Thrombophilia is not a single disease, but a disease or condition that predisposes to thromboembolism due to genetic or acquired defects in anticoagulant proteins, coagulation factors, fibrin, or the presence of acquired risk factors [1]. The first report of a relationship between venous thrombosis and tumors was made by Professor Armand Trousseau in France in 1865, which is probably the earliest recognition of thrombophilia. The main type of thromboembolism in easy embolism is venous thromboembolism.
The etiology of [etiology] is divided into two categories: hereditary and acquired [2].
I. Hereditary factors
Hereditary thrombophilia is an autosomal dominant disorder, which is prone to thrombosis due to inherited defects in anticoagulant or fibrinolytic activity.
1. Factor V Leiden (FVL) mutation FVL mutation is the most common type of hereditary thrombophilia. Arginine (Arg) at position 506 in the factor V gene is replaced by glutamine (Gln), resulting in an inactivation of FVa that is not easily cleaved. The mutated FVa can continue to express procoagulant activity on the one hand, but on the other hand, the cleavage of activated protein C (APC) is greatly reduced, resulting in activated protein C resistance (APCR), which is caused by the inability of APC to effectively hydrolyze and inactivate FVa and FVIIa, resulting in excessive thrombin production, leading to a hypercoagulable state in the body, placental microthrombosis, placental infarction, etc., and ultimately The risk of fetal growth restriction, intrauterine death, hypertensive disorders during pregnancy, placental abruption, etc. is increased.
The G20210A mutation of prothrombin (PT) is second only to the FVL mutation in the incidence of prothrombin (PT), a vitamin K-dependent coagulation factor synthesized by the liver. PT is catalyzed by the prothrombin complex to become an active thrombin, which is a key player in the balance of procoagulation, anticoagulation and fibrinolytic systems in the coagulation process, turning fibrinogen into fibrin monomers that cross-link to form a network and form thrombi. It can also bind to thrombomodulin (TM) in vascular endothelial cells and activate the protein C anticoagulation system. The incidence of this mutation is about 10% in women with adverse pregnancy outcomes and is closely associated with the occurrence of unexplained recurrent miscarriage, hypertensive disorders of pregnancy, placental abruption and fetal growth restriction.
3. Hereditary antithrombin deficiency Antithrombin (AT) is produced by the liver, vascular endothelial cells and megakaryocytes.AT is the main inhibitor of thrombin and causes conformational changes upon binding to heparin, inactivating it with its exposed arginine binding to serine residues of factors XIIa, XIa, Xa, IXa, VIIa, and IIa. There are more than 180 mutations that cause AT deficiency. there are two types of AT deficiency: type I with reduced AT content and activity, and type II with normal AT content and reduced function alone. Up to 70% of women with AT deficiency have thrombosis during this period and have a significantly higher risk of miscarriage and stillbirth [3].
4. hereditary protein C (PC) and protein S (PS) deficiency PC and PS are both vitamin K-dependent glycoproteins synthesized by the liver. pc is an inactive zymogen that becomes activated protein C (APC) when activated by the thrombin and thrombomodulin complexes on the surface of endothelial cells, which increases the activation of pc 20,000-fold. ps is an important cofactor for the anticoagulant effect of APC, and in the presence of the synergistic The incidence of thrombosis during pregnancy and puerperium in those with PS or PC deficiency is 10%-19% [4] The incidence of PC or PS deficiency in normal pregnancy and pregnancy complications is 1% and 7% [5], respectively, and can lead to recurrent spontaneous abortions.
