This is a true story: a patient was once found to have lower extremity venous thrombosis during pregnancy, the local hematologist gave low molecular heparin treatment, after improvement, the patient returned to the community hospital for maternity, her parents learned that she had used low molecular heparin during pregnancy and suggested that she be induced, because of the fear that the drug would have an effect on the fetus, the patient was actually induced at about 26 weeks, later she was pregnant again, repeated spontaneous abortion 3 times. She then prepared for another pregnancy and had 3 recurrent spontaneous abortions. Why does this phenomenon occur? We must understand some basic knowledge.
What is low molecular heparin and what is its mechanism of action?
Low molecular heparin is an anticoagulant that binds to human antithrombin III (AT-III), activates AT-III activity and inhibits coagulation factor Xa activity, which rapidly inhibits the formation of blood clots and arteriovenous thrombosis in vivo and in vitro and improves hemodynamics, but does not affect platelet aggregation or the binding of fibrinogen to platelets.
What diseases are low molecular heparin used to treat?
* Prevention and treatment of deep vein thrombosis/pulmonary embolism
* Prevention of blood clot formation during hemodialysis
* Treatment of unstable angina pectoris and non-Q-wave myocardial infarction
* Prevention of thrombosis associated with surgery
* nephrotic syndrome
* Disseminated intravascular coagulation
* Hypercoagulable states from various causes.
Why is low molecular heparin used in obstetrics and gynecology?
A subset of obstetrical and gynecological conditions, such as recurrent spontaneous abortion, intrauterine growth retardation, preeclampsia, amniotic fluid reduction, intrauterine fetal death, and other pathologic pregnancy phenomena, may predispose a small number of female patients who present with a history of these adverse pregnancies to a thrombotic predisposition, called a prethrombotic state. The prethrombotic state does not necessarily result in thrombotic disease, but may result in a variety of adverse pregnancy outcomes due to imbalance in coagulation-anticoagulation mechanisms or fibrinolytic activity and microthrombosis of the uterine spiral arteries or chorionic vessels, leading to poor perfusion of the uteroplacental circulation or even infarction. Low molecular heparin would be used in these women who are prone to thrombosis.
Who is prone to a pre-thrombotic state?
1. Hereditary thrombophilia: Autosomal dominant disorder, a group of diseases that are prone to thrombosis due to inherited defects in anticoagulant or fibrinolytic activity.
* Anticoagulant protein defects: antithrombin deficiency, protein C deficiency, protein S deficiency, etc.
* Fibrin defects: abnormal fibrinogenemia, tissue-type fibrinogen activator deficiency, increased fibrinogen activation inhibitor-1, etc.
* Metabolic defects: methylenetetrahydrofolate reductase (MTHFR) mutations and hyperhomocysteinemia.
* Elevated levels of coagulation factors: elevated levels of factor VIII, IX or D. activity, etc.
* Thrombospondin G20210A, Factor V, Factor VIII , PAI-1 4G/5G, HPA-1, fibrinogen beta chain gene mutations, etc.
2. Acquired thrombosis: It is a predisposing factor for thrombotic events in patients with hereditary factors, and several acquired factors are more likely to occur when they coexist, with venous thrombosis as the main cause.
* 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.
* Pathological high-risk factors Diabetes mellitus, liver and kidney disease, chronic wasting disease, abnormal lipid metabolism, acute spinal cord injury or hypospadias; history or family history of hypertension, diabetes mellitus, history or family history of venous thrombosis.
* Obstetric high-risk factors Pre-eclampsia and eclampsia, HELLP syndrome, placental abruption, fetal growth restriction (FGR), low amniotic fluid; history of adverse pregnancy and childbirth such as hyperemesis, multiple pregnancy, history of stillbirth and stillbirth, recurrent miscarriage; puerperal infection, postpartum hemorrhage, etc.
* Immunologic risk factors Systemic lupus erythematosus (SLE), positive antiphospholipid antibodies (including anti-cardiolipin antibodies or anti-lupus antibodies), idiopathic thrombocytopenia, immune nephropathy, etc.
