Primary antiphospholipid syndrome
【Overview】.
Antiphospholipid syndrome, a non-inflammatory autoimmune disease, is clinically manifested by symptoms such as arterial and venous thrombosis, habitual abortion and thrombocytopenia, with the presence of antiphospholipid antibodies in the serum, and the above symptoms can co-exist individually or in multiple cases.
APS can be divided into primary antiphospholipid syndrome and secondary antiphospholipid syndrome. The cause of antiphospholipid syndrome is still unclear and may be related to genetic and infectious factors. It is mostly seen in young people, with a male to female incidence ratio of 1:9 and a median age of 30 years for women. Antiphospholipid syndrome is most often seen in autoimmune diseases such as systemic lupus erythematosus or rheumatoid arthritis. In addition, there is a rare malignant antiphospholipid syndrome, which manifests itself as progressive and extensive thrombosis in a short period of time, resulting in multi-organ failure or even death.
Clinical manifestations
1. Arterial and venous thrombosis
The clinical manifestation of APS thrombosis depends on the type, location and size of the involved vessels, and can be manifested as single or multiple vessel involvement. venous thrombosis is more common in APS than arterial thrombosis. Venous thrombosis is most common in the deep veins of the lower extremities, in addition to the kidneys, liver, and retina. Arterial thrombosis is more common in the brain and upper extremities, and can also involve the kidneys, mesentery, and coronary arteries. Venous thrombosis of the limbs can cause local edema, and arterial thrombosis of the limbs can cause ischemic gangrene. PAPS should be ruled out in young people with stroke or myocardial infarction.
2.Obstetrics
Thrombosis of the placental vessels leads to placental insufficiency, which can cause habitual abortion, intrauterine distress, intrauterine growth retardation or death. The typical APS miscarriage usually occurs after 10 weeks of gestation, but it can also occur earlier, independent of the titer of anticardiolipin antibody (aCL). serious complications can occur in pregnant women with APS, including pre-eclampsia and HELLP syndrome in early stages.
3. Thrombocytopenia
Thrombocytopenia is another important manifestation of APS.
4.Other
Reticular cyanosis is a clinical manifestation in 80% of patients, and heart valve lesion is a later clinical manifestation, which requires valve replacement in severe cases. In addition there can be neuropsychiatric symptoms, including migraine, chorea, epilepsy, Green-Barre syndrome, transient bulbar palsy, etc. Ischemic osteonecrosis is extremely rare.
Table 1 Clinical manifestations of thrombosis in APS
Involved vessels
Clinical manifestations
Vein
Limb
Deep vein thrombosis
Brain
Cerebral venous sinus thrombosis
Liver
Small vein
Hepatomegaly; elevated transaminases
Large veins
Budd-Chaiari syndrome
Kidney
Renal vein thrombosis
Adrenal gland
Central? Venous thrombosis; hemorrhage, infarction, Addison’s disease
Pulmonary
Pulmonary vascular embolism; pulmonary hypertension
Large veins
Superior/inferior vena cava thrombosis
Skin
Reticular bruising.
Ocular
retinal vein thrombosis
artery
limb
Ischemic necrosis
brain
macrovascular
Stroke; transient ischemic attack; Sneddon’s syndrome
Small Vessels
Acute ischemic encephalopathy; multiple cerebral infarction dementia
Cardiac
Large vessels
Myocardial infarction; restenosis after venous bypass
Small Vessels
Acute
Circulatory failure; cardiac arrest
Chronic
Cardiac hypertrophy; arrhythmia; bradycardia
Kidney
Large blood vessels
Renal artery thrombosis; renal infarction
Small Vessels
Renal thrombotic microangiopathy
Liver
Liver infarction
Aorta
Aortic arch
Aortic arch syndrome
Abdominal aorta
Collateral thrombosis
Skin
Finger end gangrene
Ocular
Retinal artery and small artery thrombosis
Laboratory tests]
1.Serological examination of aPL
(1) Lupus anticoagulant (LA)
LA is an IgG/IgM type immunoglobulin that acts on the prothrombin complex (Xa, Va, Ca2+, and phospholipids) as well as the Tenase complex (factors IXa, VIIIa, Ca, and phospholipids), and can prolong the time of phospholipid-dependent coagulation test in vitro? Thus the assay LA is a functional test with prothrombin time (PT), activated partial thromboplastin time (APTT), white clay agglutination time (KCT) and snake venom test (dRVVT). Among them, KCT and dRVVT are more sensitive.