5, abnormal fibrinogenemia Fibrinogen (Fg) is a glycosylated protein with multiple mutation sites in its β-chain gene. Many scholars believe that fibrinogen gene polymorphism can cause increased plasma fibrinogen levels and is an independent risk factor for embolism-prone disease [6]. The pathological mechanisms may be: (1) Fg directly promotes the formation of atherosclerosis by converting to fibrin, binding to low-density lipoprotein, and stimulating vascular smooth muscle cell proliferation; elevated plasma Fg concentration enhances platelet adhesion and aggregation, leading to thrombosis. (2) Abnormal distribution of Fg: due to the deposition of fibrin in the placental villi interstitial space, fibrin-like necrosis of metaplastic vessels, resulting in decreased placental perfusion. (3) High concentration of Fg can stimulate endothelial cells and/or other cells of the vascular wall to synthesize and secrete PAI-1 in large quantities within a short period of time, leading to decreased fibrinolytic activity, thrombus formation, and occlusion of the official lumen [7].
PAI-1 is an inhibitor of tPA, which is synthesized by endothelial cells and is present in plasma and platelets, and is the main inhibitor of fibrinolytic activity in circulation. PAI-1 mutation is closely related to the occurrence of many thromboembolic diseases. In early and middle pregnancy, syncytial trophoblasts invade the uterine spiral arteries and remodel the blood vessels, and a large amount of fibrin or fibrin-like protein is deposited in the walls of small arteries, while the ability of trophoblasts to dissolve fibrin is reduced, which can cause placental microthrombosis and placental malfunction, leading to hypertensive disorders of pregnancy, FGR and other pathological pregnancies.
7. Methylenetetrahydrofolate reductase (MTHFR) C677T mutation and hyperhomocysteinemia Hyperhomocysteinemia is caused by the homocysteine (Hcy) metabolism required enzyme gene variant C677T mutation or deficiency of vitamin cofactors B6, B12 and folic acid required for metabolism due to malnutrition. Hyperhomocysteinemia has a significant inhibitory effect on chorionic vasculature formation in early pregnancy, with a marked decrease in the number of chorionic vessels, which reduces the embryonic blood supply and ultimately leads to embryonic death or the development of neural tube defects. The mechanism may be due to abnormal DNA and protein methylation, placental infarction and toxic effects on the early embryonic nervous system. In addition, it can also cause vascular endothelial damage and abnormal function, stimulate vascular smooth machine cell proliferation, disrupt the body’s coagulation and fibrinolytic system, affect lipid metabolism, and put the body in a hypercoagulable state by stimulating the production and release of oxygen free radicals, thus being associated with pathological pregnancies such as placental abruption, FGR and severe pre-eclampsia.
Second, acquired factors
Acquired factors are often predisposing factors for thrombotic events in patients with hereditary factors, and several acquired factors are more prone to thrombosis when they coexist, with venous thrombosis predominating.
1. Physiological risk factors Advanced age (age ≥ 35 years), smoking, obesity (BMI ≥ 27.0 Kg/m2), weight gain of more than 15 Kg during pregnancy; high levels of clotting factors acquired during pregnancy, etc.
2, pathological risk factors diabetes, liver and kidney diseases, chronic wasting diseases, abnormal lipid metabolism, acute spinal cord injury or lower limb paralysis; abnormal medical history and family history: history of hypertension, diabetes or family history, history of venous thrombosis or family history.
3. Obstetric high-risk factors Pre-eclampsia (severe) and eclampsia, HELLP syndrome, placental abruption, fetal growth restriction (FGR), low amniotic fluid; history of severe pregnancy vomiting, multiple pregnancy, stillbirth and stillbirth, recurrent miscarriage and other adverse maternal history; puerperal infection, postpartum hemorrhage, etc.
4. Immunological risk factors Systemic lupus erythematosus (SLE), positive antiphospholipid antibodies (including anti-cardiolipin antibodies or anti-lupus antibodies), idiopathic thrombocytopenia, immune nephropathy, etc.
5. Medical risk factors: In vitro fertilization-embryo transfer (IVF-ET), ovarian hyperstimulation syndrome (OHSS), blood transfusion for postpartum hemorrhage, cesarean section or vaginal surgery, uterine rupture, postoperative hemostatic drugs, oral contraceptives, etc. Others such as braking for more than 3 days, long distance travel or economy class syndrome, etc.
