Low molecular weight heparins: possibilities of use during pregnancy

Larisa Ivanovna Maltseva - chief obstetrician-gynecologist of the Volga Federal District, head of the Department of Obstetrics and Gynecology No. 1 of the KSMA Ministry of Health of Russia, professor There are a number of diseases, the results of treatment of which are difficult to predict. Miscarriage refers specifically to such diseases, however, the unpredictability of treatment results in the case of this pathology is of particular dramatic significance.

We talk about the effectiveness of using low-molecular-weight heparins (LMWH) for miscarriage with the chief obstetrician-gynecologist of the Volga Federal District, head of the Department of Obstetrics and Gynecology No. 1 of the State Budgetary Educational Institution of Further Professional Education of the KSMA of the Ministry of Health of Russia, Professor Larisa Ivanovna Maltseva .

— What are low molecular weight heparins?

— Heparin is the main drug with direct anticoagulant or antithrombotic action. Its effects are mediated by several plasma proteins: antithrombin III, heparin cofactor II, TFPI (extrinsic coagulation pathway inhibitor). Regular (unfractionated) heparin (NG) is a high molecular weight compound, its molecular weight is 15-20 thousand Yes, while the bioavailability is only 30%. This is determined by the heterogeneity of the structure, the ability to bind to various proteins and macrophage cells, endothelial cells, etc. In addition, unfractionated heparin is influenced by the antiheparin platelet factor, forming a specific complex with it, which can cause heparin immune thrombocytopenia and thrombosis. Large doses of heparin reduce the level of antithrombin III, which can cause hypercoagulability and also cause thrombosis. Thus, along with many advantages, regular heparin has a number of undesirable effects that low molecular weight heparin (LMWH) does not have. LMWH has a molecular weight 3-4 times less than unfractionated heparin and 100% bioavailability, due to which drugs of this group circulate in the blood longer and provide a long-lasting antithrombotic effect in significantly lower daily doses. A change in the structure of the heparin molecule, that is, a decrease in molecular weight by almost three times, entailed changes in the pharmacodynamics and pharmacokinetics of the drug. One of the most important qualitative differences between LMWH and NG is the ability not to significantly prolong such indicators as aPTT and TV, which is associated primarily with the effect on factor Xa (and not on antithrombin III) and inhibition of the extrinsic coagulation pathway. The lesser dependence of LMWH on the activity of antithrombin III allows the use of LMWH drugs in patients with a deficiency of this factor. LMWHs do not cause hypocoagulation and require virtually no laboratory monitoring during their use. Recently, the ability of LMWH to block the systemic inflammatory response, which is the basis of such conditions in obstetrics as preeclampsia, sepsis, antiphospholipid syndrome, and miscarriage, has been actively studied. In case of miscarriage, LMWH drugs are used very widely.

— What is this connected with?

— The fact is that in more than 50% of cases, according to some data, the cause of miscarriage is various forms of thrombophilia, among which antiphospholipid syndrome (APS) predominates. Its role in miscarriage and preterm pregnancy has been proven, and this obvious fact is already widely known in the obstetric community. The main treatment is LMWH drugs. Other causes of miscarriage: acute and chronic infectious diseases, genetic factors, endocrine pathology, abnormal development of the genital organs - have a lower proportion (especially with recurrent miscarriage) than thrombophilia.

— Are there any contraindications to the use of low molecular weight heparins?

Several LMWH drugs used in obstetrics are registered in Russia: nadroparin, enoxyparin, deltaparin. Contraindications for their use are hereditary or acquired thrombocytopenia and/or thrombocytopathies, defects in the plasma hemostasis - von Willebrand disease, carriage of hemophilia A or B, rare hemorrhagic defects (deficiency of factor V, V and VIII, VII, X, XI, XIII, II) . Pathology of hemostasis can be suspected by analyzing a woman’s medical history: bleeding after childbirth/abortion, menorrhagia, nosebleeds, gingival bleeding, during operations, incl. minimal (tonsillectomy, tooth extraction, etc.). LMWH are contraindicated for bleeding of any origin, high blood pressure, liver pathology with coagulopathy. In the obstetric and gynecological departments of RCH No. 2, LMWH drugs are widely used to treat miscarriage and other pathologies associated with the risk of thrombotic complications.

— What research in this direction is being conducted at the department?

— The department’s scientific interests are related to optimizing the treatment of recurrent miscarriage, premature birth and placental insufficiency. We have found that APS is often combined with chronic inflammatory diseases of the genital organs: chronic endometritis, cervicitis, colpitis. Antiphospholipid antibodies support the inflammatory process, enhancing the autoimmune component of inflammation, and LMWHs may not always reduce the level of the inflammatory response. Hence, in our opinion, the ineffectiveness of treatment for miscarriage in a number of cases with proven APS. The inclusion of natural progesterone and aspirin in small doses in the treatment complex, as well as reasonable therapy with immunoglobulins for intravenous administration, significantly reduces the level of pro-inflammatory cytokines, fibrin degradation products, increasing the effectiveness of treatment. In addition, different drugs have different anti-inflammatory activity. Research continues.

Thus, LMWHs created in 1995 turned out to be practically irreplaceable drugs for certain pathologies in obstetrics and gynecology. Alternative methods of treating APS for miscarriage in the form of plasmapheresis, large doses of immunoglobulin for intravenous administration, and aspirin are significantly inferior to LMWH in both effectiveness and safety. At the same time, the doctor must clearly understand that the use of LMWH requires skills and clear knowledge.

Gulnara Abdukaeva

Pharmacological properties

LMWH are produced from regular heparin by chemical and enzymatic depolymerization. Low molecular weight heparins have heterogeneous properties in their molecular weight and have anticoagulant activity.

