Thrombosis

Thrombosis is a condition of blood clots within the blood vessels, which reduces the blood flow. The major conditions which can cause death are acute venous and arterial thrombosis.

The types of thrombosis include deep vein thrombosis (DVT), which occurs in the deep veins, usually in the legs. If a part of that clot breaks up and travels to the lungs, it can cause a pulmonary embolism(PE), a potentially life-threatening condition. Other types include stroke and heart attack, which occur when clots block blood flow to the brain or heart, sometimes resulting in death.¹

Risk factors associated with thrombosis

Acquired risk factors:

• Surgeries, trauma, and immobilisation

The major surgeries, including orthopaedic and neurovascular surgeries and other physical trauma, may increase the risk of thrombosis

• History of thromboembolism

The rate of recurrence of thrombosis is higher in cases of permanent risk factors

• Malignancy

Cancer is a known risk factor for blood clots because it can cause the blood to become abnormally prone to clotting, a condition known as hypercoagulation. In patients with cancer, certain tumour-related factors have been found to increase the risk of developing thrombosis

• Pregnancy

This is a major risk factor for DVT because of hypercoagulation. The risk increases during the post-partum period and if multiple pregnancies are involved

• Antiphospholipid antibodies

These can increase the risk of developing DVT and arterial thrombosis, and may also lead to repeated episodes

• Chronic medical conditions

Other conditions, including cardiac, renal, haematological, rheumatological, gastrointestinal, respiratory, endocrine disorders and chronic infections, can increase the risk of DVT

Inherited risk factors

The hypercoagulable disorders will have a high risk of DVT and Arterial thrombosis. The common factor is a prothrombin gene mutation, accompanied by deficiencies in certain proteins, including protein S and protein C.

Age

The risk of developing this condition increases with age due to increased risk factors and other medical conditions.

Smoking

This is another major factor affecting blood condition, leading to thrombosis.

Obesity

An unhealthy lifestyle, causing obesity, increases the risk of thrombosis by slowing blood flow and putting pressure on the veins.

Gender

There is no discrimination between genders, but in males, there is a high risk of recurrence of thrombosis. In women, there is a high risk of thrombosis due to other factors, which include medications and therapies related to contraception.²

Oral contraceptives

The introduction of oral contraceptives as a birth control in women showed a high risk of venous thrombosis and pulmonary embolism. The long-term use of birth control is associated with myocardial infarction and stroke. Due to this research, there were some studies done with less oestrogen in oral contraceptives. This was considered safe with the observations of small haemostatic factors until recent studies challenged the concept of elimination of the risk of venous thrombosis with the reduction of oestrogen. The studies have shown that certain progesterone concentrations/levels may increase the risk of venous thrombosis. Oral contraceptives also cause arterial thrombosis.

Patients with risk factors, like calf pain or swelling, may be more prone to venous thrombosis if they are using hormonal contraceptives. These prothrombotic effects are due to increased levels of coagulant factors and decreased anticoagulant proteins, antithrombin and protein S.³

Evidence showed that women using progestin-only contraceptives are experiencing hypertension and stroke. The majority of smokers experienced an increased risk of this condition while using injectables. This potential risk is due to the existing conditions in women and poses a small risk in healthy women. There is a possibility of experiencing thrombosis due to a thrombogenic mutation, and in women with a history of venous thrombosis and arterial thrombosis, after using contraceptives.⁴

What is hormonal replacement therapy (HRT)

Around the age of 51 years, women typically experience a natural physiological change called menopause. During this phase, they may experience certain symptoms, and to help relieve these symptoms, hormonal replacement therapy is often used.⁵

After menopause, there is a reduction in oestrogen levels, which results in increased total cholesterol, LDL, lipoprotein-a, triglycerides, and reduced HDL levels. During menopause, a woman experiences weight gain, loss of lean body mass, less energy, and an increased amount of fat. These changes will influence oestrogen to operate growth hormone or insulin-like growth factors. HRT is helpful in the treatment of diabetes or insulin resistance.⁶

HRT usually involves Oestrogen therapy (Oestrogen only HRT), but if a woman still has their uterus, the oestrogen will be combined with progestin to protect the lining of the womb (endometrium)(Combined HRT). The ooestrogen can be oral, intravaginal (using an intrauterine device) or transdermal.

How does it work?

HRT is a highly effective treatment for vasomotor symptoms, especially hot flushes, reducing them by up to 87% compared to placebo. HRT also helps relieve vaginal dryness, improves sexual function and can enhance sleep quality while reducing muscle aches and joint pain.