* Medical risk factors Post-operative in vitro fertilization-embryo transfer (IVF-ET), ovarian hyperstimulation syndrome (OHSS), postpartum hemorrhage transfusion, cesarean section or vaginal surgery assisted delivery, uterine rupture, postoperative application of hemostatic drugs, oral contraceptives, etc.
Guidelines for the use of low molecular heparin in pregnancy
The American College of Chest Physicians Antithrombotic Guidelines9 (ACCP9), issued in February 2012, provide the most current, comprehensive, and integrated recommendations for the prevention, treatment, and long-term management of thrombophilia in pregnancy.
* For pregnant women, low-molecular-weight heparin is recommended for the treatment and prevention of venous thromboembolism (level of recommendation: Level 1B).
* For pregnant women with combined acute venous thromboembolism, it is recommended that anticoagulant use should be maintained until at least 6 weeks postpartum (total course of therapy for at least 3 months), preferable to a shorter duration of therapy (level of recommendation: Class 2C).
* For women who meet the laboratory diagnostic criteria for antiphospholipid antibody syndrome and have a history of three or more miscarriages that meet the clinical diagnostic criteria for antiphospholipid antibody syndrome, prenatal treatment with either a prophylactic dose or a moderate dose of plain heparin or a prophylactic dose of low molecular weight heparin combined with a low dose of aspirin (75-100 mg/d) is recommended over no treatment (level of recommendation. Grade 1B).
* No prophylactic antithrombotic therapy is recommended for women with a genetic predisposition to thrombosis and a history of one pregnancy complication (Grade 2C).
* Prophylactic antithrombotic therapy is not recommended for women with a history of 2 or more miscarriages who do not meet the diagnostic criteria for antiphospholipid antibody syndrome or thrombotic predisposition (Grade 1B).
What are the precautions for the administration of low molecular heparin?
The dose varies from person to person, not the more the better. The use of low molecular heparin can be divided into prophylactic and therapeutic doses. Preventive doses are recommended for patients without recent vascular embolism or related medical history, while therapeutic doses are recommended for patients with recent vascular embolism or related medical history; attention should also be paid to the effect of body weight on the dose; changes in blood coagulation index after dosing should guide dose adjustment, etc.
Safety during pregnancy. Low-molecular heparin belongs to FDA pregnancy drug category B. Low molecular heparin is relatively safe for the mother, and the chance of adverse drug reactions is very small. If heparin is applied for 3-6 months, it can cause allergic reactions such as osteoporosis, rash and drug fever, liver and kidney insufficiency, etc. If necessary, adjust the dose, change the drug or stop the drug. For osteoporosis, calcium and VitD can usually be applied for prevention. Low molecular heparin is not secreted in breast milk and can be used safely during lactation. Low molecular heparin is safe for the fetus and it has not been reported to cause fetal malformations. It does not cross the placental barrier and does not increase the incidence of fetal bleeding events.
What are the new advances in low molecular heparin therapy?
Low molecular heparin has other effects in addition to anticoagulation and antithrombosis. As shown in the figure.
(1) it promotes the proliferation, invasion and differentiation ability of trophoblast cells in early pregnancy and affects the level of b-HCG secreted by trophoblast cells. However, the regulatory effect of low molecular heparin on trophoblast cells is biphasic and can be inhibited or promoted depending on the concentration, not at higher doses.
②It can competitively bind antiphospholipid antibodies to avoid binding of antiphospholipid antibodies to phospholipids on the surface of vascular endothelium and platelet membranes, reducing vascular endothelial damage.
③It inhibits the activation of complement system and reduces and avoids the occurrence of immune inflammatory response of the body.
④The classical anticoagulant and pro-fibrinolytic effects improve hemodynamics.
⑤ It inhibits chemotaxis and phagocytosis of neutrophils.
In addition, low molecular heparin can alleviate hyperlipidemia and improve lipid metabolism to some extent.
So, let’s go back to the beginning of the story, it is not difficult to find out: this patient is a typical patient with easy embolism, easy embolism caused her three spontaneous abortions, the classical clinical treatment plan is: anticoagulation therapy (low molecular heparin + aspirin), and the use of low molecular heparin during pregnancy is safe and does not affect the health of mother and fetus, and that her induction of labor could be completely avoided.