(2) aCL
The current standardized test is by enzyme-linked immunosorbent assay (ELISA). 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: non-b2-GP1-dependent antibodies, mostly seen in infectious diseases; and b2-GP1-dependent antibodies, mostly seen in autoimmune diseases.
(3) Anti-b2-GPⅠ antibodies
Anti-b2-GP1 antibody has LA activity and is detected by ELISA. It has stronger correlation with thrombus than aCL, low false positive, and similar sensitivity to diagnose PAPS as aCL. It is generally believed that the anti-b2-GPⅠ antibody is more specific than the anti-cardiolipin antibody proposed by Asherson in 1988, so patients with moderate or high titers of positive anti-b2-GPⅠ antibody should be highly alert for PAPS.
(4) Other
In addition, anti-nuclear antibodies, anti-soluble nuclear antigen (ENA) antibodies and other autoantibodies should be examined to exclude other connective tissue diseases.
2.Other tests
(1) Ultrasonography
Vascular Doppler ultrasound can help to diagnose peripheral arterial thrombosis; M-mode ultrasound and cross-sectional ultrasound can help to detect heart valve structure and redundancy; ultrasound can also monitor placental function and fetal condition in the middle and late pregnancy.
(2) Imaging examinations
Imaging examinations are most meaningful for thrombus evaluation. Arteriovenous angiography can show the site of obstruction, and MRI can help clarify the size of the thrombus and the extent of the infarct.
(3) Tissue biopsy
Biopsies of skin, placenta and other tissues show intravascular thrombosis, usually without lymphocyte or leukocyte infiltration, and similarly, renal biopsies show microthrombosis of glomeruli and small arteries.
Diagnostic points]
The diagnosis of PAPS mainly relies on clinical manifestations and laboratory tests, and other autoimmune diseases, infections, tumors and other diseases causing thrombosis must be excluded. So far, there is no unified diagnostic standard internationally.
1.Diagnostic criteria
The latest classification criteria for the diagnosis of PAPS are shown in Table 2.
Table 2 Table 2 Preliminary classification criteria of antiphospholipid syndromea
Clinical manifestations
1.Vascular embolism
a) one or more arterial, venous or small vessel embolisms occurring in any tissue or organ, and
b) embolism other than superficial venous embolism confirmed by imaging, Doppler ultrasound, or histopathology, and
c) histopathologically confirmed vascular embolism without significant vessel wall inflammation.
2. morbid pregnancy
a) one or more unexplained, morphologically normal fetuses confirmed by ultrasound or direct fetal examination at or beyond the tenth week of gestation, fetal death in utero
b) one or more morphologically normal fetuses delivered prematurely at 34 weeks of gestation or less due to severe pre-eclampsia or severe placental insufficiency, or
c) three or more consecutive unexplained spontaneous abortions within 10 weeks of gestation, except for maternal anatomic and endocrine abnormalities and parental chromosomal causes.
Laboratory criteria
a) The presence of moderate or high titers of IgG and/or IgM anticardiolipin antibodies (β2GP1-dependent anticardiolipin antibodies detected by ELISA) in the blood on two or more occasions at least six weeks apart, or
b) the presence of lupus anticoagulant in plasma on two or more occasions at least six weeks apart (test performed according to the International Society for Thrombosis and Haemostasis guidelines).
a Confirmation of APS requires the presence of at least one clinical and one laboratory criterion.