Precautions for HRT

1. If the patient has a history of breast cancer

There is a possibility of recurrence, and there might be a risk of breast cancer after 4-5 years of therapy.

2. Abnormal vaginal bleeding

If there is a missed diagnosis of vaginal bleeding there is a possibility of unscheduled bleeding for 6 months of therapy. In this case investigation to exclude pelvic disease is required.

3.  Abnormal liver function

Oral HRT should be avoided in this case as they are metabolised in the liver

4. Migraine

HRT is not contraindicative, but transdermal product doses should be reduced to avoid further consequences

5. History of endometrial ovarian cancer

Endometriosis is a benign oestrogen-dependent condition which usually becomes inactive after menopause. But HRT may reactivate it, especially in women with a previous history of this condition. There is limited evidence to confirm the occurrence of this condition due to HRT after menopause. But to reduce the risk of malignant transformation of the endometriosis, oestrogen alone will not be used in the therapy. The combination of HRT or tibolone can be considered for the patient with a history of endometriosis.⁷

6. Gallbladder disease

HRT may increase the risk of gallbladder disease, especially in individuals with a previous history of the disease. Thus, the transdermal therapies are preferred.⁸

7. Thrombosis

This condition is associated with risk factors such as smoking, hypertension, obesity, surgery and malignancy. Studies have shown that oral HRT can increase the risk of venous thromboembolism (VTE) by 2 to 4 times, with the highest risk occurring in the first 6 to 12 months of treatment. Several clinical trials were stopped early due to an increased risk of VTE and cardiovascular events. The risk increases with the combined HRT compared to the oestrogen-only HRT, due to the presence of progesterone. Also, some of the routes of administration of oestrogen may cause VTE. There are some drugs which are not associated with thrombosis, like Tibolone, a synthetic drug used for the treatment of menopausal symptoms, compared to oral HRT.

8. Women with hereditary thrombophilia

This condition increases the risk of venous or arterial thrombosis. Pre-diagnosis is very important for inherited factors like Factor V Leiden and prothrombin 20210 gene mutation, along with protein S, protein C and antithrombin deficiency.

9. Women with acquired thrombophilia

It is an antiphospholipid syndrome, occurring due to the presence of antiphospholipid antibodies. This is linked to increased maternal risks, including recurrent miscarriage and preterm delivery.

Testosterone

The androgen synthesis occurs in the ovaries and adrenal glands in women. It has been proven that testosterone helps with sexual function in women after menopause. Transdermal therapy of testosterone might affect thromboembolism during the first 6 months. However, the use of testosterone in men showed no risk of thromboembolism thus, it implies gender specific therapy. Testosterone therapy is considered non-significant in women, as it has been associated with DVT.⁹

Lower risk HRT options: To reduce the risk associated with HRT, transdermal oestrogen was considered to treat menopause symptoms. HRT is no longer recommended for heart disease, as it may increase the risk of acute coronary artery disease and breast cancer.¹⁰

Summary

Thrombosis is a blood clotting medical condition in blood vesselsleadingds to reduced blood circulation and life-threatening complications like deep vein thrombosis (DVT), pulmonary embolism, stroke, and heart attack. There are various risk factors involved in thrombosis, including acquired conditions like surgery, trauma, cancer, pregnancy, and chronic illness, as well as genetic factors such as prothrombin gene mutations and protein deficiencies. Lifestyle factors like smoking, obesity, and older age also increase the risk of thrombosis. Oral contraceptives, specifically oestrogen, are linked with the increased risk of deep vein thrombosis and pulmonary embolism. Even though low-oestrogen pills were thought to be safer, newer research showed that some progestins also cause blood clotting. Women with a history of thrombosis, thrombogenic mutations or smoking are at increased risk. Also, progestin-only pills can cause hypertension and stroke, especially in smokers who take injectable forms.

Hormone replacement therapy (HRT) is used to treat menopausal symptoms. Which is also associated with thrombosis. HRT may be oestrogen-only or combined with progesterone for protection of the endometrium. Even though it is effective in reducing symptoms like hot flashes and metabolic alterations, oral HRT poses a risk of venous thromboembolism (VTE), specifically in the first six to twelve months. Thus, fewer studies found transdermal oestrogen as a safer option. Testosterone therapy in menopausal women has also been linked to DVT. Due to the cardiovascular and cancer risks, HRT is no longer commonly recommended as a means of disease prevention.