[Pathogenesis].
Thrombophilia does not necessarily occur, but may be due to imbalance in coagulation-anticoagulation mechanisms or fibrinolytic activity, microthrombosis of the uterine spiral arteries or chorionic vessels, leading to poor placental perfusion or even infarction, resulting in a variety of adverse pregnancy outcomes [8]: recurrent miscarriage, severe early-onset preeclampsia severe, neonatal coagulation abnormalities, stillbirth and stillbirth, etc. The presence of thrombophilia should be considered in the pathology of the placenta .
1. Placental pathology and maternal circulation in thrombophilia of pregnancy
Placental lesions in pregnancy-prone embolism are mainly due to inadequate maternal blood perfusion, or pregnancy may accelerate the tendency of pre-existing conditions to promote thrombosis. For example, massive fibrin deposition around the chorion, subchorionic thrombosis, fundic hematoma (also known as retroplacental hematoma), acute atherosclerosis of the spiral arteries, placental infarction, placental abruption, thin umbilical cord or reduced placental weight.
2 Embolism-prone placental lesions and fetal circulation during pregnancy
The fully developed placenta and its fetal circulation are connected to the fetus via the umbilical cord, where two arteries within the cord anastomose near the attachment of the placenta (Hyrtl’s anastomosis). This physiological anastomosis ensures that when one artery is occluded, fetal perfusion of the entire placenta is maintained. The fetal circulation in pregnancy-prone embolism is divided into circulatory disorders of the fetus and fetal vascular thrombosis.
The main circulatory disturbances in the fetus are the lack of anastomosis between the vessels of the chorionic vasculature, the formation of acute angles between horizontally and vertically oriented vessels, exposure of the walls of the chorionic vessels to toxic substances (e.g., bile acids and cytokines in meconium), and cord factors affecting umbilical blood flow (e.g., twisted, marginal, membranous, or bifurcated attachment of the cord).
Fetal vascular thrombosis is divided into occlusive and non-occlusive thrombosis, with occlusive thrombosis being more dangerous to the fetus. Fetal vascular thrombosis occurs mostly in the superficial vessels of the placenta and in the vessels of the dry villi, more commonly in the veins of the fetal surface of the placenta and in the veins within the placenta, and occasionally in association with cord thrombosis. Occlusive thrombi are seen as enlarged, swollen and hard vessels, while non-occlusive thrombi are attached thrombi and intimal cushions. Other conditions include hemorrhagic endovasculitis, choroidal vasculopathy and choroidal angiomatosis, chronic perivasculitis and terminal villous dysplasia.
[Clinical presentation]
Both hereditary thrombophilia and acquired hypercoagulable states lack typical clinical features. The most important clinical feature is the tendency to thrombosis, which eventually appears in the form of deep vein thromboembolic disease (DVT) and pulmonary embolism (PE), and the incidence of arterial thrombosis is also increased in some diseases. Therefore, the clinic should be alert to the various risk factors for embolism and the effects on mother and child: e.g., severe pre-eclampsia, placental abruption, FGR, low amniotic fluid, and recurrent miscarriage.
DVT occurs most frequently in the lower extremities, especially in the peroneal veins. Asymmetric swelling (difference in circumference >1cm), pain (positive Htoman sign) and superficial varicose veins are the three main symptoms of DVT in the lower extremities. The site of venous thrombosis can be initially estimated based on the plane of swelling in the lower extremities. Bilateral lower extremity edema is indicative of inferior vena cava thrombosis. The nature of pain is cramping or dull pain. Superficial varicose veins are a sign of increased venous pressure and establishment of collateral circulation. A significant proportion of DVT has no obvious clinical manifestations and is referred to as “silent” DVT. mesenteric vein thrombosis may present with a clinical picture similar to that of an acute abdomen.
