirin, aspirin dosage is 25mg/d. Mostly used in patients with severe thrombocytopenia and hemolytic anemia.
4.Gammaglobulin can reduce the destruction of sensitized platelets in the reticuloendothelial system, so patients with thrombocytopenia can be applied when the application of adrenocorticotropic hormone is not effective, the dose is 400-1000mg/d/kg, also can be combined with aspirin or heparin.
5. Obstetric management.
(1) Joint management by obstetrician and internist before delivery;
(2) Start prophylactic anticoagulation therapy (usually with low-dose aspirin and subcutaneous low-molecular-weight heparin) and take appropriate measures to prevent osteoporosis and thrombocytopenia (monitor platelet count for the first 2-3 weeks);
(3) Monitor fetal growth and maternal health status;
(4) Start prenatal supervision at 30 to 32 weeks of gestation;
(5) Deliver near the expected date of delivery to avoid overdue;
(6) Pay attention to adjust the dose of anticoagulation therapy during delivery to minimize the risk of thromboembolism.
(3) Treatment considerations
1, APS is the main immune factor leading to habitual abortion. It has been reported that positive APS in pregnant women is negatively correlated with fetal weight, and the incidence of preterm birth and stillbirth is significantly higher, and it is easy to combine with hypertensive disorders in pregnancy with early onset and severe disease.
2. There are no very strict diagnostic criteria for APS, and most of them adopt the diagnostic criteria proposed by Alarcon-Segovia and others. The diagnosis must be confirmed with one positive laboratory indicator (high titer level of APA) and two or more clinical manifestations. A suspicious diagnosis must have 1 clinical sign and high titer APA or 2 or more clinical signs and low titer APA.
Diagnostic criteria for APS by Alarcon-Segovia et al.
(1) presence of 2 or more of the following clinical manifestations.
(i) Habitual abortion ;
(ii) Venous thrombosis;
(3) Arterial occlusion;
(iv) Lower extremity ulcers;
⑤ reticulocutaneous cyanosis;
⑥Hemolytic anemia;
(7) Thrombocytopenia.
(2) With high level of APA antibodies. or 2 or more clinical manifestations and low titers of APA antibodies (LgG and LgM).
Suspicious diagnosis.
(1) One clinical manifestation and high titers of APA antibodies.
(2) or 2 or more clinical manifestations and low titers of APA antibodies (LgG and LgM).
3. Any anticoagulation regimen should be analyzed specifically for the clinical features of each case. If a patient with antiphospholipid syndrome in pregnancy has a history of thromboembolic disease, most authors recommend the application of full and adjusted doses of anticoagulation therapy.
4. Patients with gestational antiphospholipid syndrome should be informed of the potential risks of heparin therapy during pregnancy, including heparin-induced osteoporosis and heparin-induced thrombocytopenia. Moreover, even when heparin prophylaxis is given, pregnancy loss still occurs in 20-30%.
5. For women with antiphospholipid syndrome and in a pre-thrombotic state, postpartum anticoagulation is very important. Both heparin and warfarin can be used safely during lactation.