On average, the molecular weight of low molecular weight heparins is from 4000 to 5000 Daltons, sometimes it can vary between 1,000 and 10,000 Daltons.

All low molecular weight heparins have a number of pharmacological properties:

these substances do not have a pronounced effect on the inactivation of thrombin, due to the small parameters of the molecule, but despite this they retain the ability to inactivate factor Xa;
LMWHs bind to plasma proteins to a small extent, resulting in their strong anticoagulant effects;
these components bind to a small extent with macrophages and endothelial cells, resulting in a long half-life and prolonged action;
the drugs have almost no interaction with platelets and PF4; these properties determine their reduced incidence of thrombocytopenia.

References

National clinical guidelines for the diagnosis, treatment and prevention of venous thromboembolic complications. Association of Phlebologists of Russia, 2013-2017. — 51 p.
Zubairov, D.M. Molecular basis of blood coagulation and thrombus formation, 2000. - 360 p.
Practical recommendations for the prevention and treatment of thromboembolic complications in cancer patients, 2021. - 10 p.
Egan, G., Ensom, M. Measuring anti-factor xa activity to monitor low-molecular-weight heparin in obesity: a critical review. Can J Hosp Pharm., 2015. - Vol. 68(3). — P. 33-47.
Berges, A., Laporte, S., Epinat, M. et al. PROPHRE.75 Study Group. Anti-factor Xa activity of enoxaparin administered at prophylactic dosage to patients over 75 years old. Br J ClinPharmacol., 2007. - Vol. 64(4). — P. 428-38.
Guyton, C., Hall, E. Textbook of Medical Physiology. 13th Edition, 2015. - P. 1075-1093

Areas of application

Low molecular weight heparins are widely used in medicine in vascular surgery and phlebology. Preparations based on these components are used to treat various thrombotic diseases of veins and blood vessels, thromboembolism, varicose veins, as well as heart disease, in particular myacardial infarction.

Based on this substance, a large number of drugs have been created that help in the fight against these conditions and diseases.

Medicines containing low molecular weight heparins are used for the following conditions:

during preventive treatment of thromboembolism during orthopedic surgical interventions, as well as during general surgical interventions in the pre- and postoperative period;
for preventive therapy of thromboembolism in people who have an increased risk of its manifestation, as well as in patients who are in bed rest with acute therapeutic pathologies - with acute respiratory failure, with infectious lesions of the respiratory type, with acute heart failure;
during medical therapy for unstable angina, as well as myocardial infarction without the presence of a pathological Q wave on the ECG;
during therapeutic therapy for deep vein thrombosis in acute form;
during therapeutic treatment of pulmonary embolism;
during treatment for severe thrombosis;
for the preventive treatment of coagulation and thrombus formation in a system with extracorporeal circulation during hemodialysis and hemofiltration.

Features of the use of funds

All medications with low molecular weight heparins cannot be interchangeable; they should be used only according to the recommendations in the instructions.

It is impossible to replace one medication from LMWH to another during treatment therapy. All drugs of this type are administered subcutaneously or intravenously.

The use of these drugs intramuscularly is prohibited. The dosage of drugs is determined individually depending on the disease and examination data. Treatment and regimen of use should only be prescribed by a doctor.

Rules for the use of group drugs:

the medicine is administered using the subcutaneous route;
during insertion, it is necessary to lift the fold between the navel and the lower abdomen;
the needle is inserted vertically;
after insertion, the fold should be held for some time;
the drug can be injected into the upper shoulder or upper thigh area;
After the drug is administered, the area does not need to be rubbed.

If necessary, an anti-Xa functional type test should be performed. In these cases, blood is taken for examination 3-4 hours after injection, when the anti-Xa content in the blood reaches its highest level.

The normal content of anti-Xa in the blood plasma should be in the range of 0.2 - 0.4 IU anti-Xa/ml. The maximum permissible content is 1 - 1.5 IU anti-Xa/ml.

It is also worth remembering that all drugs in this group differ in production method, molecular weight, and activity.

How to give an injection of LMWH Clexane:

For what indications is use contraindicated?

Medicines containing low molecular weight heparins are contraindicated for the following indications:

during the occurrence of an increased allergic reaction to the active element;
for disorders in the blood coagulation system, as well as for hypocoagulation, hemorrhagic diathesis (hemophilia, thrombocytopenia, purpura, the presence of increased capillary permeability);
during hemorrhagic stroke, encephalomalacia, traumatic injuries associated with the central nervous system, acute intracranial bleeding, surgical interventions on the central nervous system, cerebral aneurysm;
for various surgical interventions of the ophthalmological type;
for retinopathy during diabetes mellitus;
in the presence of acute gastric and duodenal ulcers;
in case of bleeding of the stomach and intestines;
during pulmonary bleeding, active tuberculosis;
during severe kidney disease;
severe impairment of kidney function;
during uncontrolled arterial hypertension in severe form;
with bacterial endocarditis;
Any low molecular weight heparin is not used during pregnancy in the first trimester.

Use this group of drugs with extreme caution in the following cases:

with an increased risk of bleeding;
for gastric ulcers;
if there are circulatory disorders in the brain of the ischemic type;
if there is a recent traumatic injury or surgery on the brain;
during uncontrolled arterial hypertension;
during the presence of thrombosis of cerebral vessels;
for disorders of the functioning of the liver, kidneys, pancreas;
with intramuscular injections, epidural, spinal puncture;
during diabetes mellitus;
women over 60 years old;
within 36 hours after birth;
during neuralgic and ophthalmological surgical interventions.