2. Differential diagnosis.
The diagnosis of PAPS is difficult to confirm from clinical manifestations or laboratory tests alone. a patient with moderate to high titers of aCL or positive LA and the following conditions should be considered as possible PAPS: ① unexplained arterial or venous thrombosis; ② thrombosis occurring at uncommon sites (e.g. kidney or adrenal gland); ③ thrombosis occurring in young people; ④ recurrent thrombosis; ⑤ recurrent thrombocytopenia; ⑥ thrombosis occurring in pregnancy mid- to late-term miscarriage. Venous thrombosis should be differentiated from protein C, protein S and antithrombin III deficiency, thrombotic thrombocytopenic purpura, fibrinolytic abnormalities, nephrotic syndrome, paroxysmal nocturnal hemoglobinuria, leukoaraiosis, and thrombosis associated with oral contraceptives. Arterial thrombosis needs to be differentiated from hyperlipidemia, diabetic vasculopathy, thrombo-occlusive vasculitis, vasculitis, hypertension, and other diseases.
It is important to note that the presence of aPL does not necessarily lead to thrombosis, and positive IgG or IgM class aCL antibodies can be seen in about 12% of normal individuals. Syphilis and diseases such as AIDS, Lyme disease, infectious mononucleosis, and tuberculosis have positive antiphospholipid antibodies in 93%, 39%, 20%, and 20%, respectively. Some drugs such as phenothiazine, procainamide, chlorpromazine, hydralazine, phenytoin sodium, quinine, propranolol and oral contraceptives can also induce aPL; in addition, some malignant tumors such as melanoma, nephroblastoma, lung cancer, lymphoma and leukemia can also appear positive for aCL or anti-b2-GPⅠ antibodies.
Treatment plan and principles]
1.General principles
The treatment of PAPS is mainly symptomatic treatment, prevention of thrombosis and miscarriage reoccurrence. Generally, hormone or immunosuppressive therapy is not required, except for SAPS, such as SLE or with severe thrombocytopenia (<50×109/L),h or special cases such as hemolytic anemia. Anticoagulant therapy should be used mainly in patients with aPL positive with thrombosis or in pregnant women who are antibody positive and have a history of recurrent miscarriages. Anticoagulation is not indicated for asymptomatic antibody-positive patients. (See Table 3 for details)
Table 3 Treatment options for patients with APS with moderate or high titers of aPL
Clinical situation
Treatment
Asymptomatic
No treatment, or ASA 75 mg/d
Suspected thrombosis
ASA 75mg/d
Recurrent venous thrombosis
Warfarin, INR 2.0 to 3.0, indefinite
Arterial thrombosis
INR 3.0, indefinite
Primary pregnancy
No treatment, or ASA 75 mg/d
Single miscarriage, <10 weeks < span="">
No treatment, or ASA 75 mg/d
Recurrent miscarriage, or miscarriage after 10 weeks without thrombosis
Low-dose heparin (5000 IU, 2 doses/d) throughout pregnancy and 6 to 12 weeks postpartum
Recurrent miscarriage, or miscarriage after 10 weeks, thrombosis
Heparin treatment during the whole pregnancy and postpartum with warfarin
Reticulocutaneous cyanosis
No treatment, or ASA 75mg/d
Platelets >50×109/L
No treatment
Platelets <50×109/L
Prednisone 1~2mg/kg
2.Commonly used anticoagulant drugs
(1) Heparin and low molecular weight heparin
Heparin is an unstratified? LMWH has the following characteristics compared with heparin: ① Long half-life, heparin is 1 hour (0.4~2.5 hours), while LMWH is twice as long; ② strong antithrombotic effect, but weak anticoagulant effect; ③ small effect on platelets; ④ not easy to cause osteoporosis.
Heparin is 12,500 IU (100mg) each. In recent years, the dosage of heparin tends to be in small doses, <15,000iu per day for adults, and is used clinically by intravenous or subcutaneous injection. lmwh can be injected subcutaneously at a dose of 2,500~3,000iu, usually once a day; in larger doses, it can also be given once every 12 hours. < span="">
Monitor laboratory indicators of heparin therapy, usually with APTT, so that the heparin dose is controlled at 1.5 to 2.0 times the normal control. Hemorrhage caused by heparin overdose can be neutralized with fisetin. 1 mg of fisetin can neutralize 100 IU of heparin, and fisetin should be titrated slowly.
