Is it Safe to Use Heparin in Pregnancy?

Thrombotic disease (VTE) mainly refers to lower extremity venous system thrombosis, mainly lower extremity deep venous thrombosis (DVT), with an incidence of about 1.3 / 1000 pregnancies, and is the leading cause of maternal death in developed countries. The timely diagnosis of venous thrombosis is very important, because 25% of untreated DVT sheds into the pulmonary blood vessels and develops into pulmonary embolism, and the mortality of undiagnosed pulmonary embolism is 30%. DVT also has a high mortality rate, manifested by chronic leg pain, swelling, varicose veins, depigmented skin, and ulcers.

Basic Information

Visiting department

Obstetrics and Gynecology

Multiple groups

female

Common locations

Deep vein of lower limb

Common causes

Hypercoagulable state, venous stasis, and vascular injury are the result of the interaction of multiple risk factors; congenital or acquired thrombotic tendencies

Common symptoms

Chronic leg pain, swelling, varicose veins, skin pigmentation, and ulcers

Causes of pregnancy with thrombotic diseases

Thromboembolic diseases are the result of the interaction of multiple risk factors. Regarding the mechanism of thrombosis, as early as 1856, German pathologist Virehow pointed out: including hypercoagulable state, venous stasis and vascular injury. These three factors exist to varying degrees in pregnancy, causing pregnant women to become a high-risk group of thromboembolic diseases, and their risks are 5-6 times that of non-pregnancy.

Some women have congenital or acquired thrombotic tendencies, which is one of the important risk factors for thrombosis. Hereditary thrombotic diseases include factor Leiden mutation, prethrombin G20210A mutation, methylated tetrahydrofolate reductase (MTHFR) mutation, lack of antithrombin, protein C and S protein defects, etc. Acquired thrombosis-prone disease (also known as acquired thrombophilia) mainly refers to antiphospholipid antibody syndrome, which may be combined with or without other autoimmune diseases.

Clinical manifestations of thrombosis in pregnancy

Superficial venous thrombosis

Superficial thrombophlebitis, light systemic reaction, obvious local symptoms, obvious pain and tenderness. The pain eased or disappeared within 2 to 4 weeks.

Deep vein thrombosis

It can occur during pregnancy and postpartum. During pregnancy, due to the anatomical changes of the right iliac artery compressing the left iliac vein, 90% of DVT occurs in the left leg during pregnancy. The femoropopliteal vein is the main part, and the gastrocnemius vein can also be involved. Deep venous thrombosis may have only mild clinical manifestations, which is difficult to distinguish from pregnancy edema. Typical symptoms are unilateral leg swelling and pain, and the circumference of the lower limbs differs by more than 2 cm. Some patients may have low fever, fast pulse rate, and light white blood cell count Degree rises.

(1) Swelling of the limbs Venous thrombosis, causing impediment to blood flow return. When the thrombus is in the iliac femoral vein or the upper end of the femoral vein, it has acute onset and severe pain. The typical thrombophlebitis involving the lower limbs is called white leg. Thrombosis affects the deep venous system from the foot to the patellofemoral region. Reflex arterial spasm can cause limb extremities, chills, and weakened pulses. At this point it is likely that a significant number of clots are already present. He had tenderness in the calf muscles, popliteal fossa, and the inside of the groin. Homan sign was positive.

(2) Pain. Due to venous thrombosis, inflammation of the wall and its surroundings leads to pain around the thrombus formation. Superficial venous thrombosis is mainly caused by local inflammatory pain and tenderness in the ascending site, and deep iliac vein and femoral vein thrombosis are common. Pain, inner thigh pain, tenderness are the main causes, and the lower leg is mainly the tenderness at the deep lesions.

According to the clinical manifestations, a preliminary diagnosis can be made for most DVT, especially the above symptoms and signs appear in late pregnancy and puerperium, and the existence of DVT should be highly suspected. Further examination is needed to get a clear diagnosis.

Pregnancy with thrombotic diseases

Thrombotic superficial phlebitis generally does not require special laboratory tests. The following tests can be performed during deep venous thrombosis:

Hematological examination

(1) Detection of endothelin-1 Endothelin-1 (ET-1) is the only endothelin synthesized and secreted by vascular endothelium. ET-1 has strong vasoconstriction biological activity and stimulates the release of t-PA from endothelial cells. In the population distribution, the plasma level of ET-1 in the elderly is higher than that in the population, which may be one of the factors that susceptible to thrombosis in the elderly.