The main clinical manifestations of DVT are hemoptysis, chest pain and dyspnea, and in most cases there is no typical clinical manifestation. Pulmonary embolism should be highly suspected in patients with DVT of the lower extremities who present with chest tightness, shortness of breath, hemoptysis, or sudden syncope, and low oxygen saturation despite oxygenation, especially in patients with “silent” DVT, who may also present with pneumonia and pleural effusion, and manifestations resembling angina pectoris or even myocardial infarction.
[Screening]
Most pregnant women with embolism have defects that predispose them to embolism, such as genetic predisposition to embolism, or secondary to a disease or factor (acquired embolism). Therefore, screening requires a careful medical and family history and the presence of risk factors for embolism (all of the above mentioned causes). Each screening should be based on a weighing of the risk of developing embolism.
The diagnosis of embolism is generally divided into screening tests and confirmatory tests. However, since confirmatory tests are usually performed by DNA analysis, the results of genetic tests are clear, but there is inter-laboratory variability and the variety of mutations in some genetic predispositions to thrombophilia makes it difficult to routinely perform a comprehensive genetic analysis. In most cases, the primary cause of thrombosis is the result of multiple mechanisms that overlap. Therefore, some screening tests are the confirmatory tests used [9].
In 2006, the College of American Pathologists made consensus recommendations for evidence-based thinking on the diagnosis of thrombophilia [10].
The initial screening test is the coagulation quadruple, which includes prothrombin time (TT), prothrombin time (PT) and activated partial thromboplastin time (APTT). Screening for embolism is performed in pregnant women with fetal death in mid to late pregnancy, and a history of adverse pregnancy and delivery: for example, anticardiolipin antibody titers are performed in pregnant women with stillbirth or recurrent miscarriage. Screening for AT, PC, PS deficiency and FVL testing and genetic analysis for prothrombin G20210A should be performed in patients with unexplained recurrent or early onset venous thromboembolism at any age.
[Treatment]
1. Indications for treatment Pregnant women with clear history of hereditary thrombophilia; with family history or past history of venous thrombosis, pulmonary embolism, etc.; with or without adverse pregnancy history, such as history of 3 or more miscarriages, history of stillbirth, history of stillbirth, abnormal coagulation tests; combined systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS); with obstetric complications in this pregnancy, such as gestational diabetes, pre-eclampsia, FGR Some patients with heart disease in pregnancy, such as heart valve replacement, wind heart mitral valve lesion with atrial fibrillation.
2.Treatment measures
Research on obstetric anticoagulation therapy is relatively late, and most reports at home and abroad still lack large samples of clinical trials and controlled studies. There is no unified conclusion on the selection of anticoagulant, target, application dose and efficacy observation; at present, most of the agreed protocols are based on LMWH, and other anticoagulant drugs can be supplemented according to the condition of pregnant women themselves.
Foreign research on thrombophilia suggests that high-dose anticoagulants should be used for pregnant women who need long-term anticoagulation therapy (such as after prosthetic valve replacement), patients with anti-cardiolipin syndrome and those who have a history of thrombosis; pregnant women with thrombophilia can be treated with medium-dose anticoagulation therapy, but if thrombophilia patients have a tendency to thrombosis, such as when they are injured or bedridden for a long time, their risk increases and they should be treated with high-dose anticoagulation. Small dose anticoagulation is given to pregnant women with a history of unexplained thrombosis [11]. For pregnancy complications related to hypercoagulable disease apply low or moderate dose therapy. The treatment dose reference is LMHW5000U subcutaneously once every 12 hours or enoxaparin 80mg per day as high dose, and LMWH5000U subcutaneously once per day or enoxaparin 40mg per day as low dose. LMWH combined with low-dose aspirin has been reported abroad as the best treatment option to prevent miscarriage in embolism-prone pregnancies, but again, large-scale randomized controlled trials are lacking.
During the course of anticoagulation therapy, attention should be paid to the monitoring of effluent and coagulation indexes, and the application of LMWH should be used to maintain the D-dimer level between 0.3-0.5mg/L, and the drug should be stopped when the D-dimer is lower than 0.3mg/L. For those who need to apply warfarin sodium for a long time, control the international normalized ratio (INR) at 1.5-2.0, chyron is not recommended to change to LMWH in the first 3 months of pregnancy and before and after delivery for the benefit and risk of mother and child.