(2) Warfarin
The anticoagulation mechanism of Warfarin is to inhibit the synthesis of vitamin K-dependent coagulation factors, so bleeding caused by Warfarin overdose can be treated with vitamin K antagonism. This drug has teratogenic effects and is contraindicated in pregnant women. The half-life of this drug is 33 hours, and it usually takes 12~24 hours to take effect. It should be gradually increased from small doses, initially giving 2.5~5mg/d, and the maintenance amount varies from person to person, generally less than 7.5~10mg/d, with an average of 4~6mg/d.
Warfarin is monitored by PT and evaluated by international normalized ratio (INR). INR = patient PT/standard PT, if INR>3.0 bleeding risk increases, INR>5 bleeding risk is great.
(3) Anti-platelet agents
Anti-platelet drugs inhibit platelet adhesion, aggregation and release functions to prevent and inhibit thrombosis. They can be used as ① aspirin (ASA) to inhibit TXA2 production, usage 50~300mg/d, or sulforaphane 0.2, 3 times/d; ② dipyridamole inhibits Ca2+ activity and increases the concentration of cAMP in platelets, which can be combined with ASA, usage 25~50mg, 3 times/d; ③ ticlopidine inhibits platelet and fibrinogen attachment through ADP receptor, usage 0.25, 1~2 times/d; ④Fenflumizole inhibits TXA2 synthase, use 50mg, 2 times/d.
(4) Hydroxychloroquine
It can reduce the production of aPL, has anti-platelet aggregation effect, and recent studies suggest that it can protect aPL patients from thrombosis. Side effects include dizziness, hepatic impairment, inhibition of cardiac conduction system and fundus drug deposition, but the side effects are lighter than chloroquine and the incidence is lower. Usage 0.2~0.4/d.
3.Acute treatment
Acute thrombosis can be treated by thrombectomy, and venous thrombosis can be operated within 72 hours, while arterial thrombosis can be treated by thrombectomy or vascular bypass within 8~12 hours. If surgery is contraindicated, thrombolysis can be performed. The commonly used drugs in China include urokinase and streptokinase, and anticoagulation therapy with heparin or warfarin after thrombolysis. However, clinical experience suggests that thrombolytic drugs are not helpful, because re-embolization can occur soon.
4.Treatment in chronic period
In the chronic phase, oral anticoagulation therapy is the main treatment. Long-term anticoagulation therapy will reduce the recurrence rate of thrombosis, but it will also increase the chance of bleeding, so special attention should be paid. The INR should be monitored and controlled at 2.5~3.0 for arterial thrombosis and 2.0~3.0 for venous thrombosis, and hydroxychloroquine can be tried for patients with thrombosis even after good anticoagulation.
5.Treatment during pregnancy
Pregnant women with APS should be treated as follows: (1) no previous history of miscarriage, or miscarriage occurring in the first 10 weeks of pregnancy; usually treated with low-dose ASA; (2) previous history of miscarriage after 10 weeks of pregnancy, after confirmation of pregnancy, subcutaneous heparin 5,000 IU twice daily until discontinued before delivery; (3) previous history of thrombosis, anticoagulation with heparin or low-molecular heparin started before pregnancy, during pregnancy No need for warfarin; (4) postpartum treatment, because of the great risk of thrombosis in the first 3 months after delivery, anticoagulation therapy should be continued for 6-12 weeks after delivery; if possible, heparin can be changed to warfarin within 2-3 weeks after delivery.
6.Treatment of thrombocytopenia
Patients with mild thrombocytopenia with platelets >50×109 without combined thrombosis can be observed; patients with thrombosis and platelets <100×109 should be treated with cautious anticoagulation; platelets <5×109 are prohibited from anticoagulation, and can be treated with prednisone 1~2mg/kg/d, high dose intravenous propecia, 400mg/kg, and anticoagulation after platelets rise.
7. Malignant antiphospholipid antibody syndrome
This syndrome is often sudden onset, generally advocate anticoagulation and simultaneous use of larger doses of hormones, combined with plasma exchange and intravenous immunoglobulin if necessary.