(2) Increased thrombin-regulated protein Thrombin-regulated protein, or thrombomodulin (TM), is a single-chain anticoagulant protein that acts as a receptor for thrombin and exists on the surface of endothelial cells. TM binds to thrombin on the surface of endothelial cells to form a complex that specifically converts protein C into activated protein C (APC). TM is one of the sensitive and specific molecular markers reflecting endothelial cell damage. Increased TM on the surface of plasma or endothelial cells indicates hypercoagulability and thrombosis.

(3) Platelet examination includes platelet adhesion, increased aggregation, and increased platelet release in plasma, especially the specific proteins thrombus globulin (-TG) and platelet factor 4 (PF4) in particles and platelet particles Membrane protein GMP-140 increased, and the content of serotonin in the release of -platelet dense particles in plasma increased, while the intraplatelet concentration decreased.

(4) Increased coagulation factor activation Human coagulation factor (F: A) and antigenicity (F: Ag) levels are generally 100%. In thrombotic diseases, F: A and F: Ag can be significantly increased, and prothrombin fragments 1 + 2 (F1 + 2) and fragment 2 (F2) levels are increased.

(5) Plasma anticoagulant factors reduce the sensitivity of antithrombin-, protein C, protein S, HC-, APC, and CL-inhibitors for the diagnosis of thrombotic diseases, especially for hereditary and familial thrombosis. The diagnosis of the disease has certain clinical significance.

(6) Decreased fibrinolytic activity Fibrin (proto) degradation product (FDP) was determined to reflect fibrinolytic activity. Increased D-dimer in FDP is a sign of degradation of cross-linked fibrin. An increase in fibrin peptide A content indicates that thrombin formation has occurred, and it is an early marker of fibrinogen conversion to fibrin. A positive serum protein paracoagulation test indicates an increase in the content of soluble fibrin monomer complexes, suggesting that thrombin and plasmin production are increased. In addition, plasminogen activity measurement, t-PA and PAI measurement can also be used as indicators of fibrinolysis.

(7) Changes in Hemorheology Changes in Hemorheology are usually applied using Hematocrit (HCT), Whole Blood Viscosity, Whole Blood Reduction Viscosity, Plasma Viscosity, Red Cell Electrophoresis Time, Fibrinogen Quantification, Red Blood Cell Thixotropy and Viscosity Elasticity and other indicators to reflect changes in hemorheology in patients with thrombotic diseases. In thromboembolic diseases, whole blood or plasma viscosity increases, and red blood cell thixotropy and viscoelasticity often decrease.

2. Disease check

(1) Interventional examination venography Due to trauma to pregnant women and fetal exposure to radiation, and the intervention itself can induce and exacerbate thrombophlebitis and thrombosis, it is generally not recommended for use during pregnancy. When necessary, venography can be used to confirm the diagnosis after delivery. The main imaging feature is venous filling defect. Although venography is the gold standard for diagnosis, it is clinically replaced by non-traumatic examinations because it is invasive. Determination of radioactive fibrinogen . 125I-labeled fibrinogen was injected intravenously, and then periodically scanned in various parts of the lower limbs to determine the fibrinogen deposition site and count. This test can only detect the formation of venous thrombosis in the calf. When the value increases by more than 20%, it indicates that there is thrombosis in the deep vein. In addition, labeled fibrinogen must be given before thrombosis, otherwise fibrinogen no longer deposits on the lesion, and this test shows negative.

(2) Non-invasive tests include impedance plethysmography (IPG), color Doppler ultrasound, and MRI. IPG IPG has the advantage of a non-invasive examination method, which has diagnostic value for deep vein thrombosis of the lower extremity. Its sensitivity is 65%, but its sensitivity to DVT of the distal calf is poor. Only 30%. Doppler ultrasound vascular examination When DVT is suspected, color Doppler ultrasound is an ideal method, and it is currently the recommended first-line examination method for pregnancy. The sensitivity of this method to detect the proximal DVT of the affected area was 93%, and the specificity was 99%. MRI ultrasound diagnosis is suspicious or ultrasound examination is negative, but MRI examination is feasible when clinical suspicion is high. The anatomical phase scan of the inguinal ligament can be clearly seen, and the presence or absence of pelvic venous blood flow can be diagnosed. It can also scan sagittal and coronal planes.