3. Thrombolytic therapy
The aim of treatment is to dissolve the thrombus, rapidly restore microcirculation in the infarcted area, and obtain early perfusion of blood flow to reduce the damage to cell structure and function. Because of the high risk of thrombolytic therapy, it should be applied with extreme caution, requiring strict control of indications and time of administration, preferably within 3 hours of onset of thrombolytic therapy, and thrombolysis on the basis of anticoagulation. Urokinase is commonly used, 60,000~100,000 U/d, divided into 2~3 doses, maintained for 1~2 hours for 7~10 days. The dose can be as large as 1.2 million U, and the maintenance is 3~5 days.
Prevention
1.Raise awareness of prevention
Between 1995 and 2008, the American College of Chest Physicians (ACCP) revised the guidelines for the treatment of venous thrombosis in pregnancy three times; the screening and drug prevention and treatment of embolism in pregnancy have been continuously improved and revised. To date, thrombophilia and its pregnancy complications have received multidisciplinary attention and research is progressing. Improving the awareness and management of embolism can improve the adverse pregnancy outcomes associated with it.
2 Prevention of embolism complications
Thrombophilia complications in pregnancy include preeclampsia or (and) eclampsia due to severe placental dysfunction, FGR, low amniotic fluid, placental abruption, or morphologically normal preterm delivery and unexplained repeat miscarriages, which may not manifest clinically as thrombosis but are still at risk for adverse outcomes in subsequent pregnancies. Their prevention should include 3 aspects: risk factor identification, screening and detection of corresponding indicators and pharmacological preventive interventions.
In addition to the above-mentioned complications of pregnancy thrombophilia, for those without a history of adverse pregnancy, screening for thrombophilia indicators should be performed if coagulation abnormalities, lipid abnormalities, severe blood hypercoagulation, and clinical abnormalities such as simple hypohydramnios in mid- to late pregnancy, abnormal or progressive thickening of the placental echogenicity on ultrasound, abnormal umbilical blood flow or FGR are detected during pregnancy, especially for preterm pre-eclampsia. Coagulation-fibrinolytic system testing, autoantibody indices, placenta-fetal monitoring, amniotic fluid monitoring and dynamic observation.
Prophylactic anticoagulants, including normal heparin (UFH) and low-molecular heparin (LMWH), low-dose aspirin, and vitamin antagonists (warfarin sodium.) The ACCP recommendation for prophylactic UFH is 5000 U subcutaneously every 12 hours; moderate doses of UFH are anti-Xa 0.1 to 0.3 U/ml of UFH dose every 12 hours. The adjusted dose of FUH is the UFH dose of APTT therapeutic range, subcutaneous injection every 12 hours. Prophylactic LMWH dose: Dapsigargin 5000 U subcutaneously once daily. Tinzaparin 4500 U subcutaneously once daily; or enoxaparin 40 mg subcutaneously once daily. Moderate dose LMWH dosage: dalteparin 5,000 U subcutaneously every 12 hours. Tinzaparin 4500 U subcutaneously once daily; or enoxaparin 40 mg subcutaneously every 12 hours [12]. Most studies concluded that the application of low-dose aspirin in early pregnancy does not increase the risk of congenital malformations and that the application of low-dose aspirin (<150 mg/d) in mid- to late pregnancy is safe for the fetus. It should be applied early if the indication is clear. Other anticoagulants, such as vitamin K antagonists: warfarin sodium can cross the placenta and is avoided in early pregnancy, but can be used for postpartum anticoagulation therapy. However, for pregnant women after flap replacement, the trade-off is that warfarin should continue to be used. Whether other antioxidants such as vitamin C and vitamin E can prevent pregnancy complications in patients with easy embolism depends on additional studies.