Treatment of pregnancy with thrombotic diseases

Once venous thrombosis is diagnosed, it should be actively treated according to its type and condition to prevent the continued development and shedding of the thrombus and cause pulmonary embolism.

General treatment

Within 3 to 4 days from the onset of venous thrombosis to 7 days after the onset of thrombosis, the following treatment should be done.

(1) Absolute bed rest for 1 week. Patients should also stay in bed for 1 week after the onset of disease, but should not stay in bed for a long time to prevent new thrombosis.

(2) Raising the affected limb is conducive to venous return and swelling.

(3) An elastic bandage can be used on the affected limb to promote venous return until it is completely absorbed by the thrombus.

(4) Use magnesium sulfate (50%) solution to warm up to about 50 ° C and apply wet. Magnesium sulfate has antispasmodic, analgesic, and detumescent effects. The gauze can be replaced immediately if it dries, repeated several times a day.

(5) Sedation pain can be taken orally such as aspirin, indomethacin (indomethacin), ibuprofen (fenbutide).

(6) Anti-infective treatment, using antibiotics to treat or prevent infection.

2. Anticoagulant therapy

When clinical diagnosis of DVT, anticoagulation should be performed. You can choose low-molecular-weight heparin or whole-molecule heparin. Warfarin can be used after delivery.

Heparin is safe to use during pregnancy because it does not pass through the placenta and is not secreted in milk. APTT (partially activated thromboplastin time) also needs to be monitored during heparin treatment to control it between 1.5 and 2.5 times the control value.

Low-molecular-weight heparin has a similar or even better curative effect to heparin, and has good safety. The safety of low-molecular-weight heparin in pregnancy is also proven and easy to monitor, so it has become the drug of choice for treatment and prevention. Low-molecular-weight heparin is at least as effective as intact heparin and has fewer side effects than heparin.

Dicoumarin anticoagulants: Warfarin has a half-life of up to 32 hours and begins to function at 12 hours. It can increase the risk of miscarriage and stillbirth through the placenta. Use during early pregnancy can also lead to the risk of fetal nasal bone development or spotted epiphysis. Therefore, warfarin should be avoided during pregnancy, but it can be used postpartum without affecting breastfeeding.

Anticoagulation treatment usually lasts for 6 months, and can be changed to warfarin after delivery.

3. Handling in labor

Anticoagulant therapy should be stopped after labor. When APTT is normal (heparin is used) or low molecular weight heparin has been stopped for 12 to 24 hours, regional anesthesia can be used. There is no significant increase in bleeding during cesarean section. Protamine can be used to neutralize heparin. If the maternal general vital signs are stable, anticoagulation therapy can be restarted after 4 to 6 hours.

4. Antiplatelet drugs

(1) Aspirin inhibits prostacyclin (PGI2) and thromboxane (TXA2) can be used in small daily doses.

(2) Compound Danshen tablets also have anti-platelet agglutination effect.

5. Reduce blood viscosity

Commonly used is dextran, intravenously.

6. Thrombolytic therapy

Thrombolytic drugs are best used within 1 to 3 days of thrombosis, with large first doses. Drugs are commonly used streptokinase and urokinase.

(1) Streptokinase (SK) is a non-protease plasminogen activin, which can dissolve the surface and inside of thrombus.

(2) Urokinase (UK) is a serine protease. When a2-antilysin is not present in the blood, it has a strong hydrolytic effect on fibrin.

7. Surgical treatment

For thrombophlebitis, drug treatment is not effective, the diseased blood vessels can be removed, and the proximal vein is ligated. For deep venous thrombosis, such as patellofemoral vein thrombosis, within two days of the onset or after thrombolytic therapy is not effective, and those with obvious blood flow obstruction can be surgically removed, and if necessary, high venous ligation is performed to prevent thrombus from falling off Causes fatal pulmonary embolism.